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Sample records for autosomal dominant polycystic

  1. [Polycystic liver disease without autosomal dominant polycystic kidney disease].

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    Peces, R; González, P; Venegas, J L

    2003-01-01

    Polycystic liver disease is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. The natural history and clinical manifestations of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The occurrence of polycystic liver disease independently from polycystic kidney disease has been known for a long time. More recently, a gene for autosomal dominant polycystic liver disease has been identified on chromosome 19p 13.2-13.1. Isolated polycystic liver disease is underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis and clinical manifestations. We report here two men with polycystic liver disease no associated with ADPKD. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively.

  2. Boy with autosomal recessive polycystic kidney and autosomal dominant polycystic liver disease.

    NARCIS (Netherlands)

    Zingg-Schenk, A.; Caduff, J.; Azzarello-Burri, S.; Bergmann, C.; Drenth, J.P.H.; Neuhaus, T.J.

    2012-01-01

    BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) shows a great phenotypic variability between patients, ranging from perinatal demise to mildly affected adults. Autosomal dominant polycystic liver disease (PCLD) does not manifest in childhood. CASE-DIAGNOSIS/TREATMENT: A boy was rep

  3. Hypertension in children with autosomal dominant polycystic kidney disease (ADPKD).

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    Cadnapaphornchai, Melissa A

    2013-02-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting 1 in 1000 individuals. Previously termed "adult polycystic kidney disease", ADPKD is now known to have important clinical manifestations beginning early in life and even in utero. Hypertension is an important risk factor for progressive renal and cardiovascular disease in children with ADPKD and may signify irremediable organ injury. The purpose of this article is to review current knowledge and treatment strategies in hypertension associated with pediatric ADPKD.

  4. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease

    NARCIS (Netherlands)

    Torres, Vicente E.; Chapman, Arlene B.; Devuyst, Olivier; Gansevoort, Ron T.; Grantham, Jared J.; Higashihara, Eiji; Perrone, Ronald D.; Krasa, Holly B.; Ouyang, John; Czerwiec, Frank S.

    2012-01-01

    BACKGROUND The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V-2-receptor antagonists inhibit cyst growth and slow the decline of kidney function. METHODS In this phase 3,

  5. Sacral radicular cysts in autosomal dominant polycystic kidney disease.

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    Peces, Ramón; Peces, Carlos; Pérez-Dueñas, Virginia; Vega-Cabrera, Cristina; Campos, Isabel

    2009-10-01

    This is the first report of a case of sacral radicular cysts in a patient with autosomal dominant polycystic kidney disease (ADPKD). A 46-year-old woman with ADPKD was found to have bilateral sacral radicular cysts discovered incidentally by magnetic resonance imaging (MRI). Cysts arising from arachnoid or spinal meningeal sac should be considered one of the manifestations of a more widespread connective tissue disorder associated with ADPKD.

  6. Renal and extrarenal manifestations of autosomal dominant polycystic kidney disease

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    E.A. Romão

    2006-04-01

    Full Text Available The objective of the present study was to determine the frequency of the most common clinical features in patients with autosomal dominant polycystic kidney disease in a sample of the Brazilian population. The medical records of 92 patients with autosomal dominant polycystic kidney disease attended during the period from 1985 to 2003 were reviewed. The following data were recorded: age at diagnosis, gender, associated clinical manifestations, occurrence of stroke, age at loss of renal function (beginning of dialysis, and presence of a family history. The involvement of abdominal viscera was investigated by ultrasonography. Intracranial alterations were prospectively investigated by magnetic resonance angiography in 42 asymptomatic patients, and complemented with digital subtraction arteriography when indicated. Mean age at diagnosis was 35.1 ± 14.9 years, and mean serum creatinine at referral was 2.4 ± 2.8 mg/dL. The most frequent clinical manifestations during the disease were arterial hypertension (63.3%, lumbar pain (55.4%, an abdominal mass (47.8%, and urinary infection (35.8%. Loss of renal function occurred in 27 patients (mean age: 45.4 ± 9.5 years. The liver was the second organ most frequently affected (39.1%. Stroke occurred in 7.6% of the patients. Asymptomatic intracranial aneurysm was detected in 3 patients and arachnoid cysts in 3 other patients. In conclusion, the most common clinical features were lumbar pain, arterial hypertension, abdominal mass, and urinary infection, and the most serious complications were chronic renal failure and stroke. Both intracranial aneurysms and arachnoid cysts occurred in asymptomatic patients at a frequency of 7.14%.

  7. Why kidneys fail in autosomal dominant polycystic kidney disease.

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    Grantham, Jared J; Mulamalla, Sumanth; Swenson-Fields, Katherine I

    2011-08-23

    The weight of evidence gathered from studies in humans with hereditary polycystic kidney disease (PKD)1 and PKD2 disorders, as well as from experimental animal models, indicates that cysts are primarily responsible for the decline in glomerular filtration rate that occurs fairly late in the course of the disease. The processes underlying this decline include anatomic disruption of glomerular filtration and urinary concentration mechanisms on a massive scale, coupled with compression and obstruction by cysts of adjacent nephrons in the cortex, medulla and papilla. Cysts prevent the drainage of urine from upstream tributaries, which leads to tubule atrophy and loss of functioning kidney parenchyma by mechanisms similar to those found in ureteral obstruction. Cyst-derived chemokines, cytokines and growth factors result in a progression to fibrosis that is comparable with the development of other progressive end-stage renal diseases. Treatment of renal cystic disorders early enough to prevent or reduce cyst formation or slow cyst growth, before the secondary changes become widespread, is a reasonable strategy to prolong the useful function of kidneys in patients with autosomal dominant polycystic kidney disease.

  8. Research on autosomal dominant polycystic kidney disease in China

    Institute of Scientific and Technical Information of China (English)

    DAI Bing; MEI Chang-lin

    2006-01-01

    Objective To review the history and recent development of research on autosomal dominant polycystic kidney disease (ADPKD) in China.Data sources Both Chinese and English literatures were searched in MEDLINE/CD ROM (1979 - 2006) and the Chinese Biomedical Literature Disk (1979 - 2006).Study selection Published articles about ADPKD from mainland of China were selected. Data were mainly extracted from 58 articles which are listed in the reference section of this review.Results Some preliminary reports on cyst decompression surgeries and mutation analysis represent the contribution to the ADPKD research from China in the history. A serial of basic research and clinical studies on ADPKD in recent years also have been summarized. A technique platform for ADPKD research was firstly established. The genomics/proteomics/bioinformatics approach was introduced, which provide a lot of valuable information for understanding the pathogenesis. By denature high performance liquid chromatography (DHPLC)technique the entire PKD1 and PKD2 gene sequence screening system for Chinese Han population has been successfully established. Based on the characteristic data of Chinese patients, an integrated therapy protocol was put forward and won an advantage over the traditional therapy. Some novel experimental studies on therapy also were encouraging. Conclusions Remarkable progress of ADPKD research in China have been made recently. Still many works, including the government support, international collaboration and active participation of more Chinese nephrologists, should be enhanced to advance this process in the near future.

  9. Caffeine intake by patients with autosomal dominant polycystic kidney disease

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    Vendramini, L.C.; Nishiura, J.L.; Baxmann, A.C.; Heilberg, I.P. [Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, SP (Brazil)

    2012-07-20

    Because caffeine may induce cyst and kidney enlargement in autosomal dominant polycystic kidney disease (ADPKD), we evaluated caffeine intake and renal volume using renal ultrasound in ADPKD patients. Caffeine intake was estimated by the average of 24-h dietary recalls obtained on 3 nonconsecutive days in 102 ADPKD patients (68 females, 34 males; 39 ± 12 years) and compared to that of 102 healthy volunteers (74 females, 28 males; 38 ± 14 years). The awareness of the need for caffeine restriction was assessed. Clinical and laboratory data were obtained from the medical records of the patients. Mean caffeine intake was significantly lower in ADPKD patients versus controls (86 vs 134 mg/day), and 63% of the ADPKD patients had been previously aware of caffeine restriction. Caffeine intake did not correlate with renal volume in ADPKD patients. There were no significant differences between the renal volumes of patients in the highest and lowest tertiles of caffeine consumption. Finally, age-adjusted multiple linear regression revealed that renal volume was associated with hypertension, chronic kidney disease stage 3 and the time since diagnosis, but not with caffeine intake. The present small cross-sectional study indicated a low level of caffeine consumption by ADPKD patients when compared to healthy volunteers, which was most likely due to prior awareness of the need for caffeine restriction. Within the range of caffeine intake observed by ADPKD patients in this study (0-471 mg/day), the renal volume was not directly associated with caffeine intake.

  10. [Related reproductive issues on male autosomal dominant polycystic kidney disease].

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    Cai, Hong-cai; Shang, Xue-jun; Huang, Yu-feng

    2015-11-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a most common inherited renal disease, about 50% with a family history, although the exact etiology not yet clear. To date, ADPKD, a multisystem disorder without effective preventive and therapeutic means, has been shown to be detrimental to human health. Recent studies show that severe oligoasthenozoospermia, necrospermia, immotile sperm, azoospermia, epididymal cyst, seminal vesicle cyst, and ejaculatory duct cyst found in male ADPKD patients may lead to male infertility, though the specific mechanisms remain unknown. Structural anomaly of spermatozoa, defect of polycystin, mutation of PKD genes, and micro-deletion of the AZF gene could be the reasons for the higher incidence of abnormal semen quality in male ADPKD patients. Assisted reproductive techniques can increase the chances of pregnancy, whereas the health of the offspring should be taken into consideration. This article presents an overview of reproductive issues concerning infertile male ADPKD patients from the perspective of the morbidity, pathophysiological mechanism, diagnosis, and management of the disease.

  11. Patterns of autosomal dominant polycystic kidney diseases in black Africans

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    Fary Ka Elhadj

    2010-01-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is not well described in black Africans while some data suggesting the disease is exceptional in this race. A retrospective study of patients with ADPKD followed in nephrology department of a teaching hospital in Dakar (January 1, 1995 to December 31, 2005 was therefore undertaken. Prevalence of ADPKD was one in 250. Mean age was 47 ± 5 years with a predominance of male (57%. High blood pressure (HBP was present in 68% of patients. Other renal manifestations were flank pain, hematuria and proteinuria. Majority of patients had impaired renal function at time of diagnosis. Extra-renal cysts were essentially found in liver (45.5%, pancreas and seminal vesicles. Main complications: ESRD (51% occurred within a 6 year mean period, urinary tract infection (13% and cerebral haemorrhage (2%. HBP control, in general needed 2 or more antihypertensive drugs. Fourteen patients died, ten patients had been on haemodialysis and four others died from uremic compli-cations. In conclusion, ADPKD in black African adults is not rare and probably underdiagnosed. Early HBP and ESRD are likely more frequent than in other races. Earlier ultrasound detection and strategies to preserve renal function should be offered to at-risk individuals to improve outcomes.

  12. Renal relevant radiology: radiologic imaging in autosomal dominant polycystic kidney disease.

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    Rahbari-Oskoui, Frederic; Mittal, Ankush; Mittal, Pardeep; Chapman, Arlene

    2014-02-01

    Autosomal-dominant polycystic kidney disease is a systemic disorder and the most common hereditary renal disease, which is characterized by cyst growth, progressive renal enlargement, and development of renal failure. The cystic nature of autosomal dominant polycystic kidney disease and its renal and extrarenal complications (kidney stones, cyst hemorrhage, intracerebral aneurysm, liver cysts, cardiac valve abnormalities, etc.) give radiologic imaging studies a central role in the management of these patients. This article reviews the indications, comparative use, and limitation of various imaging modalities (ultrasonography, magnetic resonance imaging, computerized tomography scan, Positron emission tomography scan, and renal scintigraphy) for the diagnosis and management of complications in autosomal dominant polycystic kidney disease. Finally, this work provides evidence for the value of total kidney volume to predict disease progression in autosomal dominant polycystic kidney disease.

  13. An 11-Year-Old Child with Autosomal Dominant Polycystic Kidney Disease Who Presented with Nephrolithiasis

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    Fatih Firinci

    2012-01-01

    Full Text Available Patients with autosomal dominant polycystic kidney disease become symptomatic and are diagnosed usually at adulthood. The rate of nephrolithiasis in these patients is 5–10 times the rate in the general population, and both anatomic and metabolic abnormalities play role in the formation of renal stones. However, nephrolithiasis is rare in childhood age group. In this paper, an 11-year-old child with autosomal dominant polycystic kidney disease presenting with nephrolithiasis is discussed.

  14. Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

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    A.P. Bastos

    2011-07-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is one of the most common human life-threatening monogenic disorders. The disease is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease, and may include extrarenal manifestations. ADPKD is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1 and polycystin-2 (PC2, respectively. PC2 is a non-selective cation channel permeable to Ca2+, while PC1 is thought to function as a membrane receptor. The cyst cell phenotype includes increased proliferation and apoptosis, dedifferentiation, defective planar polarity, and a secretory pattern associated with extracellular matrix remodeling. The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. Activated mammalian target for rapamycin (mTOR and cell cycle dysregulation are also significant features of PKD. Based on the identification of pathways altered in PKD, a large number of preclinical studies have been performed and are underway, providing a basis for clinical trials in ADPKD and helping the design of future trials.

  15. High serum soluble α-Klotho levels in patients with autosomal dominant polycystic kidney disease.

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    Sari, Funda; Inci, Ayca; Dolu, Suleyman; Ellidag, Hamit Yasar; Cetinkaya, Ramazan; Ersoy, Fettah Fevzi

    2017-02-01

    This study aims to determine fibroblast growth factor-23 and soluble α-Klotho levels in patients with autosomal dominant polycystic kidney disease. A total of 76 patients with autosomal dominant polycystic kidney disease and 32 healthy volunteers were included in the study. Serum fibroblast growth factor-23 and soluble α-Klotho levels were measured with ELISA kits. Parathyroid hormone, phosphate, calcium, creatinine, 25-hydroxyvitamin D3 levels, urinary protein to creatinine ratio and estimated glomerular filtration rate were also measured or calculated. Patients with autosomal dominant polycystic kidney disease had significantly higher serum parathyroid hormone (pserum 25-hydroxyvitamin D3 levels (pSerum fibroblast growth factor-23, soluble α-Klotho and 25-hydroxyvitamin D3 levels were similar in all five chronic kidney disease stages of autosomal dominant polycystic kidney disease (p>0.05). Fibroblast growth factor-23 (r=-0.251, p=0.034) and soluble α-Klotho levels (r=-0.251, p=0.034) were found to be negatively correlated with estimated glomerular filtration rate. This study shows increased fibroblast growth factor-23 levels in patients with autosomal dominant polycystic kidney disease which is in harmony with the general trend in patients with chronic kidney disease of other aetiologies, but, unlike them, also a significant increase in serum soluble α-Klotho levels in patients with autosomal dominant polycystic kidney disease suggesting an aberrant production or a decreased clearance of α-Klotho molecule. Considering the unique increases in erythropoietin levels due to erythropoietin production in renal cysts, we assume, patients with autosomal dominant polycystic kidney disease may potentially have different soluble α-Klotho production/clearance characteristics than the patients with other parenchymal renal diseases.

  16. Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation.

    NARCIS (Netherlands)

    Peces, R.; Drenth, J.P.H.; Morsche, R.H.M. te; Gonzalez, P.; Peces, C.

    2005-01-01

    Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease

  17. Multiple thoracic paraspinal meningeal cysts in autosomal dominant polycystic kidney disease.

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    Coche, Emmanuel; Persu, Alexandre; Cosnard, Guy; Quoidbach, Albert; Pirson, Yves

    2003-02-01

    Spinal meningeal cysts have been reported in 3 patients as an extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). The authors report on a fourth patient with ADPKD who was found to harbor 7 thoracic meningeal cysts, appearing as paraspinal masses on plain films. The authors provide a comprehensive radiologic description of this abnormality.

  18. Improved prognosis in patients with autosomal dominant polycystic kidney disease in Denmark

    DEFF Research Database (Denmark)

    Ørskov, Bjarne; Rømming Sørensen, Vibeke; Feldt-Rasmussen, Bo;

    2010-01-01

    The introduction of new therapies, including agents that block the renin-angiotensin system, may have affected progression of autosomal dominant polycystic kidney disease (ADPKD). We investigated whether the age when reaching ESRD and survival during renal replacement therapy in Danish patients w...

  19. Management of renal cyst infection in patients with autosomal dominant polycystic kidney disease : a systematic review

    NARCIS (Netherlands)

    Lantinga, Marten A; Casteleijn, Niek F; Geudens, Alix; de Sévaux, Ruud G L; van Assen, Sander; Leliveld, Anna; Gansevoort, Ron T; Drenth, Joost P H

    2017-01-01

    BACKGROUND: Renal cyst infection is one of the complications faced by patients with autosomal dominant polycystic kidney disease (ADPKD). Cyst infection is often difficult to treat and potentially leads to sepsis and death. No evidence-based treatment strategy exists. We therefore performed a system

  20. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe

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    Spithoven, Edwin M; Kramer, Anneke; Meijer, Esther;

    2014-01-01

    BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common renal disease requiring renal replacement therapy (RRT). Still, there are few epidemiological data on the prevalence of, and survival on RRT for ADPKD. METHODS: This study used data from the ERA-EDTA Registry...

  1. A stepwise approach for effective management of chronic pain in autosomal-dominant polycystic kidney disease

    NARCIS (Netherlands)

    Casteleijn, Niek F.; Visser, Folkert W.; Drenth, Joost P. H.; Gevers, Tom J. G.; Groen, Gerbrand J.; Hogan, Marie C.; Gansevoort, Ron T.

    2014-01-01

    Chronic pain, defined as pain existing for >4-6 weeks, affects >60% of patients with autosomal-dominant polycystic disease (ADPKD). It can have various causes, indirectly or directly related to the increase in kidney and liver volume in these patients. Chronic pain in ADPKD patients is often severe,

  2. [Urinary electrolyte excretion in autosomal dominant polycystic kidney].

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    Todorov, V; Iordanova, P; Penkova, S

    1991-01-01

    In 33 patients with autosomal dominant renal polycystosis the urine excretion of the electrolytes sodium and potassium was examined and analyzed in relation to the renal function and the arterial pressure. The clearances, the urine ratio and the excreted fractions of both electrolytes were calculated. It was established that by normal renal function and without arterial hypertension there were no significant differences in the parameters studied between the patients and the healthy controls. In the patients with arterial hypertension and preserved renal function the sodium clearance and urine excretion were lower, but the differences with the normotensive patients were not statistically significant. In the patients with chronic renal failure (when diuretic was applied) higher mean values of the excreted fractions of sodium and potassium were established. The results support the thesis that hypertension in renal polycystosis is of volumetric character.

  3. Identification of a Locus for Autosomal Dominant Polycystic Liver Disease, on Chromosome 19p13.2-13.1

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    Reynolds, David M.; Falk, Cathy T.; Li, Airong; King, Bernard F.; Kamath, Patrick S.; Huston III, John; Shub, Clarence; Iglesias, Diana M.; Martin, Rodolfo S.; Pirson, Yves; Torres, Vicente E.; Somlo, Stefan

    2000-01-01

    Polycystic liver disease (PCLD) is characterized by the growth of fluid-filled cysts of biliary epithelial origin in the liver. Although the disease is often asymptomatic, it can, when severe, lead to complications requiring surgical therapy. PCLD is most often associated with autosomal dominant polycystic kidney disease (ADPKD); however, families with an isolated polycystic liver phenotype without kidney involvement have been described. The clinical presentation and histological features of ...

  4. Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease.

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    McCarty, Mark F; Barroso-Aranda, Jorge; Contreras, Francisco

    2009-12-01

    There is evidence that overactivity of both mammalian target of rapamycin (mTOR) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes importantly to the progressive expansion of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). Recent research has established that AMP-activated kinase (AMPK) can suppress the activity of each of these proteins. Clinical AMPK activators such as metformin and berberine may thus have potential in the clinical management of ADPKD. The traditional use of berberine in diarrhea associated with bacterial infections may reflect, in part, the inhibitory impact of AMPK on chloride extrusion by small intestinal enterocytes.

  5. [Massive inferior vena cava thrombosis in a patient with autosomal dominant polycystic hepatorenal disease].

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    Peces, R; Gil, F; Costero, O; Pobes, A

    2002-01-01

    We report a 68-year-old man with autosomal dominant polycystic kidney disease, who developed multiple venous thromboses (inferior vena cava, left renal vein and iliofemoral veins) caused by local compression of the intrahepatic inferior vena cava by hepatic cysts. To our knowledge this is the first reported case of inferior vena cava thrombosis caused by hepatic cysts compression. Doppler ultrasound, computed tomography, and magnetic resonance imaging were effective in documenting the venous thromboses and the underlying lesions non-invasively. Long-term anticoagulation was an efficient and safe treatment.

  6. Octreotide reduces hepatic, renal and breast cystic volume in autosomal-dominant polycystic kidney disease.

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    Peces, Ramón; Cuesta-López, Emilio; Peces, Carlos; Pérez-Dueñas, Virginia; Vega-Cabrera, Cristina; Selgas, Rafael

    2011-06-01

    A 43-year-old woman with autosomal-dominant polycystic kidney disease (ADPKD) received octreotide for 12 months, and this was associated with a 6.3% reduction in liver volume, an 8% reduction in total kidney volume and stabilization of renal function. There was also a reduction of cyst size in fibrocystic disease of breast. These data suggest that the cyst fluid accumulation in different organs from patients with ADPKD is a dynamic process which can be reversed by octreotide. This is the first report of a case of simultaneous reduction in hepatic, renal and breast cystic volume with preservation of renal function in a patient with ADPKD receiving octreotide.

  7. Multifocal renal cell carcinoma of different histological subtypes in autosomal dominant polycystic kidney disease.

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    Na, Ki Yong; Kim, Hyun-Soo; Park, Yong-Koo; Chang, Sung-Goo; Kim, Youn Wha

    2012-08-01

    Renal cell carcinoma (RCC) in autosomal dominant polycystic kidney (ADPKD) is rare. To date, 54 cases of RCC in ADPKD have been reported. Among these, only 2 cases have different histologic types of RCC. Here we describe a 45-year-old man who received radical nephrectomy for multifocal RCC with synchronous papillary and clear cell histology in ADPKD and chronic renal failure under regular hemodialysis. The case reported herein is another example of the rare pathological finding of RCC arising in a patient with ADPKD.

  8. Mechanisms and management of hypertension in autosomal dominant polycystic kidney disease.

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    Rahbari-Oskoui, Frederic; Williams, Olubunmi; Chapman, Arlene

    2014-12-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease, characterized by progressive cyst growth and renal enlargement, resulting in renal failure. Hypertension is common and occurs early, prior to loss of kidney function. Whether hypertension in ADPKD is a primary vasculopathy secondary to mutations in the polycystin genes or secondary to activation of the renin-angiotensin-aldosterone system by cyst expansion and intrarenal ischemia is unclear. Dysregulation of the primary cilium causing endothelial and vascular smooth muscle cell dysfunction is a component of ADPKD. In this article, we review the epidemiology, pathophysiology and clinical characteristics of hypertension in ADPKD and give specific recommendations for its treatment.

  9. Autosomal dominant polycystic kidney disease: recent advances in clinical management [version 1; referees: 2 approved

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    Zhiguo Mao

    2016-08-01

    Full Text Available The first clinical descriptions of autosomal dominant polycystic kidney disease (ADPKD go back at least 500 years to the late 16th century. Advances in understanding disease presentation and pathophysiology have mirrored the progress of clinical medicine in anatomy, pathology, physiology, cell biology, and genetics. The identification of PKD1 and PKD2, the major genes mutated in ADPKD, has stimulated major advances, which in turn have led to the first approved drug for this disorder and a fresh reassessment of patient management in the 21st century. In this commentary, we consider how clinical management is likely to change in the coming decade.

  10. Autosomal dominant polycystic kidney disease with diffuse proliferative glomerulonephritis - an unusual association: a case report and review of the literature

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    Kapoor Vinay

    2010-04-01

    Full Text Available Abstract Introduction Autosomal dominant polycystic kidney disease is an inherited disorder that is characterized by the development and growth of cysts in the kidneys and other organs. Urinary protein excretion is usually less than 1 g/24 hours in autosomal dominant polycystic kidney disease, and an association of nephrotic syndrome with this condition is considered rare. There are only anecdotal case reports of autosomal dominant polycystic kidney disease associated with nephrotic syndrome, with focal segmental glomerulosclerosis being the most commonly reported histopathological diagnosis. Nephrotic-range proteinuria in the presence of autosomal dominant polycystic kidney disease, with or without an accompanying decline in renal function, should be investigated by open renal biopsy to exclude coexisting glomerular disease. To the best of our knowledge, this is the first case of autosomal dominant polycystic kidney disease with histologically proven diffuse proliferative glomerulonephritis presenting with nephrotic-range proteinuria. No other reports of this could be found in a global electronic search of the literature. Case presentation We report the case of a 35-year-old Indo-Aryan man with autosomal dominant polycystic kidney disease associated with nephrotic syndrome and a concomitant decline in his glomerular filtration rate. Open renal biopsy revealed diffuse proliferative glomerulonephritis. An accurate diagnosis enabled us to manage him conservatively with a successful outcome, without the use of corticosteroid which is the standard treatment and the drug most commonly used to treat nephrotic syndrome empirically. Conclusion Despite the reluctance of physicians to carry out a renal biopsy on patients with autosomal dominant polycystic kidney disease, our case supports the idea that renal biopsy is needed in patients with polycystic kidney disease with nephrotic-range proteinuria to make an accurate diagnosis. It also illustrates the

  11. [Seminal vesicle cysts and infertility in autosomal dominant polycystic kidney disease].

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    Peces, R; Venegas, J L

    2005-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a systemic hereditary disorder characterized by bilateral diffuse renal cysts. Extrarenal involvement is a well known manifestation of ADPKD. Cysts in the liver, pancreas, lung, spleen, oesophagus, ovary, testis, epididymis, prostate, thyroid, bladder, uterus, brain, paraespinal, and seminal vesicle have also been described. The occurrence of seminal vesicle cysts is often unrecognised. We report here a man with seminal vesicle cysts and azoospermia associated with ADPKD. Seminal vesicle cysts are not uncommon in ADPKD and in some cases it is associated with infertility. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively. Studies evaluating fertility in patients with seminal vesicle cysts and ADPKD are needed.

  12. Recurrent acute pancreatitis and cholangitis in a patient with autosomal dominant polycystic kidney disease

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    Kambiz Yazdanpanah

    2013-01-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is an inherited disorder associated with multiple cyst formation in the different organs. Development of pancreatic cyst in ADPKD is often asymptomatic and is associated with no complication. A 38-year-old man with ADPKD was presented with six episodes of acute pancreatitis and two episodes of cholangitis in a period of 12 months. Various imaging studies revealed multiple renal, hepatic and pancreatic cysts, mild ectasia of pancreatic duct, dilation of biliary system and absence of biliary stone. He was managed with conservative treatment for each attack. ADPKD should be considered as a potential risk factor for recurrent acute and/or chronic pancreatitis and cholangitis.

  13. AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD IN A LARGE IRANIAN FAMILY

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    D.D. Farhud

    1999-08-01

    Full Text Available Study of a family with autosomal dominant polycystic kidney diseases (ADPKD in five generations, including 96 healthy and 47 affected individuals, has been carried out in Tehran. Investigation on individuals, including final diagnoses by clinical findings, sonography, radiography and laboratory results, have Lead to the completion of genealogical chart of the family. The affected individuals have reached a stage of the disease with confirmed occurrence of renal damages. Uncertain diagnoses, unconfirmed statements of the family members about probable presence of the disease in some other members, and also the death of some members by other reasons were not possible to be registered in the chart. Up to now the chart has been the largest and the most complete in Iran, compared with the ones reported in the available literature.

  14. Disseminated kidney tuberculosis complicating autosomal dominant polycystic kidney disease: a case report.

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    Takeshita, Hideki; Amemiya, Morimasa; Chiba, Koji; Urushibara, Masayasu; Satoh, Jun-Ichi; Noro, Akira

    2012-03-01

    Mycobacterium tuberculosis infection in patients with autosomal dominant polycystic kidney disease (ADPKD) is rare, and its diagnosis and treatment are difficult because numerous cysts are exposed to infection and antibiotics do not easily penetrate infected cysts. Here, we report the case of a 43-year-old Japanese man with disseminated urogenital tuberculosis (TB) and ADPKD without human immunodeficiency virus (HIV) infection. Delayed diagnosis and ineffective anti-TB chemotherapy worsened his condition. Finally, he underwent bilateral nephrectomy but experienced postoperative complications. In conclusion, kidney TB should be recognized as a cause of renal infection in ADPKD, and surgical treatment should be instituted without delay. The importance of early diagnosis and treatment cannot be overemphasized to prevent kidney TB deterioration.

  15. Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

    NARCIS (Netherlands)

    Harskamp, Laura R.; Gansevoort, Ron T.; Boertien, Wendy E.; van Oeveren, Wim; Engels, Gerwin E.; van Goor, Harry; Meijer, Esther

    2015-01-01

    Background and objectives Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor figands were measured

  16. Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation.

    Science.gov (United States)

    Peces, Ramón; Drenth, Joost P H; Te Morsche, Rene H M; González, Pedro; Peces, Carlos

    2005-12-28

    Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease (ADPLD) is genetically distinct from PLD associated with ADPKD, although it may have similar pathogenesis and clinical manifestations. Recently, mutations in two causative genes for ADPLD, independently from ADPKD, have been identified. We report here a family (a mother and her daughter) with a severe form of ADPLD not associated with ADPKD produced by a novel missense protein kinase C substrate 80K-H (PRKCSH) mutation (R281W). This mutation causes a severe phenotype, since the two affected subjects manifested signs of portal hypertension. Doppler sonography, computed tomography (CT) and magnetic resonance (MR) imaging are effective in documenting the underlying lesions in a non-invasive way.

  17. Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation

    Institute of Scientific and Technical Information of China (English)

    Ramón Peces; Joost PH Drenth; Rene HM te Morsche; Pedro González; Carlos Peces

    2005-01-01

    Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease (ADPLD) is genetically distinct from PLD associated with ADPKD, although it may have similar pathogenesis and clinical manifestations.Recently, mutations in two causative genes for ADPLD,independently from ADPKD, have been identified. We report here a family (a mother and her daughter) with a severe form of ADPLD not associated with ADPKD produced by a novel missense protein kinase C substrate 80K-H (PRKCSH) mutation (R281W). This mutation causes a severe phenotype, since the two affected subjects manifested signs of portal hypertension. Doppler sonography, computed tomography (CT) and magnetic resonance (MR) imaging are effective in documenting the underlying lesions in a non-invasive way.

  18. Renal failure in a patient with autosomal dominant polycystic kidney disease and coexisting dermato-polymyositis: first report in the literature.

    Science.gov (United States)

    Bahceci, Funda; Sari, Ramazan; Sarikaya, Metin; Atik, Esin; Karincaoglu, Yelda; Sevinc, Alper

    2004-06-01

    Autosomal dominant polycystic kidney disease is a multisystem disorder characterized by multiple, bilateral renal cysts and is also associated with cysts in other organs, such as the liver, pancreas, and arachnoid membranes. Dermatomyositis is a disease which mainly involves the skin and muscles, although occasionally other organs are affected. In this report, a 56-year-old male patient with a four-year history of autosomal dominant polycystic kidney disease was presented. Renal failure was exacerbated by a coexisting dermato-polymyositis. Prednisone treatment with hemodialysis improved the situation. This is the first report renal failure in a patient with autosomal dominant polycystic kidney disease and dermato-polymyositis.

  19. Autosomal dominant polycystic kidney disease: Study of clinical characteristics in an Indian population

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    Sanjay Vikrant

    2017-01-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is the most common hereditary form of kidney disease. Clinical data on this multisystem disorder are scarce from developing countries. We conducted a prospective observational study of the clinical profile of ADPKD patients at a single center over a period of six years. A total of 208 patients were studied. Majority were male (60.6% and the mean age was 45.8 ± 14.5 years. About 61.5% had early stage (Stages 1-3 of chronic kidney disease (CKD and 38.5% had advanced CKD (Stages 4 and 5. Clinical features observed included pain abdomen (46.2%, nocturia (65.9%, hematuria (21.6%, nephrolithiasis (38.9%, urinary tract infection (UTI (38.9%, hypertension (69.5%, and raised serum creatinine (54.3%. The prevalence of nocturia, hypertension, and renal dysfunction showed a significant increase with age (P = 0.001. Extrarenal manifestations were polycystic liver disease in 77 patients (37%, cysts in pancreas in two (1%, and stroke in three (1.5% (hemorrhage in 2 and infarct in 1. There was significantly higher prevalence of hypertension (P = 0.027 and nephrolithiasis (P = 0.044 in males compared to females. Ninety-two patients (44.2% had a positive family history for ADPKD. Fifteen (7.2% had kidney failure at the diagnosis of ADPKD, were hospitalized, and underwent emergency dialysis. A total of 20 patients (9.6% developed end-stage kidney disease during the study period. The age at diagnosis was higher, and there was a high prevalence of hypertension, nocturia, abdominal pain, nephrolithiasis, UTI, and renal dysfunction in Indian ADPKD patients.

  20. Is There any Effect of Urogenital Cysts on Semen Parameters in Autosomal Dominant Polycystic Kidney Disease?

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    Sami UZUN

    2015-09-01

    Full Text Available OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD is a systemic disease with cysts in many organs including the urogenital tract. The aim of the study was to evaluate the relationship between urogenital cysts, semen pathologies and infertility in ADPKD. MATERIAL and METHODS: Male ADPKD patients aged 18-60 with creatinine clearance years higher than 60 ml/min were included. All patients had magnetic resonance imaging of the urinary system and pelvis, scrotal Doppler ultrasonography and sperm analysis. The results were compared with those of a healthy control group. RESULTS: 27 patients and 17 volunteers were included. Seminal vesicle and prostate cysts were detected in four (15% and six (22% patients, respectively. Five of the 23 married patients (21% had infertility and this rate was higher than in the control group (p=0.044. The ratio of sperms with normal morphology and progressive motility was lower, and the rate of hypospermia, oligozoospermia, azospermia, asthenozoospermia and teratozoospermia were higher in the patient group. There was no significant difference between patients with/without urogenital cysts regarding seminal pathologies. CONCLUSION: Seminal abnormalities and infertility are more frequent in patients with ADPKD. Defects in spermatogenesis and sperm motility may be related to urogenital cysts as well as ciliary pathologies. There is a need for further studies evaluating the role of urogenital cysts in semen pathologies.

  1. Autosomal dominant polycystic kidney disease caused by somatic and germline mosaicism.

    Science.gov (United States)

    Tan, A Y; Blumenfeld, J; Michaeel, A; Donahue, S; Bobb, W; Parker, T; Levine, D; Rennert, H

    2015-04-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder caused by loss of function mutations of PKD1 or PKD2 genes. Although PKD1 is highly polymorphic and the new mutation rate is relatively high, the role of mosaicism is incompletely defined. Herein, we describe the molecular analysis of ADPKD in a 19-year-old female proband and her father. The proband had a PKD1 truncation mutation c.10745dupC (p.Val3584ArgfsX43), which was absent in paternal peripheral blood lymphocytes (PBL). However, very low quantities of this mutation were detected in the father's sperm DNA, but not in DNA from his buccal cells or urine sediment. Next generation sequencing (NGS) analysis determined the level of this mutation in the father's PBL, buccal cells and sperm to be ∼3%, 4.5% and 10%, respectively, consistent with somatic and germline mosaicism. The PKD1 mutation in ∼10% of her father's sperm indicates that it probably occurred early in embryogenesis. In ADPKD cases where a de novo mutation is suspected because of negative PKD gene testing of PBL, additional evaluation with more sensitive methods (e.g. NGS) of the proband PBL and paternal sperm can enhance detection of mosaicism and facilitate genetic counseling.

  2. Multiple liver cyst infection caused by Salmonella ajiobo in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Himeno, Akihiro; Suzuki, Hiromichi; Suzuki, Yumiko; Kawaguchi, Hiroshi; Isozaki, Taisuke

    2013-06-01

    Most Salmonella infections are usually self-limited; however, some cases of enteritis result in bacteremia, and there have been reports of extra-intestinal manifestations. Cyst infections are rare, and few cases have been reported. We report a 77-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) complicated with a multiple liver cyst infection caused by Salmonella ajiobo. The patient was hospitalized for fever, abdominal pain, and diarrhea. The blood culture identified Salmonella sp., but the source of infection was not detected by computed tomography or echography. The patient was initially treated with meropenem followed by fluoroquinolones for 3 weeks; however, her C-reactive protein level was high (10-20 mg/dL) even after the antimicrobial therapy. The patient had a fever again on day 51, and Salmonella sp. was detected again from 2 sets of blood cultures. Despite the antimicrobial treatment, her general condition gradually deteriorated, and she died on day 66. The autopsy revealed that most of the liver had been replaced by cysts. Several cysts filled with pus were detected and Salmonella ajiobo was identified in the pus of the infected cysts.

  3. Branched-chain amino acids enhance cyst development in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Yamamoto, Junya; Nishio, Saori; Hattanda, Fumihiko; Nakazawa, Daigo; Kimura, Toru; Sata, Michio; Makita, Minoru; Ishikawa, Yasunobu; Atsumi, Tatsuya

    2017-03-21

    Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney and liver cysts. The mammalian target of rapamycin (mTOR) cascade is one of the important pathways regulating cyst growth in ADPKD. Branched-chain amino acids (BCAAs), including leucine, play a crucial role to activate mTOR pathway. Therefore, we administered BCAA dissolved in the drinking water to Pkd1(flox/flox):Mx1-Cre (cystic) mice from four to 22 weeks of age after polyinosinic-polycytidylic acid-induced conditional Pkd1 knockout at two weeks of age. The BCAA group showed significantly greater kidney/body weight ratio and higher cystic index in both the kidney and liver compared to the placebo-treated mice. We found that the L-type amino acid transporter 1 that facilitates BCAA entry into cells is strongly expressed in cells lining the cysts. We also found increased cyst-lining cell proliferation and upregulation of mTOR and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways in the BCAA group. In vitro, we cultured renal epithelial cell lines from Pkd1 null mice with or without leucine. Leucine was found to stimulate cell proliferation, as well as activate mTOR and MAPK/ERK pathways in these cells. Thus, BCAA accelerated disease progression by mTOR and MAPK/ERK pathways. Hence, BCAA may be harmful to patients with ADPKD.

  4. Anesthetic considerations in a patient of autosomal dominant polycystic kidney disease on hemodialysis for emergency cesarean section

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    Sarita D Fernandes

    2011-01-01

    Full Text Available Renal disease, either preexisting or occurring during gestation may impair maternal and fetal health. A 35-year-old primigravida with autosomal dominant polycystic kidney disease on hemodialysis was scheduled for emergency cesarean section. She was managed successfully with low-dose intrathecal bupivacaine and fentanyl. In the case of pregnancy in such a patient, early involvement of the nephrologists along with the obstetrician can improve maternal and fetal outcome.

  5. JAK2-STAT3 pathway regulates the expression of complement factor B in autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    周晨晨

    2014-01-01

    Objective To investigate the role of JAK2-STAT3pathway in the expression of complement factor B(CFB)in autosomal dominant polycystic kidney disease(ADP KD).Methods Renal tissue samples of patients with ADPKD after nephrectomy were collected.Normal rena tissue samples as control were taken from patients afte radical nephrectomy.Renal tissue samples of Han:SPRD Cy/+rats(ADPKD model)and wild-type Han:

  6. Diagnostic Algorithm in the Management of Acute Febrile Abdomen in Patients with Autosomal Dominant Polycystic Kidney Disease

    OpenAIRE

    Neuville, Marie; Hustinx, Roland; Jacques, Jessica; Krzesinski, Jean-Marie; Jouret, François

    2016-01-01

    Background Acute febrile abdomen represents a diagnostic challenge in patients with autosomal dominant polycystic kidney disease (ADPKD). Although criteria have been proposed for cyst infection (CyI) and hemorrhage (CyH), there is a lack of comparative assessments. Furthermore, distinguishing cystic from non-cystic complications remains problematic. Design ADPKD patients presenting with abdominal pain and/or fever between 01/2005 and 06/2015 were retrospectively identified in a systematic com...

  7. Nephrotic Syndrome and Idiopathic Membranous Nephropathy Associated with Autosomal-Dominant Polycystic Kidney Disease

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    Ramón Peces

    2011-01-01

    Full Text Available We report the case of a 38-year-old male with autosomal-dominant polycystic kidney disease (ADPKD and concomitant nephrotic syndrome secondary to membranous nephropathy (MN. A 3-month course of prednisone 60 mg daily and losartan 100 mg daily resulted in resistance. Treatment with chlorambucil 0.2 mg/kg daily, low-dose prednisone, plus an angiotensin-converting enzyme inhibitor (ACEI and an angiotensin II receptor blocker (ARB for 6 weeks resulted in partial remission of his nephrotic syndrome for a duration of 10 months. After relapse of the nephrotic syndrome, a 13-month course of mycophenolate mofetil (MFM 2 g daily and low-dose prednisone produced complete remission for 44 months. After a new relapse, a second 24-month course of MFM and low-dose prednisone produced partial to complete remission of proteinuria with preservation of renal function. Thirty-six months after MFM withdrawal, complete remission of nephrotic-range proteinuria was maintained and renal function was preserved. This case supports the idea that renal biopsy is needed for ADPKD patients with nephrotic-range proteinuria in order to exclude coexisting glomerular disease and for appropriate treatment/prevention of renal function deterioration. To the best of our knowledge, this is the first reported case of nephrotic syndrome due to MN in a patient with ADPKD treated with MFM, with remission of proteinuria and preservation of renal function after more than 10 years. Findings in this patient also suggest that MFM might reduce cystic cell proliferation and fibrosis, preventing progressive renal scarring with preservation of renal function.

  8. Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease

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    Yu Chaowen

    2011-12-01

    Full Text Available Abstract Background Autosomal dominant polycystic kidney disease (ADPKD is the most common inherited renal disease with an incidence of 1 in 400 to 1000. The disease is genetically heterogeneous, with two genes identified: PKD1 (16p13.3 and PKD2 (4q21. Molecular diagnosis of the disease in at-risk individuals is complicated due to the structural complexity of PKD1 gene and the high diversity of the mutations. This study is the first systematic ADPKD mutation analysis of both PKD1 and PKD2 genes in Chinese patients using denaturing high-performance liquid chromatography (DHPLC. Methods Both PKD1 and PKD2 genes were mutation screened in each proband from 65 families using DHPLC followed by DNA sequencing. Novel variations found in the probands were checked in their family members available and 100 unrelated normal controls. Then the pathogenic potential of the variations of unknown significance was examined by evolutionary comparison, effects of amino acid substitutions on protein structure, and effects of splice site alterations using online mutation prediction resources. Results A total of 92 variations were identified, including 27 reported previously. Definitely pathogenic mutations (ten frameshift, ten nonsense, two splicing defects and one duplication were identified in 28 families, and probably pathogenic mutations were found in an additional six families, giving a total detection level of 52.3% (34/65. About 69% (20/29 of the mutations are first reported with a recurrent mutation rate of 31%. Conclusions Mutation study of PKD1 and PKD2 genes in Chinese Hans with ADPKD may contribute to a better understanding of the genetic diversity between different ethnic groups and enrich the mutation database. Besides, evaluating the pathogenic potential of novel variations should also facilitate the clinical diagnosis and genetic counseling of the disease.

  9. Nephrotic syndrome and idiopathic membranous nephropathy associated with autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Peces, Ramón; Martínez-Ara, Jorge; Peces, Carlos; Picazo, Mariluz; Cuesta-López, Emilio; Vega, Cristina; Azorín, Sebastián; Selgas, Rafael

    2011-05-05

    We report the case of a 38-year-old male with autosomal-dominant polycystic kidney disease (ADPKD) and concomitant nephrotic syndrome secondary to membranous nephropathy (MN). A 3-month course of prednisone 60 mg daily and losartan 100 mg daily resulted in resistance. Treatment with chlorambucil 0.2 mg/kg daily, low-dose prednisone, plus an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) for 6 weeks resulted in partial remission of his nephrotic syndrome for a duration of 10 months. After relapse of the nephrotic syndrome, a 13-month course of mycophenolate mofetil (MFM) 2 g daily and low-dose prednisone produced complete remission for 44 months. After a new relapse, a second 24-month course of MFM and low-dose prednisone produced partial to complete remission of proteinuria with preservation of renal function. Thirty-six months after MFM withdrawal, complete remission of nephrotic-range proteinuria was maintained and renal function was preserved. This case supports the idea that renal biopsy is needed for ADPKD patients with nephrotic-range proteinuria in order to exclude coexisting glomerular disease and for appropriate treatment/prevention of renal function deterioration. To the best of our knowledge, this is the first reported case of nephrotic syndrome due to MN in a patient with ADPKD treated with MFM, with remission of proteinuria and preservation of renal function after more than 10 years. Findings in this patient also suggest that MFM might reduce cystic cell proliferation and fibrosis, preventing progressive renal scarring with preservation of renal function.

  10. Radiologic and clinical bronchiectasis associated with autosomal dominant polycystic kidney disease.

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    Teng Moua

    Full Text Available BACKGROUND: Polycystin 1 and 2, the protein abnormalities associated with autosomal dominant polycystic kidney disease (ADPKD, are also found in airway cilia and smooth muscle cells. There is evidence of increased radiologic bronchiectasis associated with ADPKD, though the clinical and functional implications of this association are unknown. We hypothesized an increased prevalence of both radiologic and clinical bronchiectasis is associated with APDKD as compared to non-ADPKD chronic kidney disease (CKD controls. MATERIALS AND METHODS: A retrospective case-control study was performed at our institution involving consecutive ADPKD and non-ADPKD chronic kidney disease (CKD patients seen over a 13 year period with both chest CT and PFT. CTs were independently reviewed by two blinded thoracic radiologists. Manually collected clinical data included symptoms, smoker status, transplant history, and PFT findings. RESULTS: Ninety-two ADPKD and 95 non-ADPKD CKD control patients were compared. Increased prevalence of radiologic bronchiectasis, predominantly mild lower lobe disease, was found in ADPKD patients compared to CKD control (19 vs. 9%, P = 0.032, OR 2.49 (CI 1.1-5.8. After adjustment for covariates, ADPKD was associated with increased risk of radiologic bronchiectasis (OR 2.78 (CI 1.16-7.12. Symptomatic bronchiectasis occurred in approximately a third of ADPKD patients with radiologic disease. Smoking was associated with increased radiologic bronchiectasis in ADPKD patients (OR 3.59, CI 1.23-12.1. CONCLUSIONS: Radiological bronchiectasis is increased in patients with ADPKD particularly those with smoking history as compared to non-ADPKD CKD controls. A third of such patients have symptomatic disease. Bronchiectasis should be considered in the differential in ADPKD patients with respiratory symptoms and smoking history.

  11. PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease

    Science.gov (United States)

    Vouk, Katja; Strmecki, Lana; Stekrova, Jitka; Reiterova, Jana; Bidovec, Matjaz; Hudler, Petra; Kenig, Anton; Jereb, Simona; Zupanic-Pajnic, Irena; Balazic, Joze; Haarpaintner, Guido; Leskovar, Bostjan; Adamlje, Anton; Skoflic, Antun; Dovc, Reina; Hojs, Radovan; Komel, Radovan

    2006-01-01

    Background Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. Methods We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2) and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423). Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . Results Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed). We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. Conclusion In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course. PMID:16430766

  12. PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease

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    Adamlje Anton

    2006-01-01

    Full Text Available Abstract Background Autosomal dominant polycystic kidney disease (ADPKD is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. Methods We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2 and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423. Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . Results Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed. We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. Conclusion In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course.

  13. Contribution of renal innervation to hypertension in rat autosomal dominant polycystic kidney disease.

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    Gattone, Vincent H; Siqueira, Tibério M; Powell, Charles R; Trambaugh, Chad M; Lingeman, James E; Shalhav, Arieh L

    2008-08-01

    The kidney has both afferent (sensory) and efferent (sympathetic) nerves that can influence renal function. Renal innervation has been shown to play a role in the pathogenesis of many forms of hypertension. Hypertension and flank pain are common clinical manifestations of autosomal dominant (AD) polycystic kidney disease (PKD). We hypothesize that renal innervation contributes to the hypertension and progression of cystic change in rodent PKD. In the present study, the contribution of renal innervation to hypertension and progression of renal histopathology and dysfunction was assessed in male Han:SPRD-Cy/+ rats with ADPKD. At 4 weeks of age, male offspring from crosses of heterozygotes (Cy/+) were randomized into either 1) bilateral surgical renal denervation, 2) surgical sham denervation control, or 3) nonoperated control groups. A midline laparotomy was performed to allow the renal denervation (i.e., physical stripping of the nerves and painting the artery with phenol/alcohol). Blood pressure (tail cuff method), renal function (BUN) and histology were assessed at 8 weeks of age. Bilateral renal denervation reduced the cystic kidney size, cyst volume density, systolic blood pressure, and improved renal function (BUN) as compared with nonoperated controls. Operated control cystic rats had kidney weights, cyst volume densities, systolic blood pressures, and plasma BUN levels that were intermediate between those in the denervated animals and the nonoperated controls. The denervated group had a reduced systolic blood pressure compared with the operated control animals, indicating that the renal innervations was a major contributor to the hypertension in this model of ADPKD. Renal denervation was efficacious in reducing some pathology, including hypertension, renal enlargement, and cystic pathology. However, sham operation also affected the cystic disease but to a lesser extent. We hypothesize that the amelioration of hypertension in Cy/+ rats was due to the effects

  14. Berberine slows cell growth in autosomal dominant polycystic kidney disease cells

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    Bonon, Anna; Mangolini, Alessandra [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Pinton, Paolo [Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, 44121 Ferrara (Italy); Senno, Laura del [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Aguiari, Gianluca, E-mail: dsn@unife.it [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)

    2013-11-22

    Highlights: •Berberine at appropriate doses slows cell proliferation in ADPKD cystic cells. •Reduction of cell growth by berberine occurs by inhibition of ERK and p70-S6 kinase. •Higher doses of berberine cause an overall cytotoxic effect. •Berberine overdose induces apoptotic bodies formation and DNA fragmentation. •Antiproliferative properties of this drug make it a new candidate for ADPKD therapy. -- Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 μg/mL) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 μg/mL, berberine reduces cell growth in ADPKD cystic cells only enhancing G{sub 0}/G{sub 1} phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new

  15. Hyperaldosteronism and cardiovascular risk in patients with autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Lai, Silvia; Petramala, Luigi; Mastroluca, Daniela; Petraglia, Emanuela; Di Gaeta, Alessandro; Indino, Elena; Panebianco, Valeria; Ciccariello, Mauro; Shahabadi, Hossein H; Galani, Alessandro; Letizia, Claudio; D'Angelo, Anna Rita

    2016-07-01

    Hypertension is commonly associated with autosomal dominant polycystic kidney disease (ADPKD), often discovered before the onset of renal failure, albeit the pathogenetic mechanisms are not well elucidated. Hyperaldosteronism in ADPKD may contribute to the development of insulin resistance and endothelial dysfunction, and progression of cardiorenal disease. The aim of study was to evaluate the prevalence of primary aldosteronism (PA) in ADPKD patients and identify some surrogate biomarkers of cardiovascular risk.We have enrolled 27 hypertensive ADPKD patients with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, evaluating the renin-angiotensin-aldosterone system (RAAS), inflammatory indexes, nutritional status, homocysteine (Hcy), homeostasis model assessment-insulin resistance (HOMA-IR), mineral metabolism, microalbuminuria, and surrogate markers of atherosclerosis [carotid intima media thickness (cIMT), ankle/brachial index (ABI), flow mediated dilation (FMD), renal resistive index (RRI) and left ventricular mass index (LVMI)]. Furthermore, we have carried out the morpho-functional magnetic resonance imaging (MRI) with high-field 3 T Magnetom Avanto.We have divided patients into group A, with normal plasma aldosterone concentration (PAC) and group B with PA, present in 9 (33%) of overall ADPKD patients. Respect to group A, group B showed a significant higher mean value of LVMI, HOMA-IR and Hcy (P = 0.001, P = 0.004, P = 0.018; respectively), and a lower value of FMD and 25-hydroxyvitamin D (25-OH-VitD) (P = 0.037, P = 0.019; respectively) with a higher prevalence of non-dipper pattern at Ambulatory Blood Pressure Monitoring (ABPM) (65% vs 40%, P < 0.05) at an early stage of the disease.In this study, we showed a high prevalence of PA in ADPKD patients, associated to higher LVMI, HOMA-IR, Hcy, lower FMD, and 25-OH-VitD, considered as surrogate markers of atherosclerosis, compared to ADPKD patients with normal PAC values. Our

  16. Simultaneous Native Nephrectomy and Kidney Transplantation in Patients With Autosomal Dominant Polycystic Kidney Disease.

    Directory of Open Access Journals (Sweden)

    Massimiliano Veroux

    Full Text Available To evaluate the feasibility of simultaneous unilateral nephrectomy with kidney transplantation and to determine the effect of this procedure on perioperative morbidity and mortality and graft and patient survival.Between January 2000 and May 2015, 145 patients with autosomal dominant polycystic kidney disease (ADPKD underwent kidney transplantation. Of those, 40 (27.5% underwent concurrent ipsilateral native nephrectomy (group NT. Patients in group NT were compared with patients with ADPKD not undergoing concurrent nephrectomy (group NT- and asymptomatic patients undergoing pretransplant nephrectomy (group PNT.The average follow-up was 66 months. The graft survival rate at 1 and 5 years was 95% and 87.5% versus 93% and 76.2% in the NT and NT- groups, respectively (P = .903 and P = .544, respectively; 1-year patient survival was 100% for NT and 97% for NT- patients (P = .288, whereas 5-year patient survival was 100% and 92% for NT and NT- groups, respectively (P = .128. After propensity score matching (34 patients per group no significant differences were observed in 1-year (97.1% in NT and 94.1%; P = 1 and 5-year (88.2% in NT and 91.2% in NT-; P = 1 graft survival, and in 1-year (100% for both groups; P = 1 and 5-year (100% in NT and 94.1% in NT-; P = 1 patient survival. Perioperative mortality was 0% among NT and 1.2% among NT- patients, whereas perioperative surgical complications were similar in both groups. One- and 5-year graft and patient survival were similar between the NT and PNT groups, but patients in the PNT group had significantly lower levels of hemoglobin and residual diuresis volumes at the time of transplant. Moreover, PNT patients had a longer pretransplant dialysis and a longer time on the waiting list.Simultaneous unilateral nephrectomy does not have a negative effect on patient and graft survival in patients with ADPKD and is associated with low morbidity. Pretransplant nephrectomy should be restricted only to highly

  17. Extra-renal manifestations of autosomal dominant polycystic kidney disease (ADPKD): considerations for routine screening and management.

    Science.gov (United States)

    Luciano, Randy L; Dahl, Neera K

    2014-02-01

    Autosomal-dominant polycystic kidney disease (ADPKD) is a systemic disease, marked by progressive increase of bilateral renal cysts, resulting in chronic kidney disease (CKD) and often leading to end-stage renal disease (ESRD). Apart from renal cysts, patients often have extra-renal disease, involving the liver, heart and vasculature. Other less common but equally important extra-renal manifestations of ADPKD include diverticular disease, hernias, male infertility and pain. Extra-renal disease burden is often asymptomatic, but may result in increased morbidity and mortality. If the disease burden is significant, screening may prove beneficial. We review the rationale for current screening recommendations and propose some guidelines for screening and management of ADPKD patients.

  18. Chronic Kidney Pain in Autosomal Dominant Polycystic Kidney Disease : A Case Report of Successful Treatment by Catheter-Based Renal Denervation

    NARCIS (Netherlands)

    Casteleijn, Niek F.; de Jager, Rosa L.; Neeleman, M. Peer; Blankestijn, Peter J.; Gansevoort, Ron T.

    2014-01-01

    Chronic pain is a common concern in patients with autosomal dominant polycystic kidney disease (ADPKD). We report what to our knowledge is the first catheter-based renal denervation procedure in a patient with ADPKD resulting in successful management of chronic pain. The patient was a 43-year-old wo

  19. Neonatal onset autosomal dominant polycystic kidney disease (ADPKD) in a patient homozygous for a PKD2 missense mutation due to uniparental disomy.

    NARCIS (Netherlands)

    Losekoot, M.; Ruivenkamp, C.A.; Tholens, A.P.; Grimbergen, J.E.; Vijfhuizen, L.; Vermeer, S.; Dijkman, H.B.P.M.; Cornelissen, E.A.M.; Bongers, M.H.F.; Peters, D.J.

    2012-01-01

    Autosomal dominant polycystic kidney disease (ADPKD), due to a heterozygous mutation in PKD1 or PKD2, is usually an adult onset disease. Renal cystic disease is generally milder in PKD2 patients than in PKD1 patients. Recently, several PKD1 patients with a severe renal cystic phenotype due to a seco

  20. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival-an analysis of data from the ERA-EDTA Registry.

    NARCIS (Netherlands)

    Spithoven, E.M.; Kramer, A.; Meijer, E.; Orskov, B.; Wanner, C.; Abad, J.M.; Areste, N.; Torre, R.A. de la; Caskey, F.; Couchoud, C.; Finne, P.; Heaf, J.; Hoitsma, A.J.; Meester, J. de; Pascual, J.; Postorino, M.; Ravani, P.; Zurriaga, O.; Jager, K.J.; Gansevoort, R.T.

    2014-01-01

    BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common renal disease requiring renal replacement therapy (RRT). Still, there are few epidemiological data on the prevalence of, and survival on RRT for ADPKD. METHODS: This study used data from the ERA-EDTA Registry

  1. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe : prevalence and survival-an analysis of data from the ERA-EDTA Registry

    NARCIS (Netherlands)

    Spithoven, Edwin M.; Kramer, Anneke; Meijer, Esther; Orskov, Bjarne; Wanner, Christoph; Abad, Jose M.; Areste, Nuria; Alonso de la Torre, Ramon; Caskey, Fergus; Couchoud, Cecile; Finne, Patrik; Heaf, James; Hoitsma, Andries; de Meester, Johan; Pascual, Julio; Postorino, Maurizio; Ravani, Pietro; Zurriaga, Oscar; Jager, Kitty J.; Gansevoort, Ron T.

    2014-01-01

    Background. Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common renal disease requiring renal replacement therapy (RRT). Still, there are few epidemiological data on the prevalence of, and survival on RRT for ADPKD. Methods. This study used data from the ERA-EDTA Registry

  2. Automated segmentation of liver and liver cysts from bounded abdominal MR images in patients with autosomal dominant polycystic kidney disease

    Science.gov (United States)

    Kim, Youngwoo; Bae, Sonu K.; Cheng, Tianming; Tao, Cheng; Ge, Yinghui; Chapman, Arlene B.; Torres, Vincente E.; Yu, Alan S. L.; Mrug, Michal; Bennett, William M.; Flessner, Michael F.; Landsittel, Doug P.; Bae, Kyongtae T.

    2016-11-01

    Liver and liver cyst volume measurements are important quantitative imaging biomarkers for assessment of disease progression in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD). To date, no study has presented automated segmentation and volumetric computation of liver and liver cysts in these populations. In this paper, we proposed an automated segmentation framework for liver and liver cysts from bounded abdominal MR images in patients with ADPKD. To model the shape and variations in ADPKD livers, the spatial prior probability map (SPPM) of liver location and the tissue prior probability maps (TPPMs) of liver parenchymal tissue intensity and cyst morphology were generated. Formulated within a three-dimensional level set framework, the TPPMs successfully captured liver parenchymal tissues and cysts, while the SPPM globally constrained the initial surfaces of the liver into the desired boundary. Liver cysts were extracted by combined operations of the TPPMs, thresholding, and false positive reduction based on spatial prior knowledge of kidney cysts and distance map. With cross-validation for the liver segmentation, the agreement between the radiology expert and the proposed method was 84% for shape congruence and 91% for volume measurement assessed by the intra-class correlation coefficient (ICC). For the liver cyst segmentation, the agreement between the reference method and the proposed method was ICC  =  0.91 for cyst volumes and ICC  =  0.94 for % cyst-to-liver volume.

  3. The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway.

    Science.gov (United States)

    Barr, M M; DeModena, J; Braun, D; Nguyen, C Q; Hall, D H; Sternberg, P W

    2001-09-04

    Autosomal dominant polycystic kidney disease (ADPKD) strikes 1 in 1000 individuals and often results in end-stage renal failure. Mutations in either PKD1 or PKD2 account for 95% of all cases [1-3]. It has recently been demonstrated that polycystin-1 and polycystin-2 (encoded by PKD1 and PKD2, respectively) assemble to form a cation channel in vitro [4]. Here we determine that the Caenorhabditis elegans PKD1 and PKD2 homologs, lov-1 [5] and pkd-2, act in the same pathway in vivo. Mutations in either lov-1 or pkd-2 result in identical male sensory behavioral defects. Also, pkd-2;lov-1 double mutants are no more severe than either of the single mutants, indicating that lov-1 and pkd-2 act together. LOV-1::GFP and PKD-2::GFP are expressed in the same male-specific sensory neurons and are concentrated in cilia and cell bodies. Cytoplasmic, nonnuclear staining in cell bodies is punctate, suggesting that one pool of PKD-2 is localized to intracellular membranes while another is found in sensory cilia. In contrast to defects in the C. elegans autosomal recessive PKD gene osm-5 [6-8], the cilia of lov-1 and pkd-2 single mutants and of lov-1;pkd-2 double mutants are normal as judged by electron microscopy, demonstrating that lov-1 and pkd-2 are not required for ultrastructural development of male-specific sensory cilia.

  4. Combined Liver and Kidney Transplant in a Patient with Budd-Chiari Syndrome Secondary to Autosomal Dominant Polycystic Kidney Disease Associated with Polycystic Liver Disease: Report of a Case with a 9-Year Follow-Up

    Science.gov (United States)

    Ramírez de la Piscina, Patricia; Duca, Ileana; Estrada, Silvia; Calderón, Rosario; Ganchegui, Idoia; Campos, Amaia; Spicakova, Katerina; Salvador, Marta; Delgado, Elvira; Bengoa, Raquel; García-Campos, Francisco

    2014-01-01

    Polycystic liver disease (PLD) is a hereditary disease inherited by autosomal dominant trait that occurs as a frequent extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). We report a case of a 59-year-old woman diagnosed with ADPKD associated with PLD. End-stage chronic renal failure with a secondary Budd-Chiari syndrome developed during the patient's clinical course. She underwent combined liver and kidney transplantation, with a successful response over a 9-year follow-up period. PMID:24987537

  5. A comparison of seminal vesicle size on CT between autosomal dominant polycystic kidney disease (ADPKD) patients and normal subjects

    Energy Technology Data Exchange (ETDEWEB)

    Joo, Ijin; Kim, Seung Hyup; Cho, Jeong Yeon (Dept. of Radiology, Seoul National Univ. College of Medicine, Inst. of Radiation Medicine, Seoul National Univ., Seoul (Korea)), e-mail: kimsh@radcom.snu.ac.kr

    2010-06-15

    Background: Extrarenal manifestations are common in autosomal dominant polycystic kidney disease (ADPKD). Although seminal vesicles can also be involved in patients with ADPKD, little is known about the size differences of the seminal vesicles between ADPKD patients and normal subjects. Purpose: To determine whether the size of seminal vesicles in ADPKD patients is larger than that in normal subjects with the use of three-dimensional (3D) CT. Material and Methods: Using a retrospective case-control study design, we reviewed the findings of 696 male patients with an age range of 20-69 years who underwent contrast enhanced multi-detector computed tomography (MDCT) imaging of the kidney in our institution from August 2007 to July 2008. A total of 68 male patients with ADPKD comprised the study group. Another 68 age-matched non-ADPKD male patients comprised the control group. The size of bilateral seminal vesicles was assessed by measurement of the short dimension on axial, coronal, and sagittal images by the use of a picture archiving and communication system (PACS). Results: The mean width of seminal vesicles in ADPKD patients was 1.70+-0.40 cm (axial images), 1.86+-0.45 cm (coronal), and 1.59+-0.39 cm (sagittal). For control group subjects, the mean width was 1.53+-0.29 cm (axial), 1.68+-0.43 cm (coronal), and 1.48+-0.31 cm (sagittal). The mean size differences between the ADPKD and control groups for the measured widths on axial and coronal images were statistically significant (P=0.01 and P=0.02, respectively). The width as measured on axial images showed a decrease with age in the control group subjects (linear trend, P=0.005), but no significant decrease was noted in ADPKD patients. Conclusion: The seminal vesicles were demonstrated to be larger in ADPKD patients as compared with normal subjects as determined with the use of 3D CT . Keywords: Autosomal dominant polycystic kidney disease (ADPKD), seminal vesicle, computed tomography, CT

  6. A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin

    Science.gov (United States)

    2012-07-01

    magnitude, [32]), indicating that urine succinate levels could be a potential biomarker for detecting diabetic nephropathy early on in the disease progression...a drug in wide clinical use for both non-insulin dependent diabetes mellitus and Polycystic Ovary Syndrome, stimulates AMPK (10, 11). We therefore...regimens can produce AMPK activation in wild type mice. In addition, we will determine whether activation of AMPK by metformin treatment exhibits any

  7. Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Back, Susan J. [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); Andronikou, Savvas [University of the Witwatersrand, Radiology Department, Faculty of Health Sciences, Johannesburg (South Africa); Kilborn, Tracy [University of Cape Town, Red Cross War Memorial Children' s Hospital, Cape Town (South Africa); Kaplan, Bernard S. [The Children' s Hospital of Philadelphia, Division of Nephrology, Philadelphia, PA (United States); University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (United States); Darge, Kassa [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (United States)

    2015-03-01

    Genes for tuberous sclerosis complex (TSC) type 2 and autosomal-dominant polycystic kidney disease (ADPKD) type 1 are both encoded over a short segment of chromosome 16. When deletions involve both genes, an entity known as the TSC2/ADPKD1 contiguous gene syndrome, variable phenotypes of TSC and ADPKD are exhibited. This syndrome has not been reviewed in the radiology literature. Unlike renal cysts in TSC, cystic disease in TSC2/ADPKD1 contiguous gene syndrome results in hypertension and renal failure. A radiologist might demonstrate polycystic kidney disease before the patient develops other stigmata of TSC. Conversely, in patients with known TSC, enlarged and polycystic kidneys should signal the possibility of the TSC2/ADPKD1 contiguous gene syndrome and not simply TSC. Distinguishing these diagnoses has implications in prognosis, treatment and genetic counseling. To describe the clinical and imaging findings of tuberous sclerosis complex and polycystic kidney disease in seven pediatric patients. We retrospectively reviewed renal and brain imaging of children and young adults with genetically proven or high clinical suspicion for TSC2/ADPKD1 contiguous gene syndrome. We included seven pediatric patients from two referral institutions. Ages ranged from birth to 21 years over the course of imaging. The mean follow-up period was 9 years 8 months (4 years 6 months to 20 years 6 months). No child progressed to end-stage renal disease during this period. Three patients were initially imaged for stigmata of TSC, three for abdominal distension and one for elevated serum creatinine concentration. All patients developed enlarged, polycystic kidneys. The latest available imaging studies demonstrated that in 12 of the 14 kidneys 50% or more of the parenchyma was ultimately replaced by >15 cysts, resulting in significant cortical thinning. The largest cysts in each kidney ranged from 2.4 cm to 9.3 cm. Echogenic lesions were present in 13 of the 14 kidneys, in keeping with

  8. Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease: A Biomarker of Disease Progression and Therapeutic Efficacy.

    Science.gov (United States)

    Alam, Ahsan; Dahl, Neera K; Lipschutz, Joshua H; Rossetti, Sandro; Smith, Patricia; Sapir, Daniel; Weinstein, Jordan; McFarlane, Philip; Bichet, Daniel G

    2015-10-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life-threatening monogenic disorder in humans, characterized by progressive development and expansion of fluid-filled cysts in the kidneys and other organs. Ongoing cyst growth leads to progressive kidney enlargement, whereas kidney function remains stable for decades as a result of hyperfiltration and compensation by unaffected nephrons. Kidney function irreversibly declines only in the late stages of the disease, when most of the parenchyma is lost to cystic and fibrotic tissue and the remaining compensatory capacity is overwhelmed. Hence, conventional kidney function measures, such as glomerular filtration rate, do not adequately assess disease progression in ADPKD, especially in its early stages. Given the recent development of potential targeted therapies in ADPKD, it has become critically important to identify relevant biomarkers that can be used to determine the degree of disease progression and evaluate the effects of therapeutic interventions on the course of the disease. We review the current evidence to provide an informed perspective on whether total kidney volume (TKV) is a suitable biomarker for disease progression and whether TKV can be used as an efficacy end point in clinical trials. We conclude that because cystogenesis is the central factor leading to kidney enlargement, TKV appears to be an appropriate biomarker and is gaining wider acceptance. Several studies have identified TKV as a relevant imaging biomarker for monitoring and predicting disease progression and support its use as a prognostic end point in clinical trials.

  9. Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13-q23

    Energy Technology Data Exchange (ETDEWEB)

    Kimberling, W.J.; Kumar, S.; Kenyon, J.B.; Connolly, C.J. (Creighton Univ. Medical School, Omaha, NE (United States)); Gabow, P.A. (Colorado Univ. Health Sciences Center, Denver, CO (United States)); Somlo, S. (Albert Einstein School of Medicine, Bronx, NY (United States))

    1993-12-01

    At least two loci are known to exist for autosomal dominant polycystic kidney disease (ADPKD). One was localized to 16p, but the second less common locus has remained unlinked. Over 100 microsatellite markers, distributed across all chromosomes, have been typed on informative family members from the large Sicilian kindred in which the genetic heterogeneity was first discovered. Both the affected and the unaffected status of every family member used in the study were consulted in the successful localization of a second ADPKD gene to chromosome 4q. It was found to be flanked by the markers D4S231 and D4S414, defining a segment that spans about 9 cM. The new locus has been designated PKD4. This second localization will allow researchers to target another ADPKD gene for isolation in an effort to understand the pathogenesis of this common disorder. Furthermore, when flanking markers for the second ADPKD gene are used in conjunction with flanking markers for PKD1, the accuracy of the diagnosis of the subtype of ADPKD present in any particular family will be enhanced. This will improve the accuracy of linkage-based presymptomatic diagnoses by reducing the error due to genetic heterogeneity. 42 refs., 3 figs., 1 tab.

  10. Design and baseline characteristics of participants in the study of antihypertensive therapy in children and adolescents with autosomal dominant polycystic kidney disease (ADPKD).

    Science.gov (United States)

    Cadnapaphornchai, Melissa A; Fick-Brosnahan, Godela M; Duley, Irene; Johnson, Ann M; Strain, John D; DeGroff, Curt G; Schrier, Robert W

    2005-04-01

    In this manuscript, we describe our ongoing randomized clinical trial to assess the efficacy of blood pressure control with angiotensin converting enzyme (ACE) inhibition on renal cyst growth over a 5-year study period in children and young adults aged 4-21 years with autosomal dominant polycystic kidney disease (ADPKD). Baseline demographic and laboratory data for the study groups are reported. Results of this study could significantly impact the standard of care for management of ADPKD in this population.

  11. Low birth weight is associated with earlier onset of end-stage renal disease in Danish patients with autosomal dominant polycystic kidney disease

    DEFF Research Database (Denmark)

    Orskov, Bjarne; Christensen, Karl Bang; Feldt-Rasmussen, Bo

    2012-01-01

    Low-birth-weight individuals have a higher risk of hypertension and end-stage renal disease (ESRD). Here we investigated whether low birth weight was associated with earlier onset of ESRD in patients with autosomal dominant polycystic kidney disease (ADPKD). In collaboration with all Danish depar...... birth weight may contribute to considerable phenotypic variability in the progression of renal disease between individuals with ADPKD....

  12. [Autosomal recessive polycystic kidney].

    Science.gov (United States)

    Todorov, V; Penkova, S; Lalev, I

    1990-01-01

    A case of a 22 years old woman with autosomal-recessive form of kidney polycystosis is presented. The diagnosis was made in early childhood. A combination of renal anomaly and hepatic fibrosis with manifestations of portal hypertension was present. No deviations from the other internal organs were found. At the age of 12 she entered into the stage of chronic renal failure. The last five years she is on dialysis treatment. She had survived several acute bleedings from esophageal varices. The authors are of the opinion that the case is of interest since patients with autosomal-recessive renal polycystosis very rarely reach majority.

  13. Autosomal dominant lamellar ichthyosis.

    Science.gov (United States)

    Toribio, J; Fernández Redondo, V; Peteiro, C; Zulaica, A; Fabeiro, J M

    1986-08-01

    Five members of two generations of one family were affected with lamellar ichthyosis, suggesting autosomal dominant transmission. The clinical and histopathological characteristics of the cases described here are similar to those reported by Traupe et al. (1984) as autosomal dominant lamellar ichthyosis and thus confirm the existence of this new form of ichthyosis.

  14. De novo post-transplant thrombotic microangiopathy localized only to the graft in autosomal dominant polycystic kidney disease with thrombophilia

    Science.gov (United States)

    Rolla, Davide; Fontana, Iris; Ravetti, Jean Louis; Marsano, Luigina; Bellino, Diego; Panaro, Laura; Ansaldo, Francesca; Mathiasen, Lisa; Storace, Giulia; Trezzi, Matteo

    2015-01-01

    Introduction: Thrombotic microangiopathy (TMA) is a serious complication of renal transplantation and is mostly related to the prothrombotic effect of calcineurin inhibitors (CNIs). A subset of TMA (29%-38%) is localized only to the graft. Case 1: A young woman suffering from autosomal dominant polycystic kidney disease (ADPKD) underwent kidney transplant. After 2 months, she showed slow renal deterioration (serum creatinine from 1.9 to 3.1 mg/dl), without hematological signs of hemolytic-uremic syndrome (HUS); only LDH enzyme transient increase was detected. Renal biopsy showed TMA: temporary withdraw of tacrolimus and plasmapheresis was performed. The renal function recovered (serum creatinine 1.9 mg/dl). From screening for thrombophilia, we found a mutation of the Leiden factor V gene. Case 2: A man affected by ADPKD underwent kidney transplantation, with delay graft function; first biopsy showed acute tubular necrosis, but a second biopsy revealed TMA, while no altered hematological parameters of HUS was detected. We observed only a slight increase of lactate dehydrogenase (LDH) levels. The tacrolimus was halved and plasmapheresis was performed: LDH levels normalized within 10 days and renal function improved (serum creatinine from 9 to 2.9 mg/dl). We found a mutation of the prothrombin gene. Only a renal biopsy clarifies the diagnosis of TMA, but it is necessary to pay attention to light increasing level of LDH. Conclusion: Prothrombotic effect of CNIs and mTOR inhibitor, mutation of genes encoding factor H or I, anticardiolipin antibodies, vascular rejection, cytomegalovirus infection are proposed to trigger TMA; we detected mutations of factor II and Leiden factor V, as facilitating conditions for TMA in patients affected by ADPKD. PMID:26693501

  15. Somatotroph Pituitary Adenoma with Acromegaly and Autosomal Dominant Polycystic Kidney Disease – SSTR5 polymorphism and PKD1 mutation

    Science.gov (United States)

    Syro, Luis V.; Sundsbak, Jamie L.; Scheithauer, Bernd W.; Toledo, Rodrigo A.; Camargo, Mauricio; Heyer, Christina M.; Sekiya, Tomoko; Uribe, Humberto; Escobar, Jorge I.; Vasquez, Martin; Rotondo, Fabio; Toledo, Sergio P. A.; Kovacs, Kalman; Horvath, Eva; Babovic-Vuksanovic, Dusica; Harris, Peter C.

    2014-01-01

    A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0–5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48–255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.143C>A (p.L48M, rs4988483) change in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subject to extensive morphological, ultrastructural, cytogenetic and molecular studies. The question arises whether the physical proximity of the PKD1 and SSTR5 genes on chromosome 16 indicates a causal relationship between ADPKD and the somatotroph adenoma. PMID:21744088

  16. Genetic diagnosis of autosomal dominant polycystic kidney disease by targeted capture and next-generation sequencing: utility and limitations.

    Science.gov (United States)

    Qi, Xiao-Ping; Du, Zhen-Fang; Ma, Ju-Ming; Chen, Xiao-Ling; Zhang, Qing; Fei, Jun; Wei, Xiao-Ming; Chen, Dong; Ke, Hai-Ping; Liu, Xuan-Zhu; Li, Feng; Chen, Zhen-Guang; Su, Zheng; Jin, Hang-Yang; Liu, Wen-Ting; Zhao, Yan; Jiang, Hu-Ling; Lan, Zhang-Zhang; Li, Peng-Fei; Fang, Ming-Yan; Dong, Wei; Zhang, Xian-Ning

    2013-03-01

    Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, and duplication sequences of PKD1. Recently, targeted resequencing by pooling long-range polymerase chain reaction (LR-PCR) amplicons has been used in the identification of mutations in ADPKD. Despite its high sensitivity, specificity and accuracy, LR-PCR is still complicated. We performed whole-exome sequencing on two unrelated typical Chinese ADPKD probands and evaluated the effectiveness of this approach compared with Sanger sequencing. Meanwhile, we performed targeted gene and next-generation sequencing (targeted DNA-HiSeq) on 8 individuals (1 patient from one family, 5 patients and 2 normal individuals from another family). Both whole-exome sequencing and targeted DNA-HiSeq confirmed c.11364delC (p.H3788QfsX37) within the unduplicated region of PKD1 in one proband; in the other family, targeted DNA-HiSeq identified a small insertion, c.401_402insG (p.V134VfsX79), in PKD2. These methods do not overcome the screening complexity of homology. However, the true positives of variants confirmed by targeted gene and next-generation sequencing were 69.4%, 50% and 100% without a false positive in the whole coding region and the duplicated and unduplicated regions, which indicated that the screening accuracy of PKD1 and PKD2 can be largely improved by using a greater sequencing depth and elaborate design of the capture probe.

  17. Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Tan, Ying-Cai; Blumenfeld, Jon D; Anghel, Raluca; Donahue, Stephanie; Belenkaya, Rimma; Balina, Marina; Parker, Thomas; Levine, Daniel; Leonard, Debra G B; Rennert, Hanna

    2009-02-01

    Genetic testing of PKD1 and PKD2 is useful for diagnosis and prognosis of autosomal dominant polycystic kidney disease (ADPKD), particularly in asymptomatic individuals or those without a family history. PKD1 testing is complicated by the large transcript size, complexity of the gene region, and the extent of gene variations. A molecular assay was developed using Transgenomic's SURVEYOR Nuclease and WAVE Nucleic Acid High Sensitivity Fragment Analysis System to screen for PKD1 and PKD2 variants, followed by sequencing of variant gene segments, thereby reducing the sequencing reactions by 80%. This method was compared to complete DNA sequencing performed by a reference laboratory for 25 ADPKD patients from 22 families. The pathogenic potential of gene variations of unknown significance was examined by evolutionary comparison, effects of amino acid substitutions on protein structure, and effects of splice-site alterations. A total of 90 variations were identified, including all 82 reported by the reference laboratory (100% sensitivity). A total of 76 variations (84.4%) were in PKD1 and 14 (15.6%) in PKD2. Definite pathogenic mutations (seven nonsense, four truncation, and three splicing defects) were detected in 64% (14/22) of families. The remaining 76 variants included 26 missense, 33 silent, and 17 intronic changes. Two heterozygous nonsense mutations were incorrectly determined by the reference laboratory as homozygous. "Probably pathogenic" mutations were identified in an additional five families (overall detection rate 86%). In conclusion, the SURVEYOR nuclease method was comparable to direct sequencing for detecting ADPKD mutations, achieving high sensitivity with lower cost, providing an important tool for genetic analysis of complex genes.

  18. Characteristics of Intracranial Aneurysms in the Else Kröner-Fresenius Registry of Autosomal Dominant Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Hartmut P.H. Neumann

    2012-10-01

    Full Text Available Background: Patients who harbor intracranial aneurysms (IAs run a risk for aneurysm rupture and subsequent subarachnoid hemorrhage which frequently results in permanent deficits or death. Prophylactic treatment of unruptured aneurysms is possible and recommended depending on the size and location of the aneurysm as well as patient age and condition. IAs are major manifestations of autosomal dominant polycystic kidney disease (ADPKD. Current guidelines do not suggest surveillance of IAs in ADPKD except in the setting of family history if IA was known in any relative with ADPKD. Management of IAs in ADPKD is problematic because limited data exist from large studies. Methods: We established the Else Kröner-Fresenius Registry for ADPKD in Germany. Clinical data were assessed for age at diagnosis of IAs, stage of renal insufficiency, and number, location and size of IAs as well as family history of cerebral events. Patients with symptomatic or asymptomatic IAs were included. All patients with ADPKD-related IAs were offered mutation scanning of the susceptibility genes for ADPKD, the PKD1 and PKD2 genes. Results: Of 463 eligible ADPKD patients from the population base of Germany, 32 (7% were found to have IAs, diagnosed at the age of 2–71 years, 19 females and 13 males. Twenty (63% of these 32 patients were symptomatic, whereas IAs were detected in an asymptomatic stage in 12 patients. IAs were multifocal in 12 and unifocal in 20 patients. In 26 patients (81%, IAs were diagnosed before end-stage renal failure. Twenty-five out of 27 unrelated index cases (93% had no IAs or cerebral events documented in their relatives with ADPKD. In 16 unrelated index patients and 3 relatives, we detected germline mutations. The mutations were randomly distributed across the PKD1 gene in 14 and the PKD2 gene in 2 index cases. Questionnaires answered for 320/441 ADPKD patients without IAs revealed that only 45/320 (14% had MR angiography. Conclusion: In ADPKD

  19. Chronic asymptomatic pyuria precedes overt urinary tract infection and deterioration of renal function in autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Hwang Jin Ho

    2013-01-01

    Full Text Available Abstract Background Urinary tract infection (UTI occurs in 30%-50% of individuals with autosomal dominant polycystic kidney disease (ADPKD. However, the clinical relevance of asymptomatic pyuria in ADPKD patients remains unknown. Methods We retrospectively reviewed medical records of 256 ADPKD patients who registered to the ADPKD clinic at Seoul National University Hospital from Aug 1999 to Aug 2010. We defined the asymptomatic pyuria as more than 5-9 white blood cells in high-power field with no related symptoms or signs of overt UTI. Patients were categorized into 2 groups depending on its duration and frequency: Group A included non-pyuria and transient pyuria patients; Group B included recurrent and persistent pyuria patients. The association between asymptomatic pyuria and both the development of overt UTI and the deterioration of renal function were examined. Results With a mean follow-up duration of 65.3 months, 176 (68.8% out of 256 patients experienced 681 episodes of asymptomatic pyuria and 50 episodes of UTI. The annual incidence of asymptomatic pyuria was 0.492 episodes/patient/year. The patients in group B showed female predominance (58.5% vs. 42.0%, P=0.01 and experienced an upper UTI more frequently (hazard ratio: 4.612, 95% confidence interval: 1.735-12.258; P=0.002, adjusted for gender and hypertension. The annual change in estimated glomerular filtration rate (ΔeGFR was significantly larger in magnitude in group B than in group A (-2.7��4.56 vs. -1.17±5.8, respectively; P=0.01. Age and Group B found to be the independent variables for ΔeGFR and developing end-stage renal disease (16.0% vs. 4.3%, respectively; P=0.001. Conclusions Chronic asymptomatic pyuria may increase the risk of developing overt UTI and may contribute to declining renal function in ADPKD.

  20. Post transplant urinary tract infection in Autosomal dominant polycystic kidney disease a perpetual diagnostic dilema - 18-fluorodeoxyglucose - Positron emission computerized tomography - A valuable tool.

    Science.gov (United States)

    Sainaresh, Vv; Jain, Sh; Patel, Hv; Shah, Pr; Vanikar, Av; Trivedi, Hl

    2011-04-01

    Urinary tract infection (UTI) is the most common infection contracted by renal allograft recipients. In patients of autosomal dominant polycystic kidney disease (ADPKD), cyst infection presents a complex diagnostic and therapeutic challenge especially in the post transplant period. Accurate diagnosis forms the cornerstone in salvaging the graft from potentially catastrophic outcome. We describe a case of xanthogranulomatous pyelonephritis (XPN) in the native kidney in a patient of post transplant ADPKD which presented as frequently relapsing UTI with graft dysfunction where in accurate diagnosis was made possible with the aid of 18-fluorodeoxyglucose (FDG) - Positron emission computerized tomography (PET/CT).

  1. Autosomal dominant osteopetrosis revisited

    DEFF Research Database (Denmark)

    Bollerslev, Jens; Henriksen, Kim; Nielsen, Morten Frost Munk

    2013-01-01

    Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation...

  2. Rapamycin reduces kidney volume and delays the loss of renal function in a patient with autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; Pérez-Dueñas, Virginia; Cuesta-López, Emilio; Azorín, Sebastián; Selgas, Rafael

    2009-04-01

    This is the first report of a case of a reduction in kidney volume and preservation of renal function in a patient with autosomal-dominant polycystic kidney disease (ADPKD) receiving rapamycin. A 42-year-old man with ADPKD and a severe persistent bleeding from his solitary left kidney was successfully treated with tranexamic acid (TXA). He also received low-dose rapamycin for 8 months, and this was associated with a 23.5% reduction in kidney volume, improvement and stabilization of renal function, and normalization of haemoglobin levels. When treatment with rapamycin was interrupted, renal function deteriorated within an 8-month period and haemodialysis (HD) became necessary. Kidney volume increased at once, and life-threatening bleeding prompted a nephrectomy 4 months after the onset of HD. These data suggest that the reduction in kidney volume and preservation of renal function with rapamycin could be the result of the antiangiogenic, antiproliferative effects of rapamycin.

  3. Changes in causes of death and risk of cancer in Danish patients with autosomal dominant polycystic kidney didease and end-stage renal disease

    DEFF Research Database (Denmark)

    Ørskov, Bjarne; Feldt-Rasmussen, Bo Friis; Strandgaard, Svend Valdemar;

    2012-01-01

    Abstract Background. With the improved prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD), causes of death and the risk of cancer might have changed. This was investigated in a Danish population with ADPKD and end-stage renal disease (ESRD) between 1 January 1993 and 31...... December 2008. Methods. Data were retrieved from three Danish national registries and a total of 823 patients were identified of which 431 had died during the study period. The 16 years were divided into two 8-year periods and the causes of death were divided into six categories: cancer, cardiovascular...... (HR) 0.65, P = 0.008] and deaths from cerebrovascular disease decreased by 69% (HR 0.31, P = 0.0003) from the first to the second time period. There were no significant changes between the time periods in death from cancer, infection, other or unknown. From the first to the second 8-year interval...

  4. Splicing defects caused by exonic mutations in PKD1 as a new mechanism of pathogenesis in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Claverie-Martin, Felix; Gonzalez-Paredes, Francisco J; Ramos-Trujillo, Elena

    2015-01-01

    The correct splicing of precursor-mRNA depends on the actual splice sites plus exonic and intronic regulatory elements recognized by the splicing machinery. Surprisingly, an increasing number of examples reveal that exonic mutations disrupt the binding of splicing factors to these sequences or generate new splice sites or regulatory elements, causing disease. This contradicts the general assumption that missense mutations disrupt protein function and that synonymous mutations are merely polymorphisms. Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder caused mainly by mutations in the PKD1 gene. Recently, we analyzed a substantial number of PKD1 missense or synonymous mutations to further characterize their consequences on pre-mRNA splicing. Our results showed that one missense and 2 synonymous mutations induce significant defects in pre-mRNA splicing. Thus, it appears that aberrant splicing as a result of exonic mutations is a previously unrecognized cause of ADPKD.

  5. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease.

    NARCIS (Netherlands)

    Spithoven, E.M.; Kramer, A.; Meijer, E.; Orskov, B.; Wanner, C.; Caskey, F.; Collart, F.; Finne, P.; Fogarty, D.G.; Groothoff, J.W.; Hoitsma, A.J.; Nogier, M.B.; Postorino, M.; Ravani, P.; Zurriaga, O.; Jager, K.J.; Gansevoort, R.T.; Bindels, R.J.M.

    2014-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADP

  6. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease

    NARCIS (Netherlands)

    Spithoven, Edwin M.; Kramer, Anneke; Meijer, Esther; Orskov, Bjarne; Wanner, Christoph; Caskey, Fergus; Collart, Frederic; Finne, Patrik; Fogarty, Damian G.; Groothoff, Jaap W.; Hoitsma, Andries; Nogier, Marie-Beatrice; Postorino, Maurizio; Ravani, Pietro; Zurriaga, Oscar; Jager, Kitty J.; Gansevoort, Ron T.

    2014-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADP

  7. Flow-associated dilatory capacity of the brachial artery is intact in early autosomal dominant polycystic kidney disease

    DEFF Research Database (Denmark)

    Clausen, Peter; Feldt-Rasmussen, Bo; Iversen, Jens;

    2006-01-01

    females and 18 males, age 36 +/- 10 years) with polycystic kidney disease and normal renal function were compared to 27 healthy controls. The dilatory responses of the brachial artery to postischemic increased blood flow [endothelium-dependent flow-associated dilatation (FAD)] and to nitroglycerin......-selectin and von Willebrand factor antigen were also measured. RESULTS: No differences in FAD or NID were found between patients and controls (104.6 +/- 4.2 vs. 105.3 +/- 3.9%, mean +/- SD, p = 0.55, and 117.0 +/- 8.4 vs. 117.5 +/- 7.6%, p = 0.75). However, the plasma concentration of VCAM-1 was elevated...... and the plasma concentration of NOx was reduced in patients with polycystic kidney disease. CONCLUSION: Biochemical markers confirm an association between polycystic kidney disease and endothelial dysfunction. However, a normal FAD of the brachial artery suggests that the endothelial dysfunction does not involve...

  8. Ultrasound-guided percutaneous drainage and sclerotherapy in a patient with isolated autosomal dominant polycystic liver disease

    Directory of Open Access Journals (Sweden)

    Ana Barbado-Cano

    2015-03-01

    Full Text Available Isolated polycystic liver disease (IPLD is a rare genetic condition characterized by the presence of multiple liver cysts with no association with polycystic kidney disease. Most patients are asymptomatic and acute complications (cyst torsion, bleeding, infection are uncommon. Imaging techniques, including abdominal ultrasounds, computerized axial tomography, and magnetic resonance imaging, represent a vital diagnostic modality. They are also useful for therapy support in this disease. Below we report a peculiar case of a female patient recently diagnosed with IPLD who, having received treatment with ultrasound-guided percutaneous drainage and sclerotherapy for a giant liver cyst, showed symptom and laboratory improvement.

  9. Feasibility of measuring renal blood flow by phase-contrast magnetic resonance imaging in patients with autosomal dominant polycystic kidney disease

    Energy Technology Data Exchange (ETDEWEB)

    Spithoven, E.M.; Meijer, E.; Boertien, W.E.; Gaillard, C.A.J.M.; Jong, P.E. de; Gansevoort, R.T. [University of Groningen, Department of Nephrology, Community and Occupational Medicine, University Medical Center Groningen, PO Box 30.001, RB Groningen (Netherlands); Borns, C.; Kappert, P.; Greuter, M.J.W.; Jagt, E. van der [University of Groningen, Department of Radiology, Community and Occupational Medicine, University Medical Center Groningen, Groningen (Netherlands); Vart, P. [University of Groningen, Department of Health Sciences, Community and Occupational Medicine, University Medical Center Groningen, Groningen (Netherlands)

    2016-03-15

    Renal blood flow (RBF) has been shown to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). We investigated the feasibility and accuracy of phase-contrast RBF by MRI (RBF{sub MRI}) in ADPKD patients with a wide range of estimated glomerular filtration rate (eGFR) values. First, we validated RBF{sub MRI} measurement using phantoms simulating renal artery hemodynamics. Thereafter, we investigated in a test-set of 21 patients intra- and inter-observer coefficient of variation of RBF{sub MRI}. After validation, we measured RBF{sub MRI} in a cohort of 91 patients and compared the variability explained by characteristics indicative for disease severity for RBF{sub MRI} and RBF measured by continuous hippuran infusion. The correlation in flow measurement using phantoms by phase-contrast MRI was high and fluid collection was high (CCC=0.969). Technical problems that precluded RBF{sub MRI} measurement occurred predominantly in patients with a lower eGFR (34% vs. 16%). In subjects with higher eGFRs, variability in RBF explained by disease characteristics was similar for RBF{sub MRI} compared to RBF{sub Hip,} whereas in subjects with lower eGFRs, this was significantly less for RBF{sub MRI}. Our study shows that RBF can be measured accurately in ADPKD patients by phase-contrast, but this technique may be less feasible in subjects with a lower eGFR. (orig.)

  10. Percutaneous Nephrolithotomy under Ultrasound Guidance in Patients with Renal Calculi and Autosomal Dominant Polycystic Kidney Disease: A Report of 11 Cases

    Directory of Open Access Journals (Sweden)

    Xiao Wang

    2017-01-01

    Full Text Available Nephrolithiasis accelerates the renal failure in the patients with ADPKD. In order to evaluate the role of percutaneous nephrolithotomy in management of calculus in these patients, 11 patients with autosomal dominant polycystic kidney disease and renal stones were included in the study. Two patients had bilateral renal stones. All patients were treated by percutaneous nephrolithotomy under ultrasound guidance. 13 percutaneous nephrolithotomy procedures were performed in 1 stage by the urology team under ultrasound guidance. 5 people received second operation with flexible nephroscopy in lateral position. The success rate and morbidity and mortality of the technique and hospital stay were recorded. Results. The puncture procedure was fully successful in all cases. The renal function improved in these patients. 5 patients had moderate fever after the surgery. 5 patients received flexible nephroscopy to take out the residual calculi. 2 persons had ESWL therapy after the surgery. Conclusion. PCNL is an ideal, safe, and effective method to remove the stones from those patients with no definite increase in the risk of complication. The outcome and stone-free rate are satisfactory comparable to the PCNL in the patients without ADPKD.

  11. Intermediate volume on computed tomography imaging defines a fibrotic compartment that predicts glomerular filtration rate decline in autosomal dominant polycystic kidney disease patients.

    Science.gov (United States)

    Caroli, Anna; Antiga, Luca; Conti, Sara; Sonzogni, Aurelio; Fasolini, Giorgio; Ondei, Patrizia; Perico, Norberto; Remuzzi, Giuseppe; Remuzzi, Andrea

    2011-08-01

    Total kidney and cyst volumes have been used to quantify disease progression in autosomal dominant polycystic kidney disease (ADPKD), but a causal relationship with progression to renal failure has not been demonstrated. Advanced image processing recently allowed to quantify extracystic tissue, and to identify an additional tissue component named "intermediate," appearing hypoenhanced on contrast-enhanced computed tomography (CT). The aim of this study is to provide a histological characterization of intermediate volume, investigate its relation with renal function, and provide preliminary evidence of its role in long-term prediction of functional loss. Three ADPKD patients underwent contrast-enhanced CT scans before nephrectomy. Histological samples of intermediate volume were drawn from the excised kidneys, and stained with hematoxylin and eosin and with saturated picrosirius solution for histological analysis. Intermediate volume showed major structural changes, characterized by tubular dilation and atrophy, microcysts, inflammatory cell infiltrate, vascular sclerosis, and extended peritubular interstitial fibrosis. A significant correlation (r = -0.69, P < 0.001) between relative intermediate volume and baseline renal function was found in 21 ADPKD patients. Long-term prediction of renal functional loss was investigated in an independent cohort of 13 ADPKD patients, followed for 3 to 8 years. Intermediate volume, but not total kidney or cyst volume, significantly correlated with glomerular filtration rate decline (r = -0.79, P < 0.005). These findings suggest that intermediate volume may represent a suitable surrogate marker of ADPKD progression and a novel therapeutic target.

  12. Refining the localization of the PKD2 locus on chromosome 4q by linkage analysis in Spanish families with autosomal dominant polycystic kidney disease type 2

    Energy Technology Data Exchange (ETDEWEB)

    San Millan, J.L.; Viribay, M.; Peral, B.; Moreno, F. [Unidad de Genetica Molecular, Madrid (Spain); Martinez, I. [Hospital de Galdacano (Spain); Weissenbach, J. [Genethon, Evry (France)

    1995-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder. At least two distinct forms of ADPKD are now well defined. In {approximately}86% of affected European families, a gene defect localized to 16p13.3 was responsible for ADPKD, while a second locus has been recently localized to 4q13-q23 as candidate for the disease in the remaining families. We present confirmation of linkage to microsatellite markers on chromosome 4q in eight Spanish families with ADPKD, in which the disease was not linked to 16p13.3. By linkage analysis with marker D4S423, a maximum lod score of 9.03 at a recombination fraction of .00 was obtained. Multipoint linkage analysis, as well as a study of recombinant haplotypes, placed the PKD2 locus between D4S1542 and D4S1563, thereby defining a genetic interval of {approximately}1 cM. The refined map will serve as a genetic framework for additional genetic and physical mapping of the region and will improve the accuracy of presymptomatic diagnosis of PKD2. 25 refs., 4 figs., 1 tab.

  13. Cyst Ablation Using a Mixture of N-Butyl Cyanoacrylate and Iodized Oil in Patients with Autosomal Dominant Polycystic Kidney Disease: the Long-Term Results

    Energy Technology Data Exchange (ETDEWEB)

    Kim, See Hyung; Kim, Seung Hyup; Cho, Jeong Yeon [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2009-08-15

    We wanted to assess the long-term results of cyst ablation with using N-butyl cyanoacrylate (NBCA) and iodized oil in patients with autosomal dominant polycystic kidney disease (ADPKD) and symptomatic cysts. Cyst ablation using a mixture of NBCA and iodized oil was performed in 99 cysts from 21 patients who had such symptoms as abdominal distension and pain. The collapse or reaccumulation of the ablated cysts after the procedure was assessed during the follow-up period of 36 to 90 months. The treatment effects, including symptom relief, and the clinical data such as the blood pressure and serum creatinine levels were also assessed, together with the complications. The procedure was technically successful in all 99 cysts from the 21 patients. Any procedure-related significant complications were not detected. Seventy-seven of 99 cysts (78%) were successfully collapsed on the follow-up CT. Twenty-two cysts showed reaccumulation during long-term follow-up period. The clinical symptoms were relieved in 17 of the 21 patients (76%). Four of 12 patients (33%) with hypertension and two of six patients (33%) with azotemia were improved. End stage renal disease (ESRD) occurred in six of the 21 patients (28%) during the follow-up period. The mean age of ESRD in our patients was 57 years. The mean time interval for the development of ESRD was 19 months. Ablation using a mixture of NBCA and iodized oil may be an effective, safe method for obtaining symptom relief in patients with ADPKD.

  14. Network analysis of a Pkd1-mouse model of autosomal dominant polycystic kidney disease identifies HNF4α as a disease modifier.

    Directory of Open Access Journals (Sweden)

    Luis F Menezes

    Full Text Available Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID's 173900, 601313, 613095 leads to end-stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles and an inducible Cre recombinase, we intensively analyzed the relationship between renal maturation and cyst formation by applying transcriptomics and metabolomics to follow disease progression in a large number of animals induced before P10. Weighted gene co-expression network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. Knowledge-based Ingenuity Pathway Analysis (IPA software identifies HNF4α as a likely network node. These results are further supported by a meta-analysis of 1,114 published gene expression arrays in Pkd1 wild-type tissues. These analyses also predict that metabolic pathways are key elements in postnatal kidney maturation and early steps of cyst formation. Consistent with these findings, urinary metabolomic studies show that Pkd1 cystic mutants have a distinct profile of excreted metabolites, with pathway analysis suggesting altered activity in several metabolic pathways. To evaluate their role in disease, metabolic networks were perturbed by inactivating Hnf4α and Pkd1. The Pkd1/Hnf4α double mutants have significantly more cystic kidneys, thus indicating that metabolic pathways could play a role in Pkd1-cystogenesis.

  15. Cyst infection in hospital-admitted autosomal dominant polycystic kidney disease patients is predominantly multifocal and associated with kidney and liver volume

    Energy Technology Data Exchange (ETDEWEB)

    Balbo, B.E.P. [Divisão de Nefrologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Sapienza, M.T.; Ono, C.R. [Divisão de Medicina Nuclear, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Jayanthi, S.K. [Divisão de Radiologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Dettoni, J.B. [Divisão de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Castro, I.; Onuchic, L.F. [Divisão de Nefrologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2014-06-13

    Positron-emission tomography/computed tomography (PET/CT) has improved cyst infection (CI) management in autosomal dominant polycystic kidney disease (ADPKD). The determinants of kidney and/or liver involvement, however, remain uncertain. In this study, we evaluated clinical and imaging factors associated with CI in kidney (KCI) and liver (LCI) in ADPKD. A retrospective cohort study was performed in hospital-admitted ADPKD patients with suspected CI. Clinical, imaging and surgical data were analyzed. Features of infected cysts were evaluated by PET/CT. Total kidney (TKV) and liver (TLV) volumes were measured by CT-derived multiplanar reconstruction. CI was detected in 18 patients who experienced 24 episodes during an interval of 30 months (LCI in 12, KCI in 10 and concomitant infection in 2). Sensitivities of CT, magnetic resonance imaging and PET/CT were 25.0, 71.4, and 95.0%. Dysuria (P<0.05), positive urine culture (P<0.01), and previous hematuria (P<0.05) were associated with KCI. Weight loss (P<0.01) and increased C-reactive protein levels (P<0.05) were associated with LCI. PET/CT revealed that three or more infected cysts were present in 70% of the episodes. TKV was higher in kidney-affected than in LCI patients (AUC=0.91, P<0.05), with a cut-off of 2502 mL (72.7% sensitivity, 100.0% specificity). TLV was higher in liver-affected than in KCI patients (AUC=0.89, P<0.01) with a cut-off of 2815 mL (80.0% sensitivity, 87.5% specificity). A greater need for invasive procedures was observed in LCI (P<0.01), and the overall mortality was 20.8%. This study supports PET/CT as the most sensitive imaging method for diagnosis of cyst infection, confirms the multifocal nature of most hospital-admitted episodes, and reveals an association of kidney and liver volumes with this complication.

  16. Polycystic kidney disease

    Science.gov (United States)

    Cysts - kidneys; Kidney - polycystic; Autosomal dominant polycystic kidney disease; ADPKD ... Polycystic kidney disease (PKD) is passed down through families (inherited). The 2 inherited forms of PKD are autosomal dominant ...

  17. Hippo通路在常染色体显性多囊肾病中的作用%Role of Hippo pathway in autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    贺靓靓; 胡文娟; 梅长林; 胡惠民; 付丽丽

    2015-01-01

    目的 探讨Hippo通路分子在常染色体显性多囊肾病(ADPKD)发病机制中的作用,寻找可能的药物治疗靶点.方法 采用免疫荧光染色、Western印迹和实时定量PCR技术检测Han:SPRD大鼠杂合型和ADPKD患者肾组织Hippo通路分子分布、表达量以及磷酸化水平的差异.小干扰RNA特异性抑制囊肿衬里上皮细胞(WT9-12) YAP (Yes kinaseassociated protein)、TAZ(transcriptional coactivator with PDZ binding motif)和LATS1(large tumor suppressor kinase1)的表达后观察对细胞增殖、凋亡和细胞周期的影响.结果 与野生型大鼠相比,Han:SPRD杂合型大鼠囊肿衬里上皮细胞LATS1表达降低;YAP表达量及去磷酸化活化水平增加;TAZ表达与分布无明显改变.ADPKD患者肾组织中,Hippo通路分子MST1/2(macrophage stimulating1/2)、LATS1 mRNA表达显著低于正常对照(P<0.05),而YAP mRNA表达水平显著高于正常对照(P<0.05).抑制WT9-12细胞LATS1表达,能促进细胞增殖和分裂;下调YAP表达阻滞细胞于分裂间期,抑制增殖;下调TAZ表达对细胞增殖和周期无显著影响.结论 ADPKD中Hippo通路效应因子YAP去磷酸化活性增强可能是导致疾病发生、发展的重要原因之一.体外实验证实下调YAP表达可抑制肾囊肿衬里上皮细胞分裂增殖,提示YAP的表达和活性是潜在的多囊肾病治疗靶点.%Objective To explore the role of Hippo pathway in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD),and find potential targets for drug therapy.Methods By means of immunofluorescence staining,Western blotting,Real-time PCR,the differences of sublocalization,expression and phosphorylation level about Hippo pathway molecules in Han:SPRD (cy/+) and ADPKD patients compared with the control were observed.Knockdown Yes kinaseassociated protein (YAP),transcriptional coactivator with PDZ binding motif (TAZ) and large tumor suppressor kinase1 (LATS1) in cystic lining epithelium cell line WT9

  18. 托伐普坦治疗常染色体显性多囊性肾病患者的研究进展%Progress of tolvaptan in treatment of patients with autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    刘玉法; 陈广新; 刘纳新; 苏立军

    2014-01-01

    通过搜索PubMed,ScienceDirect,万方,CNKI数据库,选择1990~2014年文献,对托伐普坦治疗常染色体显性多囊性肾病(autosomal dominant polycystic kidney disease,ADPKD)研究情况进行综述、总结。常染色体显性多囊肾病是一种慢性进行性疾病,可显著地增加经济负担和致死率。目前尚没有特定药物用于治疗或延缓该病的进程。ADPKD患者早期使用托伐普坦可减慢疾病进程,但可能伴发频繁的、严重的不良事件,需密切监护。%Databases of PubMed,CNKI,ScienceDirect and Wanfang were searched,and the literatures were selected from 1990 to 2014,to review the studies of tolvaptan on autosomal dominant polycystic kidney disease(ADPKD).ADPKD is a chronic progressive disease which significantly enhance the economy burden and death rate.No specific drug can be used to treat or prevent the progress of ADPKD.Tolvaptan applicated in early phase could prolong the progress of ADPKD,but with frequent and serious adverse events.

  19. Autosomal Recessive Polycystic Kidney Disease: Antenatal Diagnosis and Histopathological Correlation

    Directory of Open Access Journals (Sweden)

    Dayananda Kumar Rajanna

    2013-01-01

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is one of the most common inheritable disease manifesting in infancy and childhood with a frequency of 1:6,000 to 1:55,000 births. The patient in her second trimester presented with a history of amenorrhea. Ultrasound examination revealed bilateral, enlarged, hyperechogenic kidneys, placentomegaly, and severe oligohydramnios. The pregnancy was terminated. An autopsy was performed on the fetus. Both the kidneys were found to be enlarged and the cut surface showed numerous cysts. The liver sections showed changes due to fibrosis. The final diagnosis of autosomal recessive polycystic kidney disease was made based on these findings. In this article, we correlate the ante-natal ultrasound and histopathological findings in autosomal recessive polycystic kidney disease.

  20. Autosomal dominant adult neuronal ceroid lipofuscinosis

    NARCIS (Netherlands)

    Nijssen, Peter C.G.

    2011-01-01

    this thesis investigates a family with autosomal dominant neuronal ceroid lipofuscinosis, with chapters on clinical neurology, neuropathology, neurogenetics, neurophysiology, auditory and visual aspects.

  1. Autosomal-dominant osteopetrosis: An incidental finding

    Directory of Open Access Journals (Sweden)

    Rajathi Maria

    2010-01-01

    Full Text Available Osteopetrosis is a descriptive term that refers to a group of rare, heritable disorders of the skeleton. Osteopetrotic conditions vary greatly in their presentation and severity, from just as an incidental finding on radiographs to causing life-threatening complications such as bone marrow suppression. It is caused by failure of osteoclast development and function. Osteopetrosis can be inherited as autosomal-recessive, autosomal-dominant or as X-linked traits, with the most severe forms being the autosomal-recessive ones. The severity of the disease is mild to moderate in the autosomal-dominant forms, with normal life expectancy. Diagnosis is largely based on clinical and radiographic evaluation. The present paper reports a case of autosomal-dominant osteopetrosis complicated by osteomyelitis with a short review of the condition.

  2. Complete Heart Block with Diastolic Heart Failure and Pulmonary Edema Secondary to Enlarging Previously Diagnosed Thrombosed Aneurysm of Sinus of Valsalva in a Patient with History of Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    Eltawansy, Sherif Ali; Thomas, Maria Joana; Daniels, Jeffrey

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is associated with vascular aneurysms that can affect any part of the vascular tree, like ascending aorta or coronary arteries. Sinus of Valsalva is known as an anatomical dilation at the root of aorta above the aortic valve and very few cases show aneurysm at that site in patients with ADPKD. Sinus of Valsalva aneurysm (SVA) can present with rupture and acute heart failure and infective endocarditis or could be asymptomatic accidentally discovered during cardiac catheterization. We report a case of a 76-year-old male with a unique constellation of cardiovascular anomalies associated with ADPKD. Patient was previously diagnosed with aneurysms affecting ascending aorta, sinus of Valsalva, and coronary arteries. Several years later, he came with complete heart block which was discovered later to be secondary to enlargement of his previously diagnosed thrombosed SVA. His case was complicated with acute heart failure and pulmonary edema. Conclusion. Patients with ADPKD can present with extrarenal manifestations. In our case, aneurysm at sinus of Valsalva was progressively enlarging and presented with complete heart block. PMID:25861484

  3. A follow-up study of autosomal dominant polycystic kidney disease with intracranial aneurysms using 3.0 T three-dimensional time-of-flight magnetic resonance angiography

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Tao; Wang, Peng; Qian, Yi [Department of Radiology, Changzheng Hospital, Second Military Medical University, Shanghai (China); Zheng, Xuan [Clinical Nutrition Department of Changhai Hospital, Second Military Medical University, Shanghai (China); Xiao, Liaoyuan [Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai (China); Yu, Shengqiang, E-mail: yushengqiang_cz@163.com [Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai (China); Liu, Shiyuan, E-mail: laijiangtaotao@163.com [Department of Radiology, Changzheng Hospital, Second Military Medical University, Shanghai (China)

    2013-11-01

    Objective: Autosomal dominant polycystic kidney disease (ADPKD) patients have an increased risk for intracranial aneurysms (IAs). Our aim was to screen and follow up the unruptured intracranial aneurysms (UIAs) detected by 3.0 T three-dimensional time-of-flight magnetic resonance angiography (3D-TOF MRA) in patients with ADPKD in order to evaluate the growth of UIAs and the value of 3D-TOF MRA. Methods: From 2011 to 2012, we followed up UIAs detected in 40 ADPKD patients who had MRA examinations with an interval of at least 36 months. All MRA examinations were performed on a 3 T system (Achieva X-Series, Philips Medical Systems) with a Sense-Head-8 receiver head coil. The acquired data sets were transferred to a workstation (EWS, Philips Medical) to perform maximum intensity projection (MIP) and volume rendering (VR) with a specialized software package (Philips Medical). The size of UIAs was determined as the longest diameter in transverse or vertical measurement. UIAs that grew more than 20% were considered as enlarged. Results: Fifty UIAs were found in 40 previously examined ADPKD patients who underwent 3.0 T 3D-TOF MRA follow-ups. No patients ever had treatment before the second examination. The longest diameter of all follow-up UIAs was less than 10 mm and mean diameter was 3.64 ± 2.25 mm. UIAs in only 4 patients (10%) were considered as enlarged. None of the 50 IAs in the 40 ADPKD patients ruptured during the MRA follow-up period. Conclusion: 3.0 T 3D-TOF MRA was feasible for UIAs follow-up in ADPKD patients. The chance of enlargement and rupture of UIAs in ADPKD patients was not higher than in the general population.

  4. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Spithoven, Edwin M; Kramer, Anneke; Meijer, Esther; Orskov, Bjarne; Wanner, Christoph; Caskey, Fergus; Collart, Frederic; Finne, Patrik; Fogarty, Damian G; Groothoff, Jaap W; Hoitsma, Andries; Nogier, Marie-Béatrice; Postorino, Maurizio; Ravani, Pietro; Zurriaga, Oscar; Jager, Kitty J; Gansevoort, Ron T

    2014-12-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADPKD patients, but with inconclusive results. To help resolve this we determined changes in RRT incidence rates as an indicator for increasing effective renoprotection over time in ADPKD. We analyzed data from the European Renal Association-European Dialyses and Transplant Association Registry on 315,444 patients starting RRT in 12 European countries between 1991 and 2010, grouped into four 5-year periods. Of them, 20,596 were due to ADPKD. Between the first and last period the mean age at onset of RRT increased from 56.6 to 58.0 years. The age- and gender-adjusted incidence rate of RRT for ADPKD increased slightly over the four periods from 7.6 to 8.3 per million population. No change over time was found in the incidence of RRT for ADPKD up to age 50, whereas in recent time periods the incidence in patients above the age of 70 clearly increased. Among countries there was a significant positive association between RRT take-on rates for non-ADPKD kidney disease and ADPKD. Thus, the increased age at onset of RRT is most likely due to an increased access for elderly ADPKD patients or lower competing risk prior to the start of RRT rather than the consequence of effective emerging renoprotective treatments for ADPKD.

  5. MRI of autosomal dominant pure spastic paraplegia

    DEFF Research Database (Denmark)

    Krabbe, K; Nielsen, J E; Fallentin, E

    1997-01-01

    We examined 16 patients with autosomal dominant pure spastic paraplegia (HSP) and 15 normal controls matched for age and sex using MRI of the brain and spinal cord. Images were assessed qualitatively by two independent radiologists, blinded to the clinical diagnosis. Areas of the brain and corpus...

  6. Causes analysis of 652 hospital stays in patients with autosomal dominant polycystic kidney disease%常染色体显性多囊肾病患者652次住院原因分析

    Institute of Scientific and Technical Information of China (English)

    戎殳; 李林; 孙丽君; 徐成钢; 郁胜强; 赵学智; 叶朝阳; 梅长林; 马熠熠; 陈冬平; 张彤; 孙海棚; 贺靓靓; 李兰君; 陈舟; 程烨

    2012-01-01

    Objective To analyze the causes of 652 hospitalizations in the patients with autosomal dominant polycystic kidney disease (ADPKD).Methods The medical records of all ADPKD inpatients in our hospital from January 1,1990 to December 31,2010 were collected.The differences of hospitalization causes in different age,gender and period were analyzed.Results (1)In 652 hospitalizations,the most common cause was lumbar pain (15.2%),followed by cystic bleeding (14.6%),aggravating renal failure (10.1%),dialysis-related problems (9.4%),renal transplant related issues (8.3%),renal replacement therapy for ESRD (8.0%),urinary tract infection (6.4%),end stage renal failure (5.8%),hypertension (4.1%),renal cyst volume enlargement (3.7%),finding polycystic kidney disease (2.1%),urinary lithiasis (1.8%) and others (10.4%).(2)Younger patients were admitted into hospital because of polycystic kidney bleeding and finding PKD.With the increase of patients age,hospitalization due to dialysis-related problems increased,while many middle-aged patients were hospitalized because of back pain.(3)Male patients were admitted into hospital for aggravating renal failure,ESRD,kidney transplantation-related problems and urinary lithiasis,while female patients mainly for lumbar pain,dialysis-related problems and urinary tract infection.(4)The proportion was significantly reduced with time of finding PKD,renal failure and polycystic kidney bleeding,the proportion of renal cysts increasing and aggravating renal failure increased,there was a significant increase in the proportion of patients with hypertension,while a significant decrease in the proportion of patients with uncontrolled hypertension,and the average SBP was also significantly reduced.Conclusions The highest rate of hospitalization of ADPKD patients is in 40 to 60 age group.Cause of admission varies with age and gender,and changes with the change of time.Over the past decade,the proportion of hospitalization due to

  7. Autosomal dominant rolandic epilepsy with speech dyspraxia.

    Science.gov (United States)

    Scheffer, I E

    2000-01-01

    Autosomal Dominant Rolandic Epilepsy with Speech Dyspraxia (ADRESD) is a rare disorder which highlights the relationship between Benign Rolandic Epilepsy (BRE) and speech and language disorders. Subtle speech and language disorders have recently been well characterised in BRE. ADRESD is associated with long term, more severe speech and language difficulties. The time course of rolandic epilepsy in ADRESD is typical of that of BRE. ADRESD is inherited in an autosomal dominant manner with anticipation. It is postulated that the anticipation may be due to an, as yet unidentified, triplet repeat expansion in a gene for rolandic epilepsy. BRE follows complex inheritance but it is possible that ADRESD may hold some valuable clues to the pathogenesis of BRE.

  8. Clinical neurogenetics: autosomal dominant spinocerebellar ataxia.

    Science.gov (United States)

    Shakkottai, Vikram G; Fogel, Brent L

    2013-11-01

    The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging because of phenotypic overlap among causes, and a stratified and systematic approach is essential. Recent advances include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models that may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole-exome sequencing, to improve diagnosis.

  9. Autosomal dominant craniosynostosis of the sutura metopica.

    Science.gov (United States)

    Hennekam, R C; Van den Boogaard, M J

    1990-11-01

    Trigonocephaly due to craniosynostosis of the sutura metopica was found in two sibs with normal intelligence. Both were microcephalic. The father had a sloping forehead and possibly partial metopic craniosynostosis. The paternal grandfather had a bony ridge at the upper half of the metopic suture without significant head deformity. A paternal sister was possibly also affected. None of the affected persons showed significant other anomalies. Craniosynostosis of the metopic suture may be an autosomal dominantly inherited disorder, not associated with functional brain or other abnormalities.

  10. Enamelin and autosomal-dominant amelogenesis imperfecta.

    Science.gov (United States)

    Hu, J C-C; Yamakoshi, Y

    2003-01-01

    Dental enamel forms as a progressively thickening extracellular layer by the action of proteins secreted by ameloblasts. The most abundant enamel protein is amelogenin, which is expressed primarily from a gene on the X-chromosome (AMELX). The two most abundant non-amelogenin enamel proteins are ameloblastin and enamelin, which are expressed from the AMBN and ENAM genes, respectively. The human AMBN and ENAM genes are located on chromosome 4q13.2. The major secretory products of the human AMELX, AMBN, and ENAM genes have 175, 421, and 1103 amino acids, respectively, and are all post-translationally modified, secreted, and processed by proteases. Mutations in AMELX have been shown to cause X-linked amelogenesis imperfecta (AI), which accounts for 5% of AI cases. Mutations in ENAM cause a severe form of autosomal-dominant smooth hypoplastic AI that represents 1.5%, and a mild form of autosomal-dominant local hypoplastic AI that accounts for 27% of AI cases in Sweden. The discovery of mutations in the ENAM gene in AI kindreds proved that enamelin is critical for proper dental enamel formation and that it plays a role in human disease. Here we review how enamelin was discovered, what is known about enamelin protein structure, post-translational modifications, processing by proteases, and its potentially important functional properties such as its affinity for hydroxyapatite and influence on crystal growth in vitro. The primary structures of human, porcine, mouse, and rat enamelin are compared, and the human enamelin gene, its structure, chromosomal localization, temporal and spatial patterns of expression, and its role in the etiology of amelogenesis imperfecta are discussed.

  11. MRI of autosomal dominant pure spastic paraplegia

    Energy Technology Data Exchange (ETDEWEB)

    Krabbe, K.; Fallentin, E.; Herning, M. [Danish Research Center of Magnetic Resonance, Hvidovre Hospital, Kettegaard alle 30, DK-2650 Hvidovre (Denmark); Nielsen, J.E.; Fenger, K. [Institute of Medical Biochemistry and Genetics, Laboratory of Medical Genetics, Section of Neurogenetics, University of Copenhagen (Denmark)

    1997-10-01

    We examined 16 patients with autosomal dominant pure spastic paraplegia (HSP) and 15 normal controls matched for age and sex using MRI of the brain and spinal cord. Images were assessed qualitatively by two independent radiologists, blinded to the clinical diagnosis. Areas of the brain and corpus callosum on one midsagittal slice and the area of the brain on one axial slice were measured and a ``corpus-callosum index`` expressing the size of the corpus callosum relative to that of the brain was calculated. Cross-sectional areas and anteroposterior and transverse diameters of the spinal cord at the levels of C 2, C 5, T 3, T 6, T 9 and T 11 were measured. No significant differences between patients and controls were found on qualitative evaluation of the images. The patients had a significantly smaller corpus callosum and ``corpus-callosum index`` than controls. This finding, not reported previously, might indicate that the disease process in pure HSP is not confined to the spinal cord. The anteroposterior diameters of the spinal cord at T 3 and T 9 were significantly smaller in patients than in controls. This might correspond to the degeneration of the pyramidal tracts and the dorsal columns described at neuropathological examination. (orig.). With 1 fig., 3 tabs.

  12. Autosomal dominant inheritance of left ventricular outflow tract obstruction

    NARCIS (Netherlands)

    Wessels, Marjolein; Berger, Rudolphus; Frohn-Mulder, Ingrid M E; Roos-Hesselink, Jolien W; Hoogeboom, Jeanette J M; Mancini, Grazia S; Bartelings, Margot M; Krijger, Ronald de; Wladimiroff, Jury W; Niermeijer, Martinus F; Grossfeld, Paul; Willems, Patrick J

    2005-01-01

    Most nonsyndromic congenital heart malformations (CHMs) in humans are multifactorial in origin, although an increasing number of monogenic cases have been reported recently. We describe here four new families with presumed autosomal dominant inheritance of left ventricular outflow tract obstruction

  13. Genetics Home Reference: autosomal dominant partial epilepsy with auditory features

    Science.gov (United States)

    ... Facebook Share on Twitter Your Guide to Understanding Genetic Conditions Search MENU Toggle navigation Home Page Search ... Conditions Genes Chromosomes & mtDNA Resources Help Me Understand Genetics Home Health Conditions ADPEAF autosomal dominant partial epilepsy ...

  14. Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy.

    Science.gov (United States)

    Kelly, K J; Zhang, Jizhong; Han, Ling; Kamocka, Malgorzata; Miller, Caroline; Gattone, Vincent H; Dominguez, Jesus H

    2015-01-01

    Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA.

  15. Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy.

    Directory of Open Access Journals (Sweden)

    K J Kelly

    Full Text Available Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA.

  16. Coincidence the Autosomal Recessive Polycystic Kidney Disease With Placenta Membranacea (A Probably Genetic Relation with PKHD1 Gene

    Directory of Open Access Journals (Sweden)

    Ehsan Hosseini

    2016-05-01

    Full Text Available Placenta membranacea is one of the most barley anomalies happens in pregnancy defined by chorionic villi (partially or completely covered the fetus membrane. Autosomal recessive polycystic kidney disease in fetus is also a rare case with an incidence of 1: 20,000 live births resulting in a 30% death rate in neonates. In this case for the first time, we reported a placenta membranacea and autosomal recessive polycystic kidney disease occurred with together. A 25-year-old woman was admitted at 16 weeks of gestation for inducing abortion with autosomal recessive polycystic kidney disease in fetus diagnosed in routine sonography fellowship. Post-delivery examination revealed a placenta totally enveloped the fetus, oligohydramnious and bilateral enlarged polycystic kidneys of fetus. Histological study indicated umbilicus has only one artery and one vein as well as autosomal recessive polycystic kidney disease and directly attachment of chorionic villi to fetal membrane eventually diagnosed as complete placenta membranacea. The etiology of placenta membranacea is not completely clarified. As autosomal recessive polycystic kidney disease is a result of mutation in PKHD1 gene, so our finding may be initiates a new investigation about genetic relation between placenta membranacea and autosomal recessive polycystic kidney disease.

  17. Associação entre aneurismas de aorta abdominal infrarrenal e doença renal policística autossômica dominante: relato de caso Association between infrarenal abdominal aortic aneurysm and autosomal dominant polycystic kidney disease: a case report

    Directory of Open Access Journals (Sweden)

    Milton Alves das Neves Junior

    2009-06-01

    Full Text Available A doença renal policística dominante é uma das doenças renais hereditárias mais comuns, podendo apresentar manifestações extrarrenais vasculares de importância clínica, como aneurismas intracranianos, aneurismas aórticos e dissecções arteriais. Relatamos o caso de um paciente masculino, com 66 anos de idade, renal crônico não-dialítico por doença renal policística dominante, com aneurisma de aorta abdominal infrarrenal assintomático, diagnosticado por ultrassonografia de rotina e operado eletivamente com sucesso. A doença renal policística dominante é uma síndrome genética, associada aos genes PDK1 e PDK2 no cromossomo 16. A expressão desses genes na parede dos vasos leva ao seu enfraquecimento, favorecendo a formação de aneurismas. A produção de metaloproteinases pelos túbulos renais também estaria relacionada às doenças vasculares desses pacientes. Tais doenças se apresentam como importantes fatores de mortalidade precoce e morbidade dos portadores de doença renal policística dominante e, como usualmente são assintomáticas, justifica-se o uso de propedêutica armada e tratamento precoce.Autosomal dominant polycystic kidney disease (ADPKD is one of the most common hereditary renal diseases, which may present important clinical extrarenal vascular manifestations, such as intracranial and aortic aneurysms and artery dissections. We report the case of a 66-year-old male chronic renal out-of-dialysis patient, with dominant polycystic kidney disease, presenting an asymptomatic infrarenal abdominal aortic aneurysm diagnosed by routine ultrasonography, submitted to successful elective surgery. ADPKD is a genetic syndrome, associated with PDK1 and PDK2 genes on chromosome 16. The expression of these genes in the vessel walls leads to vessel wall weakening, favoring aneurysm formation. In addition, metalloproteinase production by kidney tubules could be related to vascular diseases in ADPKD patients. These are

  18. The role of noise and positive feedback in the onset of autosomal dominant diseases

    Directory of Open Access Journals (Sweden)

    Bosl William J

    2010-06-01

    Full Text Available Abstract Background Autosomal dominant (AD diseases result when a single mutant or non-functioning gene is present on an autosomal chromosome. These diseases often do not emerge at birth. There are presently two prevailing theories explaining the expression of AD diseases. One explanation originates from the Knudson two-hit theory of hereditary cancers, where loss of heterozygosity or occurrence of somatic mutations impairs the function of the wild-type copy. While these somatic second hits may be sufficient for stable disease states, it is often difficult to determine if their occurrence necessarily marks the initiation of disease progression. A more direct consequence of a heterozygous genetic background is haploinsufficiency, referring to a lack of sufficient gene function due to reduced wild-type gene copy number; however, haploinsufficiency can involve a variety of additional mechanisms, such as noise in gene expression or protein levels, injury and second hit mutations in other genes. In this study, we explore the possible contribution to the onset of autosomal dominant diseases from intrinsic factors, such as those determined by the structure of the molecular networks governing normal cellular physiology. Results First, simple models of single gene insufficiency using the positive feedback loops that may be derived from a three-component network were studied by computer simulation using Bionet software. The network structure is shown to affect the dynamics considerably; some networks are relatively stable even when large stochastic variations in are present, while others exhibit switch-like dynamics. In the latter cases, once the network switches over to the disease state it remains in that state permanently. Model pathways for two autosomal dominant diseases, AD polycystic kidney disease and mature onset diabetes of youth (MODY were simulated and the results are compared to known disease characteristics. Conclusions By identifying the

  19. [Autosomal dominant cerebellar ataxias in the Netherlands: a national inventory

    NARCIS (Netherlands)

    Warrenburg, B.P.C. van de

    2001-01-01

    OBJECTIVE: To provide a comprehensive estimate of the number of Dutch autosomal dominant cerebellar ataxias (ADCA) families and patients and thus estimate the minimal prevalence of ADCA in the Netherlands. Furthermore, to observe the relative frequency of SCA mutations and to study genotype-phenotyp

  20. Aneurisma gigante do segmento intracavernoso da carótida interna associado a doença renal policística autossômica dominante: relato de caso Giant aneurysm of the intracavernous internal carotid artery associated with autosomal dominant polycystic kidney disease: case report

    Directory of Open Access Journals (Sweden)

    Keven F. Ponte

    2006-09-01

    Full Text Available Apresenta-se o caso de mulher de 60 anos com doença renal policística autossômica dominante (DRPAD que desenvolveu quadro de cefaléia e oftalmoplegia completa à direita. A TC levantou a hipótese de um aneurisma gigante do segmento intracavernoso da carótida interna direita, o que foi confirmado pela arteriografia. Realizou-se, então, tratamento endovascular por oclusão do vaso parental com molas destacáveis no segmento supraclinóideo. A paciente evoluiu com a interrupção da cefaléia e com redução parcial da ptose e da oftalmoplegia. Neste artigo, enfatiza-se a relação entre DRPAD e aneurismas intracranianos. Comenta-se a história natural dos aneurismas originados no segmento intracavernoso da artéria carótida interna e comparam-se as opções terapêuticas no manejo destas lesões.We report the case of a 60 years-old woman with autosomal dominant polycystic kidney disease (ADPKD that presented with headache and right complete ophthalmoplegia. The CT scan raised the possibility of a giant aneurysm of the right intracavernous internal carotid artery, confirmed by angiography. The patient underwent endovascular occlusion of parent vessel with detachable coils, then she presented interruption of headache and partial recovery of ptosis and ophthalmoplegia. We emphasize the relationship between ADPKD and intracranial aneurysms. We also discuss the natural history and compare the therapeutic options for the management of giant aneurysms of the cavernous portion of the carotid artery.

  1. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease

    OpenAIRE

    Bateman, R. J.; Aisen, P.S.; De Strooper, B.; Fox, N C.; Lemere, C. A.; Ringman, J.M.; Salloway, S.; Sperling, R. A.; Windisch, M.; Xiong, C.

    2011-01-01

    Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are...

  2. Pain determinants of pain in autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    José Luiz Nishiura

    2013-09-01

    Full Text Available Pain is the most common symptom reported by ADPKD patients, afflicting approximately 60% of cases and may result from renal hemorrhage, calculi, urinary tract infections, cyst rupture, or due to stretching of the capsule or traction of the renal pedicle. We have recently investigated pain patterns in AD-PKD patients using a translated version of a pain questionnaire specific for AD-PKD population. The questionnaire revealed that 67% patients with ADPKD exhibited some type of pain. The findings of that study emphasized that pain appeared early in the course of ADPKD, when patients still exhibited preserved renal function. In the present study, a multivariate logistic regression analysis disclosed that renal volume (9-fold increased risk and nephrolithiasis (4-fold increased risk were the most important determinant factors for pain in ADPKD patients with preserved renal function, after adjustments for the presence of hypertension and duration of the disease.

  3. Guadalajara camptodactyly type III: a new probably autosomal dominant syndrome.

    Science.gov (United States)

    Figuera, L E; Ramírez-Dueñas, M L; Dávalos, I P; Cantú, J M

    2002-10-01

    A Mexican family is presented with the main clinical features of camptodactyly, a distinctive facial appearance because of ocular hypertelorism, telecanthus, symblepharon and spinal defects. Other clinical manifestations included: multiple nevi, simplified ears, retrognathia, congenital shortness of the sternocleidomastoid muscle, thin hands and feet, a small penis and mild mental retardation. Radiographic studies revealed spina bifida occulta at cervical and dorso-lumbar levels, increased bone trabeculae, cortical thickening and delayed bone age. The presence of five affected members through four generations suggests autosomal dominant inheritance although no male-to-male transmission was documented. The authors propose this as a new entity, and have designated it Guadalajara camptodactyly type III.

  4. PENCALC: a program for penetrance estimation in autosomal dominant diseases

    Directory of Open Access Journals (Sweden)

    Andréa R.V. Russo Horimoto

    2010-01-01

    Full Text Available We present a computer program developed for estimating penetrance rates in autosomal dominant diseases by means of family kinship and phenotype information contained within the pedigrees. The program also determines the exact 95% credibility interval for the penetrance estimate. Both executable (PenCalc for Windows and web versions (PenCalcWeb of the software are available. The web version enables further calculations, such as heterozygosity probabilities and assessment of offspring risks for all individuals in the pedigrees. Both programs can be accessed and down-loaded freely at the home-page address http://www.ib.usp.br/~otto/software.htm.

  5. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Benzinger, Tammie L S; Blazey, Tyler; Jack, Clifford R; Koeppe, Robert A; Su, Yi; Xiong, Chengjie; Raichle, Marcus E; Snyder, Abraham Z; Ances, Beau M; Bateman, Randall J; Cairns, Nigel J; Fagan, Anne M; Goate, Alison; Marcus, Daniel S; Aisen, Paul S; Christensen, Jon J; Ercole, Lindsay; Hornbeck, Russ C; Farrar, Angela M; Aldea, Patricia; Jasielec, Mateusz S; Owen, Christopher J; Xie, Xianyun; Mayeux, Richard; Brickman, Adam; McDade, Eric; Klunk, William; Mathis, Chester A; Ringman, John; Thompson, Paul M; Ghetti, Bernardino; Saykin, Andrew J; Sperling, Reisa A; Johnson, Keith A; Salloway, Stephen; Correia, Stephen; Schofield, Peter R; Masters, Colin L; Rowe, Christopher; Villemagne, Victor L; Martins, Ralph; Ourselin, Sebastien; Rossor, Martin N; Fox, Nick C; Cash, David M; Weiner, Michael W; Holtzman, David M; Buckles, Virginia D; Moulder, Krista; Morris, John C

    2013-11-19

    Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

  6. LAMB3 mutations causing autosomal-dominant amelogenesis imperfecta.

    Science.gov (United States)

    Kim, J W; Seymen, F; Lee, K E; Ko, J; Yildirim, M; Tuna, E B; Gencay, K; Shin, T J; Kyun, H K; Simmer, J P; Hu, J C-C

    2013-10-01

    Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related.

  7. Frontonasal dysplasia: a family presenting autosomal dominant inheritance pattern.

    Science.gov (United States)

    Koçak, H; Ceylaner, G

    2009-01-01

    Frontonasal dysplasia (FND, also called frontonasal dysostosis or median cleft face syndrome) includes a spectrum of abnormalities affecting the eyes, forehead and nose, and resulting from midfacial dysraphia. The clinical picture is highly variable, but major findings in FND include ocular hypertelorism, a broad nasal root, median cleft affecting nose or both the nose and upper lip, and widow's peak. It is usually a sporadic disorder, although a few familial cases have been reported. We report here a three-generation family with multiple affected members with frontonasal dysplasia. This observation suggests autosomal dominant inheritance. Furthermore, some of the features e.g. over-riding toes, nail changes, vertical crease on plantar region of the feet in the index patient were not reported up to now.

  8. [Autosomal recessive polycystic kidney disease and complex nephronophtisis medullary cystic disease].

    Science.gov (United States)

    2008-12-01

    Reseach during the past decade has led to the discovery that defects in some proteins that localize to primary cilia or the basal body are the main contributors to renal cyst development. Autosomal recessive polycystic disease and nephronophthisis- medullary cystic kidney disease are named ciliopathies. The cilium is a microtubule-based organelle that is found on most mammalian cells. Cilia-mediated hypothesis has evolved into the concept of cystogenesis, cilia bend by fluid initiate a calcium influx that prevents cyst formation. Cilia might sense stimuli in the cell enviroment and control cell polarity and mitosis. A new set of pathogenic mechanisms in renal cystic disease defined new therapeutic targets, control of intracellular calcium, inhibition of cAMP and down regulation cannonical Wnt signaling.

  9. The renin-angiotensin system and hypertension in autosomal recessive polycystic kidney disease.

    Science.gov (United States)

    Goto, Miwa; Hoxha, Nita; Osman, Rania; Dell, Katherine Macrae

    2010-12-01

    Hypertension is a well-recognized complication of autosomal recessive polycystic kidney disease (ARPKD). The renin-angiotensin system (RAS) is a key regulator of blood pressure; however, data on the RAS in ARPKD are limited and conflicting, showing both up- and down-regulation. In the current study, we characterized intrarenal and systemic RAS activation in relationship to hypertension and progressive cystic kidney disease in the ARPKD orthologous polycystic kidney (PCK) rat. Clinical and histological measures of kidney disease, kidney RAS gene expression by quantitative real-time PCR, angiotensin II (Ang II) immunohistochemistry, and systemic Ang I and II levels were assessed in 2-, 4-, and 6-month-old cystic PCK and age-matched normal rats. PCK rats developed hypertension and progressive cystic kidney disease without significant worsening of renal function or relative kidney size. Intrarenal renin, ACE and Ang II expression was increased significantly in cystic kidneys; angiotensinogen and Ang II Type I receptor were unchanged. Systemic Ang I and II levels did not differ. This study demonstrates that intrarenal, but not systemic, RAS activation is a prominent feature of ARPKD. These findings help reconcile previous conflicting reports and suggest that intrarenal renin and ACE gene upregulation may represent a novel mechanism for hypertension development or exacerbation in ARPKD.

  10. Pathogenesis and treatment of hypertension in polycystic kidney disease

    NARCIS (Netherlands)

    Neumann, J; Ligtenberg, G; Klein, IHHT; Blankestijn, PJ

    2002-01-01

    Purpose of review Hypertension is common in patients with autosomal dominant polycystic kidney disease. It may contribute to cardiovascular risk and to progression of renal failure. Recent findings Apart from fluid overload and renin activation, hypertensive patients with autosomal dominant polycyst

  11. Progresión de la Poliquistosis renal autosómica dominante: Influencia de polimorfismos de genes de sintasa endotelial del óxido nítrico (ecNOS y del sistema renina-angiotensina Glomerular filtration rate decline in autosomic dominant polycystic kidney disease. Influence of endothelial NO synthase (ecNOS and renin angiotensin system gene polymorphisms

    Directory of Open Access Journals (Sweden)

    Pablo Azurmendi

    2004-04-01

    Full Text Available La velocidad de progresión (VdP de la poliquistosis renal autosómica dominante (PQRAD es variable. Estudiamos la asociación de los polimorfismos AGTM235T (angiotensinógeno, AT1A1166C (ATR1 y ecNOSGlu298Asp (NO sintasa endotelial con la VdP en 88 pacientes. VdP fue estimada por 1/Cr pl vs edad. Consideramos edades de Cr pl 2 y 6 mg/dl como comienzo de progresión (E2 y arribo a insuficiencia renal crónica terminal (E6, respectivamente. Los polimorfismos se estudiaron por PCR-RFLP. El grupo en su totalidad presentó VdP (ml/min/año de 6.9±0.5, E2 y E6 de 48.9±1.3 y 55.0±1.4 años y tensión arterial media (TAM de 111.2±1.2 mmHg. Según E6 observamos dos grupos (£ y > a 55 años. En £ 55 (fenotipo PKD1, n=42, E2 y E6 del genotipo CC de AT1A1166C fueron 36.0±1.2 y 41.4±0.9 años vs. AA-AC (42.8±1.0 y 47.5±0.8, p Glomerular filtration rate decline (GFRd is variable in autosomic dominant polycystic kidney disease (ADPKD. In 88 ADPKD patients, GFRd was assessed by 1/S Cr and compared with the association to AT1A1166C (AT1R, AGTM235T (angiotensinogen and ecNOSGlu298Asp (NO endothelial synthase polymorphisms. Age at S Cr values of 2 and 6 mg/dl were assumed as beginning of progressive phase (A2 and end-stage-renal disease (A6, respectively. Polymorphisms were studied by PCR-RFLP. The group as a whole showed GFRd (ml/min/year of 6.9±0.5; A2 and A6 of 48.9±1.3 and 55.0±1.4 years and mean arterial pressure of 111.2±1.2 mmHg. When A6 was considered, two populations were defined (£ and > 55 years. In £ 55 (assumed as PKD1 phenotype (n=42, A2 and A6 of the AT11166CC genotype were 36.0±1.2 and 41.4±0.9 years vs AA-AC (42.8±1.0 and 47.5±0.8, p<0.001. A2 and A6 of the ecNOS298Asp/Asp genotype were 34.8±1.5 and 41.1±0.6 years vs. Glu/Glu-Glu/Asp (42.4±0.9 and 47.1±0.8, p<0.02. In AGT235TT genotype, GFRd was 12.4±2.2 ml/min/year vs MM-MT (7.9±0.7, p<0.03. This difference was also observed when all ADPKD patients were considered (TT

  12. PARK1 gene mutation of autosomal dominant Parkinson's disease family

    Institute of Scientific and Technical Information of China (English)

    Ligang Jiang; Guohua Hu; Qiuhui Chen; Ying Zhang; Xinyu Hu; Jia Fan; Lifeng Liu; Rui Guo; Yajuan Sun; Yixhi Zhang

    2011-01-01

    Studies have shown that PARK1 gene is associated with the autosomal dominant inheritance of Parkinson's disease.PARK1 gene contains two mutation sites, namely Ala30Pro and AIa53Thr, which are located on exons 3 and 4, respectively.However, the genetic loci of the pathogenic genes remain unclear.In this study, blood samples were collected from 11 members of a family with high prevalence of Parkinson's disease, including four affected cases, five suspected cases,and two non-affected cases.Point mutation screening of common mutation sites on PARK1 gene exon 4 was conducted using PCR, to determine the genetic loci of the causative gene for Parkinson's disease.Gene identification and sequencing results showed that a T base deletion mutation was observed in the PARK1 gene exon 4 of all 11 collected samples.It was confirmed that the PARKf gene exon 4 gene mutation is an important pathogenic mutation for Parkinson's disease.

  13. Autosomal dominant cyclic hematopoiesis: Genetics, phenotype, and natural history

    Energy Technology Data Exchange (ETDEWEB)

    Palmer, S.E.; Stephens, K.; Dale, D.C. [Univ. of Washington, Seattle, WA (United States)

    1994-09-01

    Autosomal dominant cyclic hematopoiesis (ADCH; cyclic neutropenia) is a rare disorder manifested by transient neutropenia that recurs every three weeks. To facilitate mapping the ADCH gene by genetic linkage analysis, we studied 9 ADCH families with 42 affected individuals. Pedigrees revealed AD inheritance with no evidence for decreased penetrance. Similar intra- and interfamilial variable expression was observed, with no evidence to support heterogeneity. At least 3 families displayed apparent new mutations. Many adults developed chronic neutropenia, while offspring always cycled during childhood. Children displayed recurrent oral ulcers, gingivitis, lymphadenopathy, fever, and skin and other infections with additional symptoms. Interestingly, there were no cases of neonatal infection. Some children required multiple hospitalizations for treatment. Four males under age 18 died of Clostridium sepsis following necrotizing enterocolitis; all had affected mothers. No other deaths due to ADCH were found; most had improvement of symptoms and infections as adults. Adults experienced increased tooth loss prior to age 30 (16 out of 27 adults, with 9 edentulous). No increase in myelodysplasia, malignancy, or congenital anomalies was observed. Recombinant G-CSF treatment resulted in dramatic improvement of symptoms and infections. The results suggest that ADCH is not a benign disorder, especially in childhood, and abdominal pain requires immediate evaluation. Diagnosis of ADCH requires serial blood counts in the proband and at least one CBC in relatives to exclude similar disorders. Genetic counseling requires specific histories as well as CBCs of each family member at risk to determine status regardless of symptom history, especially to assess apparent new mutations.

  14. Impaired default network functional connectivity in autosomal dominant Alzheimer disease

    Science.gov (United States)

    Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith; Benzinger, Tammie L.S.; Jack, Clifford; Ances, Beau M.; Sullivan, Caroline A.; Salloway, Stephen P.; Ringman, John M.; Koeppe, Robert A.; Marcus, Daniel S.; Thompson, Paul; Saykin, Andrew J.; Correia, Stephen; Schofield, Peter R.; Rowe, Christopher C.; Fox, Nick C.; Brickman, Adam M.; Mayeux, Richard; McDade, Eric; Bateman, Randall; Fagan, Anne M.; Goate, Allison M.; Xiong, Chengjie; Buckles, Virginia D.; Morris, John C.

    2013-01-01

    Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease. PMID:23884042

  15. AUTOSOMAL DOMINANT HYPOCALCEMIA (HYPOPARATHYROIDISM TYPES 1 AND 2

    Directory of Open Access Journals (Sweden)

    Kelly Lauter Roszko

    2016-10-01

    Full Text Available Extracellular calcium is essential for life and its concentration in the blood is maintained within a narrow range. This is achieved by a feedback loop that receives input from the calcium-sensing receptor (CASR, expressed on the surface of parathyroid cells. In response to low ionized calcium, the parathyroids increase secretion of parathyroid hormone (PTH which increases serum calcium. The CASR is also highly expressed in the kidneys, where it regulates the reabsorption of calcium from the primary filtrate. Autosomal dominant hypocalcemia (ADH type 1 is caused by heterozygous activating mutations in the CASR which increase the sensitivity of the CASR to extracellular ionized calcium. Consequently, PTH synthesis and secretion is suppressed at normal ionized calcium concentrations. Patients present with hypocalcemia, hyperphosphatemia, low magnesium levels, and low or low-normal levels of PTH. Urinary calcium excretion is typically increased due to the decrease in circulating PTH concentrations and by the activation of the renal tubular CASR. Therapeutic attempts using CASR antagonists (calcilytics to treat ADH are currently under investigation. Recently, heterozygous mutations in the alpha subunit of the G protein G11 (GNA11 have been identified in patients with ADH, and this has been classified as ADH type 2. ADH2 mutations lead to a gain-of-function of Gα11, a key mediator of CASR signaling. Therefore, the mechanism of hypocalcemia appears similar to that of activating mutations in the CASR, namely an increase in the sensitivity of parathyroid cells to extracellular ionized calcium. Studies of activating mutations in the CASR and gain-of-function mutations in GNA11 can help define new drug targets and improve medical management of patients with ADH types 1 and 2.

  16. Chorioretinal dysplasia-microcephaly-mental retardation syndrome : Another family with autosomal dominant inheritance

    NARCIS (Netherlands)

    Hordijk, R; VandeLogt, F; Houtman, WA; VanEssen, AJ

    1996-01-01

    We describe a boy and his father with the chorioretinal dysplasia-microcephaly-mental retardation syndrome (CDMMS). Our report extends the phenotypic spectrum of autosomal dominant CDMMS by describing microphthalmia for the first time in an autosomal dominant family. The boy was also severely mental

  17. A retrospective study on management of gross hematuria in autosomal dominant polycystic kidney disease patients%常染色体显性多囊肾病患者并发肉眼血尿治疗方法的回顾研究

    Institute of Scientific and Technical Information of China (English)

    马熠熠; 陈冬平; 梅长林; 郁胜强; 戎殳; 张彤; 李林

    2012-01-01

    目的 寻找治疗常染色体显性多囊肾病(ADPKD)并发肉眼血尿的理想疗法.方法 1993年以来曾在我科住院治疗以及目前在我科多囊肾病专科门诊定期就诊随访的ADPKD患者为对象.收集ADPKD患者出现肉眼血尿时的平均年龄、性别构成、肾功能水平、诱发因素、治疗方案、症状持续时间、血小板计数、凝血参数、肾脏囊肿大小等资料,分别以不同的肉眼血尿诱发因素及治疗方案进行分组,比较其各指标间的差异.结果 共筛选出ADPKD患者905例.279例(男150例,女129例)曾有肉眼血尿病史,其中146例能提供完整的病史和治疗经过,而只有101例能提供相关的实验室检查结果.在这101例中,肉眼血尿可出现在慢性肾脏病(CKD)任何一期;GFR为(56.4±44.1)ml·min-1·(1.73 m2)-1;症状持续时间(8.8±8.0)d;男、女患者症状持续时间差异无统计学意义[(8.2±7.3)d比(9.5±8.8)d,P=0.426);凝血参数均在正常参考范围内,其中91例患者血小板计数正常.不同诱发因素导致的肉眼血尿持续时间差异有统计学意义(P<0.05).卧床休息组症状持续时间显著短于其他组患者(P<0.05).各组间血小板计数、凝血酶时间和国际标准化比值等差异无统计学意义.结论 对出现肉眼血尿的ADPKD患者应首先明确其诱因.卧床休息应作为核心治疗措施.在考虑使用止血药物时建议使用抗纤维蛋白溶解类药物,不需要预防性使用抗生索.%Objective To seauch the ideal management for gross hematuria in autosomal dominant polycystic kidney disease (ADPKD).Methods ADPKD patients who were ever hospitalized and followed up in our department since 1993 were enrolled in the study.Demographic and clinical data were colloected,such as gender,age of gross hematuria,level of renal function,causative factors,management strategies,duration of gross hematuria,blood platelet count,activated partial thromboplastin time,prothrombin time

  18. Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney-related phenotypes.

    Science.gov (United States)

    Büscher, Rainer; Büscher, Anja K; Weber, Stefanie; Mohr, Julia; Hegen, Bianca; Vester, Udo; Hoyer, Peter F

    2014-10-01

    Autosomal recessive polycystic kidney disease (ARPKD), although less frequent than the dominant form, is a common, inherited ciliopathy of childhood that is caused by mutations in the PKHD1-gene on chromosome 6. The characteristic dilatation of the renal collecting ducts starts in utero and can present at any stage from infancy to adulthood. Renal insufficiency may already begin in utero and may lead to early abortion or oligohydramnios and lung hypoplasia in the newborn. However, there are also affected children who have no evidence of renal dysfunction in utero and who are born with normal renal function. Up to 30 % of patients die in the perinatal period, and those surviving the neonatal period reach end stage renal disease (ESRD) in infancy, early childhood or adolescence. In contrast, some affected patients have been diagnosed as adults with renal function ranging from normal to moderate renal insufficiency to ESRD. The clinical spectrum of ARPKD is broader than previously recognized. While bilateral renal enlargement with microcystic dilatation is the predominant clinical feature, arterial hypertension, intrahepatic biliary dysgenesis remain important manifestations that affect approximately 45 % of infants. All patients with ARPKD develop clinical findings of congenital hepatic fibrosis (CHF); however, non-obstructive dilation of the intrahepatic bile ducts in the liver (Caroli's disease) is seen at the histological level in only a subset of patients. Cholangitis and variceal bleeding, sequelae of portal hypertension, are life-threatening complications that may occur more often in advanced cases of liver disease. In this review we focus on common and uncommon kidney-related and non-kidney-related phenotypes. Clinical management of ARPKD patients should include consideration of potential problems related to these manifestations.

  19. Oculopharyngeal Weakness, Hypophrenia, Deafness, and Impaired Vision: A Novel Autosomal Dominant Myopathy with Rimmed Vacuoles

    Directory of Open Access Journals (Sweden)

    Ting Chen

    2016-01-01

    Conclusions: We reported a novel autosomal dominant myopathy with rimmed vacuoles characterized by dysarthria, dysphagia, external ophthalmoplegia, limb weakness, hypophrenia, deafness, and impaired vision, but the causative gene has not been found and needs further study.

  20. Imaging of the Macula Indicates Early Completion of Structural Deficit in Autosomal-Dominant Optic Atrophy

    DEFF Research Database (Denmark)

    Rönnbäck, Cecilia; Milea, Dan; Larsen, Michael

    2013-01-01

    Optical coherence tomography (OCT) enables 3-dimensional imaging of the retina, including the layer of ganglion cells that supplies the optic nerve with its axons. We tested OCT as means of diagnosing and phenotyping autosomal-dominant optic atrophy (ADOA)....

  1. A gene for autosomal dominant congenital nystagmus localizes to 6p12

    Energy Technology Data Exchange (ETDEWEB)

    Kerrison, J.B.; Arnould, V.J.; Koenekoop, R.K. [Johns Hopkins Hospital, Baltimore, MD (United States)] [and others

    1996-05-01

    Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at {theta} = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor mystagmus to an 18-cM region between D6S271 and D6S455. 16 refs., 1 fig., 1 tab.

  2. DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome

    DEFF Research Database (Denmark)

    White, Janson; Mazzeu, Juliana F; Hoischen, Alexander

    2015-01-01

    Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical ......Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non...

  3. Autosomal dominant familial spastic paraplegia: Tight linkage to chromosome 15q

    Energy Technology Data Exchange (ETDEWEB)

    Fink, J.K.; Wu, C.B.; Jones, S.M.; Lesicki, A.; Reinglass, T. [Univ. of Michigan, Ann Arbor, MI (United States); Sharp, G.B.; Lange, B.M. [Arkansas Children`s Hospital, Little Rock, AR (United States); Varvil, T.; Otterud, B.; Leppert, M. [Univ. of Utah, Salt Lake City, UT (United States)

    1995-01-01

    Autosomal dominant, uncomplicated familial spastic paraplegia (FSP) is a genetically heterogeneous disorder characterized by insidiously progressive lower-extremity spasticity. Recently, a locus on chromosome 14q was shown to be tightly linked with the disorder in one of three families. We performed linkage analysis in a kindred with autosomal dominant uncomplicated FSP. After excluding the chromosome 14q locus, we observed tight linkage of the disorder to a group of markers on chromosome 15q (maximum two-point lod score 9.70; {theta} = .05). Our results clearly establish the existence of a locus for autosomal dominant FSP in the centromeric region of chromosome 15q. Comparing clinical and genetic features in FSP families linked to chromosome 14q with those linked to chromosome 15q may provide insight into the pathophysiology of this disorder. 34 refs., 1 fig., 1 tab.

  4. Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy

    Science.gov (United States)

    Burley, Kate; Whyte, Claire S.; Westbury, Sarah K.; Walker, Mary; Stirrups, Kathleen E.; Turro, Ernest; Chapman, Oliver G.; Reilly-Stitt, Christopher; Mutch, Nicola J.

    2016-01-01

    Thrombomodulin-associated coagulopathy (TM-AC) is a newly recognized dominant bleeding disorder in which a p.Cys537Stop variant in the thrombomodulin (TM) gene THBD, results in high plasma TM levels and protein C-mediated suppression of thrombin generation. Thrombin in complex with TM also activates thrombin-activatable fibrinolysis inhibitor (TAFI). However, the effect of the high plasma TM on fibrinolysis in TM-AC is unknown. Plasma from TM-AC cases and high-TM model control samples spiked with recombinant soluble TM showed reduced tissue factor–induced thrombin generation. Lysis of plasma clots from TM-AC cases was significantly delayed compared with controls but was completely restored when TM/thrombin-mediated TAFI activation was inhibited. Clots formed in blood from TM-AC cases had the same viscoelastic strength as controls but also showed a TAFI-dependent delay in fibrinolysis. Delayed fibrinolysis was reproduced in high-TM model plasma and blood samples. Partial restoration of thrombin generation with recombinant activated factor VII or activated prothrombin complex concentrate did not alter the delayed fibrinolysis in high-TM model blood. Our finding of a previously unrecognized fibrinolytic phenotype indicates that bleeding in TM-AC has a complex pathogenesis and highlights the pivotal role of TM as a regulator of hemostasis. PMID:27436851

  5. Analysis of missense variants in the PKHD1-gene in patients with autosomal recessive polycystic kidney disease (ARPKD).

    Science.gov (United States)

    Losekoot, Monique; Haarloo, Cathleen; Ruivenkamp, Claudia; White, Stefan J; Breuning, Martijn H; Peters, Dorien J M

    2005-11-01

    Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease characterized by enlarged kidneys and congenital hepatic fibrosis. Given the poor prognosis for the majority of children with the severe perinatal ARPKD phenotype, there is a regular request for prenatal testing. ARPKD is caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, which consists of 86 exons that are variably assembled into a number of alternatively spliced transcripts. The longest transcript, comprising 67 exons, encodes the protein fibrocystin/polyductin. We have set up mutation analysis by direct sequencing of these 67 exons. In 39 mainly Dutch families we identified: 11 nonsense mutations, 15 deletions/insertions, 5 splice site mutations, and 39 missense mutations. To classify missense variants we combined evolutionary conservation, using the human, chimpanzee, dog, mouse, chicken and frog Pkhd1 sequences, with the Grantham score for chemical differences. Thirty-three missense mutations were considered pathogenic and seven were classified as rare, probably pathogenic variants. In addition to sequence analysis, multiplex ligation-dependent probe amplification (MLPA) was used to identify multiple exon deletions. However, no large deletions in the PKHD1 gene were identified. In 31 index patients two mutations were found, in 6 patients one mutation was found, leading to a mutation detection rate of 87%. The analysis of amino acid conservation as well as applying the Grantham score for chemical differences allowed us to determine the pathogeneity for nearly all new missense mutations and thus proved to be useful tools to classify missense variants.

  6. Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Pedro Cena Rivero

    2016-02-01

    Full Text Available The Polycystic Kidney Disease (PKD is a genetic disease which is characterized by the gradual emergence of cystic lesions in the kidneys, which replace the renal parenchyma causing deterioration of its function to stage 5. The PKD is one of the causes of Chronic Kidney Disease on renal replacement therapy (RRT. The Polycystic Kidney Disease has two patterns of inheritance: autosomal dominant pattern and the autosomal recessive pattern. The dominant form is more common but less severe than autosomal recessive form. PKD is known that is caused by mutations in several loci of the human genome. The autosomal dominant form can be caused by mutations in two different genes (PKD1 and PKD2, unlike the autosomal recessive form only has a causal gene (PKHD1. At present the international scientific community efforts toward deeper understanding of the pathophysiology of this entity for the purpose of developing therapeutic alternatives that avoid the appearance of cysts or progression of those already in place. The aim is to systematize the available scientific knowledge about Polycystic Kidney Disease and provide a source of consultation update on clinical characteristics and therapeutic options for patients with PKD

  7. A new mutation causing autosomal dominant periodic fever syndrome in a Danish family

    DEFF Research Database (Denmark)

    Weyhreter, Heike; Schwartz, Marianne; Kristensen, Tim D;

    2003-01-01

    We describe four members in a family of 8 individuals over 3 generations with the autosomal dominant inherited periodic fever syndrome tumor necrosis factor receptor-associated periodic syndrome (TRAPS). The patients had recurrent episodes of fever, abdominal pain, arthritis, and rash. We examine...

  8. Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG4) using direct mutation detection

    DEFF Research Database (Denmark)

    Nielsen, Jørgen E; Koefoed, Pernille; Kjaergaard, Susanne

    2004-01-01

    OBJECTIVE: To present a report on prenatal diagnosis using direct SPG4 gene analysis in a family with autosomal dominant hereditary spastic paraplegia (AD-HSP). METHODS: Genetic linkage and haplotype analysis were previously carried out with chromosome 2p markers. DNA was obtained from affected...

  9. MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease

    NARCIS (Netherlands)

    Stoffels, Monique; Szperl, Agata; Simon, Anna; Netea, Mihai G.; Plantinga, Theo S.; van Deuren, Marcel; Kamphuis, Sylvia; Lachmann, Helen J.; Cuppen, Edwin; Kloosterman, Wigard P.; Frenkel, Joost; van Diemen, Cleo C.; Wijmenga, Cisca; van Gijn, Marielle; van der Meer, Jos W. M.

    2014-01-01

    Objectives Autoinflammatory disorders are disorders of the innate immune system. Standard genetic testing provided no correct diagnosis in a female patient from a non-consanguineous family of British descent with a colchicine-responsive autosomal dominant periodic fever syndrome. We aimed to unravel

  10. Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1

    NARCIS (Netherlands)

    Hogewind, B.F.T.; Pennings, R.J.E.; Hol, F.A.; Kunst, H.P.M.; Hoefsloot, E.H.; Cruysberg, J.R.M.; Cremers, C.W.R.J.

    2010-01-01

    PURPOSE: To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series. METHODS: Seven members of a Dutch family underwent ophthalmological, otological, and genetica

  11. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy

    NARCIS (Netherlands)

    Ostergaard, P.; Simpson, M.A.; Mendola, A.; Vasudevan, P.; Connell, F.C.; Impel, A. van; Moore, A.T.; Loeys, B.L.; Ghalamkarpour, A.; Onoufriadis, A.; Martinez-Corral, I.; Devery, S.; Leroy, J.G.; Laer, L. van; Singer, A.; Bialer, M.G.; McEntagart, M.; Quarrell, O.; Brice, G.; Trembath, R.C.; Schulte-Merker, S.; Makinen, T.; Vikkula, M.; Mortimer, P.S.; Mansour, S.; Jeffery, S.

    2012-01-01

    We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a mic

  12. A new mutation causing autosomal dominant periodic fever syndrome in a Danish family

    DEFF Research Database (Denmark)

    Weyhreter, Heike; Schwartz, Marianne; Kristensen, Tim D

    2003-01-01

    We describe four members in a family of 8 individuals over 3 generations with the autosomal dominant inherited periodic fever syndrome tumor necrosis factor receptor-associated periodic syndrome (TRAPS). The patients had recurrent episodes of fever, abdominal pain, arthritis, and rash. We examined...

  13. Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy

    DEFF Research Database (Denmark)

    Almind, Gitte J; Grønskov, Karen; Milea, Dan;

    2011-01-01

    Autosomal dominant optic atrophy (ADOA, Kjer disease, MIM #165500) is the most common form of hereditary optic neuropathy. Mutations in OPA1 located at chromosome 3q28 are the predominant cause for ADOA explaining between 32 and 89% of cases. Although deletions of OPA1 were recently reported...

  14. Somatostatin analogues for treatment of polycystic liver disease

    NARCIS (Netherlands)

    Gevers, T.J.G.; Drenth, J.P.H.

    2011-01-01

    PURPOSE OF REVIEW: The present review summarizes the existing knowledge on polycystic liver disease (PCLD) and highlights the progress made in medical treatment for this condition in the past year. RECENT FINDINGS: PCLD is associated with autosomal dominant polycystic kidney disease (ADPKD) and auto

  15. Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q

    Energy Technology Data Exchange (ETDEWEB)

    Forsman, K.; Lind. L.; Westermark, E. [Univ. of Umea (Sweden)] [and others

    1994-09-01

    Amelogenesis imperfecta (AI), a disorder affecting the formation of enamel, is significantly more common in Northern Sweden than in other parts of the world. The disease is genetically and clinically heterogenous, and autosomal dominant, autosomal recessive and X-linked inheritance patterns have been recognized. Linkage analysis has identified two different loci for X-linked AI, one of which is identical to the gene encoding the enamel protein amelogenin. However, in families with an autosomal inheritance pattern for AI, the genetic basis of the disease still remains unknown. We report a linkage analysis study performed on three Swedish families where the affected members had an autosomal dominant variant of AI (ADAI) clinically characterized as local hypoplastic. Significant linkage to microsatellite markers on chromosome 4q were obtained, with a maximum lod score of 5.55 for the marker D4S428. Recombinations in the family localized the ADAI locus to the interval between D4S392 and D4S395. This chromosome region contains both a locus for the dental disorder dentinogenesis imperfecta and the albumin gene. Serum albumin has been suggested to play a role in enamel formation, and the albumin gene is therefore a candidate gene for this genetic disease.

  16. Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

    Science.gov (United States)

    Stojanov, Dragan; Aracki-Trenkic, Aleksandra; Vojinovic, Slobodan; Ljubisavljevic, Srdjan; Benedeto-Stojanov, Daniela; Tasic, Aleksandar; Vujnovic, Sasa

    2015-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an autosomal dominant vascular disorder. Diagnosis and follow-up in patients with CADASIL are based mainly on magnetic resonance imaging (MRI). MRI shows white matter hyperintensities (WMHs), lacunar infarcts and cerebral microbleeds (CMBs). WMHs lesions tend to be symmetrical and bilateral, distributed in the periventricular and deep white matter. The anterior temporal lobe and external capsules are predilection sites for WMHs, with higher specificity and sensitivity of anterior temporal lobe involvement compared to an external capsule involvement. Lacunar infarcts are presented by an imaging signal that has intensity of cerebrospinal fluid in all MRI sequences. They are localized within the semioval center, thalamus, basal ganglia and pons. CMBs are depicted as focal areas of signal loss on T2 images which increases in size on the T2*-weighted gradient echo planar images (“blooming effect”). PMID:25725137

  17. Locus heterogeneity in autosomal dominant spinocerebellar ataxia: Evidence for the existence of a fifth locus

    Energy Technology Data Exchange (ETDEWEB)

    Sarrazin, J.; Rouleau, G.A. [Montreal General Hospital, Quebec (Canada); Andermann, E. [Montreal Neurological Institute and Hospital, Quebec (Canada)] [and others

    1994-09-01

    The autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. To date, four loci have been identified: the SCA-1 locus (on chromosome (chr) 6p), the SCA-2 locus (on chr 12q), the SCA-3/MJD locus (on chr 14q), and more recently an SCA-4 locus was described (chr 16q) in a Utah kindred. We have studied one large French Canadian kindred with four generations of living affected individuals segregating an autosomal dominant form of SCA. Linkage analysis using anonymous DNA markers which flank the four previously described loci significantly excludes the French Canadian kindred from the SCA-1, SCA-2, SCA-3/MJD and SCA-4 loci. Therefore a fifth, still unmapped, SCA locus remains to be identified.

  18. [Clinical and molecular study in a family with autosomal dominant hypohidrotic ectodermal dysplasia].

    Science.gov (United States)

    Callea, Michele; Cammarata-Scalisi, Francisco; Willoughby, Colin E; Giglio, Sabrina R; Sani, Ilaria; Bargiacchi, Sara; Traficante, Giovanna; Bellacchio, Emanuele; Tadini, Gianluca; Yavuz, Izzet; Galeotti, Angela; Clarich, Gabriella

    2017-02-01

    Hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by deficiency in development of structure derived from the ectoderm and is caused by mutations in the genes EDA, EDAR, or EDARADD. Phenotypes caused by mutations in these three may exhibit similar clinical features, explained by a common signaling pathway. Mutations in EDA gene cause X linked HED, which is the most common form. Mutations in EDAR and EDARADD genes cause autosomal dominant and recessive form of HED. The most striking clinical findings in HED are hypodontia, hypotrichosis and hypohidrosis that can lead to episodes of hyperthermia. We report on clinical findings in a child with HED with autosomal dominant inheritance pattern with a heterozygous mutation c.1072C>T (p.Arg358X) in the EDAR gene. A review of the literature with regard to other cases presenting the same mutation has been carried out and discussed.

  19. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in a Chinese pedigree

    Institute of Scientific and Technical Information of China (English)

    Erhe Xu; Huiqing Dong; Milan Zhang; Min Xu

    2012-01-01

    The present study enrolled a Chinese family that comprised 34 members and spanned three generations. Eight members were diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and disease diagnoses corresponded with autosomal incomplete dominance inheritance. The primary clinical manifestations included paralysis, dysarthria, and mild cognitive deficits. Magnetic resonance imaging revealed diffuse leukoencephalopathy with involvement of bilateral anterior temporal lobes, in particular the pons. In addition, multiple cerebral infarction was identified in the proband. Sural nerve biopsy findings of the proband revealed granular osmophilic material deposits in the extracellular matrix, which were adjacent to smooth muscle cells of dermal arterioles. Screening exons 2-4 for NOTCH 3 mutations by direct sequencing did not reveal any abnormalities.

  20. A novel HSF4 mutation in a Chinese family with autosomal dominant congenital cataract.

    Science.gov (United States)

    Liu, Ling; Zhang, Qing; Zhou, Lu-xin; Tang, Zhao-hui

    2015-04-01

    This study was aimed to identify the mutation of the whole coding region of shock transcription factor 4 (HSF4) gene in a Chinese family with autosomal dominant congenital cataract (ADCC). All exons of HSF4 were amplified by PCR. Sequence analysis of PCR products was performed. Restriction fragment length polymorphism (RFLP) analysis was conducted to confirm the pathogenic mutation. The results showed that a C to T substitution occurred at nucleotide 331 in patients of this family, leading to the replacement of the amino acid arginine-111 with cysteine in exon 3. RFLP analysis showed that the amino acid change was co-segregated with all affected individuals. It was concluded that the new mutation of c.331C>T in HSF4 DNA may be responsible for the autosomal dominant congenital cataract in this family.

  1. Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation.

    Science.gov (United States)

    Thomas, Shery; Thomas, Mervyn G; Andrews, Caroline; Chan, Wai-Man; Proudlock, Frank A; McLean, Rebecca J; Pradeep, Archana; Engle, Elizabeth C; Gottlob, Irene

    2014-03-01

    Autosomal-dominant idiopathic infantile nystagmus has been linked to 6p12 (OMIM 164100), 7p11.2 (OMIM 608345) and 13q31-q33 (OMIM 193003). PAX6 (11p13, OMIM 607108) mutations can also cause autosomal-dominant nystagmus, typically in association with aniridia or iris hypoplasia. We studied a large multigenerational white British family with autosomal-dominant nystagmus, normal irides and presenile cataracts. An SNP-based genome-wide analysis revealed a linkage to a 13.4-MB region on chromosome 11p13 with a maximum lod score of 2.93. A mutation analysis of the entire coding region and splice junctions of the PAX6 gene revealed a novel heterozygous missense mutation (c.227C>G) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p.(P76R). The amino-acid variation p.(P76R) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid. Eye movement recordings showed a significant intrafamilial variability of horizontal, vertical and torsional nystagmus. High-resolution in vivo imaging of the retina using optical coherence tomography (OCT) revealed features of foveal hypoplasia, including rudimentary foveal pit, incursion of inner retinal layers, short photoreceptor outer segments and optic nerve hypoplasia. Thus, this study presents a family that segregates a PAX6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities. Moreover, it is the first study showing detailed characteristics using eye movement recordings of autosomal-dominant nystagmus in a multigenerational family with a novel PAX6 mutation.

  2. Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME: Probable first family from India

    Directory of Open Access Journals (Sweden)

    Chandra Mohan Sharma

    2014-01-01

    Full Text Available Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME is an extremely rare syndrome characterized by familial occurrence of postural and action-induced tremors of the hands but showing electrophysiologic findings of cortical reflex myoclonus. Patients also have cognitive decline and tonic-clonic seizures, often precipitated by sleep deprivation or photic stimulation. We describe probably the first family from India of this ill-defined syndrome.

  3. A missense mutation S228P in the CRYBB1 gene causes autosomal dominant congenital cataract

    Institute of Scientific and Technical Information of China (English)

    WANG Jun; MA Xu; GU Feng; LIU Ning-pu; HAO Xiao-lin; WANG Kai-jie; WANG Ning-li; ZHU Si-quan

    2007-01-01

    Background Congenital cataract is a highly heterogeneous disorder at both the genetic and phenotypic levels. This study was conducted to identify disease locus for autosomal dominant congenital cataracts in a four generation Chinese family.Methods Family history and clinical data were recorded. All the members were genotyped with microsatellite markers which are close to the known genetic loci for autosomal congenital cataracts. Two-point Lod scores were obtained using the MLINK of the LINKAGE program package (ver 5.1). Candidate genes were amplified by polymerase chain reaction (PCR) and direct cycle sequencing.Results The maximum Lod score of Zmax=2.11 was obtained with three microsatellite markers D22S258, D22S315,and D22S1163 at recombination fraction θ= 0. Haplotype analysis showed that the disease gene was localized to a 18.5 Mbp region on chromosome 22 flanked by markers D22S1174 and D22S270, spanning the β-crystallin gene cluster. A c.752T-->C mutation in exon 6 of CRYBB1 gene, which resulted in a heterozygous S228P mutation in predicted protein,was found to cosegregate with cataract in the family.Conclusions This study identified a novel mutation in CRYBB1 gene in a Chinese family with autosomal dominant congenital cataract. These results provide strong evidence that CRYBB1 is a pathogenic gene for congenital cataract.

  4. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Rodriguez-Vieitez, Elena; Saint-Aubert, Laure; Carter, Stephen F; Almkvist, Ove; Farid, Karim; Schöll, Michael; Chiotis, Konstantinos; Thordardottir, Steinunn; Graff, Caroline; Wall, Anders; Långström, Bengt; Nordberg, Agneta

    2016-03-01

    Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear

  5. Genetic linkage studies in autosomal dominant ataxia families with an MJD phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Silveira, I.; Lopes-Cendes, I.; Paciel, P. [McGill Univ., Montreal (Canada)] [and others

    1994-09-01

    Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration which was originally described in patients originating from the Portuguese islands of the Azores. The first non-Portuguese kindred was described in 1979 and was an American black family originating from North Carolina. Since then the number of pedigrees of non-Azorean, non-Portuguese origin has increased with families being reported from other European countries, as well as Brazil, Japan, India, The United States and Australia. The autosomal dominant ataxias are a clinically and genetically heterogeneous group of disorders. To date, genetic analysis of families with autosomal dominant ataxias has permitted the identification of four loci, the SCA1 (spinocerebellar ataxia type 1) locus on chromosome 6p, the SCA2 locus on chromosome 12q, a third locus on chromosome 14q, the MJD/SCA3 and, more recently, the DRPLA (Dentatorubral-pallidoluysian atrophy) locus on chromosome 12p. We ascertained a total of 181 individuals with 60 affected from eight Indian, two Brazilian and one Sicilian-American family; all of them have received the clinical diagnosis of MJD. Recently, we have begun molecular genetic studies in these families in order to test these four candidate regions. The SCA1 mutation and the DRPLA mutation has been found to be an expansion of a CAG repeat. Direct analysis of the SCA1 and DRPLA expansion has been performed in all families and no expansion was found in the affected individuals. We are now running flanking markers for the SCA2 and MJD/SCA3 loci. These results will also be presented.

  6. Autosomal Dominant Inheritance of a Predisposition to Thoracic Aortic Aneurysms and Dissections and Intracranial Saccular Aneurysms

    Science.gov (United States)

    Regalado, Ellen; Medrek, Sarah; Tran-Fadulu, Van; Guo, Dong-Chuan; Pannu, Hariyadarshi; Golabbakhsh, Hossein; Smart, Suzanne; Chen, Julia H.; Shete, Sanjay; Kim, Dong H.; Stern, Ralph; Braverman, Alan C.; Milewicz, Dianna M.

    2013-01-01

    A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (p <0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty-nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable.I these families, routine cerebral and aortic imaging for at risk members could prove beneficial for timely medical and surgical management to prevent a cerebral hemorrhage or aortic dissection. PMID:21815248

  7. Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia

    NARCIS (Netherlands)

    Schelhaas, H J; Ippel, P F; Hageman, G; Sinke, R J; van der Laan, E N; Beemer, F A

    2001-01-01

    The autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders characterised by progressive cerebellar dysfunction in combination with a variety of other associative features. Since 1993 ADCAs have been increasingly characterised in terms of their genetic

  8. Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3.

    Science.gov (United States)

    Chong, Jessica X; Burrage, Lindsay C; Beck, Anita E; Marvin, Colby T; McMillin, Margaret J; Shively, Kathryn M; Harrell, Tanya M; Buckingham, Kati J; Bacino, Carlos A; Jain, Mahim; Alanay, Yasemin; Berry, Susan A; Carey, John C; Gibbs, Richard A; Lee, Brendan H; Krakow, Deborah; Shendure, Jay; Nickerson, Deborah A; Bamshad, Michael J

    2015-05-01

    Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

  9. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy

    DEFF Research Database (Denmark)

    Winkelmann, Juliane; Lin, Ling; Schormair, Barbara

    2012-01-01

    Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT.......GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding...

  10. [Mapping of pathogenic genes in two families with autosomal dominant ichthyosis vulgaris].

    Science.gov (United States)

    Gong, Hui-Yong; Zhang, Jing; Hu, Zheng-Mao; Wu, Ling-Qian; Liang, De-Sheng; Xie, Zhi-Guo; Pan, Qian; Bu, Feng-Xiao; Peng, Yu; Xia, Kun; Xia, Jia-Hui

    2008-07-01

    To localize the pathogenic genes of autosomal dominant ichthyosis vulgaris, we ascertained two ichthyosis vulgaris families from Hunan Province. Venous blood samples were collected from affected and unaffected family members and genomic DNA was extracted. We then performed genome scan and linkage analysis using microsatellite markers around known ichthyosis vulgaris loci in chromosomes 1 and 10. In family 1, the locus linked to ichthyosis vulgaris was located near D1S498 (1q21), which overlapped with known ichthyosis vulgaris loci. In family 2, however, all known loci for ichthyosis vulgaris were excluded and the new locus remains to be identified.

  11. Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy

    Directory of Open Access Journals (Sweden)

    Larsen Michael

    2011-04-01

    Full Text Available Abstract Background Autosomal dominant optic atrophy (ADOA, Kjer disease, MIM #165500 is the most common form of hereditary optic neuropathy. Mutations in OPA1 located at chromosome 3q28 are the predominant cause for ADOA explaining between 32 and 89% of cases. Although deletions of OPA1 were recently reported in ADOA, the frequency of OPA1 genomic rearrangements in Denmark, where ADOA has a high prevalence, is unknown. The aim of the study was to identify copy number variations in OPA1 in Danish ADOA patients. Methods Forty unrelated ADOA patients, selected from a group of 100 ADOA patients as being negative for OPA1 point mutations, were tested for genomic rearrangements in OPA1 by multiplex ligation probe amplification (MLPA. When only one probe was abnormal results were confirmed by additional manually added probes. Segregation analysis was performed in families with detected mutations when possible. Results Ten families had OPA1 deletions, including two with deletions of the entire coding region and eight with intragenic deletions. Segregation analysis was possible in five families, and showed that the deletions segregated with the disease. Conclusion Deletions in the OPA1 gene were found in 10 patients presenting with phenotypic autosomal dominant optic neuropathy. Genetic testing for deletions in OPA1 should be offered for patients with clinically diagnosed ADOA and no OPA1 mutations detected by DNA sequencing analysis.

  12. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report.

    Science.gov (United States)

    Eckardt, Kai-Uwe; Alper, Seth L; Antignac, Corinne; Bleyer, Anthony J; Chauveau, Dominique; Dahan, Karin; Deltas, Constantinos; Hosking, Andrew; Kmoch, Stanislav; Rampoldi, Luca; Wiesener, Michael; Wolf, Matthias T; Devuyst, Olivier

    2015-10-01

    Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.

  13. Gene mapping of autosomal dominant retinitis pigmentosa in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    DAI Li-li; SUN Da-wei; WANG Zheng; FU Song-bin; HUANG Shang-zhi; ZHANG Zhong-yu; ZENG Guang; PENG Shao-min

    2009-01-01

    Background The autosomal dominant form of retinitis pigmentosa (ADRP) can be caused by mutations in 14 genes and further loci remains to be identified. This study was intended to identify mutations in a Chinese pedigree with ADRP. Methods A large Chinese family with retinitis pigmentosa was collected. The genetic analysis of the family suggested an autosomal dominant pattern. Microsatellite (STR) markers tightly linked to genes known to be responsible for ADRP were selected for linkage analysis. Exons along with adjacent splice junctions of PRPF31 were amplified by polymerase chain reaction (PCR) and screened by direct sequencing.Results The caused gene of ADRP was mapped to 19q13.4 between markers D19S572 and D19S877, with a maximum LOD score of 3.01 at marker D19S418 (recombination fraction=0).Conclusion The affected gene linked to the 19q13.4 in a Chinese family with ADRP, which is different from other mutations at the same loci in other Chinese families.

  14. Familial clustering of medullary sponge kidney is autosomal dominant with reduced penetrance and variable expressivity.

    Science.gov (United States)

    Fabris, Antonia; Lupo, Antonio; Ferraro, Pietro M; Anglani, Franca; Pei, York; Danza, Francesco M; Gambaro, Giovanni

    2013-02-01

    Medullary sponge kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium nephrolithiasis. Approximately 12% of recurrent stone formers have MSK, which is generally considered a sporadic disorder. Since its discovery, three pedigrees have been described in which an apparently autosomal dominant inheritance was suggested. Here, family members of 50 patients with MSK were systematically investigated by means of interviews, renal imaging, and biochemical studies in an effort to establish whether MSK is an inheritable disorder. Twenty-seven MSK probands had 59 first- and second-degree relatives of both genders with MSK in all generations. There were progressively lower mean levels of serum calcium, urinary sodium, pH, and volume, combined with higher serum phosphate and potassium from probands to relatives with bilateral, to those with unilateral, and to those unaffected by MSK. This suggests that most affected relatives have a milder form of MSK than the probands, which would explain why they had not been so diagnosed. Thus, our study provides strong evidence that familial clustering of MSK is common, and has an autosomal dominant inheritance, a reduced penetrance, and variable expressivity.

  15. Linkage of the late onset autosomal dominant familial spastic paraplegia (DFSPII) to chromosome 2p markers

    Energy Technology Data Exchange (ETDEWEB)

    Hentati, A.; Wasserman, B.; Siddique, T. [Northwestern Univ. Medical School, Chicago, IL (United States)] [and others

    1994-09-01

    Pure familial spastic paraplegias (FSP) is a neurodegenerative disease characterized by spasticity of lower limbs. FSP in inherited as an autosomal dominant (DFSP) or an autosomal recessive (RFSP) trait. DFSP has been classified into early onset (DFSPI) and late onset (DFSPII) based on the mean age of onset in families. A locus for RFSP has been mapped to chromosome 8, while a locus for DFSPI has been mapped to chromosome 14q. Genetic locus heterogeneity was observed in both of these forms. The location of DFSPII locus (or loci) is unknown. We collected DNA samples from 81 individuals including 26 affecteds from three DFSPII families (9998, 840, 581). The mean age of onset of systems was 26.5, 42.5, and 35.2 years, respectively. We first tested 156 DNA markers distributed throughout the human 22 autosomes with family 9998 and positive lod scores were obtained with chromosome 2p markers D2S174 (Z({theta})=2.93 at {theta}=0.00), D2S146 (Z({theta})=1.03 at {theta}=0.00) and D2S177 (Z({theta})=1.04 at {theta}=0.00). Analysis of the 2 additional families confirmed the linkage with a peak lod score of Z({theta})=4.62 at {theta}=0.105 with D2S174. The multipoint linkage analysis using the map D2S175-10cM-D2S174-14cM-D2DS177 suggested that the DFSPII locus most likely maps between D2S174 and D2S177 with Z({theta})=6.11. There was no evidence in our data supporting genetic locus heterogeneity for the DFSPII.

  16. Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group.

    Directory of Open Access Journals (Sweden)

    Yi Su

    Full Text Available Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer's Network (DIAN, an autosomal dominant Alzheimer's disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer's disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.

  17. Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer’s Disease: Results from the DIAN Study Group

    Science.gov (United States)

    Su, Yi; Blazey, Tyler M.; Owen, Christopher J.; Christensen, Jon J.; Friedrichsen, Karl; Joseph-Mathurin, Nelly; Wang, Qing; Hornbeck, Russ C.; Ances, Beau M.; Snyder, Abraham Z.; Cash, Lisa A.; Koeppe, Robert A.; Klunk, William E.; Galasko, Douglas; Brickman, Adam M.; McDade, Eric; Ringman, John M.; Thompson, Paul M.; Saykin, Andrew J.; Ghetti, Bernardino; Sperling, Reisa A.; Johnson, Keith A.; Salloway, Stephen P.; Schofield, Peter R.; Masters, Colin L.; Villemagne, Victor L.; Fox, Nick C.; Förster, Stefan; Chen, Kewei; Reiman, Eric M.; Xiong, Chengjie; Marcus, Daniel S.; Weiner, Michael W.; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L. S.

    2016-01-01

    Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer’s Network (DIAN), an autosomal dominant Alzheimer’s disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer’s disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted. PMID:27010959

  18. Fetal polycystic kidney disease: Pathological overview

    Directory of Open Access Journals (Sweden)

    Sunita B Patil

    2013-01-01

    Full Text Available Polycystic kidney disease is a rare developmental anomaly inherited as autosomal dominant or autosomal recessive. It is characterized by cystic dilatation of the collecting ducts frequently associated with hepatic involvement and progression to renal failure. It is included in the differential diagnosis of cystic diseases of the kidney. We report a case of polycystic kidney disease, in 22 weeks fetus incidentally detected on routine antenatal ultrasonography and confirmed by fetal autopsy. This report elucidates the importance of early diagnosis and intervention in cystic kidney diseases.

  19. Fine localization of the locus for autosomal dominant retinitis pigmentosa on chromosome 17p

    Energy Technology Data Exchange (ETDEWEB)

    Goliath, R.; Janssens, P.; Beighton, P. [Univ. of Cape Town (South Africa)] [and others

    1995-10-01

    The term {open_quotes}retintis pigmentosa{close_quotes} (RP) refers to a group of inherited retinal degenerative disorders. Clinical manifestations include night-blindness, with variable age of onset, followed by constriction of the visual field that may progress to total loss of sight in later life. Previous studies have shown that RP is caused by mutations within different genes and may be inherited as an X-linked recessive (XLRRP), autosomal recessive (ARRP), or autosomal dominant (ADRP) trait. The AD form of this group of conditions has been found to be caused by mutations within the rhodopsin gene in some families and the peripherin/RDS gene in others. In addition, some ADRP families have been found to be linked to anonymous markers on 8cen, 7p, 7q,19q, and, more recently, 17p. The ADRP gene locus on the short arm of chromosome 17 was identified in a large South African family (ADRP-SA) of British origin. The phenotypic expression of the disorder, which has been described elsewhere is consistent in the pedigree with an early onset of disease symptoms. In all affected subjects in the family, onset of symptoms commenced before the age of 10 years. 16 refs., 3 figs., 1 tab.

  20. Autosomal dominant familial spastic paraplegia; Linkage analysis and evidence for linkage to chromosome 2p

    Energy Technology Data Exchange (ETDEWEB)

    Figlewicz, D.A. [Univ. of Rochester, NY (United States); Dube, M.P.; Rouleau, G.A. [McGill Univ., Montreal (Canada)] [and others

    1994-09-01

    Familial spastic paraplegia (FSP) is a degenerative disorder of the motor system characterized by progressive weakness and spasticity of the lower limbs. Little is known about the pathophysiology of this disorder. FSP can be inherited as an autosomal dominant (AD), autosomal recessive, or X-linked trait. We have undertaken linkage analysis for a group of 36 AD FSP families from which we have collected blood samples from 427 individuals, including 148 affected individuals. Typing of polymorphic markers has allowed us to exclude more than 50% of the genome. Recently, linkage for AD FSP to a locus on chromosome 14q was reported. Our AD FSP kindreds were tested for linkage to markers spanning the 20 cM region between D14S69 and D14S66; however, we were not able to establish linkage for any of our families to chromosome 14. Lod scores suggestive of linkage for some AD FSP kindreds have been obtained for markers on chromosome 2p. We have tested seven polymorphic markers spanning the region between D2S405 and D2S177. Our highest aggregate lod score, including all families tested, was obtained at the locus D2S352: 2.4 at 20 cM. Results from HOMOG analysis for linkage heterogeneity will be reported.

  1. Late onset autosomal dominant cerebellar ataxia a family description and linkage analysis with the hla system

    Directory of Open Access Journals (Sweden)

    Walter O. Arruda

    1991-09-01

    Full Text Available A family suffering an autosomal dominant form of late onset hereditary cerebellar ataxia is described. Eight affected family members were personally studied, and data from another four were obtained through anamnesis. The mean age of onset was 37.1±5.4 years (27-47 years. The clinical picture consisted basically of a pure ataxic cerebellar syndrome. CT-scan disclosed diffuse cerebellar atrophy with relative sparing of the brainstem (and no involvement of supratentorial structures. Neurophysiological studies (nerve conduction, VEP and BAEP were normal. Twenty-six individuals were typed for HLA histocompatibility antigens. Lod scores were calculated with the computer program LINKMAP. Close linkage of the ataxia gene with the HLA system in this family could be excluded - 0==0,02, z=(-2,17 - and the overall analysis of the lod scores suggest another chromossomal location than chromosome 6.

  2. A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

    Science.gov (United States)

    Zhou, Yu; Zhai, Yaru; Huang, Lulin; Gong, Bo; Li, Jie; Hao, Fang; Wu, Zhengzheng

    2016-01-01

    Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC) in a Chinese family using next-generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499Tcongenital cataract population and illustrated the important role of CRYBB2 in the genetics research of congenital cataract. PMID:28025620

  3. Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans.

    Science.gov (United States)

    Berry, Vanita; Gregory-Evans, Cheryl; Emmett, Warren; Waseem, Naushin; Raby, Jacob; Prescott, DeQuincy; Moore, Anthony T; Bhattacharya, Shomi S

    2013-12-01

    Congenital cataracts are an important cause of bilateral visual impairment in infants. Through genome-wide linkage analysis in a four-generation family of Irish descent, the disease-associated gene causing autosomal-dominant congenital nuclear cataract was mapped to chromosome 4p16.1. The maximum logarithm of odds (LOD) score was 2.62 at a recombination fraction θ=0, obtained for marker D4S432 physically close to the Wolfram gene (WFS1). By sequencing the coding regions and intron-exon boundaries of WFS1, we identified a DNA substitution (c.1385A-to-G) in exon 8, causing a missense mutation at codon 462 (E462G) of the Wolframin protein. This is the first report of a mutation in this gene causing an isolated nuclear congenital cataract. These findings suggest that the membrane trafficking protein Wolframin may be important for supporting the developing lens.

  4. Autosomal dominant rolandic epilepsy and speech dyspraxia: a new syndrome with anticipation.

    Science.gov (United States)

    Scheffer, I E; Jones, L; Pozzebon, M; Howell, R A; Saling, M M; Berkovic, S F

    1995-10-01

    We describe a family of 9 affected individuals in three generations with nocturnal oro-facio-brachial partial seizures, secondarily generalized partial seizures, and centro-temporal epileptiform discharges, associated with oral and speech dyspraxia and cognitive impairment. The speech disorder was prominent, but differed from that of Landau-Kleffner syndrome and of epilepsy with continuous spike and wave during slow-wave sleep. The electroclinical features of this new syndrome of autosomal dominant rolandic epilepsy resemble those of benign rolandic epilepsy, a common inherited epilepsy of childhood. This family shows clinical anticipation of the seizure disorder, the oral and speech dyspraxia, and cognitive dysfunction, suggesting that the genetic mechanism could be expansion of an unstable triplet repeat. Molecular studies on this syndrome, where the inheritance pattern is clear, could also be relevant to identifying a gene for benign rolandic epilepsy where anticipation does not occur and the mode of inheritance is uncertain.

  5. Primary shunt hyperbilirubinaemia in a large four-generation family confirming autosomal dominant genetic disorder

    Institute of Scientific and Technical Information of China (English)

    Chun-Lian Wang; Xiao-Wei Liu; Fang-Gen Lu; Xiao-Ping Wu; Chun-Hui Ouyang; Dong-Ye Yang

    2006-01-01

    AIM: To describe the pattern of inheritance and confirm the diagnosdc criteria of primary shunt hyperbilirubinaemia (PSH).METHODS: Forty members of a family pedigree across four generations were included in this study. All family members were interviewed and investigated by physical examination, hematology and liver function test and the pattern of inheritance was analyzed.RESULTS: Nine of the forty family members suffered primary shunt hyperbilirubinaemia. The mature erythrocytes of the propositus were irregular in shape and size.The pedigree showed transmission of the trait through four generations with equal distribution in male and female. No individual with a primary shunt hyperbilirubinaemia was born to unaffected parents. The penetrance was complete in adult.CONCLUSION: The pattern of inheritance is autosomal dominant. The abnormality of erythrocytes and decrease in white blood cell could be supplemented in the diagnosis of PSH. The PSH is a genetic disorder and could by renamed as hereditary shunt hyperbilirubinaemia.

  6. Autosomal dominant coralliform cataract related to a missense mutation of the γD-crystallin gene

    Institute of Scientific and Technical Information of China (English)

    徐伟珍; 郑树; 徐世杰; 黄薇; 姚克; 张苏展

    2004-01-01

    Background Congenital cataract is a sight-threatening disease that affects about 1-6 cases per 10?@000 live births and causes 10%-30% of all blindness in children. About 25% of all cases are due to genetic defects. We identified autosomal dominant congenital coralliform cataracts-related genetic defect in a four-generation Chinese family.Methods Complete ophthalmological examinations were performed prior to lens extraction. Lens samples were then studied by electron microscopy. Genomic DNA from family members were examined using whole-genomic linkage analysis, with two-point logarithm of odds (LOD) scores calculated using the Linkage program package (version 5.1). Mutation analysis of candidate genes was performed by direct sequencing. Finally, a three-dimensional protein model was predicted using Swiss-Model (version 2.0).Results Eleven of the 23 examined individuals had congenital cataracts. Ultrastructure studies revealed crystal deposits in the lens, and granules extensively dispersed in transformed lens fiber cells. The maximum two-point LOD score, 3.5 at θ=0.1, was obtained for the marker D2S325. Mutation analysis of the γ-crystallin (CRYG) gene cluster identified a mutation (P23T) in exon 2 of γD-crystallin (CRYGD). Protein structure modeling demonstrated that the P23T mutation caused a subtle change on the surface of the γD protein.Conclusions The results suggest that the coralliform cataract phenotype is due to a mutated CRYGD gene, and that this sequence change is identical to one reported by Santhiya to be related to another distinct clinical condition, lamellar cataract. This study provides evidence that this same genetic defect may be associated with a different phenotype. This is the first report identifying the genetic defect associated with an autosomal dominant congenital coralliform cataract.

  7. Mutational screening of 320 Brazilian patients with autosomal dominant spinocerebellar ataxia.

    Science.gov (United States)

    Cintra, Vívian Pedigone; Lourenço, Charles Marques; Marques, Sandra Elisabete; de Oliveira, Luana Michelli; Tumas, Vitor; Marques, Wilson

    2014-12-15

    Autosomal dominant spinocerebellar ataxias (SCAs) are a clinical and genetically heterogeneous group of debilitating neurodegenerative diseases that are related to at least 36 different genetic loci; they are clinically characterized by progressive cerebellar ataxia and are frequently accompanied by other neurological and non-neurological manifestations. The relative frequency of SCA varies greatly among different regions, presumably because of a founder effect or local ethnicities. Between July 1998 and May 2012, we investigated 320 Brazilian patients with an SCA phenotype who belonged to 150 unrelated families with an autosomal dominant inheritance pattern and 23 sporadic patients from 13 Brazilian states. A total of 265 patients (82.8%) belonging to 131 unrelated families (87.3%) were found to have a definite mutation, and SCA3 accounted for most of the familial cases (70.7%), followed by SCA7 (6%), SCA1 (5.3%), SCA2 (2.7%), SCA6 (1.3%), SCA8 (0.7%) and SCA10 (0.7%). In the Ribeirão Preto mesoregion, which is located in the northeast part of São Paulo State, the prevalence of SCA3 was approximately 5 per 100,000 inhabitants, which is the highest prevalence found in Brazil. No mutation was found in the SCA12, SCA17 and DRPLA genes, and all the sporadic cases remained without a molecular diagnosis. This study further characterizes the spectrum of SCA mutations found in Brazilian patients, which suggests the existence of regional differences and demonstrates the expansion of the SCA8 locus in Brazilian families.

  8. Clinical features and linkage analysis for a Chinese family with autosomal dominant central areolar choroidal dystrophy

    Institute of Scientific and Technical Information of China (English)

    MA Kai; LIU Ning-pu; YANG Xiu-fen; HAN Cui; ZHANG Ning; XU Jun; LIU Shou-bin; LU Hal; Torkel Snellingen; WANG Ning-li

    2009-01-01

    Background A Chinese family with autosomal dominant central areolar choroidal dystrophy (CACD) was identified.The purpose of this study was to collect the clinical findings from the family and to identify the genetic entity by linkage nalysis.Methods Forty-three individuals from 3 generations of the family underwent ophthalmologic examinations, including best-corrected visual acuity, examination of the anterior segments, and inspection of the ocular fundus after pharmacologic mydriasis. Affected family members further underwent color vision test, color fundus photography,fluorescein angiography, automated perimetry, and electroretinography. The family was followed up for 30 months.Peripheral venous blood or buccal swabs were collected from each family member and genomic DNA was extracted.Linkage analysis was performed for candidate genes or loci using microsatellite markers.Results Seven family members in 3 continuous generations were diagnosed as having autosomal dominant CACD.The family showed progressive development of the disease, affecting both male and female. Age of onset of visual disturbances varied between 11 and 50 years. Phenotypic variability among affected individuals was apparent and ranged from relatively normal-appearing fundus with mild parafoveal pigment mottling to geographic atrophy of the macula. Fluorescein angiography showed hyperfluorescent parafoveal changes in early stage or well-demarcated area of chorioretinal atrophy with enhanced visibility of the residual underlying choroidal vessels in the late stage. Peripheral retina and visual fields were normal in affected individuals. Electroretinogram showed normal or mild reduction in the photopic amplitude. Eight candidate genes (STGD4, RCD1, peripherin/RDS, GUCA1A, RIMS1, UNC119, GUC Y2D, and AIPL1) and two genetic loci (4p15.2-16.3, and 17p13) were excluded to be responsible for the disease by linkage analysis.Conclusions The clinical findings of this Chinese family with CACD shared

  9. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Huang Lijia

    2012-09-01

    Full Text Available Abstract Background Congenital nonprogressive spinocerebellar ataxia is characterized by early gross motor delay, hypotonia, gait ataxia, mild dysarthria and dysmetria. The clinical presentation remains fairly stable and may be associated with cerebellar atrophy. To date, only a few families with autosomal dominant congenital nonprogressive spinocerebellar ataxia have been reported. Linkage to 3pter was demonstrated in one large Australian family and this locus was designated spinocerebellar ataxia type 29. The objective of this study is to describe an unreported Canadian family with autosomal dominant congenital nonprogressive spinocerebellar ataxia and to identify the underlying genetic causes in this family and the original Australian family. Methods and Results Exome sequencing was performed for the Australian family, resulting in the identification of a heterozygous mutation in the ITPR1 gene. For the Canadian family, genotyping with microsatellite markers and Sanger sequencing of ITPR1 gene were performed; a heterozygous missense mutation in ITPR1 was identified. Conclusions ITPR1 encodes inositol 1,4,5-trisphosphate receptor, type 1, a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood. Our study demonstrates for the first time that, in addition to spinocerebellar ataxia type 15, alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia; highlighting important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum.

  10. Autosomal dominant familial spastic paraplegia: Tight linkage to chromosome 15q

    Energy Technology Data Exchange (ETDEWEB)

    Fink, J.K.; Wu, C.T.B.; Jones, S.M.

    1994-09-01

    Familial spastic paraplegia (FSP) (MIM No.18260) constitutes a clinically and genetically diverse group of disorders that share the primary feature of progressive, severe, lower extremity spasticity. FSP is classified according to the mode of inheritance and whether progressive spasticity occurs in isolation ({open_quotes}uncomplicated FSP{close_quotes}) or with other neurologic abnormalities ({open_quotes}complicated FSP{close_quotes}), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, or deafness. Recently, autosomal dominant, uncomplicated FSP was shown to be genetically heterogeneous and tightly linked to a group of microsatellite markers on chromosome 14q in one large kindred. We examined 126 members of a non-consanguineous North American kindred of Irish descent. FSP was diagnosed in 31 living subjects who developed insidiously progressive gait disturbance between ages 12 and 35 years. Using genetic linkage analysis to microsatellite DNA polymorphisms, we showed that the FSP locus on chromosome 14q was exluded from linkage with the disorder in our family. Subsequently, we searched for genetic linkage between the disorder and microsatellite DNA polymorphisms spanning approximately 50% of the genome. We observed significantly positive, two-point maximum lod scores (Z) for markers on chromosome 15q: D15S128 (Z=9.70, {theta}=0.05), D15S165 (Z=3.30, {theta}=0.10), and UT511 (Z=3.86, {theta}=0.10). Our data clearly establishes that one locus for autosomal dominant, uncomplicated FSP is mapped to the pericentric region of chromosome 15q. Identifying genes responsible for chromosome 15q-linked and chromosome 14q-linked FSP will greatly advance our understanding of this condition and hopefully other inherited and degenerative brain and spinal cord disorders that are also characterized by axonal degeneration.

  11. Oculopharyngeal Weakness, Hypophrenia, Deafness, and Impaired Vision: A Novel Autosomal Dominant Myopathy with Rimmed Vacuoles

    Institute of Scientific and Technical Information of China (English)

    Ting Chen; Xiang-Hui Lu; Hui-Fang Wang; Rui Ban; Hua-Xu Liu; Qiang Shi; Qian Wang

    2016-01-01

    Background:Myopathies with rimmed vacuoles are a heterogeneous group of muscle disorders with progressive muscle weakness and varied clinical manifestations but similar features in muscle biopsies.Here,we describe a novel autosomal dominant myopathy with rimmed vacuoles in a large family with 11 patients of three generations affected.Methods:A clinical study including family history,obstetric,pediatric,and development history was recorded.Clinical examinations including physical examination,electromyography (EMG),serum creatine kinase (CK),bone X-rays,and brain magnetic resonance imaging (MRI) were performed in this family.Open muscle biopsies were performed on the proband and his mother.To find the causative gene,the whole-exome sequencing was carried out.Results:Disease onset was from adolescence to adulthood,but the affected patients of the third generation presented an earlier onset and more severe clinical manifestations than the older generations.Clinical features were characterized as dysarthria,dysphagia,external ophthalmoplegia,limb weakness,hypophrenia,deafness,and impaired vision.However,not every patient manifested all symptoms.Serum CK was mildly elevated and EMG indicated a myopathic pattern.Brain MRI showed cerebellum and brain stem mildly atrophy.Rimmed vacuoles and inclusion bodies were observed in muscle biopsy.The whole-exome sequencing was performed,but the causative gene has not been found.Conclusions:We reported a novel autosomal dominant myopathy with rimmed vacuoles characterized by dysarthria,dysphagia,external ophthalmoplegia,limb weakness,hypophrenia,deafness,and impaired vision,but the causative gene has not been found and needs further study.

  12. Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease

    Science.gov (United States)

    Benzinger, Tammie L. S.; Blazey, Tyler; Jack, Clifford R.; Koeppe, Robert A.; Su, Yi; Xiong, Chengjie; Raichle, Marcus E.; Snyder, Abraham Z.; Ances, Beau M.; Bateman, Randall J.; Cairns, Nigel J.; Fagan, Anne M.; Goate, Alison; Marcus, Daniel S.; Aisen, Paul S.; Christensen, Jon J.; Ercole, Lindsay; Hornbeck, Russ C.; Farrar, Angela M.; Aldea, Patricia; Jasielec, Mateusz S.; Owen, Christopher J.; Xie, Xianyun; Mayeux, Richard; Brickman, Adam; McDade, Eric; Klunk, William; Mathis, Chester A.; Ringman, John; Thompson, Paul M.; Ghetti, Bernardino; Saykin, Andrew J.; Sperling, Reisa A.; Johnson, Keith A.; Salloway, Stephen; Correia, Stephen; Schofield, Peter R.; Masters, Colin L.; Rowe, Christopher; Villemagne, Victor L.; Martins, Ralph; Ourselin, Sebastien; Rossor, Martin N.; Fox, Nick C.; Cash, David M.; Weiner, Michael W.; Holtzman, David M.; Buckles, Virginia D.; Moulder, Krista; Morris, John C.

    2013-01-01

    Major imaging biomarkers of Alzheimer’s disease include amyloid deposition [imaged with [11C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [18F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer’s disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer’s disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease. PMID:24194552

  13. A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin

    Science.gov (United States)

    2013-07-01

    inhibitors). Cells were homogenized in a tight-fitting Dounce homogenizer, chilled on ice for 10 min, and then rotated for 15 min. Nonidet P - 40 was added to...cells counted from each of n=6 mice) in comparison to 10.6±3.6% s.e.m. (450 cells counted from each of n=4 mice) in metformin-treated mice ( p ɘ.0074...situ. AMPK activation levels were assessed by staining sections with an antibody directed against p -AMPK. We find that treatment with 375 mg/kg

  14. Potential Deleterious Effects of Vasopressin in Chronic Kidney Disease and Particularly Autosomal Dominant Polycystic Kidney Disease

    NARCIS (Netherlands)

    Meijer, E.; Boertien, W. E.; Zietse, R.; Gansevoort, R. T.

    2011-01-01

    The antidiuretic hormone vasopressin is crucial for regulating free water clearance in normal physiology. However, it has also been hypothesized that vasopressin has deleterious effects on the kidney. Vasopressin is elevated in animals and patients with chronic kidney disease. Suppression of vasopre

  15. Asymmetric dimethylarginine and lipid peroxidation products in early autosomal dominant polycystic kidney disease

    DEFF Research Database (Denmark)

    Wang, Dan; Strandgaard, S.; Borresen, M.L.

    2008-01-01

    of nitric oxide synthase and the lipid peroxidation product 13-hydroxyoctadecadienoic acid (HODE) as a marker of oxidative stress in patients with early ADPKD. Study Design: Cross-sectional study. Setting & Participants: Patients with early ADPKD (n = 27) and age-matched volunteers (n = 30) from a single...... academic medical center. Factor: Patients with ADPKD versus controls. Outcomes & Measurement: Plasma (P) levels, urinary (U) excretion, and urinary clearance (C) of ADMA and HODE. Because of multiple comparisons, P for significance is considered less than 0.0167. Results: Patients with ADPKD had......-sectional nature of study, and limited number of markers of oxidative stress. Conclusions: P-ADMA and P-HODE levels are increased in patients with early ADPKD. Increased P-ADMA level is related to decreased CADMA and is accompanied by oxidative stress. Am J Kidney Dis 51:184-191. (c) 2008 by the National Kidney...

  16. Morphologic,mechanical and functional sonographic parameters of arteries in autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    戎殳

    2006-01-01

    Objective To investigate whether the risk factors of cardiovascular disease exist in early stage of ADPKD patients with normal renal function. Methods Morphologic , mechanical and functional sonographic parameters of arteries were examined by high-frequency ultrasonography in 32 hypertensive and 28 normotensive ADPKD patients with preserved renal function, 25 patients with es-

  17. Bilineal inheritance of type 1 autosomal dominant polycystic kidney disease (ADPKD) and recurrent fetal loss.

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; Coto, Eliecer; Selgas, Rafael

    2008-10-01

    We report for the first time a family with type 1 ADPKD in which the marriage between affected non-consanguinous individuals resulted in two live-born heterozygous offspring and two fetuses lost in mid-pregnancy. Given a 25% chance for mutant compound heterozygosity in the offspring of this family, our findings suggest that compound heterozygosity of PKD1 mutations in humans may be embryonically lethal.

  18. A Three-Generation Family with Idiopathic Facial Palsy Suggesting an Autosomal Dominant Inheritance with High Penetrance

    Directory of Open Access Journals (Sweden)

    Christian Grønhøj Larsen

    2015-01-01

    Full Text Available Idiopathic facial palsy (IFP, also known as Bell’s palsy, is a common neurologic disorder, but recurrent and familial forms are rare. This case series presents a three-generation family with idiopathic facial palsy. The mode of inheritance of IFP has previously been suggested as autosomal dominant with low or variable penetrance, but the present family indicates an autosomal dominant trait with high or complete penetrance. Chromosome microarray studies did not reveal a pathogenic copy number variation, which could enable identification of a candidate gene.

  19. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

    Science.gov (United States)

    Burrage, Lindsay C; Charng, Wu-Lin; Eldomery, Mohammad K; Willer, Jason R; Davis, Erica E; Lugtenberg, Dorien; Zhu, Wenmiao; Leduc, Magalie S; Akdemir, Zeynep C; Azamian, Mahshid; Zapata, Gladys; Hernandez, Patricia P; Schoots, Jeroen; de Munnik, Sonja A; Roepman, Ronald; Pearring, Jillian N; Jhangiani, Shalini; Katsanis, Nicholas; Vissers, Lisenka E L M; Brunner, Han G; Beaudet, Arthur L; Rosenfeld, Jill A; Muzny, Donna M; Gibbs, Richard A; Eng, Christine M; Xia, Fan; Lalani, Seema R; Lupski, James R; Bongers, Ernie M H F; Yang, Yaping

    2015-12-03

    Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

  20. Cyclic mood disorder heralding adult-onset autosomal dominant leucodystrophy: a clinical masquerader.

    Science.gov (United States)

    Jain, Rajendra S; Prakash, Swayam; Raghavendra, B S; Nagpal, Kadam; Handa, Rahul

    2014-06-01

    Leucodystrophies are a heterogeneous group of progressive white matter diseases which may be inherited in dominant, recessive or X-linked fashion depending on the type. Adrenoleucodystrophy (ALD) and metachromatic leucodystrophy (MLD) are rather commoner forms of leucodystrophies whereas krabbes disease, alexander disease, cannavans disease etc. are of less common type. Adult-onset autosomal dominant leucodystrophy (ADLD) is a lately described rarer form of leucodystrophy with perhaps no case report from India. Various leucodystrophies may have different clinical presentations, ranging from subtle cognitive and psychiatric manifestations to gross motor disabilities, visual impairment and seizure. Psychiatric manifestations in the form of psychoses and frank schizophrenia are commonly described in MLD. Depression though uncommonly reported in MLD, cyclic mood disorders have been rarely described in any form of leucodystrophies. We are reporting an eye opener, a case of ADLD which masqueraded as a rapid cyclic mood disorder for initial four years, later to be followed by progressive neurological signs and symptoms. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as rapid cyclic mood disorder in the world literature.

  1. Novel LDB3 Mutation in a Patient With Autosomal Dominant Myofibrillar Myopathy

    Directory of Open Access Journals (Sweden)

    Talebi

    2016-01-01

    Full Text Available Introduction Myofibrillar myopathy (MFM is a rare human disease, characterized by a distinct histopathological pattern of myofibrillar degeneration and protein aggregates. LDB3 protein encoded by this gene is a key Z-disk protein that interacts with α-actinin and protein kinase C. Case Presentation In this paper, we identified the novel heterozygous, and hence, dominant mutation in the LIM domain-binding protein 3 gene (LDB3 in a patient affected by myofibrillar myopathy (MFM. We performed direct sequencing in an Iranian patient with autosomal-dominant inheritance of MFM characterized by clinical features, and we identified a heterozygous missense mutation in exon 10, c.1687A > G (p.Ile563Val in the LDB3 gene on chromosome 10:88476524. Conclusions Bioinformatics analyses using SIFT, Mutation Taster and Polyphen-2 indicated that p.Ile563Val was predicted to be damaging, disease causing, and probably damaging to and causing LDB3 dysfunction. As such, this mutation produces novel protein coding transcripts, which might explain the MFM phenotype in the patient.

  2. Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics

    Directory of Open Access Journals (Sweden)

    Fujioka Shinsuke

    2011-05-01

    Full Text Available Abstract Type I autosomal dominant cerebellar ataxia (ADCA is a type of spinocerebellar ataxia (SCA characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA. Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical

  3. BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Lim, Yen Ying; Hassenstab, Jason; Cruchaga, Carlos; Goate, Alison; Fagan, Anne M; Benzinger, Tammie L S; Maruff, Paul; Snyder, Peter J; Masters, Colin L; Allegri, Ricardo; Chhatwal, Jasmeer; Farlow, Martin R; Graff-Radford, Neill R; Laske, Christoph; Levin, Johannes; McDade, Eric; Ringman, John M; Rossor, Martin; Salloway, Stephen; Schofield, Peter R; Holtzman, David M; Morris, John C; Bateman, Randall J

    2016-10-01

    SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val66 homozygotes, 48 Met66 carriers). Among preclinical mutation carriers, Met66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val66 homozygotes and Met66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease.

  4. Autosomal dominant inheritance of cardiac valves anomalies in two families: extended spectrum of left-ventricular outflow tract obstruction.

    NARCIS (Netherlands)

    Wessels, M.W.; Laar, I.M. van de; Roos-Hesselink, J.W.; Strikwerda, S.; Majoor-Krakauer, D.F.; Vries, L.B.A. de; Kerstjens-Frederikse, W.S.; Vos, Y.J.; Graaf, B.M. de; Bertoli-Avella, A.M.; Willems, P.J.

    2009-01-01

    Only a limited number of families with clear monogenic inheritance of nonsyndromic forms of congenital valve defects have been described. We describe two multiplex pedigrees with a similar nonsyndromic form of heart valve anomalies that segregate as an autosomal dominant condition. The first family

  5. Autosomal Dominant Inheritance of Cardiac Valves Anomalies in Two Families : Extended Spectrum of Left-Ventricular Outflow Tract Obstruction

    NARCIS (Netherlands)

    Wessels, Maria W.; van de Laar, Ingrid M. B. H.; Roos-Hesselink, Jolien; Strikwerda, Sipke; Majoor-Krakauer, Danielle F.; de Vries, Bert B. A.; Kerstjens-Frederikse, Wilhelmina S.; Vos, Yvonne J.; de Graaf, Bianca M.; Bertoli-Avella, Aida M.; Willems, Patrick J.

    2009-01-01

    Only a limited number of families with clear monogenic inheritance of nonsyndromic forms of congenital valve defects have been described. We describe two multiplex pedigrees with a similar nonsyndromic form of heart valve anomalies that segregate as an autosomal dominant condition. The first family

  6. Autosomal dominant rhegmatogenous retinal detachment associated with an Arg453Ter mutation in the COL2A1 gene.

    NARCIS (Netherlands)

    Go, S.L.; Maugeri, A.; Mulder, J.J.S.; Driel, M.A. van; Cremers, F.P.M.; Hoyng, C.B.

    2003-01-01

    PURPOSE: To investigate the clinical features and molecular causes of autosomal dominant rhegmatogenous retinal detachment (RRD) in two large families. METHODS: Clinical examination and linkage analysis of both families using markers flanking the COL2A1 gene associated with Stickler syndrome type 1,

  7. C-terminal truncations in human 3 '-5 ' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

    NARCIS (Netherlands)

    Richards, Anna; van den Maagdenberg, Arn M. J. M.; Jen, Joanna C.; Kavanagh, David; Bertram, Paula; Spitzer, Dirk; Liszewski, M. Kathryn; Barilla-LaBarca, Maria-Louise; Terwindt, Gisela M.; Kasai, Yumi; McLellan, Mike; Grand, Mark Gilbert; Vanmolkot, Kaate R. J.; de Vries, Boukje; Wan, Jijun; Kane, Michael J.; Mamsa, Hafsa; Schaefer, Ruth; Stam, Anine H.; Haan, Joost; Paulus, T. V. M. de Jong; Storimans, Caroline W.; van Schooneveld, Mary J.; Oosterhuis, Jendo A.; Gschwendter, Andreas; Dichgans, Martin; Kotschet, Katya E.; Hodgkinson, Suzanne; Hardy, Todd A.; Delatycki, Martin B.; Hajj-Ali, Rula A.; Kothari, Parul H.; Nelson, Stanley F.; Frants, Rune R.; Baloh, Robert W.; Ferrari, Michel D.; Atkinson, John P.

    2007-01-01

    Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activ

  8. Urodynamic evaluation of patients with autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24

    DEFF Research Database (Denmark)

    Jensen, L N; Gerstenberg, T; Kallestrup, E B

    1998-01-01

    OBJECTIVES: There are at least three clinically indistinguishable but genetically different types of autosomal dominant pure spastic paraplegia (ADPSP). Lower urinary tract symptoms are often present but have not been described in a homogeneous patient population. In this study lower urinary tract...

  9. A Mutation in VEGFC, a Ligand for VEGFR3, is Associated with Autosomal Dominant Milroy-like Primary Lymphedema

    NARCIS (Netherlands)

    Gordon, K.; Schulte, D.; Brice, G.; Simpson, M.A.; Roukens, M.G.; Impel, Van A.; Connell, F.; Kalidas, K.; Jeffery, S.; Mortimer, P.S.; Mansour, S.; Schulte-Merker, S.; Ostergaard, P.

    2013-01-01

    Rationale: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic het

  10. DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss

    NARCIS (Netherlands)

    Hildebrand, M.S.; Morin, M.; Meyer, N.C.; Mayo, F.; Modamio-Hoybjor, S.; Mencia, A.; Olavarrieta, L.; Morales-Angulo, C.; Nishimura, C.J.; Workman, H.; DeLuca, A.P.; Castillo, I. del; Taylor, K.R.; Tompkins, B.; Goodman, C.W.; Schrauwen, I.; Wesemael, M.V.; Lachlan, K.; Shearer, A.E.; Braun, T.A.; Huygen, P.L.M.; Kremer, J.M.J.; Camp, G. van; Moreno, F.; Casavant, T.L.; Smith, R.J.; Moreno-Pelayo, M.A.

    2011-01-01

    The prevalence of DFNA8/DFNA12 (DFNA8/12), a type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from AD

  11. Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study

    Science.gov (United States)

    Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent

    2008-01-01

    Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…

  12. Autosomal Dominant Pseudohypoaldosteronism Type 1 in an Infant with Salt Wasting Crisis Associated with Urinary Tract Infection and Obstructive Uropathy

    Directory of Open Access Journals (Sweden)

    Sasigarn A. Bowden

    2013-01-01

    Full Text Available Type 1 pseudohypoaldosteronism (PHA1 is a salt wasting syndrome caused by renal resistance to aldosterone. Primary renal PHA1 or autosomal dominant PHA1 is caused by mutations in mineralocorticoids receptor gene (NR3C2, while secondary PHA1 is frequently associated with urinary tract infection (UTI and/or urinary tract malformations (UTM. We report a 14-day-old male infant presenting with severe hyperkalemia, hyponatremic dehydration, metabolic acidosis, and markedly elevated serum aldosterone level, initially thought to have secondary PHA1 due to the associated UTI and posterior urethral valves. His serum aldosterone remained elevated at 5 months of age, despite resolution of salt wasting symptoms. Chromosomal microarray analysis revealed a deletion of exons 3–5 in NR3C2 in the patient and his asymptomatic mother who also had elevated serum aldosterone level, confirming that he had primary or autosomal dominant PHA1. Our case raises the possibility that some patients with secondary PHA1 attributed to UTI and/or UTM may instead have primary autosomal dominant PHA1, for which genetic testing should be considered to identify the cause, determine future recurrence risk, and possibly prevent the life-threatening salt wasting in a subsequent family member. Future clinical research is needed to investigate the potential overlapping between secondary PHA1 and primary autosomal dominant PHA1.

  13. A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene

    DEFF Research Database (Denmark)

    Højlund, Kurt; Hansen, Torben; Lajer, Maria

    2004-01-01

    a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia. The findings demonstrate...

  14. A gene for autosomal dominant hearing loss on the short arm of chromosome 1

    Energy Technology Data Exchange (ETDEWEB)

    Van Camp, G.; Coucke, P.; Willems, P.J. [and others

    1994-09-01

    Hearing loss is the most common form of sensory impairment and many cases are attributable to genetic causes. The genetic defects underlying several syndromic forms of deafness have been identified, but little is known about the causes of non-syndromic hereditary deafness which accounts for the majority of inherited hearing loss. We report here a large Indonesian family with non-syndromal postlingual hearing loss starting in the high frequencies and showing autosomal dominant inheritance. To locate the gene responsible for the hearing loss in this family, we performed a genome search by genetic linkage analysis with microsatellite markers distributed over the whole genome. We have mapped the gene causing deafness in an extended Indonesian family to chromosome 1p with a multipoint lod score higher than 7. Two other smaller families, showing a similar hereditary hearing loss, were also tested for linkage with chromosome 1p. One family originating from the U.S. was linked to this new locus with a multipoint lod score exceeding 5. In another family from the Netherlands this locus was excluded. The flanking markers D1S255 and D1S211 define a region of 6 cM on chromosome 1p which is likely to contain the deafness gene present in the Indonesian and American family.

  15. Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database.

    Science.gov (United States)

    Ringman, John M; Monsell, Sarah; Ng, Denise W; Zhou, Yan; Nguyen, Andy; Coppola, Giovanni; Van Berlo, Victoria; Mendez, Mario F; Tung, Spencer; Weintraub, Sandra; Mesulam, Marek-Marsel; Bigio, Eileen H; Gitelman, Darren R; Fisher-Hubbard, Amanda O; Albin, Roger L; Vinters, Harry V

    2016-03-01

    Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal β-amyloid protein precursor processing.

  16. A recurrent deletion mutation in OPA1 causes autosomal dominant optic atrophy in a Chinese family

    Science.gov (United States)

    Zhang, Liping; Shi, Wei; Song, Liming; Zhang, Xiao; Cheng, Lulu; Wang, Yanfang; Ge, Xianglian; Li, Wei; Zhang, Wei; Min, Qingjie; Jin, Zi-Bing; Qu, Jia; Gu, Feng

    2014-11-01

    Autosomal dominant optic atrophy (ADOA) is the most frequent form of hereditary optic neuropathy and occurs due to the degeneration of the retinal ganglion cells. To identify the genetic defect in a family with putative ADOA, we performed capture next generation sequencing (CNGS) to screen known retinal disease genes. However, six exons failed to be sequenced by CNGS in optic atrophy 1 gene (OPA1). Sequencing of those exons identified a 4 bp deletion mutation (c.2983-1_2985del) in OPA1. Furthermore, we sequenced the transcripts of OPA1 from the patient skin fibroblasts and found there is six-nucleotide deletion (c.2984-c.2989, AGAAAG). Quantitative-PCR and Western blotting showed that OPA1 mRNA and its protein expression have no obvious difference between patient skin fibroblast and control. The analysis of protein structure by molecular modeling suggests that the mutation may change the structure of OPA1 by formation of an alpha helix protruding into an existing pocket. Taken together, we identified an OPA1 mutation in a family with ADOA by filling the missing CNGS data. We also showed that this mutation affects the structural intactness of OPA1. It provides molecular insights for clinical genetic diagnosis and treatment of optic atrophy.

  17. A novel autosomal dominant inclusion body myopathy linked to 7q22.1-31.1.

    Directory of Open Access Journals (Sweden)

    Yan Lu

    Full Text Available We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15-21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM, which traced the disease to a new locus on chromosome 7q22.1-31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4, spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder.

  18. A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3.

    Science.gov (United States)

    Mendoza, Gustavo; Pemberton, Trevor J; Lee, Kwanghyuk; Scarel-Caminaga, Raquel; Mehrian-Shai, Ruty; Gonzalez-Quevedo, Catalina; Ninis, Vasiliki; Hartiala, Jaana; Allayee, Hooman; Snead, Malcolm L; Leal, Suzanne M; Line, Sergio R P; Patel, Pragna I

    2007-01-01

    Amelogenesis imperfecta (AI) is a collective term used to describe phenotypically diverse forms of defective tooth enamel development. AI has been reported to exhibit a variety of inheritance patterns, and several loci have been identified that are associated with AI. We have performed a genome-wide scan in a large Brazilian family segregating an autosomal dominant form of AI and mapped a novel locus to 8q24.3. A maximum multipoint LOD score of 7.5 was obtained at marker D8S2334 (146,101,309 bp). The disease locus lies in a 1.9 cM (2.1 Mb) region according to the Rutgers Combined Linkage-Physical map, between a VNTR marker (at 143,988,705 bp) and the telomere (146,274,826 bp). Ten candidate genes were identified based on gene ontology and microarray-facilitated gene selection using the expression of murine orthologues in dental tissue, and examined for the presence of a mutation. However, no causative mutation was identified.

  19. Anomalous superficial radial nerve: a patient with probable autosomal dominant inheritance of the anomaly.

    Science.gov (United States)

    Kuruvilla, Abraham; Laaksonen, Satu; Falck, Björn

    2002-11-01

    The sensory symptoms due to lesions of the superficial branch of the radial nerve are usually limited to the dorsolateral area of the hand. We describe a 40-year-old woman who presented with numbness of the dorsomedial aspect of the right hand following arthroplasty of the wrist. Clinically, the sensory loss suggested a lesion of the dorsal branch of the ulnar nerve. However, nerve conduction studies showed that the sensory loss was due to a lesion of a branch of the superficial branch of the radial nerve. The patient had bilateral, anomalous innervation of the dorsum of the hand-the dorsal branch of the ulnar nerve could not be demonstrated with nerve conduction techniques and the superficial branch of the radial nerve innervated most of the dorsum of the hand. Antidromic stimulation of the dorsal branch of the ulnar nerve and superficial branch of the radial nerve with paired surface recording of sensory nerve action potentials from the dorsolateral (radial side) and dorsomedial (ulnar side) hand is useful for evaluating this anomaly. Our patient had two children, one of them with a similar anomaly. This suggests an autosomal dominant inheritance of the anomaly.

  20. A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene

    Science.gov (United States)

    Meunier, Isabelle; Bocquet, Béatrice; Labesse, Gilles; Zeitz, Christina; Defoort-Dhellemmes, Sabine; Lacroux, Annie; Mauget-Faysse, Martine; Drumare, Isabelle; Gamez, Anne-Sophie; Mathieu, Cyril; Marquette, Virginie; Sagot, Lola; Dhaenens, Claire-Marie; Arndt, Carl; Carroll, Patrick; Remy-Jardin, Martine; Cohen, Salomon Yves; Sahel, José-Alain; Puech, Bernard; Audo, Isabelle; Mrejen, Sarah; Hamel, Christian P.

    2016-01-01

    To revisit the autosomal dominant Sorsby fundus dystrophy (SFD) as a syndromic condition including late-onset pulmonary disease. We report clinical and imaging data of ten affected individuals from 2 unrelated families with SFD and carrying heterozygous TIMP3 mutations (c.572A > G, p.Y191C, exon 5, in family 1 and c.113C > G, p.S38C, exon 1, in family 2). In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma. In the preceding generation, the mother died of pulmonary emphysema and she was blind after the age of 50. Her two great-grandsons (<20 years), had abnormal Bruch Membrane thickness, a sign of eye disease. In family 2, eye and lung diseases were also associated in two generations, both occurred later, and lung disease was moderate (bronchiectasis). This is the first report of a syndromic SFD in line with the mouse model uncovering the role of TIMP3 in human lung morphogenesis and functions. The TIMP3 gene should be screened in familial pulmonary diseases with bronchiectasis, associated with a medical history of visual loss. In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations. PMID:27601084

  1. A novel GJA8 mutation (p.V44A causing autosomal dominant congenital cataract.

    Directory of Open Access Journals (Sweden)

    Yanan Zhu

    Full Text Available To examine the mechanism by which a novel connexin 50 (Cx50 mutation, Cx50 V44A, in a Chinese family causes suture-sparing autosomal dominant congenital nuclear cataracts.Family history and clinical data were recorded and direct gene sequencing was used to identify the disease-causing mutation. The Cx50 gene was cloned from a human lens cDNA library. Connexin protein distributions were assessed by fluorescence microscopy. Hemichannel functions were analyzed by dye uptake assay. Formation of functional channels was assessed by dye transfer experiments.Direct sequencing of the candidate GJA8 gene revealed a novel c.131T>C transition in exon 2, which cosegregated with the disease in the family and resulted in the substitution of a valine residue with alanine at codon 44 (p. V44A in the extracellular loop 1 of the Cx50 protein. Both Cx50 and Cx50V44A formed functional gap junctions, as shown by the neurobiotin transfer assay. However, unlike wild-type Cx50, Cx50V44A was unable to form open hemichannels in dye uptake experiments.This work identified a unique congenital cataract in the Chinese population, caused by the novel mutation Cx50V44A, and it showed that the V44A mutation specifically impairs the gating of the hemichannels but not the gap junction channels. The dysfunctional hemichannels resulted in the development of human congenital cataracts.

  2. A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

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    Yu Zhou

    2016-01-01

    Full Text Available Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC in a Chinese family using next-generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499T

  3. Erythropoietin Slows Photoreceptor Cell Death in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa.

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    Tonia S Rex

    Full Text Available To test the efficacy of systemic gene delivery of a mutant form of erythropoietin (EPO-R76E that has attenuated erythropoietic activity, in a mouse model of autosomal dominant retinitis pigmentosa.Ten-day old mice carrying one copy of human rhodopsin with the P23H mutation and both copies of wild-type mouse rhodopsin (hP23H RHO+/-,mRHO+/+ were injected into the quadriceps with recombinant adeno-associated virus (rAAV carrying either enhanced green fluorescent protein (eGFP or EpoR76E. Visual function (electroretinogram and retina structure (optical coherence tomography, histology, and immunohistochemistry were assessed at 7 and 12 months of age.The outer nuclear layer thickness decreased over time at a slower rate in rAAV.EpoR76E treated as compared to the rAAV.eGFP injected mice. There was a statistically significant preservation of the electroretinogram at 7, but not 12 months of age.Systemic EPO-R76E slows death of the photoreceptors and vision loss in hP23H RHO+/-,mRHO+/+ mice. Treatment with EPO-R76E may widen the therapeutic window for retinal degeneration patients by increasing the number of viable cells. Future studies might investigate if co-treatment with EPO-R76E and gene replacement therapy is more effective than gene replacement therapy alone.

  4. A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia

    Science.gov (United States)

    Mencacci, Niccolo E.; Rubio-Agusti, Ignacio; Zdebik, Anselm; Asmus, Friedrich; Ludtmann, Marthe H.R.; Ryten, Mina; Plagnol, Vincent; Hauser, Ann-Kathrin; Bandres-Ciga, Sara; Bettencourt, Conceição; Forabosco, Paola; Hughes, Deborah; Soutar, Marc M.P.; Peall, Kathryn; Morris, Huw R.; Trabzuni, Daniah; Tekman, Mehmet; Stanescu, Horia C.; Kleta, Robert; Carecchio, Miryam; Zorzi, Giovanna; Nardocci, Nardo; Garavaglia, Barbara; Lohmann, Ebba; Weissbach, Anne; Klein, Christine; Hardy, John; Pittman, Alan M.; Foltynie, Thomas; Abramov, Andrey Y.; Gasser, Thomas; Bhatia, Kailash P.; Wood, Nicholas W.

    2015-01-01

    Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%–50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D. PMID:25983243

  5. A novel OPA1 mutation in a Chinese family with autosomal dominant optic atrophy

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    Zhang, Juanjuan; Yuan, Yimin; Lin, Bing; Feng, Hao; Li, Yan [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Dai, Xianning; Zhou, Huihui [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China); Dong, Xujie [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Liu, Xiao-Ling, E-mail: lxl@mail.eye.ac.cn [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Guan, Min-Xin, E-mail: min-xin.guan@cchmc.org [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China); Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang 310012 (China); Division of Human Genetics, Cincinnati Children' s Hospital Medical Center, OH 45229 (United States)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer We report the characterization of a four-generation large Chinese family with ADOA. Black-Right-Pointing-Pointer We find a new heterozygous mutation c.C1198G in OPA1 gene which may be a novel pathogenic mutation in this pedigree. Black-Right-Pointing-Pointer We do not find any mitochondrial DNA mutations associated with optic atrophy. Black-Right-Pointing-Pointer Other factors may also contribute to the phenotypic variability of ADOA in this pedigree. -- Abstract: A large four-generation Chinese family with autosomal dominant optic atrophy (ADOA) was investigated in the present study. Eight of the family members were affected in this pedigree. The affected family members exhibited early-onset and progressive visual impairment, resulting in mild to profound loss of visual acuity. The average age-at-onset was 15.9 years. A new heterozygous mutation c.C1198G was identified by sequence analysis of the 12th exon of the OPA1 gene. This mutation resulted in a proline to alanine substitution at codon 400, which was located in an evolutionarily conserved region. This missense mutation in the GTPase domain was supposed to result in a loss of function for the encoded protein and act through a dominant negative effect. No other mutations associated with optic atrophy were found in our present study. The c.C1198G heterozygous mutation in the OPA1 gene may be a novel key pathogenic mutation in this pedigree with ADOA. Furthermore, additional nuclear modifier genes, environmental factors, and psychological factors may also contribute to the phenotypic variability of ADOA in this pedigree.

  6. Autosomal dominant pseudohypoaldosteronism type 1 with a novel splice site mutation in MR gene

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    Kaito Hiroshi

    2009-11-01

    Full Text Available Abstract Background Autosomal dominant pseudohypoaldosteronism type 1 (PHA1 is a rare inherited condition that is characterized by renal resistance to aldosterone as well as salt wasting, hyperkalemia, and metabolic acidosis. Renal PHA1 is caused by mutations of the human mineralcorticoid receptor gene (MR, but it is a matter of debate whether MR mutations cause mineralcorticoid resistance via haploinsufficiency or dominant negative mechanism. It was previously reported that in a case with nonsense mutation the mutant mRNA was absent in lymphocytes because of nonsense mediated mRNA decay (NMD and therefore postulated that haploinsufficiency alone can give rise to the PHA1 phenotype in patients with truncated mutations. Methods and Results We conducted genomic DNA analysis and mRNA analysis for familial PHA1 patients extracted from lymphocytes and urinary sediments and could detect one novel splice site mutation which leads to exon skipping and frame shift result in premature termination at the transcript level. The mRNA analysis showed evidence of wild type and exon-skipped RT-PCR products. Conclusion mRNA analysis have been rarely conducted for PHA1 because kidney tissues are unavailable for this disease. However, we conducted RT-PCR analysis using mRNA extracted from urinary sediments. We could demonstrate that NMD does not fully function in kidney cells and that haploinsufficiency due to NMD with premature termination is not sufficient to give rise to the PHA1 phenotype at least in this mutation of our patient. Additional studies including mRNA analysis will be needed to identify the exact mechanism of the phenotype of PHA.

  7. Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population.

    Science.gov (United States)

    Alex, Livy; Chahil, Jagdish Kaur; Lye, Say Hean; Bagali, Pramod; Ler, Lian Wee

    2012-06-01

    Hypercholesterolemia is caused by different interactions of lifestyle and genetic determinants. At the genetic level, it can be attributed to the interactions of multiple polymorphisms, or as in the example of familial hypercholesterolemia (FH), it can be the result of a single mutation. A large number of genetic markers, mostly single nucleotide polymorphisms (SNP) or mutations in three genes, implicated in autosomal dominant hypercholesterolemia (ADH), viz APOB (apolipoprotein B), LDLR (low density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9), have been identified and characterized. However, such studies have been insufficiently undertaken specifically in Malaysia and Southeast Asia in general. The main objective of this study was to identify ADH variants, specifically ADH-causing mutations and hypercholesterolemia-associated polymorphisms in multiethnic Malaysian population. We aimed to evaluate published SNPs in ADH causing genes, in this population and to report any unusual trends. We examined a large number of selected SNPs from previous studies of APOB, LDLR, PCSK9 and other genes, in clinically diagnosed ADH patients (n=141) and healthy control subjects (n=111). Selection of SNPs was initiated by searching within genes reported to be associated with ADH from known databases. The important finding was 137 mono-allelic markers (44.1%) and 173 polymorphic markers (55.8%) in both subject groups. By comparing to publicly available data, out of the 137 mono-allelic markers, 23 markers showed significant differences in allele frequency among Malaysians, European Whites, Han Chinese, Yoruba and Gujarati Indians. Our data can serve as reference for others in related fields of study during the planning of their experiments.

  8. Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia

    Energy Technology Data Exchange (ETDEWEB)

    Hedera, P. [University of Michigan, Department of Neurology, Ann Arbor, MI (United States); Vanderbilt University, Department of Neurology, Nashville, TN (United States); Eldevik, O.P.; Maly, P. [University of Michigan, Department of Radiology, Ann Arbor, MI (United States); Rainier, S. [University of Michigan, Department of Neurology, Ann Arbor, MI (United States); Fink, J.K. [University of Michigan, Department of Neurology, Ann Arbor, MI (United States); Ann Arbor Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center, Ann Arbor, MI (United States)

    2005-10-01

    Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower extremity weakness and spasticity. HSP pathology involves axonal degeneration that is most pronounced in the terminal segments of the longest descending (pyramidal) and ascending (dorsal columns) tracts. In this study, we compared spinal cord magnetic resonance imaging (MRI) in 13 HSP patients with four different types of autosomal dominant hereditary spastic paraplegia (SPG3A, SPG4, SPG6, and SPG8) with age-matched control subjects. The cross-section area of HSP subjects at cervical level C2 was 59.42{+-}12.57 mm{sup 2} and at thoracic level T9 was 28.58{+-}5.25 mm{sup 2}. Both of these values were less than in the healthy controls (p<0.001). The degree of cord atrophy was more prominent in patients with SPG6 and SPG8 who had signs of severe cord atrophy (47.60{+-}6.58 mm{sup 2} at C2, 21.40{+-}2.4 mm{sup 2} at T9) than in subjects with SPG3 and SPG4 (66.0{+-}8.94 mm{sup 2} at C2, p<0.02; 31.75{+-}2.76 mm{sup 2} at T9, p<0.001). These observations indicate that spinal cord atrophy is a common finding in the four genetic types of HSP. Spinal cord atrophy was more severe in SPG6 and SPG8 HSP subjects than in other types of HSP we studied. This may suggest a different disease mechanism with more prominent axonal degeneration in these two types of HSP when compared with HSP due to spastin and atlastin mutations. (orig.)

  9. Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia.

    Science.gov (United States)

    Vaca, Gerardo; Vàzquez, Alejandra; Magaña, Marìa Teresa; Ramìrez, Marìa Lourdes; Dàvalos, Ingrid P; Martìnez, Esperanza; Marìn, Bertha; Carrillo, Gabriela

    2011-10-01

    The goal of this project was to identify families with autosomal dominant hypercholesterolemia (ADH) to facilitate early detection and treatment and to provide genetic counselling as well as to approximate the mutational diversity of ADH in Mexico. Mutational analysis of the LDLR and APOB genes in 62 index cases with a clinical and/or biochemical diagnosis of ADH was performed. Twenty-five mutations (24 LDLR, 1 APOB) were identified in 38 index cases. A total of 162 individuals with ADH were identified using familial segregation analysis performed in 269 relatives of the index cases. In addition, a novel PCSK9 mutation, c.1850 C>A (p.Ala617Asp), was detected. The LDLR mutations showed the following characteristics: (1) four mutations are novel: c.695 -1G>T, c.1034_1035insA, c.1586 G>A, c.2264_2273del; (2) the most common mutations were c.682 G>A (FH-Mexico), c.1055 G>A (FH-Mexico 2), and c.1090 T>C (FH-Mexico 3); (3) five mutations were identified in 3 or more apparently unrelated probands; (4) three mutations were observed in a true homozygous state; and (5) four index cases were compound heterozygous, and one was a carrier of two mutations in the same allele. These results suggest that, in Mexico, ADH exhibits allelic heterogeneity with 5 relatively common LDLR mutations and that mutations in the APOB gene are not a common cause of ADH. This knowledge is important for the genotype-phenotype correlation and for optimising both cholesterol lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of ADH in Mexico.

  10. The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy.

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    Andrea eBecchetti

    2015-02-01

    Full Text Available Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE is a focal epilepsy with attacks typically arising in the frontal lobe during non rapid eye movement (NREM sleep. It is characterized by clusters of complex and stereotyped hypermotor seizures, frequently accompanied by sudden arousals. Cognitive and psychiatric symptoms may be also observed. Approximately 12% of the ADNFLE families carry mutations on genes coding for subunits of the heteromeric neuronal nicotinic receptors (nAChRs. This is consistent with the widespread expression of these receptors, particularly the α4β2* subtype, in the neocortex and thalamus. However, understanding how mutant nAChRs lead to partial frontal epilepsy is far from being straightforward because of the complexity of the cholinergic regulation in both developing and mature brains. The relation with the sleep-waking cycle must be also explained. We discuss some possible pathogenetic mechanisms in the light of recent advances about the nAChR role in prefrontal regions as well as the studies carried out in murine models of ADNFLE. Functional evidence points to alterations in prefrontal GABA release, and the synaptic unbalance probably arises during the cortical circuit maturation. Although most of the available functional evidence concerns mutations on nAChR subunit genes, other genes have been recently implicated in the disease, such as KCNT1 (coding for a Na+-dependent K+ channel, DEPD5 (Dishevelled, Egl-10 and Pleckstrin Domain-containing protein 5, and CRH (Corticotropin-Releasing Hormone. Overall, the uncertainties about both the etiology and the pathogenesis of ADNFLE point to the current gaps in our knowledge the regulation of neuronal networks in the cerebral cortex.

  11. Clinical aspects of an autosomal dominantly inherited hearing impairment linked to the DFNA60 locus on chromosome 2q23.1-2q23.3

    NARCIS (Netherlands)

    Beelen, E. van; Schraders, M.; Huygen, P.L.M.; Oostrik, J.; Plantinga, R.F.; Drunen, W.J. van; Collin, R.W.J.; Kooper, D.P.; Pennings, R.J.E.; Cremers, C.W.R.J.; Kremer, H.; Kunst, H.P.M.

    2013-01-01

    A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region w

  12. Retinal vessel diameters decrease with macular ganglion cell layer thickness in autosomal dominant optic atrophy and in healthy subjects

    DEFF Research Database (Denmark)

    Rönnbäck, Cecilia; Grønskov, Karen; Larsen, Michael

    2014-01-01

    PURPOSE: To investigate retinal trunk vessel diameters in subjects with autosomal dominant optic atrophy (ADOA) and mutation-free healthy relatives. METHODS: This cross-sectional study included 52 ADOA patients with the optic atrophy 1 (OPA1) exon 28 (c.2826_2836delinsGGATGCTCCA) mutation (age 8....... are a consequence rather than the cause of inner retinal hypoplasia or atrophy, although longitudinal studies are needed to confirm this hypothesis....

  13. Tinea imbricata: autosomal dominant pattern of susceptibility in a polygamous indigenous family of the Nahuatl zone in Mexico.

    Science.gov (United States)

    Bonifaz, A; Araiza, J; Koffman-Alfaro, Susana; Paredes-Solis, Vanessa; Cuevas-Covarrubias, S; Rivera, M R

    2004-08-01

    We report on 9 confirmed cases of tinea imbricata (Tokelau, infection due to Trichophyton concentricum) out of 16 family members. They had a common mother with three different fathers. The genetic analysis of the family suggests an autosomal dominant pattern of susceptibility. Most cases (8/9) were presented as concentric and lamellar forms. One patient also had onychomycosis due to T. concentricum. Only two out of nine cases had a positive response to trichophytin.

  14. Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype–Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

    OpenAIRE

    Böhm, Johann; Biancalana, Valérie; DeChene, Elizabeth T; Bitoun, Marc; Pierson, Christopher R.; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A.; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S.

    2012-01-01

    Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad ge...

  15. Two novel mutations of CLCN7 gene in Chinese families with autosomal dominant osteopetrosis (type II).

    Science.gov (United States)

    Zheng, Hui; Shao, Chong; Zheng, Yan; He, Jin-Wei; Fu, Wen-Zhen; Wang, Chun; Zhang, Zhen-Lin

    2016-07-01

    Autosomal dominant osteopetrosis type II (ADO-II) is a heritable bone disorder characterized by osteosclerosis, predominantly involving the spine (vertebral end-plate thickening, or rugger-jersey spine), the pelvis ("bone-within-bone" structures) and the skull base. Chloride channel 7 (CLCN7) has been reported to be the causative gene. In this study, we aimed to identify the pathogenic mutation in four Chinese families with ADO-II. All 25 exons of the CLCN7 gene, including the exon-intron boundaries, were amplified and sequenced directly in four probands from the Chinese families with ADO-II. The mutation site was then identified in other family members and 250 healthy controls. In family 1, a known missense mutation c.296A>G in exon 4 of CLCN7 was identified in the proband, resulting in a tyrosine (UAU) to cysteine (UGU) substitution at p.99 (Y99C); the mutation was also identified in his affected father. In family 2, a novel missense mutation c.865G>C in exon 10 was identified in the proband, resulting in a valine (GUC) to leucine (CUC) substitution at p.289 (V289L); the mutation was also identified in her healthy mother and sister. In family 3, a novel missense mutation c.1625C>T in exon 17 of CLCN7 was identified in the proband, resulting in an alanine (GCG) to valine (GUG) substitution at p.542 (A542V); the mutation was also identified in her father. In family 4, a hot spot, R767W (c.2299C>T, CGG>TGG), in exon 24 was found in the proband which once again proved the susceptibility of the site or the similar genetic background in different races. Moreover, two novel mutations, V289L and A542V, occurred at a highly conserved position, found by a comparison of the protein sequences from eight vertebrates, and were predicted to have a pathogenic effect by PolyPhen-2 software, which showed "probably damaging" with a score of approximately 1. These mutation sites were not identified in 250 healthy controls. Our present findings suggest that the novel missense

  16. A novel frameshift mutation of POU4F3 gene associated with autosomal dominant non-syndromic hearing loss

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hee Keun [Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu (Korea, Republic of); Park, Hong-Joon [Soree Ear Clinic, Seoul (Korea, Republic of); Lee, Kyu-Yup [Vestibulocochlear Research Center, College of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Rekil, E-mail: rkpark@wku.ac.kr [Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyungpook National University, Daegu (Korea, Republic of); Kim, Un-Kyung, E-mail: kimuk@knu.ac.kr [Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu (Korea, Republic of)

    2010-06-04

    Autosomal dominant mutations in the transcription factor POU4F3 gene are associated with non-syndromic hearing loss in humans; however, there have been few reports of mutations in this gene worldwide. We performed a mutation analysis of the POU4F3 gene in 42 unrelated Koreans with autosomal dominant non-syndromic hearing loss, identifying a novel 14-bp deletion mutation in exon 2 (c.662del14) in one patient. Audiometric examination revealed severe bilateral sensorineural hearing loss in this patient. The novel mutation led to a truncated protein that lacked both functional POU domains. We further investigated the functional distinction between wild-type and mutant POU4F3 proteins using in vitro assays. The wild-type protein was completely localized in the nucleus, while the truncation of protein seriously affected its nuclear localization. In addition, the mutant failed to activate reporter gene expression. This is the first report of a POU4F3 mutation in Asia, and moreover our data suggest that further investigation will need to delineate ethnicity-specific genetic background for autosomal dominant non-syndromic hearing loss within Asian populations.

  17. External Ocular Manifestations in Autosomal Dominant Dystrophic Epidermolysis Bullosa; a Case Report

    Directory of Open Access Journals (Sweden)

    Manizheh Mahdavi

    2008-11-01

    Full Text Available

    PURPOSE: To present a case of autosomal dominant dystrophic epidermolysis bullosa with symblepharon formation due to eye rubbing. CASE REPORT: A 10-year-old girl suffering from blistering and ulcerative lesions of the trunk and palms and dystrophic nails since childhood was referred to our clinic with a symblepharon connecting the medial portion of the right upper lid to the superonasal quadrant of the cornea. The central cornea in both eyes exhibited mild subepithelial opacification. She had history of eye rubbing due to foreign body sensation in the right eye, resulting in red eye and blister-like conjunctival lesions since three years ago. She had previously undergone surgical symblepharon removal leading to more severe recurrence of the condition. CONCLUSION: Dominant dystrophic epidermolysis bullosa may be accompanied by external ocular manifestations. Protection of the eye from minor trauma such as rubbing may help prevent ocular complications.

  1. Ser217Cys mutation in the Ig Ⅱ domain of FGFR3 in a Chinese family with autosomal dominant achondroplasia

    Institute of Scientific and Technical Information of China (English)

    ZHANG Shi-rong; ZHOU Xiao-qing; REN Xiang; WANG Tian-tian; YUAN Ming-xiong; WANG Qing; LIU Jing-yu; LIU Mu-gen

    2007-01-01

    @@ Achondroplasia (ACH) is the most common form of skeletal dysplasia characterized by disproportionately short stature, lumbar lordosis, relative macrocephaly and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. The combined frequency of the disease has been estimated to be 1 in 15 000 live births.1 ACH is inherited in autosomal dominant fashion with a complete penetrance, more than 80% of affected individuals have de novo mutations associated with increased paternal age.

  2. High Resolution Ultrasonography for Assessment of Renal Cysts in the PCK Rat Model of Autosomal Recessive Polycystic Kidney Disease

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    Sarika Kapoor

    2016-03-01

    Full Text Available Background/Aims: The PCK rat model of polycystic kidney disease is characterized by the progressive development of renal medullary cysts. Here, we evaluated the suitability of high resolution ultrasonography (HRU to assess the kidney and cyst volume in PCK rats, testing three different ultrasound image analysis methods, and correlating them with kidneys weights and histological examinations. Methods: After inducing anesthesia, PCK rats (n=18 were subjected to HRU to visualize the kidneys, to perform numeric and volumetric measurements of the kidney and any cysts observed, and to generate 3-dimensional images of the cysts within the kidney parenchyma. Results: HRU provided superior information in comparison to microscopic analysis of stained kidney sections. HRU-based kidney volumes correlated strongly with kidney weights (R2=0.809; PConclusion: HRU represents a useful diagnostic tool for kidney and cyst volume measurements in PCK rats. Sequential HRU examinations may be useful to study the effect of drugs on cyst growth without the need to euthanize experimental animals.

  3. DGAT2 Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease.

    Science.gov (United States)

    Hong, Young Bin; Kang, Junghee; Kim, Ji Hyun; Lee, Jinho; Kwak, Geon; Hyun, Young Se; Nam, Soo Hyun; Hong, Hyun Dae; Choi, Yu-Ri; Jung, Sung-Chul; Koo, Heasoo; Lee, Ji Eun; Choi, Byung-Ok; Chung, Ki Wha

    2016-05-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and is a genetically and clinically heterogeneous disorder. We examined a Korean family in which two individuals had an autosomal-dominant axonal CMT with early-onset, sensory ataxia, tremor, and slow disease progression. Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O-acyltransferase 2 (DGAT2) gene. DGAT2 encodes an endoplasmic reticulum-mitochondrial-associated membrane protein, acyl-CoA:diacylglycerol acyltransferase, which catalyzes the final step of the triglyceride (TG) biosynthesis pathway. The patient showed consistently decreased serum TG levels, and overexpression of the mutant DGAT2 significantly inhibited the proliferation of mouse motor neuron cells. Moreover, the variant form of human DGAT2 inhibited the axonal branching in the peripheral nervous system of zebrafish. We suggest that mutation of DGAT2 is the novel underlying cause of an autosomal-dominant axonal CMT2 neuropathy. This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies.

  4. Mutation Analysis Identifies GUCY2D as the Major Gene Responsible for Autosomal Dominant Progressive Cone Degeneration

    Science.gov (United States)

    Kitiratschky, Veronique B. D.; Wilke, Robert; Renner, Agnes B.; Kellner, Ulrich; Vadalà, Maria; Birch, David G.; Wissinger, Bernd; Zrenner, Eberhart; Kohl, Susanne

    2017-01-01

    Purpose Heterozygous mutations in the GUCY2D gene, which encodes the membrane-bound retinal guanylyl cyclase-1 protein (RetGC-1), have been shown to cause autosomal dominant inherited cone degeneration and cone–rod degeneration (adCD, adCRD). The present study was a comprehensive screening of the GUCY2D gene in 27 adCD and adCRD unrelated families of these rare disorders. Methods Mutation analysis was performed by direct sequencing as well as PCR and subsequent restriction length polymorphism analysis (PCR/RFLP). Haplotype analysis was performed in selected patients by using microsatellite markers. Results GUCY2D gene mutations were identified in 11 (40%) of 27 patients, and all mutations clustered to codon 838, including two known and one novel missense mutation: p.R838C, p.R838H, and p.R838G. Haplotype analysis showed that among the studied patients only two of the six analyzed p.R838C mutation carriers shared a common haplotype and that none of the p.R838H mutation carriers did. Conclusions GUCY2D is a major gene responsible for progressive autosomal dominant cone degeneration. All identified mutations localize to codon 838. Haplotype analysis indicates that in most cases these mutations arise independently. Thus, codon 838 is likely to be a mutation hotspot in the GUCY2D gene. PMID:18487367

  5. Novel A CTG1 mutation causing autosomal dominant non-syndromic hearing impairment in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Theγ-actin(ACTG1)gene is a cytoplasmic nonmuscle actin gene,which encodes a major cytoskeletal protein in the sensory hair cells of the cochlea.Mutations in ACTG1 were found to cause autosomal dominant,progressive,sensorineural hearing loss linked to the DFNA 20/26 locus on chromosome 17q25.3 in European and American families,respectively.In this study,a novel missense mutation (c.364A>G;p.I122V)co-segregated with the affected individuals in the family and did not exist in the unaffected family members and 150 unrelated normal controls.The alteration of residue I1e122 was predicted to damage its interaction with actin-binding proteins,which may cause disruption of hair cell organization and function.These findings strongly suggested that the I122V mutation in ACTG1 caused autosomal dominant non-syndromic hearing impairment in a Chinese family and expanded the spectrum of ACTG1 mutations causing hearing loss.

  6. An unusual case of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy with occipital lobe involvement

    Directory of Open Access Journals (Sweden)

    Bhavesh Trikamji

    2016-01-01

    Full Text Available Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL is an autosomal dominant angiopathy caused by a mutation in the notch 3 gene on chromosome 19. Clinically, patients may be asymptomatic or can present with recurrent ischemic episodes and strokes leading to dementia, depression, pseudobulbar palsy, and hemi- or quadraplegia. Additional manifestations that have been described include migraine (mostly with aura, psychiatric disturbances, and epileptic seizures. Neuroimaging is essential to the diagnosis of CADASIL. On imaging CADASIL is characterized by symmetric involvement by confluent lesions located subcortically in the frontal and temporal lobes as well as in the insula, periventricularly, in the centrum semiovale, in the internal and external capsule, basal ganglia, and brain stem; with relative sparing of the fronto-orbital and the occipital subcortical regions. We describe a 49 year old male with CADASIL with absence of temporal lobe findings on MRI but predominant lesions within the periventricular white matter, occipital lobes with extension into the subcortical frontal lobes, corpus callosum and cerebellar white matter. Although CADASIL characteristically presents with anterior temporal lobe involvement, these findings may be absent and our case addresses the atypical imaging findings in CADASIL.

  7. A novel mutation in the TECTA gene in a Chinese family with autosomal dominant nonsyndromic hearing loss.

    Directory of Open Access Journals (Sweden)

    Yu Su

    Full Text Available TECTA-related deafness can be inherited as autosomal-dominant nonsyndromic deafness (designated DFNA or as the autosomal-recessive version. The α-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Using targeted DNA capture and massively parallel sequencing (MPS, we screened 42 genes known to be responsible for human deafness in a Chinese family (Family 3187 in which common deafness mutations had been ruled out as the cause, and identified a novel mutation, c.257-262CCTTTC>GCT (p. Ser86Cys; p. Pro88del in exon 3 of the TECTA gene in the proband and his extended family. All affected individuals in this family had moderate down-sloping hearing loss across all frequencies. To our knowledge, this is the second TECTA mutation identified in Chinese population. This study demonstrates that targeted genomic capture, MPS, and barcode technology might broaden the availability of genetic testing for individuals with undiagnosed DFNA.

  8. Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

    Science.gov (United States)

    Bichet, Daniel G; Bockenhauer, Detlef

    2016-03-01

    Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration.

  9. Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta

    Directory of Open Access Journals (Sweden)

    Sandra Gutiérrez

    2012-01-01

    Full Text Available In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI. 22 individuals (15 affected and seven unaffected belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates.

  10. Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta.

    Science.gov (United States)

    Gutiérrez, Sandra; Torres, Diana; Briceño, Ignacio; Gómez, Ana Maria; Baquero, Eliana

    2012-07-01

    In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI). 22 individuals (15 affected and seven unaffected) belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected) belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI) that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates.

  11. Initial evaluation of hepatic T1 relaxation time as an imaging marker of liver disease associated with autosomal recessive polycystic kidney disease (ARPKD).

    Science.gov (United States)

    Gao, Ying; Erokwu, Bernadette O; DeSantis, David A; Croniger, Colleen M; Schur, Rebecca M; Lu, Lan; Mariappuram, Jose; Dell, Katherine M; Flask, Chris A

    2016-01-01

    Autosomal recessive polycystic kidney disease (ARPKD) is a potentially lethal multi-organ disease affecting both the kidneys and the liver. Unfortunately, there are currently no non-invasive methods to monitor liver disease progression in ARPKD patients, limiting the study of potential therapeutic interventions. Herein, we perform an initial investigation of T1 relaxation time as a potential imaging biomarker to quantitatively assess the two primary pathologic hallmarks of ARPKD liver disease: biliary dilatation and periportal fibrosis in the PCK rat model of ARPKD. T1 relaxation time results were obtained for five PCK rats at 3 months of age using a Look-Locker acquisition on a Bruker BioSpec 7.0 T MRI scanner. Six three-month-old Sprague-Dawley (SD) rats were also scanned as controls. All animals were euthanized after the three-month scans for histological and biochemical assessments of bile duct dilatation and hepatic fibrosis for comparison. PCK rats exhibited significantly increased liver T1 values (mean ± standard deviation = 935 ± 39 ms) compared with age-matched SD control rats (847 ± 26 ms, p = 0.01). One PCK rat exhibited severe cholangitis (mean T1  = 1413 ms), which occurs periodically in ARPKD patients. The observed increase in the in vivo liver T1 relaxation time correlated significantly with three histological and biochemical indicators of biliary dilatation and fibrosis: bile duct area percent (R = 0.85, p = 0.002), periportal fibrosis area percent (R = 0.82, p = 0.004), and hydroxyproline content (R = 0.76, p = 0.01). These results suggest that hepatic T1 relaxation time may provide a sensitive and non-invasive imaging biomarker to monitor ARPKD liver disease.

  12. The aquaporin-2 water channel in autosomal dominant primary nocturnal enuresis.

    NARCIS (Netherlands)

    Deen, P.M.T.; Dahl, N.; Caplan, M.J.

    2002-01-01

    PURPOSE: Nocturnal enuresis is one of the most common diagnoses in a pediatric clinic. Recently, linkage analysis revealed a 2-point lod score of 4.2 in 6 families with dominant primary nocturnal enuresis around the aquaporin-2 (AQP2) water channel locus. Since primary nocturnal enuresis is ameliora

  13. The R1947X mutation of NF1 causing autosomal dominant neurofibromatosis type 1 in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    Qinbo Yang; Changzheng Huang; Xiaoying Yang; Yinfu Feng; Qing Wang; Mugen Liu

    2008-01-01

    Neurofibromatosis type 1 is a common autosomal dominant disorder with a high rate of penetrance. It is caused by the mutation of the tumor suppressor gene NF1, which encodes neurofibromin. The main function of neurofibromin is down-regulating the biological activity of the proto-oncoprotein Ras by acting as a Ras-specific GTPase activating protein. In this study, we identified a Chinese family affected with neurofibromatosis type 1. The known gene NF1 associated with NF1 was studied by linkage analysis and by direct sequencing of the entire coding region and exon-intron boundaries of the NF1 gene. The R1947X mutation of NF1 was identified, which was co-segregated with affected individuals in the Chinese family, but not present in unaffected family members. This is the first report, which states that the R1947X mutation of NF1 may be one of reasons for neurofibromatosis type 1 in Chinese population.

  14. Novel LDB3 Mutation in a Patient With Autosomal Dominant Myofibrillar Myopathy

    OpenAIRE

    2016-01-01

    Introduction Myofibrillar myopathy (MFM) is a rare human disease, characterized by a distinct histopathological pattern of myofibrillar degeneration and protein aggregates. LDB3 protein encoded by this gene is a key Z-disk protein that interacts with α-actinin and protein kinase C. Case Presentation In this paper, we identified the novel heterozygous, and hence, dominant mutation in the LIM domain-binding protein 3 gene (LDB3) in ...

  15. Autosomal dominant mesomandibular fibro-osseous dysplasia: a self-resolving inherited fibro-osseous lesion of the jaws.

    Science.gov (United States)

    Koutlas, Ioannis G; Forsman, Cynthia L; Kyrkanides, Stephanos; Oetting, William S; Petryk, Anna

    2012-01-01

    A hereditary congenital condition characterized by a fibro-osseous lesion sharing some features with fibrous dysplasia and affecting the middle aspect of the mandible is presented. The condition was initially described as congenital monostotic fibrous dysplasia in two siblings, a male and a female. However, there is sufficient evidence that the disorder is autosomal dominant since it has been encountered in two of four children, both males, of the female propositus and one child, a boy, of the male propositus. All patients presented at birth or right after birth with enlargement of the middle part of the mandible. Radiographs from affected individuals have shown mesomandibular enlargement with irregular trabeculation akin of "ground-glass" appearance. Histologically, samples from all patients revealed woven bone proliferation in a cellular fibroblastic stroma. Interestingly, the originally described siblings, now in their 30s, have no evidence of jaw lesions either radiographically or clinically, thus indicating that the condition is self-limiting or self-resolving. An autosomal dominant mode of inheritance with apparent male predilection is favored. The molecular basis of this condition is currently unknown. However, the location of the lesions in the middle aspect of the mandible suggests dysregulation of Bone Morphogenetic Protein (BMP) signaling since BMPs regulate mandibular morphogenesis in utero, particularly in the medial region as well as postnatal bone remodeling. Immunohistochemical evaluation for a BMP-binding protein Twisted Gastrulation (TWSG1) revealed mosaic pattern of staining, with some cells, including osteoclasts, strongly stained and others exhibiting faint or no staining, thus supporting active regulation of BMP signaling within the lesion. Future investigations will determine if dysregulation of BMP signaling plays a causative role or rather reflects secondary activation of repair mechanisms and/or bone remodeling.

  16. Autosomal dominant mesomandibular fibro-osseous dysplasia: a self-resolving inherited fibro-osseous lesion of the jaws

    Directory of Open Access Journals (Sweden)

    Ioannis eKoutlas

    2012-12-01

    Full Text Available A hereditary congenital condition characterized by a fibro-osseous lesion sharing some features with fibrous dysplasia and affecting the middle aspect of the mandible is presented. The condition was initially described as congenital monostotic fibrous dysplasia in two siblings, a male and a female. However, there is sufficient evidence that the disorder is autosomal dominant since it has been encountered in two of four children, both males, of the female propositus and one child, a boy, of the male propositus. All patients presented at birth or right after birth with enlargement of the middle part of the mandible. Radiographs from affected individuals have shown mesomandibular enlargement with irregular trabeculation akin of ground-glass appearance. Histologically, samples from all patients revealed woven bone proliferation in a cellular fibroblastic stroma. Interestingly, the originally described siblings, now in their 30s, have no evidence of jaw lesions either radiographically or clinically, thus indicating that the condition is self-limiting or self-resolving. An autosomal dominant mode of inheritance with apparent male predilection is favored. The molecular basis of this condition is currently unknown. However, the location of the lesions in the middle aspect of the mandible suggests dysregulation of Bone Morphogenetic Protein signaling since BMPs regulate mandibular morphogenesis in utero, particularly in the medial region as well as postnatal bone remodeling. Immunohistochemical evaluation for a BMP-binding protein Twisted Gastrulation revealed mosaic pattern of staining, with some cells, including osteoclasts, strongly stained and others exhibiting faint or no staining, thus supporting active regulation of BMP signaling within the lesion. Future investigations will determine if dysregulation of BMP signaling plays a causative role or rather reflects secondary activation of repair mechanisms and/or bone remodeling.

  17. Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.

    Science.gov (United States)

    Ajroud-Driss, Senda; Fecto, Faisal; Ajroud, Kaouther; Lalani, Irfan; Calvo, Sarah E; Mootha, Vamsi K; Deng, Han-Xiang; Siddique, Nailah; Tahmoush, Albert J; Heiman-Patterson, Terry D; Siddique, Teepu

    2015-01-01

    Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5% of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.

  18. Sodium pump distribution is not reversed in the DBA/2FG-pcy, polycystic kidney disease model mouse.

    Science.gov (United States)

    Kawa, G; Nagao, S; Yamamoto, A; Omori, K; Komatz, Y; Takahashi, H; Tashiro, Y

    1994-06-01

    Recently, it has been reported that Na,K-ATPase in the renal epithelia of human autosomal dominant polycystic kidney disease and cpk mouse, a murine model of autosomal recessive polycystic kidney disease, mislocates to apical plasma membrane and that mislocated Na,K-ATPase causes the cyst formation. Whether the DBA/2FG-pcy mice, which are presumably a suitable model for autosomal dominant polycystic kidney disease, also exhibit the reversal polarity of Na,K-ATPase localization was examined. Kidneys of newborn DBA/2FG-pcy mice, and those at early and late stages of cyst development were examined by immunohistochemical techniques. At any stage, abnormal distribution of Na,K-ATPase on the apical membranes of tubular epithelial cells could not be detected. It is suggested that cysts can be formed without reversed polarity of Na,K-ATPase distribution in pcy mice.

  19. Impaired cleavage of preproinsulin signal peptide linked to autosomal-dominant diabetes.

    Science.gov (United States)

    Liu, Ming; Lara-Lemus, Roberto; Shan, Shu-ou; Wright, Jordan; Haataja, Leena; Barbetti, Fabrizio; Guo, Huan; Larkin, Dennis; Arvan, Peter

    2012-04-01

    Recently, missense mutations upstream of preproinsulin's signal peptide (SP) cleavage site were reported to cause mutant INS gene-induced diabetes of youth (MIDY). Our objective was to understand the molecular pathogenesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production to examine the earliest events of insulin biosynthesis, highlighting molecular mechanisms underlying β-cell failure plus a novel strategy that might ameliorate the MIDY syndrome. We find that whereas preproinsulin-A(SP23)S is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is inefficiently cleaved at an improper site, producing two subpopulations of molecules. Both show impaired oxidative folding and are retained in the endoplasmic reticulum (ER). Preproinsulin-A(SP24)D also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavior. Upon increased expression of ER-oxidoreductin-1, preproinsulin-A(SP24)D remains blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and increasing wild-type insulin production. We conclude that the efficiency of SP cleavage is linked to the oxidation of (pre)proinsulin. In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as well as that of coexpressed wild-type proinsulin. Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin production in patients with MIDY.

  20. Two pedigrees of autosomal dominant atrioventricular canal defect (AVCD): Exclusion from the critical region on 8p

    Energy Technology Data Exchange (ETDEWEB)

    Amati, F.; Mari, A.; Mingarelli, R. [Universita Tor Vergata, Rome (Italy)] [and others

    1995-07-03

    Atrioventricular canal defects (AVCD) constitute the predominant congenital heart defect in Down`s syndrome. For this reason, a candidate gene involved in atrioventricular canal development was previously searched and excluded in dominant pedigrees of AVCD, using linkage analysis of polymorphisms from chromosome 21. Because of the striking association between 8p deletion and AVCD, a search for an AVCD gene was carried out in two pedigrees of individuals with autosomal dominant AVCD using a set of DNA markers of the 8pter{r_arrow}q12 region. These two families include affected individuals and subjects who have transmitted the defect but are not clinically affected. Two-point lod scores were significantly negative for all markers at penetrance levels of 90% and 50%. Multipoint analysis excluded the region covered by the markers LPL-D8S262 and 30 cM to either side of this area. This result corroborates heterogeneity of this heart defect and indicates that the genetic basis of familial AVCD is different from AVCD associated to either trisomy 21 or 8p deletion. 25 refs., 3 figs., 2 tabs.

  1. A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin. Addendum

    Science.gov (United States)

    2014-07-01

    a tight-fitting Dounce homogenizer, chilled on ice for 10 min, and then rotated for 15 min. Nonidet P - 40 was added to a final concentration of 1...Biol. 2011;7(10):701-11. 40 . Jaakkola P , Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, et...counted from each of n=6 mice) in comparison to 10.6±3.6% s.e.m. (450 cells counted from each of n=4 mice) in metformin-treated mice ( p ɘ.0074). To

  2. Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease: The TEMPO 3:4 Clinical Trial

    Directory of Open Access Journals (Sweden)

    Maria V. Irazabal

    2016-11-01

    Discussion: Prognostic enrichment strategies such as the entry criteria used for TEMPO 3:4 or preferably the proposed image classification should be used in RCTs for ADPKD to increase power and to reduce cost.

  3. Diagnosis and management of polycystic liver disease.

    Science.gov (United States)

    Gevers, Tom J G; Drenth, Joost P H

    2013-02-01

    Polycystic liver disease (PLD) is arbitrarily defined as a liver that contains >20 cysts. The condition is associated with two genetically distinct diseases: as a primary phenotype in isolated polycystic liver disease (PCLD) and as an extrarenal manifestation in autosomal dominant polycystic kidney disease (ADPKD). Processes involved in hepatic cystogenesis include ductal plate malformation with concomitant abnormal fluid secretion, altered cell-matrix interaction and cholangiocyte hyperproliferation. PLD is usually a benign disease, but can cause debilitating abdominal symptoms in some patients. The main risk factors for growth of liver cysts are female sex, exogenous oestrogen use and multiple pregnancies. Ultrasonography is very useful for achieving a correct diagnosis of a polycystic liver and to differentiate between ADPKD and PCLD. Current radiological and surgical therapies for symptomatic patients include aspiration-sclerotherapy, fenestration, segmental hepatic resection and liver transplantation. Medical therapies that interact with regulatory mechanisms controlling expansion and growth of liver cysts are under investigation. Somatostatin analogues are promising; several clinical trials have shown that these drugs can reduce the volume of polycystic livers. The purpose of this Review is to provide an update on the diagnosis and management of PLD with a focus on literature published in the past 4 years.

  4. Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5.

    Directory of Open Access Journals (Sweden)

    Nellie Y Loh

    Full Text Available Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1. Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5 and 6 (Trpv6 genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P. Compared to wild-type littermates, heterozygous (Trpv5(682P/+ and homozygous (Trpv5(682P/682P mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ∼10% of males developed tubulointerstitial nephritis. Trpv5(682P/682P mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D(3 concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5(682P/+ and Trpv5(682P/682P mice consistent with a trafficking defect. In addition, Trpv5(682P/682P mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D(28K, consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings

  5. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3

    NARCIS (Netherlands)

    Verbeek, D S; van de Warrenburg, B P; Wesseling, P; Pearson, P L; Kremer, H P; Sinke, R J

    2004-01-01

    We report upon a Dutch autosomal dominant cerebellar ataxia (ADCA) family, clinically characterized by a late-onset (>40 years), slowly progressive, isolated spinocerebellar ataxia (SCA). Neuropathological examination in one affected subject showed neuronal loss in the Purkinje cell layer, dentate n

  6. Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia

    NARCIS (Netherlands)

    Bolar, N.A.; Golzio, C.; Zivna, M.; Hayot, G.; Hemelrijk, C. van; Schepers, D.; Vandeweyer, G.; Hoischen, A.; Huyghe, J.R.; Raes, A.; Matthys, E.; Sys, E.; Azou, M.; Gubler, M.C.; Praet, M.; Van Camp, G.; McFadden, K.; Pediaditakis, I.; Pristoupilova, A.; Hodanova, K.; Vyletal, P.; Hartmannova, H.; Stranecky, V.; Hulkova, H.; Baresova, V.; Jedlickova, I.; Sovova, J.; Hnizda, A.; Kidd, K.; Bleyer, A.J.; Spong, R.S.; Vande Walle, J.; Mortier, G.; Brunner, H.; Van Laer, L.; Kmoch, S.; Katsanis, N.; Loeys, B.L.

    2016-01-01

    Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are respon

  7. Genetic heterogeneity in adult dominant polycystic kidney disease in Cypriot families.

    Science.gov (United States)

    Constantinou-Deltas, C D; Papageorgiou, E; Boteva, K; Christodoulou, K; Breuning, M H; Peter, D J; Pierides, A

    1995-04-01

    Polycystic kidney disease is an inherited heterogeneous disorder that affects approximately 1:1000 Europeans. It is characterized mainly by the formation of cysts in the kidney that lead to end-stage renal failure with late age of onset. Three loci have been identified, PKD1 on the short arm of chromosome 16, which has recently been isolated and characterized, PKD2 on the long arm of chromosome 4, and a third locus of unknown location, that is apparently much rarer. In families that transmit the PKD2 gene there is a significantly later age of onset of symptoms, compared with families that transmit the PKD1 gene, and in general they present with milder progression of symptomatology. For the first time we attempted molecular genetic analysis in seven Cypriot families using highly polymorphic markers around the PKD1 and PKD2 genes. Our data showed that there is genetic and phenotypic heterogeneity among these families. For four of the families we obtained strong evidence for linkage to the PKD1 locus. In two of these families linkage to PKD1 was strengthened by excluding linkage to PKD2 with the use of marker D4S423. In three other families we showed linkage to the PKD2 locus. In the largest of these families one recombinant placed marker D4S1534 distal to D4S231, thereby rendering it the closest proximal marker known to us to date. The application of molecular methods allowed us to make presymptomatic diagnosis for a number of at-risk individuals.

  8. High-Resolution En Face Images of Microcystic Macular Edema in Patients with Autosomal Dominant Optic Atrophy

    Directory of Open Access Journals (Sweden)

    Kiyoko Gocho

    2013-01-01

    Full Text Available The purpose of this study was to investigate the characteristics of microcystic macular edema (MME determined from the en face images obtained by an adaptive optics (AO fundus camera in patients with autosomal dominant optic atrophy (ADOA and to try to determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL by using the advantage of AO. Six patients from 4 families with ADOA underwent detailed ophthalmic examinations including spectral domain optical coherence tomography (SD-OCT. Mutational screening of all coding and flanking intron sequences of the OPA1 gene was performed by DNA sequencing. SD-OCT showed a severe reduction in the retinal nerve fiber layer (RNFL thickness in all patients. A new splicing defect and two new frameshift mutations with premature termination of the Opa1 protein were identified in three families. A reported nonsense mutation was identified in one family. SD-OCT of one patient showed MME in the inner nuclear layer (INL of the retina. AO images showed microcysts in the en face images of the INL. Our data indicate that AO is a useful method to identify MME in neurodegenerative diseases and may also help determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL.

  9. Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia.

    Science.gov (United States)

    Si-Tayeb, Karim; Idriss, Salam; Champon, Benoite; Caillaud, Amandine; Pichelin, Matthieu; Arnaud, Lucie; Lemarchand, Patricia; Le May, Cédric; Zibara, Kazem; Cariou, Bertrand

    2016-01-01

    Proprotein convertase subtilisin kexin type 9 (PCSK9) is a critical modulator of cholesterol homeostasis. Whereas PCSK9 gain-of-function (GOF) mutations are associated with autosomal dominant hypercholesterolemia (ADH) and premature atherosclerosis, PCSK9 loss-of-function (LOF) mutations have a cardio-protective effect and in some cases can lead to familial hypobetalipoproteinemia (FHBL). However, limitations of the currently available cellular models preclude deciphering the consequences of PCSK9 mutation further. We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL. To achieve our goal, urine-sample-derived somatic cells were reprogrammed into hiPSCs by using episomal vectors. UhiPSC were efficiently differentiated into hepatocyte-like cells (HLCs). Compared to control cells, cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (Pcells originally derived from an individual with FHBL (HLC-R104C/V114A) displayed a strong decrease in PCSK9 secretion (-89.7%; Pcells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function.

  10. Type II autosomal dominant osteopetrosis: radiological features in two families containing five members with asymptomatic and uncomplicated disease

    Energy Technology Data Exchange (ETDEWEB)

    Fotiadou, Anastasia; Kiriakou, Vera; Tsitouridis, Ioannis [Papageorgiou Hospital, Radiology Department, Thessaloniki (Greece); Arvaniti, Maria [Genimatas Hospital, Radiology Department, Thessaloniki (Greece)

    2009-10-15

    In this study we analysed the imaging patterns in two families containing five members with asymptomatic and uncomplicated autosomal dominant osteopetrosis (ADO II), and we report new and uncommon radiological manifestations. These findings might be useful in the context of reducing the incidence of fractures and other orthopaedic complications. Diffuse pelvic sclerosis on radiographs was observed incidentally in two patients. Both cases were asymptomatic, and the patients had never suffered a fracture. The suggestion of ADO II was raised. A detailed medical history, an imaging survey, and a haematological study were obtained so that other rare causes of osteosclerosis could be ruled out. No genetic study was conducted. All their first-degree relatives were also examined. Bony sclerosis was observed in five patients, and the radiological findings were analysed. A not previously reported thickening of the skull base without cranial nerve palsy or optic nerve atrophy was revealed in all patients. Scoliosis was present in three of them. This has been reported previously only once in ADO II. No lower limb deformity was detected. This study provided information on the pattern of radiological features in familial asymptomatic ADO II. These data on new and rare imaging findings will increase the diagnostic awareness of physicians and will guide a thorough investigation of the entire family. This might result in a consequent decrease in the incidence of fractures and other orthopaedic complications. (orig.)

  11. Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes–Brocks Syndrome

    Science.gov (United States)

    Webb, Bryn D.; Metikala, Sanjeeva; Wheeler, Patricia G.; Sherpa, Mingma D.; Houten, Sander M.; Horb, Marko E.; Schadt, Eric E.

    2017-01-01

    A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419* variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419* protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes–Brocks syndrome. PMID:28054444

  12. Mitochondrial oxidative phosphorylation compensation may preserve vision in patients with OPA1-linked autosomal dominant optic atrophy.

    Science.gov (United States)

    Van Bergen, Nicole J; Crowston, Jonathan G; Kearns, Lisa S; Staffieri, Sandra E; Hewitt, Alex W; Cohn, Amy C; Mackey, David A; Trounce, Ian A

    2011-01-01

    Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.

  13. A ninth locus (RP18) for autosomal dominant retinitis pigmentosa maps in the pericentromeric region of chromosome 1.

    Science.gov (United States)

    Xu, S Y; Schwartz, M; Rosenberg, T; Gal, A

    1996-08-01

    We studied a large Danish family of seven generations in which autosomal dominant retinitis pigmentosa (adRP), a heterogeneous genetic form of retinal dystrophy, was segregating. After linkage had been excluded to all known adRP loci on chromosomes 3q, 6p, 7p, 7q, 8q, 17p, 17q and 19q, a genome screening was performed. Positive lod scores suggestive of linkage with values ranging between Z = 1.58-5.36 at theta = 0.04-0.20 were obtained for eight loci on proximal 1p and 1q. Close linkage without recombination and a maximum lod score of 7.22 at theta = 0.00 was found between the adRP locus (RP18) in this family and D1S498 which is on 1q very near the centromere. Analysis of multiply informative meioses suggests that in this family D1S534 and D1S305 flank RP18 in interval 1p13-q23. No linkage has been found to loci from this chromosomal region in six other medium sized adRP families in which the disease locus has been excluded from all known chromosomal regions harbouring an adRP gene or locus suggesting that there is (at least) one further adRP locus to be mapped in the future.

  14. SDOCT Thickness Measurements of Various Retinal Layers in Patients with Autosomal Dominant Optic Atrophy due to OPA1 Mutations

    Directory of Open Access Journals (Sweden)

    Andrea M. Schild

    2013-01-01

    Full Text Available Purpose. To specify thickness values of various retinal layers on macular spectral domain Optical Coherence Tomography (SDOCT scans in patients with autosomal dominant optic atrophy (ADOA compared to healthy controls. Methods. SDOCT volume scans of 7 patients with ADOA (OPA-1 mutation and 14 healthy controls were quantitatively analyzed using manual grading software. Mean thickness values for the ETDRS grid subfields 5–8 were calculated for the spaces neurosensory retina, retinal nerve fiber layer (RNFL, ganglion cell layer (GCL, a combined space of inner plexiform layer/outer plexiform layer/inner nuclear layer (IPL+INL+OPL, and a combined space of outer nuclear layer/photoreceptor layers (ONL+PL. Results. ADOA patients showed statistically significant lower retinal thickness values than controls (. RNFL ( and GCL thicknesses ( were significantly lower in ADOA patients. There was no difference in IPL+INL+OPL and in ONL+PL thickness. Conclusion. Manual subanalysis of macular SDOCT volume scans allowed detailed subanalysis of various retinal layers. Not only RNFL but also GCL thicknesses are reduced in the macular area of ADOA patients whereas subjacent layers are not involved. Together with clinical findings, macular SDOCT helps to identify patients with suspicion for hereditary optic neuropathy before genetic analysis confirms the diagnosis.

  15. Identification and functional analysis of GJA8 mutation in a Chinese family with autosomal dominant perinuclear cataracts.

    Directory of Open Access Journals (Sweden)

    Dongmei Su

    Full Text Available Congenital cataract is a clinically and genetically heterogeneous group of eye disorders that causes visual impairment and childhood blindness. The purpose of this study was to identify the genetic defect associated with autosomal dominant congenital perinuclear cataract in a Chinese family. A detailed family history and clinical data of the family were recorded, and candidate gene sequencing was performed to screen for mutation-causing disease in our study. Direct sequencing revealed a c.601G>A (p.E201K transversion in exon 2 of GJA8. This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members or 100 unrelated controls. The function and mechanism of novel GJA8 point mutation E201K in Chinese patients were then investigated in this study. We found E201K aberrantly located in cytoplasm and prevented its location in the plasma membrane. Induction of E201K expression led to a decrease in cell growth and viability by MTT (3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay. Our study provides important evidence that GJA8 is a disease-causing gene for congenital cataract and that mutation of GJA8 has a potential causative effect.

  16. Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment

    Directory of Open Access Journals (Sweden)

    Christian R Halvorson

    2010-06-01

    Full Text Available Christian R Halvorson1, Matthew S Bremmer1, Stephen C Jacobs11Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USAAbstract: Both autosomal dominant and recessive polycystic kidney disease are conditions with severe associated morbidity and mortality. Recent advances in the understanding of the genetic and molecular pathogenesis of both ADPKD and ARPKD have resulted in new, targeted therapies designed to disrupt cell signaling pathways responsible for the abnormal cell proliferation, dedifferentiation, apoptosis, and fluid secretion characteristic of the disease. Herein we review the current understanding of the pathophysiology of these conditions, as well as the current treatments derived from our understanding of the mechanisms of these diseases.Keywords: Polycystic kidney disease, autosomal dominant, recessive, end stage renal disease

  17. A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma.

    Science.gov (United States)

    Liu, Chunqiao; Widen, Sonya A; Williamson, Kathleen A; Ratnapriya, Rinki; Gerth-Kahlert, Christina; Rainger, Joe; Alur, Ramakrishna P; Strachan, Erin; Manjunath, Souparnika H; Balakrishnan, Archana; Floyd, James A; Li, Tiansen; Waskiewicz, Andrew; Brooks, Brian P; Lehmann, Ordan J; FitzPatrick, David R; Swaroop, Anand

    2016-04-01

    Ocular coloboma is a common eye malformation resulting from incomplete fusion of the optic fissure during development. Coloboma is often associated with microphthalmia and/or contralateral anophthalmia. Coloboma shows extensive locus heterogeneity associated with causative mutations identified in genes encoding developmental transcription factors or components of signaling pathways. We report an ultra-rare, heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) that was identified independently in two branches of a large family with autosomal dominant non-syndromic coloboma. FZD5 has a single-coding exon and consequently a transcript with this frameshift variant is not a canonical substrate for nonsense-mediated decay. FZD5 encodes a transmembrane receptor with a conserved extracellular cysteine rich domain for ligand binding. The frameshift mutation results in the production of a truncated protein, which retains the Wingless-type MMTV integration site family member-ligand-binding domain, but lacks the transmembrane domain. The truncated protein was secreted from cells, and behaved as a dominant-negative FZD5 receptor, antagonizing both canonical and non-canonical WNT signaling. Expression of the resultant mutant protein caused coloboma and microphthalmia in zebrafish, and disruption of the apical junction of the retinal neural epithelium in mouse, mimicking the phenotype of Fz5/Fz8 compound conditional knockout mutants. Our studies have revealed a conserved role of Wnt-Frizzled (FZD) signaling in ocular development and directly implicate WNT-FZD signaling both in normal closure of the human optic fissure and pathogenesis of coloboma.

  18. Surgical management of polycystic liver disease

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Adult polycystic liver disease (PCLD) is an autosomal dominant condition commonly associated with autosomal dominant polycystic kidney disease (ADPKD). However in the last decade, it has been recognized that there is a distinct form of autosomal dominant PCLD that arises without concomitant ADPKD. Early knowledge of the pathogenesis was gained from the study of hepatic cysts in patients with ADPKD. Bile duct overgrowth after embryogenesis results in cystic hepatic dilatations that are known as biliary microhamartomas or von Meyenburg complexes. Further dilatation arises from cellular proliferation and fluid secretion into these cysts.There is a variable, broad spectrum of manifestations of PCLD. Although PCLD is most often asymptomatic,massive hepatomegaly can lead to disabling symptoms of abdominal pain, early satiety, persistent nausea,dyspnea, ascites, biliary obstruction, and lower body edema. Complications of PCLD include cyst rupture and cyst infection. Also, there are associated medical problems, especially intracranial aneurysms and valvular heart disease, which clinicians need to be aware of and evaluate in patients with PCLD. In asymptomatic patients, no treatment is indicated for PCLD. In the symptomatic patient, surgical therapy is the mainstay of treatment tailored to the extent of disease for each patient. Management options include cyst aspiration and sclerosis, open or laparoscopic fenestration, liver resection with fenestration, and liver transplantation.The surgical literature discussing treatment of PCLD,including techniques, outcomes, and complication rates,are summarized in this review.

  19. The genetics of hybrid male sterility between the allopatric species pair Drosophila persimilis and D. pseudoobscura bogotana: dominant sterility alleles in collinear autosomal regions.

    Science.gov (United States)

    Chang, Audrey S; Noor, Mohamed A F

    2007-05-01

    F(1) hybrid male sterility is thought to result from interactions between loci on the X chromosome and dominant-acting loci on the autosomes. While X-linked loci that contribute to hybrid male sterility have been precisely localized in many animal taxa, their dominant autosomal interactors have been more difficult to localize precisely and/or have been shown to be of relatively smaller effect. Here, we identified and mapped at least four dominant autosomal factors contributing to hybrid male sterility in the allopatric species pair Drosophila persimilis and D. pseudoobscura bogotana. Using these results, we tested predictions of reduced recombination models of speciation. Consistent with these models, three of the four QTL associated with hybrid male sterility occur in collinear (uninverted) regions of these genomes. Furthermore, these QTL do not contribute significantly to hybrid male sterility in crosses between the sympatric species D. persimilis and D. pseudoobscura pseudoobscura. The autosomal loci identified in this study provide the basis for introgression mapping and, ultimately, for molecular cloning of interacting genes that contribute to F(1) hybrid sterility.

  20. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16

    NARCIS (Netherlands)

    C.J. Ward (Christopher); B. Peral (Belén); J. Hughes (Jim); S. Thomas (Siep); V. Gamble (Vicki); A.B. MacCarthy (Angela); J. Sloane-Stanley (Jackie); P. Buckle (Peter); P. Kearney (Peter); D. Higgs (Douglas); C. Ratcliffe; P.C. Harris (Peter); J.H. Roelfsema (Jeroen); L. Spruit (Lia); J.J. Saris (Jasper); H.G. Dauwerse (Hans); D. Peters (Dorien); M.H. Breuning (Martijn); M.D. Nellist (Mark); P.T. Brook-Carter (Phillip); M.M. Maheshwar (Magitha); I. Cordeiro (Isabel); H. Santos (Heloisa); P. Cabral (Pedro); J. Sampson (Julian); L.A.J. Janssen (Bart); A.L.W. Hesseling-Janssen (Arjenne); A.M.W. van den Ouweland (Ans); H.J.F.M.M. Eussen (Bert); S. Verhoef; D. Lindhout (Dick); D.J.J. Halley (Dicky)

    1994-01-01

    textabstractAutosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently results in renal fallure due to progressive cyst development. The major locus, PKD1, maps to 16p13.3. We identified a chromosome translocation associated with ADPKD that disrupts a gene (PBP

  1. Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy.

    Directory of Open Access Journals (Sweden)

    Georgia Perganta

    Full Text Available Autosomal dominant optic atrophy (ADOA is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1(Q285STOP mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

  2. Nephroangiosclerosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: is NOTCH3 mutation the common culprit?

    Science.gov (United States)

    Guerrot, Dominique; François, Arnaud; Boffa, Jean-Jacques; Boulos, Nada; Hanoy, Melanie; Legallicier, Bruno; Triquenot-Bagan, Aude; Guyant-Marechal, Lucie; Laquerriere, Annie; Freguin-Bouilland, Caroline; Ronco, Pierre; Godin, Michel

    2008-08-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic arterial disease characterized by impairment of vascular smooth muscle cell structure and function related to NOTCH3 mutations. Pathological findings include pathognomonic granular osmiophilic material (GOM) deposition with nonspecific hyalinization within the artery wall in a variety of tissues. The main clinical presentation is iterative strokes in young adults despite the lack of cardiovascular risk factors, leading to early dementia. Although arteriosclerosis and GOM have been found in kidneys from patients with CADASIL, kidney disease has been described only once up to now, in association with immunoglobulin A nephropathy. We report the case of a 61-year-old patient with a medical history of CADASIL and recent mild hypertension. His mother also showed neuropsychiatric symptoms and end-stage renal disease of unknown cause. The patient had a chronic kidney disease defined by means of estimated glomerular filtration rate using the 4-variable Modification of Diet in Renal Disease Study equation of 58 mL/min/1.73 m(2) associated with mild proteinuria and intermittent microscopic hematuria. Renal histological analysis showed severe arteriosclerosis and mild interstitial fibrosis. Glomeruli did not show mesangial immunoglobulin A deposition or focal segmental proliferation. Electron microscopic analysis showed typical GOM deposition in the vicinity of altered vascular smooth muscle cells in interlobular and juxtaglomerular arteries. The nephroangiosclerosis-like lesions were unusually severe in contrast to the recent mild hypertension. The presence of GOM strongly suggests that renal lesions were related to the NOTCH3 mutation. Here, we describe the first case of familial occurrence of kidney disease with decreased kidney function in the absence of coexisting nephropathy in patients with CADASIL. We discuss the role of NOTCH3 mutation in the pathogenesis

  3. Identification of a Novel Gene on 10q22.1 Causing Autosomal Dominant Retinitis Pigmentosa (adRP).

    Science.gov (United States)

    Daiger, Stephen P; Sullivan, Lori S; Bowne, Sara J; Koboldt, Daniel C; Blanton, Susan H; Wheaton, Dianna K; Avery, Cheryl E; Cadena, Elizabeth D; Koenekoop, Robert K; Fulton, Robert S; Wilson, Richard K; Weinstock, George M; Lewis, Richard A; Birch, David G

    2016-01-01

    Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites.

  4. Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy.

    Science.gov (United States)

    Perganta, Georgia; Barnard, Alun R; Katti, Christiana; Vachtsevanos, Athanasios; Douglas, Ron H; MacLaren, Robert E; Votruba, Marcela; Sekaran, Sumathi

    2013-01-01

    Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1(Q285STOP) mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

  5. MRI assessment of fetal autosomal recessive polycystic kidney disease%常染色体隐性遗传性多囊肾病胎儿的MRI表现

    Institute of Scientific and Technical Information of China (English)

    董素贞; 朱铭; 钟玉敏; 张弘; 潘慧红

    2014-01-01

    目的 探讨MRI对常染色体隐性遗传性多囊肾病(ARPKD)胎儿的诊断价值.方法 回顾性分析2005年7月至2013年12月间产前超声检查提示异常,然后行MR检查,并经引产后尸解或病理证实的ARPKD胎儿16例.MR扫描序列主要采用稳态自由进动(SSFP)序列、单次激发快速自旋回波(SSTSE)序列和快速加权序列T1WI.将产前MRI、超声表现与引产后尸解或病理结果进行对照分析.结果 16例ARPKD患儿均表现为双侧肾脏体积明显增大,SSTSE序列肾髓质弥漫性高信号小囊肿.11例合并羊水过少,11例合并双肺发育不良,6例合并肝纤维化.11例双肺发育不良和6例肝脏轻度纤维化超声均未提示,肾脏病变超声误诊1例,MRI诊断均正确.结论 MRI诊断胎儿ARPKD具有明显优势,不受羊水量的影响,能准确评价肾脏及肺异常.%Objective To explore the value of MRI on fetal autosomal recessive polycystic kidney disease (ARPKD).Methods Sixteen pregnant women,aged from 28 to 38 years (average 30 years) and with gestation age from 22 to 36 weeks (average 25 weeks) underwent MR scanning with a 1.5 T MR unit within 24 to 48 hours after ultrasound examinations.The imaging sequences included steady-state free-precession (SSFP) sequence,single-shot turbo spin echo (SSTSE) sequence and T1-weighted fast imaging sequence.Prenatal US and MR imaging findings were compared with autopsy or pathological results.Results A total of 16 cases of ARPKD showed bilateral markedly enlarged kidneys and diffuse high signal small cysts in renal medulla on SSTSE sequence.Among the 16 cases,11 cases were with oligohydramnios,1 1 cases were with pulmonary hypoplasia,and 6 cases were with hepatic fibrosis.Eleven cases of pulmonary hypoplasia and 6 cases of hepatic fibrosis were all missed by US.For the diagnosis of the renal anomalies,US missed one case.MRI diagnosis was correct in all these cases.Conclusions MRI shows great advantages on the diagnosis of fetal ARPKD

  6. Autosomal dominant familial spastic paraplegia: Reduction of the FSPI candidate region on chromosome 14q to 7 cM and locus heterogeneity

    Energy Technology Data Exchange (ETDEWEB)

    Gispert, S.; Santos, N.; Auburger, G.; Damen, R.; Voit, T. [University Hospital, Duesseldorf (Germany); Schulz, J.; Klockgether, T. [University Hospital, Tuebingen (Germany); Orozco, G. [Hospital Lenin, Holguin (Cuba); Kreuz, F. [Technical Univ., Dresden (Netherlands); Weissenbach, J. [Unite de Genetique, Paris (France)

    1995-01-01

    Three large pedigrees of Germany descent with autosomal dominant {open_quotes}pure{close_quotes} familial spastic paraplegia (FSP) were characterized clinically and genetically. Haplotype and linkage analyses, with microsatellites covering the FSP region on chromosome 14q (locus FSP1), were performed. In pedigree W, we found a haplotype that cosegregates with the disease and observed three crossing-over events, reducing the FSP1 candidate region to 7 cM; in addition, the observation of apparent anticipation in this family suggests a trinucleotide repeat expansion as the mutation. In pedigree D and S, the gene locus could be excluded from the whole FSP1 region, confirming the locus heterogeneity of autosomal dominant FSP. 11 refs., 2 figs., 2 tabs.

  7. Brief Screening of Vascular Cognitive Impairment in Patients With Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Without Dementia

    OpenAIRE

    2016-01-01

    Background and Purpose - Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of cerebral small vessel disease leading to early-onset stroke and dementia, with younger patients frequently showing subclinical deficits in cognition. At present, there are no targeted cognitive screening measures for this population. However, the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA) have shown utilit...

  8. Polycystic kidney disease in four British shorthair cats with successful treatment of bacterial cyst infection.

    Science.gov (United States)

    Nivy, R; Lyons, L A; Aroch, I; Segev, G

    2015-09-01

    Polycystic kidney disease is the most common inherited disorder in cats. Renal cysts progressively increase in size and number, resulting in a gradual decrease in kidney function. An autosomal dominant mutation in exon 29 of the polycystin-1 gene has been identified, mostly in Persian and Persian-related breeds. This case study describes polycystic kidney disease in four British shorthair cats, of which two had the same genetic mutation reported in Persian and Persian-related cats. This likely reflects introduction of this mutation into the British shorthair breeding line because of previous outcrossing with Persian cats. An infected renal cyst was diagnosed and successfully treated in one of the cats. This is a commonly reported complication in human polycystic kidney disease, and to the authors' knowledge has not previously been reported in cats with polycystic kidney disease.

  9. Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

    Science.gov (United States)

    Coppieters, Frauke; Roels, Dimitri; De Jaegere, Sarah; Flipts, Helena; De Zaeytijd, Julie; Walraedt, Sophie; Claes, Charlotte; Fransen, Erik; Van Camp, Guy; Depasse, Fanny; Casteels, Ingele; de Ravel, Thomy

    2017-01-01

    Purpose Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5–30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular

  10. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa.

    Science.gov (United States)

    Bakondi, Benjamin; Lv, Wenjian; Lu, Bin; Jones, Melissa K; Tsai, Yuchun; Kim, Kevin J; Levy, Rachelle; Akhtar, Aslam Abbasi; Breunig, Joshua J; Svendsen, Clive N; Wang, Shaomei

    2016-03-01

    Reliable genome editing via Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. As proof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin gene carrying the dominant S334ter mutation (Rho(S334)) in rats that model severe autosomal dominant retinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination with electroporation generated allele-specific disruption of Rho(S334), which prevented retinal degeneration and improved visual function.

  11. Denaturing high-performance liquid chromatography to diagnose cerebral autosomal dominant arteriopathy in Chinese patients with subcortical infarcts and leukoencephalopathy

    Institute of Scientific and Technical Information of China (English)

    Xiaomei Tang; Biao Chen

    2008-01-01

    BACKGROUND: Notch3 mutations are the molecular genetic foundation for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Of all currently available detection methods, direct sequencing or restriction enzymes are frequently used, but the cost is relatively high, because the Notch3 gene is composed of many exons and mutational sites are widely distributed. Denaturing high-performance liquid chromatography (DHPLC) exhibits high efficiency and specificity and has been applied to gene detection. To date, there has no report regarding DHPLC in gene detection of large-scale CADASIL families in China. OBJECTIVE: To explore the application and value of DHPLC in the diagnosis of CADASIL by a mutation screening for Notch3 gene in CADASIL probands and their family members. DESIGN, TIME AND SETTING: A comparative observation was performed at the Genetic Diagnosis Laboratory of Institute of Geriatrics, Xuanwu Hospital of Capital Medical University and the Key Laboratory for Neurodegenerative Disease of the Ministry of Education between August 2003 and May 2004. PARTICIPANTS: Fourteen CADASIL patients and their family members, comprising eight males and six females, aged 38-62 years, were included. Their key features included recurrent sub-cortical ischemic events and vascular dementia. In addition, 100 healthy physical examinees were selected as controls, including 52 males and 48 females, aged 56-72 years, who had no neurodegenerative disease or psychosis, and no history or high risk for cerebrovascular disease. METHODS: DNA was extracted from white blood cells. Ten hotspots of the Notch3 gene for sequence variation were first amplified by PCR, and the products were detected using DHPLC. Exons exhibiting a variant in the DHPLC profile underwent another PCR amplification, followed by DNA sequencing to identify the mutation type. In addition, patients with normal DHPLC peak profiles underwent PCR amplification for the remaining

  12. Brain imaging and blood biomarker abnormalities in children with autosomal-dominant Alzheimer's disease: A cross-sectional Study

    Science.gov (United States)

    Quiroz, Y.T.; Schultz, A.; Chen, K.; Protas, H.; Brickhouse, M.; Fleisher, A.S.; Langbaum, J.B.; Thiyyagura, P.; Fagan, A.M.; Shah, A.R.; Muniz, M.; Arboleda-Velasquez, JF; Munoz, C.; Garcia, G.; Acosta-Baena, N.; Giraldo, M.; Tirado, V.; Ramirez, D.; Tariot, PN; Dickerson, B.C.; Sperling, R.A.; Lopera, F.; Reiman, E.M.

    2015-01-01

    IMPORTANCE Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). OBJECTIVE To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation–carrying and noncarrying children with ADAD. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellin, Colombia, between August 2011 and June 2012. MAIN OUTCOMES AND MEASURES All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding–dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. RESULTS Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task–related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were −0.590 [0.50] for noncarriers and −0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation

  13. A novel candidate locus on chromosome 11p14.1-p11.2 for autosomal dominant hereditary spastic paraplegia

    Institute of Scientific and Technical Information of China (English)

    ZHAO Guo-hua; TANG Bei-sha; HU Zheng-mao; SHEN Lu; JIANG Hong; REN Zhi-jun; LIU Xiao-min; XIA Kun; GUO Peng; PAN Qian

    2008-01-01

    Background Hereditary spastic paraplegia(HSP)is a group of inherited neurodegenerative disorders with the shared characteristics of slowly progressive spasticity and weakness of the lower limbs.Thirteen loci for autosomal dominant HSP have been mapped.Methods A Chinese family with HSP was found in the Shandong province and Inner Mongolia Autonomous Region of China and genomic DNA of all 19 family members was isolated.After exclusion of known autosomal dominant loci,a genome wide scan and linkage analysis were performed.Results The known autosomal dominant loci of SPG3A,SPG4,SPG6,SPG8,SPG9,SPG10,SPGl2,SPG13,SPG17,SPG19,SPG29,SPG31 and SPG33 were excluded by linkage analysis.The results of a genome wide scan demonstrated candidate linkage to a locus on chromosome 11p14.1-p11.2,over an 18.88 cM interval between markers D11S1324 and D11S1933.A maximal,two point LOD score of 2.36 for marker D11S935 at a recombination fraction(Φ)of 0 and a multipoint LOD score of 2.36 for markers D11S1776,D11S1751,D11S1392,D11S4203,D11S935,D11S4083,and D11S4148at Φ=0,suggest linkage to this locus.Conclusion The HSP neuropathy in this family may represent a novel genetic entity,which will facilitate discovery of this causative gene.

  14. Induced pluripotent stem cells derived from a patient with autosomal dominant familial neurohypophyseal diabetes insipidus caused by a variant in the AVP gene

    DEFF Research Database (Denmark)

    Toustrup, Lise Bols; Zhou, Yan; Kvistgaard, Helene

    2017-01-01

    Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by variants in the arginine vasopressin (AVP) gene. Here we report the generation of induced pluripotent stem cells (iPSCs) from a 42-year-old man carrying an adFNDI causing variant in exon 1 of the AVP gene using...... lentivirus-mediated nuclear reprogramming. The iPSCs carried the expected variant in the AVP gene. Furthermore, the iPSCs expressed pluripotency markers; displayed in vitro differentiation potential to the three germ layers and had a normal karyotype consistent with the original fibroblasts. This iPSC line...

  15. Genotype-phenotype correlation for DFNA22: characterization of non-syndromic, autosomal dominant, progressive sensorineural hearing loss due to MYO6 mutations

    DEFF Research Database (Denmark)

    Tranebjærg, Lisbeth; Rendtorff, Nanna D; Topsakal, Vedat;

    2010-01-01

    Clinical and audiological examination was done in 2 Belgian families with autosomal dominant sensorineural hearing loss (SNHL) linked to DFNA22. Nineteen subjects in family 1 had mild to moderate SNHL starting in the third decade. The hearing loss was characterized by a flat audiogram affecting all...... tested frequencies with statistically significant progression. In family 2 eleven subjects were affected with mild to moderate SNHL starting in the second decade. Most of them showed a flat audiogram, but some had mid-frequency hearing loss. Significant progression of thresholds was present at 4 and 8 k...

  16. c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family

    Science.gov (United States)

    Dantas, Vitor G.L.; Lezirovitz, Karina; Yamamoto, Guilherme L.; Moura de Souza, Carolina Fischinger; Ferreira, Simone Gomes; Mingroni-Netto, Regina C.

    2014-01-01

    We studied a family presenting 10 individuals affected by autosomal dominant deafness in all frequencies and three individuals affected by high frequency hearing loss. Genomic scanning using the 50k Affymetrix microarray technology yielded a Lod Score of 2.1 in chromosome 14 and a Lod Score of 1.9 in chromosome 22. Mapping refinement using microsatellites placed the chromosome 14 candidate region between markers D14S288 and D14S276 (8.85 cM) and the chromosome 22 near marker D22S283. Exome sequencing identified two candidate variants to explain hearing loss in chromosome 14 [PTGDR – c.G894A:p.R298R and PTGER2 – c.T247G:p.C83G], and one in chromosome 22 [MYH9, c.G2114A:p.R705H]. Pedigree segregation analysis allowed exclusion of the PTGDR and PTGER2 variants as the cause of deafness. However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype. This gene has been previously described as mutated in autosomal dominant hereditary hearing loss and corresponds to DFNA17. The mutation identified in our study is the same described in the prior report. Thus, although linkage studies suggested a candidate gene in chromosome 14, we concluded that the mutation in chromosome 22 better explains the hearing loss phenotype in the Brazilian family. PMID:25505834

  17. Clinical and molecular analysis of a Chinese family with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel missense mutation in the vasopressin-neurophysin II gene.

    Science.gov (United States)

    Luo, Yongfeng; Wang, Binbin; Qiu, Yu; Zhang, Chuan; Jin, Chengluo; Zhao, Yakun; Zhu, Qingguo; Ma, Xu

    2012-08-01

    The objective of this study is to identify the genetic defects in a Chinese family with autosomal dominant familial neurohypophyseal diabetes insipidus. Complete physical examination, fluid deprivation, and DDAVP tests were performed in three affected and three healthy members of the family. Genomic DNA was extracted from leukocytes of venous blood of these individuals for polymerase chain reaction amplification and direct sequencing of all three coding exons of arginine vasopressin-neurophysin II (AVP-NPII) gene. Seven members of this family were suspected to have symptomatic vasopressin-deficient diabetes insipidus. The water deprivation test in all the patients confirmed the diagnosis of vasopressin-deficient diabetes insipidus, with the pedigree demonstrating an autosomal dominant inheritance. Direct sequence analysis revealed a novel mutation (c.193T>A) and a synonymous mutation (c.192C>A) in the AVP-NPII gene. The missense mutation resulted in the substitution of cysteine by serine at a highly conserved codon 65 of exon 2 of the AVP-NPII gene in all affected individuals, but not in unaffected members. We concluded that a novel missense mutation in the AVP-NPII gene caused neurohypophyseal diabetes insipidus in this family, due to impaired neurophysin function as a carrier protein for AVP. The Cys65 is essential for NPII in the formation of a salt bridge with AVP. Presence of this mutation suggests that the portion of the neurophysin peptide encoded by this sequence is important for the normal expression of vasopressin.

  18. Autosomal P[ovoD1] dominant female-sterile insertions in Drosophila and their use in generating germ-line chimeras.

    Science.gov (United States)

    Chou, T B; Noll, E; Perrimon, N

    1993-12-01

    The 'dominant female-sterile' technique used to generate germ-line mosaics in Drosophila is a powerful tool to determine the tissue specificity (germ line versus somatic) of recessive female-sterile mutations as well as to analyze the maternal effect of recessive zygotic lethal mutations. This technique requires the availability of germ-line-dependent, dominant female-sterile (DFS) mutations that block egg laying but do not affect viability. To date only one X-linked mutation, ovoD1 has been isolated that completely fulfills these criteria. Thus the 'DFS technique' has been largely limited to the X-chromosome. To extend this technique to the autosomes, we have cloned the ovoD1 mutation into a P-element vector and recovered fully expressed P[ovoD1] insertions on each autosomal arm. We describe the generation of these P[ovoD1] strains as well as demonstrate their use in generating germ-line chimeras. Specifically, we show that the Gap1 gene, which encodes a Drosophila homologue of mammalian GTPase-activating protein, is required in somatic follicle cells for embryonic dorsoventral polarity determination.

  19. Mapping of the locus for autosomal dominant amelogenesis imperfecta (AIH2) to a 4-Mb YAC contig on chromosome 4q11-q21

    Energy Technology Data Exchange (ETDEWEB)

    Kaerrman, C.; Holmgren, G.; Forsman, K. [Univ. Hospital, Umea (Sweden)]|[Univ. of Umea (Sweden)] [and others

    1997-01-15

    Amelogenesis imperfecta (Al) is a clinically and genetically heterogeneous group of inherited enamel defects. We recently mapped a locus for autosomal dominant local hypoplastic amelogenesis imperfecta (AIH2) to the long arm of chromosome 4. The disease gene was localized to a 17.6-cM region between the markers D4S392 and D4S395. The albumin gene (ALB), located in the same interval, was a candidate gene for autosomal dominant AI (ADAI) since albumin has a potential role in enamel maturation. Here we describe refined mapping of the AIH2 locus and the construction of marker maps by radiation hybrid mapping and yeast artificial chromosome (YAC)-based sequence tagged site-content mapping. A radiation hybrid map consisting of 11 microsatellite markers in the 5-cM interval between D4S409 and D4S1558 was constructed. Recombinant haplotypes in six Swedish ADAI families suggest that the disease gene is located in the interval between D4S2421 and ALB. ALB is therefore not likely to be the disease-causing gene. Affected members in all six families share the same allele haplotypes, indicating a common ancestral mutation in all families. The AIH2 critical region is less than 4 cM and spans a physical distance of approximately 4 Mb as judged from radiation hybrid maps. A YAC contig over the AIH2 critical region including several potential candidate genes was constructed. 35 refs., 4 figs., 1 tab.

  20. Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele

    Science.gov (United States)

    Radhakrishna, Uppala; Nath, Swapan K; McElreavey, Ken; Ratnamala, Uppala; Sun, Celi; Maiti, Amit K; Gagnebin, Maryline; Béna, Frédérique; Newkirk, Heather L; Sharp, Andrew J; Everman, David B; Murray, Jeffrey C; Schwartz, Charles E; Antonarakis, Stylianos E; Butler, Merlin G

    2017-01-01

    Background Omphalocele is a congenital birth defect characterised by the presence of internal organs located outside of the ventral abdominal wall. The purpose of this study was to identify the underlying genetic mechanisms of a large autosomal dominant Caucasian family with omphalocele. Methods and findings A genetic linkage study was conducted in a large family with an autosomal dominant transmission of an omphalocele using a genome-wide single nucleotide polymorphism (SNP) array. The analysis revealed significant evidence of linkage (non-parametric NPL = 6.93, p=0.0001; parametric logarithm of odds (LOD) = 2.70 under a fully penetrant dominant model) at chromosome band 1p31.3. Haplotype analysis narrowed the locus to a 2.74 Mb region between markers rs2886770 (63014807 bp) and rs1343981 (65757349 bp). Molecular characterisation of this interval using array comparative genomic hybridisation followed by quantitative microsphere hybridisation analysis revealed a 710 kb duplication located at 63.5–64.2 Mb. All affected individuals who had an omphalocele and shared the haplotype were positive for this duplicated region, while the duplication was absent from all normal individuals of this family. Multipoint linkage analysis using the duplication as a marker yielded a maximum LOD score of 3.2 at 1p31.3 under a dominant model. The 710 kb duplication at 1p31.3 band contains seven known genes including FOXD3, ALG6, ITGB3BP, KIAA1799, DLEU2L, PGM1, and the proximal portion of ROR1. Importantly, this duplication is absent from the database of genomic variants. Conclusions The present study suggests that development of an omphalocele in this family is controlled by overexpression of one or more genes in the duplicated region. To the authors’ knowledge, this is the first reported association of an inherited omphalocele condition with a chromosomal rearrangement. PMID:22499347

  1. A novel 3-base pair deletion of the CRYAA gene identified in a large Chinese pedigree featuring autosomal dominant congenital perinuclear cataract.

    Science.gov (United States)

    Kong, X D; Liu, N; Shi, H R; Dong, J M; Zhao, Z H; Liu, J; Li-Ling, J; Yang, Y X

    2015-01-23

    Congenital cataract is caused by reduced transparency of the lens resulting from metabolic disorders during the fetal period. The disease shows great heterogeneity both clinically and genetically. We identified a 4-generation ethnic Han Chinese family affected by autosomal dominant congenital perinuclear cataract. The patients underwent full clinical and ophthalmologic examinations to rule out any concomitant disorders. Blood samples were collected and genomic DNA was extracted. Potential mutations in the candidate gene alpha A crystallin (CRYAA) were screened. Prenatal diagnosis was then provided for a fetus of the affected proband by chorionic villus sampling. In all patients, DNA sequencing of the CRYAA gene revealed a novel 3-bp deletion mutation in exon 3 (c.246_248delCGC), which led to deletion of codon 117 encoding arginine (p.117delR) in the peptide chain. The same mutation was not found among unaffected and healthy individuals. Bioinformatic analysis revealed that although the c.246_248delCGC is an 'in-frame' mutation, removal of arginine resulted in a significant change in the protein structure. The fetus did not possess this mutation and was confirmed to be healthy at 1-year follow-up. A novel disease-causing mutation, c.246_248delCGC (p.117delR), of the CRYAA gene has been identified in a Chinese family with autosomal-type perinuclear congenital cataracts. This is also the first report of prenatal diagnosis of this type of congenital cataract.

  2. Autosomal dominant precocious osteoarthropathy due to a mutation of the cartilage oligomeric matrix protein (COMP) gene: further expansion of the phenotypic variations of COMP defects

    Energy Technology Data Exchange (ETDEWEB)

    Kawaji, Hiroyuki [Department of Orthopaedic Surgery, Sanyudo Hospital, 6-1-219 Chuou, Yonezawa, Yamagata 992-0045 (Japan); Nishimura, Gen [Department of Radiology, Nasu Chuou Hospital, Tochigi (Japan); Watanabe, Sobei; Sasaki, Akira; Sano, Tokuhisa [Department of Orthopaedic Surgery, Tohoku Kohsei-Nenkin Hospital, Miyagi (Japan); Mabuchi, Akihiko; Ikeda, Toshiyuki; Ikegawa, Shiro [Laboratory for Bone and Joint Diseases, SNP Research Center, Tokyo (Japan); Ohashi, Hirofumi [Division of Medical Genetics, Saitama Children' s Medical Center, Saitama (Japan)

    2002-12-01

    We report on a Japanese family of four generations with an autosomal dominant precocious osteoarthropathy. The cardinal clinical manifestations of affected individuals were painful weight-bearing large joints, which started in late childhood or adolescence. The radiological hallmarks included coxa plana, mild epiphyseal dysplasia of the knee, and round talar domes with tibiotalar slant in childhood, which evolved into degenerative joint diseases in adulthood. The disease phenotype was cosegregated with a mutation of the cartilage oligomeric matrix protein (COMP) gene in the family members, who underwent molecular evaluation. COMP mutations have been reported in a mild form of multiple epiphyseal dysplasia (MED), Ribbing type, as well as allied disorders with more severe manifestations, such as MED Fairbank type and pseudoachondroplasia. Unlike previously reported cases with the Ribbing type, the present patients did not have short stature or brachydactyly. This report expands further the phenotypic variations of COMP defects. (orig.)

  3. 常染色体隐性遗传多囊肾病 PKHD1基因检测%Detection of PKHD1 gene in autosomal recessive polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    宋红霞; 孙春梅; 韩蓁; 李媛; 周熙惠

    2013-01-01

    Objective To identify and analyze mutation in polycystic kidney and hepatic disease 1 ( PKHD1 ) in one abortion fetus of autosomal recessive polycystic kidney disease ( ARPKD).Methods Genome DNA was extracted from peripheral venous blood sampled from the fetus and his parents .PCR amplification and DNA direct sequencing and other technical means were adopted to perform gene mutation analysis of PKHD1.Results The following DNA sequence variations were found , ISV7+51G>T in intron 7, c.1587T>C(p. N529N) in exon 17, c.3785C>T(p.A1262V) in exon 32, which caused amino acid substitution from Alanine to Valine .Conclusion The variation of PKHD1 sequence may be involved in the pathogenesis of ARPKD .The sequence analysis of PKHD1 gene can be used as an effective method for prenatal diagnosis .%目的对1例引产的常染色体隐性遗传性多囊肾病胎儿的多囊肾/多囊肝病变1基因( PKHD1)进行基因突变鉴定和结果分析。方法采集引产胎儿及其父母外周静脉血,分别提取基因组DNA,应用PCR扩增、DNA直接测序等技术手段对该胎儿及其父母进行PKHD1基因突变分析。结果胎儿PKHD1基因出现几种序列变异:PKHD1基因第7号内含子发生ISV7+51G>T变异;第17号外显子发生c.1587T>C(p.N529N)变异;第32号外显子发生c.3785C>T(p.A1262V)变异,导致编码PKHD1蛋白多肽链第1262号氨基酸由丙氨酸变为缬氨酸。结论 PKHD1基因序列变异可能是常染色体隐性遗传性多囊肾病的病因,PKHD1基因检测可作为产前筛查的有效诊断手段。

  4. Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behçet's disease

    Science.gov (United States)

    Shigemura, Tomonari; Kaneko, Naoe; Kobayashi, Norimoto; Kobayashi, Keiko; Takeuchi, Yusuke; Nakano, Naoko; Masumoto, Junya; Agematsu, Kazunaga

    2016-01-01

    Objective Although Behçet's disease (BD) is a chronic inflammatory disorder of uncertain aetiology, the existence of familial BD with autosomal-dominant traits suggests that a responsibility gene (or genes) exists. We investigated a Japanese family with a history of BD to search for pathogenic mutations underlying the biological mechanisms of BD. Methods 6 patients over 4 generations who had suffered from frequent oral ulcers, genital ulcers and erythaema nodosum-like lesions in the skin were assessed. Whole-exome sequencing was performed on genomic DNA, and cytokine production was determined from stimulated mononuclear cells. Inflammatory cytokine secretion and Nod2-mediated NF-κB activation were analysed using the transfected cells. Results By whole-exome sequencing, we identified a common heterozygous missense mutation in A20/TNFAIP3, a gene known to regulate NF-κB signalling, for which all affected family members carried a heterozygous C243Y mutation in the ovarian tumour domain. Mononuclear cells obtained from the proband and his mother produced large amounts of interleukin 1β, IL-6 and tumour necrosis factor α (TNF-a) on stimulation as compared with those from normal controls. Although inflammatory cytokine secretion was suppressed by wild-type transfected cells, it was suppressed to a much lesser extent by mutated C243Y A20/TNFAIP3-transfected cells. In addition, impaired suppression of Nod2-mediated NF-κB activation by C243Y A20/TNFAIP3 was observed. Conclusions A C243Y mutation in A20/TNFAIP3 was likely responsible for increased production of human inflammatory cytokines by reduced suppression of NF-κB activation, and may have accounted for the autosomal-dominant Mendelian mode of BD transmission in this family. PMID:27175295

  5. Examination of the presynaptic dopaminergic system using positron emission tomography in a family with autosomal dominant parkinsonism and dementia due to pallido-ponto-nigral degeneration (PPNO)

    Energy Technology Data Exchange (ETDEWEB)

    Cordes, M. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)]|[Strahlenklinik und Poliklinik, Universitaetsklinikum Rudolf Virchow, Freie Univ. Berlin (Germany); Wszolek, Z.K. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)]|[Section of Neurology, Univ. of Nebraska Medical Center, Omaha, NE (United States); Pfeiffer, R.F. [Section of Neurology, Univ. of Nebraska Medical Center, Omaha, NE (United States); Calne, D.B. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)

    1993-12-31

    We report positron emission tomography (PET) examinations of presynaptic nigrostriatal dopaminergic function in a large family with an autosomal dominant neuro-degenerative disorder characterized pathologically by pallido-ponto-nigral degeneration, and clinically by parkinsonism, dystonia, paresis of conjugate gaze, apraxia of eyelid opening and closing, pyramidal tract dysfunction, and urinary incontinence. Dopaminergic function was studied and quantified with [{sup 18}F]-L-6-fluorodopa (6 FD) and PET in five affected patients, 13 individuals at-risk, and 15 similarly aged controls. The rate constant K{sub i} (mL/striatum/min) for 6 FD was decreased in all patients. None of the individuals at risk had reduced 6 FD uptake. In fact, three of them had increased values. Repeat scans have revealed a fall in 6 FD uptake in two out of the three with initially high constants. This may reflect a preclinical stage of involvement, but longer observation is necessary. (orig.) [Deutsch] Wir berichten ueber Untersuchungen der praesynaptischen dopaminergen Funktion mit der Positronenemissionstomographie bei einer grossen Familie mit autosomal-dominant vererbtem Parkinsonismus und Demenz. Die Erkrankung ist pathologisch-anatomisch gekennzeichnet durch eine pallido-ponto-nigrale Degeneration. Klinisch bestehen ein Parkinsonismus, Dystonien, eine Apraxie der Augenoeffnung und -schliessung, pyramidale Dysfunktionen und eine Harninkontinenz. Die praesynaptische dopaminerge Funktion wurde untersucht und quantifiziert mittels [{sup 18}F]-L-6-Fluorodopa (6FD) PET bei fuenf erkrankten Patienten, 13 Risikopatienten und 15 Kontrollpersonen vergleichbaren Alters. Die Transportkonstante K{sub i} (ml/Striatum/min) fuer die striatale Aufnahme des Radiotracers war bei allen erkrankten Patienten erniedrigt. Von den 13 Risikopatienten hatte keiner eine reduzierte Aufnahme von 6FD. Drei Risikopatienten zeigten sogar Werte fuer K{sub i}, die oberhalb des Referenzbereiches der Kontrollpersonen lagen

  6. Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.

    Science.gov (United States)

    Bolar, Nikhita Ajit; Golzio, Christelle; Živná, Martina; Hayot, Gaëlle; Van Hemelrijk, Christine; Schepers, Dorien; Vandeweyer, Geert; Hoischen, Alexander; Huyghe, Jeroen R; Raes, Ann; Matthys, Erve; Sys, Emiel; Azou, Myriam; Gubler, Marie-Claire; Praet, Marleen; Van Camp, Guy; McFadden, Kelsey; Pediaditakis, Igor; Přistoupilová, Anna; Hodaňová, Kateřina; Vyleťal, Petr; Hartmannová, Hana; Stránecký, Viktor; Hůlková, Helena; Barešová, Veronika; Jedličková, Ivana; Sovová, Jana; Hnízda, Aleš; Kidd, Kendrah; Bleyer, Anthony J; Spong, Richard S; Vande Walle, Johan; Mortier, Geert; Brunner, Han; Van Laer, Lut; Kmoch, Stanislav; Katsanis, Nicholas; Loeys, Bart L

    2016-07-07

    Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.

  7. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, genetic homogeneity, and mapping of the locus within a 2-cM interval

    Energy Technology Data Exchange (ETDEWEB)

    Ducros, A.; Alamowitch, S.; Nagy, T. [INSERM U25, Paris (France)] [and others

    1996-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified autosomal dominant cerebral arteriopathy characterized by the recurrence of subcortical infarcts leading to dementia. A genetic linkage analysis conducted in two large families recently allowed us to map the affected gene on chromosome 19 in a 12-cM interval bracketed by D19S221 and D19S215. In the present study, these first 2 families and 13 additional ones, including a total of 199 potentially informative meiosis, have been genotyped with eight polymorphic markers located between D19S221 and D19S215. All families were linked to chromosome 19. The highest combined lod score (Z{sub max} = 37.24 at {theta} = .01) was obtained with marker D19S841, a new CA{sub n} microsatellite marker that we isolated from chromosome 19 cosmids. The recombinant events observed within these families were used to refine the genetic mapping of CADASIL within a 2-cM interval that is now bracketed by D19S226 and D19S199 on 19p13.1. These data strongly suggest the genetic homogeneity of this recently identified condition and establish the value of its clinical and neuroimaging diagnostic criteria. Besides their importance for the ongoing positional cloning of the CADASIL gene, these data help to refine the genetic mapping of CADASIL relative to familial hemiplegic migraine and hereditary paroxysmal cerebellar ataxia, conditions that we both mapped within the same chromosome 19 region. 35 refs., 5 figs., 2 tabs.

  8. Clinical aspects of an autosomal dominantly inherited hearing impairment linked to the DFNA60 locus on chromosome 2q23.1-2q23.3.

    Science.gov (United States)

    van Beelen, E; Schraders, M; Huygen, P L M; Oostrik, J; Plantinga, R F; van Drunen, W; Collin, R W J; Kooper, D P; Pennings, R J E; Cremers, C W R J; Kremer, H; Kunst, H P M

    2013-06-01

    A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region within the DFNA60 locus located on chromosome 2 in q22.1-24.1. A pedigree spanning four generations was established with 13 affected individuals. Linkage analysis demonstrated that the locus extended over a 2.96 Mb region flanked by markers D2S2335 and D2S2275. The audiograms mainly showed a distinctive U-shaped configuration. Deterioration of hearing started at a wide age range, from 12 to 40 years. Cross-sectional analysis showed rapid progression of hearing impairment from mild to severe, between the ages of 40 and 60 years, a phenomenon that is also observed in DFNA9 patients. The results of the individual longitudinal analyses were generally in line with those obtained by the cross-sectional analysis. Speech recognition scores related to the level of hearing impairment (PTA1,2,4 kHz) appeared to be fairly similar to those of presbyacusis patients. It is speculated that hearing impairment starting in mid-life, as shown by DFNA60 patients, could play a role in the development of presbyacusis. Furthermore, speech recognition did not deteriorate appreciably before the sixth decade of life. We conclude that DFNA60 should be considered in hearing impaired patients who undergo a rapid progression in middle age and are negative for DFNA9. Furthermore, cochlear implantation resulted in good rehabilitation in two DFNA60 patients.

  9. Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib.

    Science.gov (United States)

    Fröhlich, Leopold F; Mrakovcic, Maria; Steinborn, Ralf; Chung, Ung-Il; Bastepe, Murat; Jüppner, Harald

    2010-05-18

    Approximately 100 genes undergo genomic imprinting. Mutations in fewer than 10 imprinted genetic loci, including GNAS, are associated with complex human diseases that differ phenotypically based on the parent transmitting the mutation. Besides the ubiquitously expressed Gsalpha, which is of broad biological importance, GNAS gives rise to an antisense transcript and to several Gsalpha variants that are transcribed from the nonmethylated parental allele. We previously identified two almost identical GNAS microdeletions extending from exon NESP55 to antisense (AS) exon 3 (delNESP55/delAS3-4). When inherited maternally, both deletions are associated with erasure of all maternal GNAS methylation imprints and autosomal-dominant pseudohypoparathyroidism type Ib, a disorder characterized by parathyroid hormone-resistant hypocalcemia and hyperphosphatemia. As for other imprinting disorders, the mechanisms resulting in abnormal GNAS methylation are largely unknown, in part because of a paucity of suitable animal models. We now showed in mice that deletion of the region equivalent to delNESP55/delAS3-4 on the paternal allele (DeltaNesp55(p)) leads to healthy animals without Gnas methylation changes. In contrast, mice carrying the deletion on the maternal allele (DeltaNesp55(m)) showed loss of all maternal Gnas methylation imprints, leading in kidney to increased 1A transcription and decreased Gsalpha mRNA levels, and to associated hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism. Besides representing a murine autosomal-dominant pseudohypoparathyroidism type Ib model and one of only few animal models for imprinted human disorders, our findings suggest that the Nesp55 differentially methylated region is an additional principal imprinting control region, which directs Gnas methylation and thereby affects expression of all maternal Gnas-derived transcripts.

  10. Repair of rhodopsin mRNA by spliceosome-mediated RNA trans-splicing: a new approach for autosomal dominant retinitis pigmentosa.

    Science.gov (United States)

    Berger, Adeline; Lorain, Stéphanie; Joséphine, Charlène; Desrosiers, Melissa; Peccate, Cécile; Voit, Thomas; Garcia, Luis; Sahel, José-Alain; Bemelmans, Alexis-Pierre

    2015-05-01

    The promising clinical results obtained for ocular gene therapy in recent years have paved the way for gene supplementation to treat recessively inherited forms of retinal degeneration. The situation is more complex for dominant mutations, as the toxic mutant gene product must be removed. We used spliceosome-mediated RNA trans-splicing as a strategy for repairing the transcript of the rhodopsin gene, the gene most frequently mutated in autosomal dominant retinitis pigmentosa. We tested 17 different molecules targeting the pre-mRNA intron 1, by transient transfection of HEK-293T cells, with subsequent trans-splicing quantification at the transcript level. We found that the targeting of some parts of the intron promoted trans-splicing more efficiently than the targeting of other areas, and that trans-splicing rate could be increased by modifying the replacement sequence. We then developed cell lines stably expressing the rhodopsin gene, for the assessment of phenotypic criteria relevant to the pathogenesis of retinitis pigmentosa. Using this model, we showed that trans-splicing restored the correct localization of the protein to the plasma membrane. Finally, we tested our best candidate by AAV gene transfer in a mouse model of retinitis pigmentosa that expresses a mutant allele of the human rhodopsin gene, and demonstrated the feasibility of trans-splicing in vivo. This work paves the way for trans-splicing gene therapy to treat retinitis pigmentosa due to rhodopsin gene mutation and, more generally, for the treatment of genetic diseases with dominant transmission.

  11. Recent advances in the cell biology of polycystic kidney disease.

    Science.gov (United States)

    Smyth, Brendan J; Snyder, Richard W; Balkovetz, Daniel F; Lipschutz, Joshua H

    2003-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a significant familial disorder, crossing multiple ethnicities as well as organ systems. The goal of understanding and, ultimately, curing ADPKD has fostered collaborative efforts among many laboratories, mustered on by the opportunity to probe fundamental cellular biology. Here we review what is known about ADPKD including well-accepted data such as the identification of the causative genes and the fact that PKD1 and PKD2 act in the same pathway, fairly well-accepted concepts such as the "two-hit hypothesis," and somewhat confusing information regarding polycystin-1 and -2 localization and protein interactions. Special attention is paid to the recently discovered role of the cilium in polycystic kidney disease and the model it suggests. Studying ADPKD is important, not only as an evaluation of a multisystem disorder that spans a lifetime, but as a testament to the achievements of modern biology and medicine.

  12. DVL3 Alleles Resulting in a −1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome

    Science.gov (United States)

    White, Janson J.; Mazzeu, Juliana F.; Hoischen, Alexander; Bayram, Yavuz; Withers, Marjorie; Gezdirici, Alper; Kimonis, Virginia; Steehouwer, Marloes; Jhangiani, Shalini N.; Muzny, Donna M.; Gibbs, Richard A.; van Bon, Bregje W.M.; Sutton, V. Reid; Lupski, James R.; Brunner, Han G.; Carvalho, Claudia M.B.

    2016-01-01

    Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a −1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow syndrome, all variants in DVL3 result in a −1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations. PMID:26924530

  13. Frequency analysis of autosomal dominant spinocerebellar ataxias in mainland Chinese patients and clinical and molecular characterization of spinocerebellar ataxia type 6

    Institute of Scientific and Technical Information of China (English)

    JIANG Hong; TANG Bei-sha; XU Bo; ZHAO Guo-hua; SHEN Lu; TANG Jian-guang; LI Qing-hua; XIA Kun

    2005-01-01

    Background Dominantly inherited spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous group of neurodegenerative disorders. This study was to further assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, SCA8, SCA10, SCA12, SCA14, SCA17 and DRPLA (dentatorubro-pallidoluysian atrophy) in mainland Chinese, and to specifically characterize mainland Chinese patients with SCA6 in terms of clinical and molecular features.Methods Using a molecular approach, we investigated SCA in 120 mainland Chinese families with dominantly inherited ataxias and in 60 mainland Chinese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 13 patients from 4 families. Results SCA3/MJD was the most common type of autosomal dominant SCA in mainland Chinese, accounting for 83 patients from 59 families (49.2%), followed by SCA2[8(6.7%)], SCA1[7(5.8%)], SCA6[4(3.3%)], SCA7[1(0.8%)], SCA8(0%), SCA10(0%), SCA12(0%), SCA14(0%), SCA17(0%) and DRPLA(0%). The genes responsible for 41 (34.2%) of dominantly inherited SCA families remain to be determined. Among the 60 patients with sporadic ataxias in the present series, 3 (5.0%) was found to harbor SCA3 mutations while none was found to harbor SCA6 mutations. In the 4 families with SCA6, significant anticipation was found in the absence of genetic instability on transmission.Conclusion A geographic cluster of families with SCA6 subtype was initially identified in a mainland Chinese population.

  14. Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

    Directory of Open Access Journals (Sweden)

    Doroteya Raykova

    Full Text Available Pure hair and nail ectodermal dysplasia (PHNED comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH. Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.

  15. Targeted Genes Sequencing Identified a Novel 15 bp Deletion on GJA8 in a Chinese Family with Autosomal Dominant Congenital Cataracts

    Institute of Scientific and Technical Information of China (English)

    Han-Yi Min; Peng-Peng Qiao; Asan; Zhi-Hui Yan; Hui-Feng Jiang; Ya-Ping Zhu; Hui-Qian Du

    2016-01-01

    Background:Congenital cataract (CC) is the leading cause of visual impairment or blindness in children worldwide.Because of highly genetic and clinical heterogeneity,a molecular diagnosis of the lens disease remains a challenge.Methods:In this study,we tested a three-generation Chinese family with autosomal dominant CCs by targeted sequencing of 45 CC genes on next generation sequencing and evaluated the pathogenicity of the detected mutation by protein structure,pedigree validation,and molecular dynamics (MD) simulation.Results:A novel 15 bp deletion on GJA8 (c.426_440delGCTGGAGGGGACCCT or p.143_147delLEGTL) was detected in the family.The deletion,concemed with an in-frame deletion of 5 amino acid residues in a highly evolutionarily conserved region within the cytoplasmic loop domain of the gap junction channel protein connexin 50 (Cx50),was in full cosegregation with the cataract phenotypes in the family but not found in 1100 control exomes.MD simulation revealed that the introduction of the deletion destabilized the Cx50 gap junction channel,indicating the deletion as a dominant-negative mutation.Conclusions:The above results support the pathogenic role of the 15 bp deletion on GJA8 in the Chinese family and demonstrate targeted genes sequencing as a resolution to molecular diagnosis of CCs.

  16. A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth) mouse associated with autosomal dominant hearing loss in a Chinese family.

    Science.gov (United States)

    Zhao, Yali; Wang, Dayong; Zong, Liang; Zhao, Feifan; Guan, Liping; Zhang, Peng; Shi, Wei; Lan, Lan; Wang, Hongyang; Li, Qian; Han, Bing; Yang, Ling; Jin, Xin; Wang, Jian; Wang, Jun; Wang, Qiuju

    2014-01-01

    Mutations in the transmembrane channel-like gene 1 (TMC1) can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR) test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K) in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear.

  17. A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth mouse associated with autosomal dominant hearing loss in a Chinese family.

    Directory of Open Access Journals (Sweden)

    Yali Zhao

    Full Text Available Mutations in the transmembrane channel-like gene 1 (TMC1 can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear.

  18. Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.

    Science.gov (United States)

    Bonne, G; Mercuri, E; Muchir, A; Urtizberea, A; Bécane, H M; Recan, D; Merlini, L; Wehnert, M; Boor, R; Reuner, U; Vorgerd, M; Wicklein, E M; Eymard, B; Duboc, D; Penisson-Besnier, I; Cuisset, J M; Ferrer, X; Desguerre, I; Lacombe, D; Bushby, K; Pollitt, C; Toniolo, D; Fardeau, M; Schwartz, K; Muntoni, F

    2000-08-01

    Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease

  19. Solving a 50 year mystery of a missing OPA1 mutation: more insights from the first family diagnosed with autosomal dominant optic atrophy

    Directory of Open Access Journals (Sweden)

    Zrenner Eberhart

    2010-06-01

    Full Text Available Abstract Background Up to the 1950s, there was an ongoing debate about the diversity of hereditary optic neuropathies, in particular as to whether all inherited optic atrophies can be ascribed to Leber's hereditary optic neuropathy (LHON or represent different disease entities. In 1954 W. Jaeger published a detailed clinical and genealogical investigation of a large family with explicit autosomal dominant segregation of optic atrophy thus proving the existence of a discrete disease different from LHON, which is nowadays known as autosomal dominant optic atrophy (ADOA. Since the year 2000 ADOA is associated with genomic mutations in the OPA1 gene, which codes for a protein that is imported into mitochondria where it is required for mitochondrial fusion. Interestingly enough, the underlying mutation in this family has not been identified since then. Results We have reinvestigated this family with the aim to identify the mutation and to further clarify the underlying pathomechanism. Patients showed a classical non-syndromic ADOA. The long term deterioration in vision in the two teenagers examined 50 years later is of particular note 5/20 to 6/120. Multiplex ligation probe amplification revealed a duplication of the OPA1 exons 7-9 which was confirmed by long distance PCR and cDNA analysis, resulting in an in-frame duplication of 102 amino acids. Segregation was verified in 53 available members of the updated pedigree and a penetrance of 88% was calculated. Fibroblast cultures from skin biopsies were established to assess the mitochondrial network integrity and to qualitatively and quantitatively study the consequences of the mutation on transcript and protein level. Fibroblast cultures demonstrated a fragmented mitochondrial network. Processing of the OPA1 protein was altered. There was no correlation of the OPA1 transcript levels and the OPA1 protein levels in the fibroblasts. Intriguingly an overall decrease of mitochondrial proteins was observed

  20. Osteoclasts from patients with autosomal dominant osteopetrosis type I caused by a T253I mutation in low-density lipoprotein receptor-related protein 5 are normal in vitro, but have decreased resorption capacity in vivo

    DEFF Research Database (Denmark)

    Henriksen, Kim; Gram, Jeppe; Høegh-Andersen, Pernille;

    2005-01-01

    Autosomal dominant osteopetrosis type I (ADOI) is presumably caused by gain-of-function mutations in the LRP5 gene. Patients with a T253I mutation in LRP5 have a high bone mass phenotype, characterized by increased mineralizing surface index but abnormally low numbers of small osteoclasts...

  1. A novel splice site mutation of the arginine vasopressin-neurophysin II gene identified in a kindred with autosomal dominant familial neurohypophyseal diabetes insipidus.

    Science.gov (United States)

    Tae, Hyun-Jung; Baek, Ki-Hyun; Shim, Sun-Mi; Yoo, Soon-Jib; Kang, Moo-Il; Cha, Bong-Yun; Lee, Kwang-Woo; Son, Ho-Young; Kang, Sung-Koo

    2005-01-01

    Autosomal dominant familial neurohypophyseal diabetes insipidus is an inherited deficiency of arginine vasopressin (AVP), and this is caused by mutations in the AVP-neurophysin II (AVP-NP II) gene. Most of these mutations have been located in the signal peptide or in the NP II moiety. In the present study, we have analyzed the AVP-NP II gene in a Korean family. Clinical and genetic studies were performed on three members of the family, and on a normal healthy unrelated individual. The diagnosis of neurohypophyseal diabetes insipidus was done by performing a fluid deprivation test and a vasopressin challenge. For genetic analysis, the genomic DNA was extracted and the AVP-NP II gene was amplified by polymerase chain reaction (PCR). Clinical assessment of the affected individuals confirmed the diagnosis of neurohypophyseal diabetes insipidus. Genetic analysis of the AVP-NP II gene revealed a novel deletion mutation of a single nucleotide (guanine) within the splice acceptor site of intron 2 (IVS2 +1 delG). The affected individuals were heterozygous for this mutation. We also demonstrated through RT-PCR analysis of the mutant gene that this mutation resulted in the retention of intron 2 during pre-mRNA splicing. We concluded that a novel splicing mutation in the AVP-NP II gene causes neurohypophyseal diabetes insipidus in this family.

  2. Mislocalisation of BEST1 in iPSC-derived retinal pigment epithelial cells from a family with autosomal dominant vitreoretinochoroidopathy (ADVIRC)

    Science.gov (United States)

    Carter, David A.; Smart, Matthew J. K.; Letton, William V. G.; Ramsden, Conor M.; Nommiste, Britta; Chen, Li Li; Fynes, Kate; Muthiah, Manickam N.; Goh, Pollyanna; Lane, Amelia; Powner, Michael B.; Webster, Andrew R.; da Cruz, Lyndon; Moore, Anthony T.; Coffey, Peter J.; Carr, Amanda-Jayne F.

    2016-01-01

    Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare, early-onset retinal dystrophy characterised by distinct bands of circumferential pigmentary degeneration in the peripheral retina and developmental eye defects. ADVIRC is caused by mutations in the Bestrophin1 (BEST1) gene, which encodes a transmembrane protein thought to function as an ion channel in the basolateral membrane of retinal pigment epithelial (RPE) cells. Previous studies suggest that the distinct ADVIRC phenotype results from alternative splicing of BEST1 pre-mRNA. Here, we have used induced pluripotent stem cell (iPSC) technology to investigate the effects of an ADVIRC associated BEST1 mutation (c.704T > C, p.V235A) in patient-derived iPSC-RPE. We found no evidence of alternate splicing of the BEST1 transcript in ADVIRC iPSC-RPE, however in patient-derived iPSC-RPE, BEST1 was expressed at the basolateral membrane and the apical membrane. During human eye development we show that BEST1 is expressed more abundantly in peripheral RPE compared to central RPE and is also expressed in cells of the developing retina. These results suggest that higher levels of mislocalised BEST1 expression in the periphery, from an early developmental stage, could provide a mechanism that leads to the distinct clinical phenotype observed in ADVIRC patients. PMID:27653836

  3. The impact of the availability of prevention studies on the desire to undergo predictive testing in persons at risk for autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Hooper, Megan; Grill, Joshua D; Rodriguez-Agudelo, Yaneth; Medina, Luis D; Fox, Michelle; Alvarez-Retuerto, Ana Isabel; Wharton, David; Brook, Jenny; Ringman, John M

    2013-09-01

    Persons at risk for autosomal dominant neurodegenerative diseases provide the opportunity to efficiently test preventive interventions. Only a minority of such persons, however, choose to undergo revealing genetic testing, presenting a challenge to enrollment. Thirty-four preclinical Latinos (n = 26) and non-Latinos at risk for familial Alzheimer's disease (FAD) unaware of their genetic status were administered a questionnaire exploring their interest in undergoing revealing genetic testing at baseline and in the context of eligibility for four prevention trials of increasing invasiveness. Forty-four percent of subjects expressed a baseline interest in undergoing revealing testing which increased to 85% in order to be eligible for a study of an oral drug "felt to be very safe." If there were a 50% chance of receiving placebo, this number dropped to 62% (p = 0.02). Among those not interested in a study involving a 50% chance of receiving placebo, a range of 5% to 40% chance of receiving placebo was given as acceptable. For more invasive studies, living in the United States (as opposed to Mexico) positively influenced the likelihood of participating. Our data suggest that clinical trial designs in which persons must confront their genetic status prior to enrollment are feasible. Study designs to minimize the likelihood of being placed on placebo or provide the eventual administration of the drug through open-label extensions should be considered.

  4. Exome sequencing identifies a novel frameshift mutation of MYO6 as the cause of autosomal dominant nonsyndromic hearing loss in a Chinese family.

    Science.gov (United States)

    Cheng, Jing; Zhou, Xueya; Lu, Yu; Chen, Jing; Han, Bing; Zhu, Yuhua; Liu, Liyang; Choy, Kwong-Wai; Han, Dongyi; Sham, Pak C; Zhang, Michael Q; Zhang, Xuegong; Yuan, Huijun

    2014-11-01

    Autosomal dominant types of nonsyndromic hearing loss (ADNSHL) are typically postlingual in onset and progressive. High genetic heterogeneity, late onset age, and possible confounding due to nongenetic factors hinder the timely molecular diagnoses for most patients. In this study, exome sequencing was applied to investigate a large Chinese family segregating ADNSHL in which we initially failed to find strong evidence of linkage to any locus by whole-genome linkage analysis. Two affected family members were selected for sequencing. We identified two novel mutations disrupting known ADNSHL genes and shared by the sequenced samples: c.328C>A in COCH (DFNA9) resulting in a p.Q110K substitution and a deletion c. 2814_2815delAA in MYO6 (DFNA22) causing a frameshift alteration p.R939Tfs*2. The pathogenicity of novel coding variants in ADNSHL genes was carefully evaluated by analysis of co-segregation with phenotype in the pedigree and in light of established genotype-phenotype correlations. The frameshift deletion in MYO6 was confirmed as the causative variant for this pedigree, whereas the missense mutation in COCH had no clinical significance. The results allowed us to retrospectively identify the phenocopy in one patient that contributed to the negative finding in the linkage scan. Our clinical data also supported the emerging genotype-phenotype correlation for DFNA22.

  5. Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation.

    Science.gov (United States)

    Frykholm, Carina; Klar, Joakim; Arnesson, Hanna; Rehnman, Anna-Carin; Lodahl, Marianne; Wedén, Ulla; Dahl, Niklas; Tranebjærg, Lisbeth; Rendtorff, Nanna D

    2015-05-25

    Linkage to an interval overlapping the DFNA10 locus on chromosome 6q22-23 was found through genome wide linkage analysis in a seven-generation Swedish family segregating postlingual, autosomal dominant nonsyndromic sensorineural hearing impairment. A novel heterozygous frame-shift mutation (c.579_580insTACC, p.(Asp194Tyrfs*52)) in EYA4 was identified that truncates the so-called variable region of the protein. The mutation is predicted to result in haploinsufficiency of the EYA4 product. No evidence for dilated cardiomyopathy was found in the family, contrasting to a previous family with a deletion resulting in a similar truncation in the variable region. A highly variable age of onset was seen in the mutation carriers. For assessment of the aetiology of this variability, clinical and audiometric data analyses were performed. The affected family members all had similar cross-sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DFNA10 family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy.

  6. A novel locus (CORD12 for autosomal dominant cone-rod dystrophy on chromosome 2q24.2-2q33.1

    Directory of Open Access Journals (Sweden)

    Meunier Isabelle

    2011-04-01

    Full Text Available Abstract Background Rod-cone dystrophy, also known as retinitis pigmentosa (RP, and cone-rod dystrophy (CRD are degenerative retinal dystrophies leading to blindness. To identify new genes responsible for these diseases, we have studied one large non consanguineous French family with autosomal dominant (ad CRD. Methods Family members underwent detailed ophthalmological examination. Linkage analysis using microsatellite markers and a whole-genome SNP analysis with the use of Affymetrix 250 K SNP chips were performed. Five candidate genes within the candidate region were screened for mutations by direct sequencing. Results We first excluded the involvement of known adRP and adCRD genes in the family by genotyping and linkage analysis. Then, we undertook a whole-genome scan on 22 individuals in the family. The analysis revealed a 41.3-Mb locus on position 2q24.2-2q33.1. This locus was confirmed by linkage analysis with specific markers of this region. The maximum LOD score was 2.86 at θ = 0 for this locus. Five candidate genes, CERKL, BBS5, KLHL23, NEUROD1, and SF3B1 within this locus, were not mutated. Conclusion A novel locus for adCRD, named CORD12, has been mapped to chromosome 2q24.2-2q33.1 in a non consanguineous French family.

  7. Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma.

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    Donna S Mackay

    Full Text Available Primary open-angle glaucoma (POAG is a clinically important and genetically heterogeneous cause of progressive vision loss as a result of retinal ganglion cell death. Here we have utilized trio-based, whole-exome sequencing to identify the genetic defect underlying an autosomal dominant form of adult-onset POAG segregating in an African-American family. Exome sequencing identified a novel missense variant (c.418C>T, p.Arg140Trp in exon-5 of the gene coding for epidermal growth factor (EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1 that co-segregated with disease in the family. Linkage and haplotype analyses with microsatellite markers indicated that the disease interval overlapped a known POAG locus (GLC1H on chromosome 2p. The p.Arg140Trp substitution was predicted in silico to have damaging effects on protein function and transient expression studies in cultured cells revealed that the Trp140-mutant protein exhibited increased intracellular accumulation compared with wild-type EFEMP1. In situ hybridization of the mouse eye with oligonucleotide probes detected the highest levels of EFEMP1 transcripts in the ciliary body, cornea, inner nuclear layer of the retina, and the optic nerve head. The recent finding that a common variant near EFEMP1 was associated with optic nerve-head morphology supports the possibility that the EFEMP1 variant identified in this POAG family may be pathogenic.

  8. Heterogeneidade genética em atrofia óptica autossômica dominante Genetic heterogeneity in autosomal dominant optic atrophy

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    Juliana Maria Ferraz Sallum

    2002-08-01

    locus para esta doença.Purpose: Autosomal dominant optic atrophy is a hereditary optic neuropathy characterized by progressive visual loss in childhood, color vision anomalies, visual field defects and temporal pallor of the optic disc. This disease has been mapped to a 1.4 cM interval in chromosome 3q28-29 between markers D3S3669 and D3S3562. One family was mapped to chromosome 18q12.2-12.3. Linkage analysis in three families with autosomal dominant optic atrophy with polymorphic DNA markers for chromosome 3q28-29 and 18q12.2-12.3. Methods: 57 individuals from three families underwent ophthalmological examination. Genomic DNA was extracted from blood samples. Linkage analysis was performed between the disease and 11 polymorphic markers around 3q28-qter and 18q12.2-12.3. Polymerase chain reaction (PCR fragments sizes were identified in a scanner gel using a 373 DNA sequencer. These numbers were used as alleles for pedigree analysis. The lod scores were calculated using the MLINK program. Results: All three families presented optic atrophy with autosomal dominant pattern of inheritance, variable expression and high penetrance. Two families were linked to 3q28-29 markers. A maximal lod score of 3.56, at a recombination fraction of zero, was obtained using the marker D3S3669 in one family. The linkage area was defined in a 2 cM interval by haplotype analysis between markers D3S2418 and D3S1305, because patients III.4 and III.14 showed crossing-overs. The third family was not linked to 3q28-29 neither to 18q12.2-12.3. Conclusions: There is genetic heterogeneity in autosomal dominant optic atrophy, because the third family did not map to any known locus. And a third locus for this disease may exist.

  9. RHO Mutations (p.W126L and p.A346P in Two Japanese Families with Autosomal Dominant Retinitis Pigmentosa

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    Satoshi Katagiri

    2014-01-01

    Full Text Available Purpose. To investigate genetic and clinical features of patients with rhodopsin (RHO mutations in two Japanese families with autosomal dominant retinitis pigmentosa (adRP. Methods. Whole-exome sequence analysis was performed in ten adRP families. Identified RHO mutations for the cosegregation analysis were confirmed by Sanger sequencing. Ophthalmic examinations were performed to evaluate the RP phenotypes. The impact of the RHO mutation on the rhodopsin conformation was examined by molecular modeling analysis. Results. In two adRP families, we identified two RHO mutations (c.377G>T (p.W126L and c.1036G>C (p.A346P, one of which was novel. Complete cosegregation was confirmed for each mutation exhibiting the RP phenotype in both families. Molecular modeling predicted that the novel mutation (p.W126L might impair rhodopsin function by affecting its conformational transition in the light-adapted form. Clinical phenotypes showed that patients with p.W126L exhibited sector RP, whereas patients with p.A346P exhibited classic RP. Conclusions. Our findings demonstrated that the novel mutation (p.W126L may be associated with the phenotype of sector RP. Identification of RHO mutations is a very useful tool for predicting disease severity and providing precise genetic counseling.

  10. Identification of a Novel Mutation in BRD4 that Causes Autosomal Dominant Syndromic Congenital Cataracts Associated with Other Neuro-Skeletal Anomalies

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    Jin, Hyun-Seok; Kim, Jeonhyun; Kwak, Woori; Jeong, Hyeonsoo; Lim, Gyu-Bin

    2017-01-01

    Congenital cataracts can occur as a non-syndromic isolated ocular disease or as a part of genetic syndromes accompanied by a multi-systemic disease. Approximately 50% of all congenital cataract cases have a heterogeneous genetic basis. Here, we describe three generations of a family with an autosomal dominant inheritance pattern and common complex phenotypes, including bilateral congenital cataracts, short stature, macrocephaly, and minor skeletal anomalies. We did not find any chromosomal aberrations or gene copy number abnormalities using conventional genetic tests; accordingly, we conducted whole-exome sequencing (WES) to identify disease-causing genetic alterations in this family. Based on family WES data, we identified a novel BRD4 missense mutation as a candidate causal variant and performed cell-based experiments by ablation of endogenous BRD4 expression in human lens epithelial cells. The protein expression levels of connexin 43, p62, LC3BII, and p53 differed significantly between control cells and cells in which endogenous BRD4 expression was inhibited. We inferred that a BRD4 missense mutation was the likely disease-causing mutation in this family. Our findings may improve the molecular diagnosis of congenital cataracts and support the use of WES to clarify the genetic basis of complex diseases. PMID:28076398

  11. Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis

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    Radhakrishna, U.; Mehenni, H.; Antonarakis, S.E. [Geneva Medical School (Switzerland)] [and others

    1997-03-01

    Postaxial polydactyly type-A (PAP-A) in humans is an autosomal dominant trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is well formed and articulates with the fifth, or extra, metacarpal/metatarsal, and thus it is usually functional. In order to map the gene responsible for PAP-A, we studied a five-generation Indian family of 37 individuals (15 of whom were affected). A genomewide search with highly informative polymorphic markers on part of the pedigree showed linkage between the PAP-A phenotype and markers on chromosome 7p15-q11.23 (no crossovers were found with D7S526, D7S795, D7S528, D7S521, D7S691, D7S667, D7S478, D7S1830, D7S803, D7S801, or ELN). The highest LOD score was obtained with marker D7S801 (Z{sub max} = 4.21; {theta} = 0). Haplotype analysis enabled the mapping of the PAP-A phenotype in this family between markers D7S2848 and D7S669. Analysis of additional families with PAP-A will narrow down the critical genomic region, facilitate positional cloning of the PAP-A gene, and/or uncover potential genetic heterogeneity. 42 refs., 4 figs., 1 tab.

  12. SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15.

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    Hee-Jin Kim

    Full Text Available Autosomal dominant non-syndromic hearing loss (AD-NSHL is one of the most common genetic diseases in human and is well-known for the considerable genetic heterogeneity. In this study, we utilized whole exome sequencing (WES and linkage analysis for direct genetic diagnosis in AD-NSHL. The Korean family had typical AD-NSHL running over 6 generations. Linkage analysis was performed by using genome-wide single nucleotide polymorphism (SNP chip and pinpointed a genomic region on 5q31 with a significant linkage signal. Sequential filtering of variants obtained from WES, application of the linkage region, bioinformatic analyses, and Sanger sequencing validation identified a novel missense mutation Arg326Lys (c.977G>A in the POU homeodomain of the POU4F3 gene as the candidate disease-causing mutation in the family. POU4F3 is a known disease gene causing AD-HSLH (DFNA15 described in 5 unrelated families until now each with a unique mutation. Arg326Lys was the first missense mutation affecting the 3(rd alpha helix of the POU homeodomain harboring a bipartite nuclear localization signal sequence. The phenotype findings in our family further supported previously noted intrafamilial and interfamilial variability of DFNA15. This study demonstrated that WES in combination with linkage analysis utilizing bi-allelic SNP markers successfully identified the disease locus and causative mutation in AD-NSHL.

  13. The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis.

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    Petit, Florence; Jourdain, Anne-Sophie; Holder-Espinasse, Muriel; Keren, Boris; Andrieux, Joris; Duterque-Coquillaud, Martine; Porchet, Nicole; Manouvrier-Hanu, Sylvie; Escande, Fabienne

    2016-01-01

    The expression gradient of the morphogen Sonic Hedgehog (SHH) is crucial in establishing the number and the identity of the digits during anteroposterior patterning of the limb. Its anterior ectopic expression is responsible for preaxial polydactyly (PPD). Most of these malformations are due to the gain-of-function of the Zone of Polarizing Activity Regulatory Sequence, the only limb-specific enhancer of SHH known to date. We report a family affected with a novel condition associating PPD and hypertrichosis of the upper back, following an autosomal dominant mode of inheritance. This phenotype is consistent with deregulation of SHH expression during limb and follicle development. In affected members, we identified a 2 kb deletion located ~240 kb upstream from the SHH promoter. The deleted sequence is capable of repressing the transcriptional activity of the SHH promoter in vitro, consistent with a silencer activity. We hypothesize that the deletion of this silencer could be responsible for SHH deregulation during development, leading to a PPD-hypertrichosis phenotype.

  14. A missense mutation in the alpha-actinin 1 gene (ACTN1 is the cause of autosomal dominant macrothrombocytopenia in a large French family.

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    Paul Guéguen

    Full Text Available Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22 with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln in the alpha-actinin 1 gene (ACTN1 that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes.

  15. Cystogenic potential of CD133+ progenitor cells of human polycystic kidneys.

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    Carvalhosa, Raquel; Deambrosis, Ilaria; Carrera, Paola; Pasquino, Chiara; Rigo, Francesca; Ferrari, Maurizio; Lasaponara, Fedele; Ranghino, Andrea; Biancone, Luigi; Segoloni, Giuseppe; Bussolati, Benedetta; Camussi, Giovanni

    2011-09-01

    In autosomal dominant polycystic kidney disease, cysts arise focally and disrupt normal renal tissue leading to renal failure. In the present study, we show that cyst-lining cells express the stem cell marker CD133. CD133+ progenitor cells isolated from polycystic kidney, carrying mutations of PKD genes, showed a dedifferentiated phenotype similar to CD133+ progenitor cells from normal kidney. However, these cells were more proliferative and presented a defective epithelial differentiation phenotype with respect to normal renal CD133+ cells as they were not able to express all tubular epithelial cell markers when cultured in epithelial differentiation medium. Polycystic CD133+ cells, in contrast to normal renal CD133+ cells, formed cysts in vitro in a three-dimensional culture system and in vivo when injected subcutaneously within Matrigel in SCID mice. Rapamycin treatment reduced in vitro proliferation of polycystic CD133+ cells and decreased cystogenesis both in vitro and in vivo. The in vitro epithelial differentiation was only partially improved by rapamycin. These results indicate that polycystic CD133+ cells retain a dedifferentiated phenotype and the ability to generate cysts.

  16. Association between Nephrolithiasis, Hypertension and Obesity in Polycystic Kidney Disease

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    Valbona Bajrami

    2015-12-01

    Full Text Available AIM: We aim to define the correlations between nephrolithiasis, hypertension, age and obesity in patients with autosomal dominant polycystic kidney disease (ADPKD in Albania. MATERIAL AND METHODS: We included 100 patients with autosomal dominant polycystic kidney from 2011 to 2014. The patients underwent X-ray and renal ultrasonography. We performed the metabolic evaluation of blood and urine. RESULTS: The patients with renal stones had a higher level of mean systolic and diastolic blood pressure compared with patients without stones (155 ± 12 mmHg vs. 145 ± 8 mmHg, and 105 ± 0.9 mmHg vs. 92 ± 1.28 mmHg, respectively. Patients with renal stones were older (47 ± 15 vs. 38 ± 5 years, had a higher prevalence of obesity [body mass index (BMI: 28 ± 2.4 vs. 25.7 ± 0.6], had higher levels of total cholesterol level (220 ± 5 mg/dl vs. 203 ± 4 mg/dl as well as triglyceride levels (160 ± 9 mg/dl vs. 126 ± 4 mg/dl, compared with no renal stone individuals. CONCLUSION: ADPKD patients with renal stones in our study had a higher mean level of systolic and diastolic blood pressure, BMI and cholesterol and triglycerides levels compared with individuals without renal stones.

  17. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease.

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    Boertien, Wendy E; Meijer, Esther; de Jong, Paul E; Bakker, Stephan J L; Czerwiec, Frank S; Struck, Joachim; Oberdhan, Dorothee; Shoaf, Susan E; Krasa, Holly B; Gansevoort, Ron T

    2013-12-01

    Vasopressin V2-receptor antagonists may delay disease progression in ADPKD. Trials with V2-receptor antagonists have been performed predominantly in patients with an estimated creatinine clearance of 60 ml/min or more. Here we determined renal hemodynamic effects of the V2-receptor antagonist tolvaptan in 27 patients with ADPKD at various stages of chronic kidney disease: group A: >60, group B: 30-60, and group C: chronic kidney disease stages 1 through 4, but minor GFR drops may be observed in individual patients.

  18. Estimating glomerular filtration rate using the new CKD-EPI equation and other equations in patients with autosomal dominant polycystic kidney disease

    DEFF Research Database (Denmark)

    Orskov, Bjarne; Strandgaard, Svend; Ørskov, Bjarne;

    2010-01-01

    (CKD-EPI) equation, the Cockcroft-Gault equation adjusted for body surface area and the MDRD equation with cystatin C. Performance was evaluated by mean bias, precision and accuracy. RESULTS: The MDRD equation with cystatin C had 97% of GFR estimates within 30% of measured GFR (accuracy). Both the CKD......-EPI and Cockcroft-Gault equations had an accuracy of 90% whereas the MDRD equation had an accuracy of 83%. This difference of accuracy was especially marked with GFR >60 ml/min/1.73 m(2). CONCLUSION: For estimating GFR in ADPKD patients the MDRD equation with cystatin C incorporated had the best performance...

  19. Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH).

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    Dong, Bingzi; Endo, Itsuro; Ohnishi, Yukiyo; Kondo, Takeshi; Hasegawa, Tomoka; Amizuka, Norio; Kiyonari, Hiroshi; Shioi, Go; Abe, Masahiro; Fukumoto, Seiji; Matsumoto, Toshio

    2015-11-01

    Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a

  20. Three novel and the common Arg677Ter RP1 protein truncating mutations causing autosomal dominant retinitis pigmentosa in a Spanish population

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    Antiñolo Guillermo

    2006-04-01

    Full Text Available Abstract Background Retinitis pigmentosa (RP, a clinically and genetically heterogeneous group of retinal degeneration disorders affecting the photoreceptor cells, is one of the leading causes of genetic blindness. Mutations in the photoreceptor-specific gene RP1 account for 3–10% of cases of autosomal dominant RP (adRP. Most of these mutations are clustered in a 500 bp region of exon 4 of RP1. Methods Denaturing gradient gel electrophoresis (DGGE analysis and direct genomic sequencing were used to evaluate the 5' coding region of exon 4 of the RP1 gene for mutations in 150 unrelated index adRP patients. Ophthalmic and electrophysiological examination of RP patients and relatives according to pre-existing protocols were carried out. Results Three novel disease-causing mutations in RP1 were detected: Q686X, K705fsX712 and K722fsX737, predicting truncated proteins. One novel missense mutation, Thr752Met, was detected in one family but the mutation does not co-segregate in the family, thereby excluding this amino acid variation in the protein as a cause of the disease. We found the Arg677Ter mutation, previously reported in other populations, in two independent families, confirming that this mutation is also present in a Spanish population. Conclusion Most of the mutations reported in the RP1 gene associated with adRP are expected to encode mutant truncated proteins that are approximately one third or half of the size of wild type protein. Patients with mutations in RP1 showed mild RP with variability in phenotype severity. We also observed several cases of non-penetrant mutations.

  1. Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity

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    Othmane, K.B.; Loprest, L.J.; Wilkinson, K.M. (Duke Univ. Medical Center, Durham, NC (United States)); Middleton, L.T. (Cyprus Institute of Neurology and Genetics, Nicosia (Cyprus)) (and others)

    1993-08-01

    Charcot-Marie-Tooth (CMT) disease type 2 (CMT2) is an inherited peripheral neuropathy characterized by variable age of onset and normal or slightly diminished nerve conduction velocity. CMT2 is pathologically and genetically distinct from CMT type 1 (CMT1). While CMT1 has been shown to be genetically heterogeneous, no chromosomal localization has been established for CMT2. The authors have performed pedigree linkage analysis in six large autosomal dominant CMT2 families and have demonstrated linkage and heterogeneity to a series of microsatellites (D1S160, D1S170, D1S244, D1S228 and D1S199) in the distal region of the short arm of chromosome 1. Significant evidence for heterogeneity was found using admixture analyses and the two-point lod scores. Admixture analyses using the multipoint results for the markers D1S244, D1S228, and D1S199 supported the two-point findings. Three families, DUK662, DUK1241, and 1523 gave posterior probabilities of 1.0, 0.98, and 0.88 of being of the linked type. Multipoint analysis examining the [open quotes]linked[close quotes] families showed that the most favored location for the CMT2A gene is within the interval flanked by D1S244 and D1S228 (odds approximately 70:1 of lying within versus outside that interval). These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrate further heterogeneity in the CMT phenotype.

  2. N-CAM dysfunction and unexpected accumulation of PSA-NCAM in brain of adult-onset autosomal-dominant leukodystrophy.

    Science.gov (United States)

    Piccinini, Marco; Buccinnà, Barbara; De Marco, Giovanni; Lupino, Elisa; Ramondetti, Cristina; Grifoni, Silvia; Votta, Barbara; Giordana, Maria Teresa; Rinaudo, Maria Teresa

    2010-03-01

    Previously, myelin from cerebral white matter (CWM) of two subjects of a family with orthochromatic adult-onset autosomal-dominant leukodystrophy (ADLD) was disclosed to exhibit defective large isoform of myelin-associated glycoprotein (L-MAG) and patchy distribution only in the elder subject. L-MAG and neural cell adhesion molecule (N-CAM) (N-CAM 180, 140, and 120) are structurally related and concur to myelin/axon interaction. In early developmental stages, in neurons and glia N-CAM is converted into polysialylated (PSA)-NCAM by two sialyltransferases sialyltransferase-X (STX) and polysialyltransferase-1 (PST). Notably, PSA-NCAM disrupts N-CAM adhesive properties and is nearly absent in the adult brain. Here, CWM extracts and myelin of the two subjects were searched for the expression pattern of the N-CAM isoforms and PSA-NCAM, and their CWM was evaluated for N-CAM, STX and PST gene copy number and gene expression as mRNA. Biochemically, we disclosed that in CWM extracts and myelin from both subjects, PSA-NCAM accumulates, N-CAM 180 considerably increases, N-CAM 140 is modestly modified and N-CAM 120 remarkably decreases; duplication of genes encoding N-CAM, STX and PST was not revealed, whereas PST mRNA was clearly increased. Immunohistochemically, in CWM of both subjects, we found an unusually diffuse accumulation of PSA-NCAM without inflammation markers. PSA-NCAM persistence, up-regulated PST mRNA and previously uncovered defective L-MAG may be early pathogenetic events in this ADLD form.

  3. Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.

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    Takehiko Naito

    Full Text Available The present study of KCNQ4 mutations was carried out to 1 determine the prevalence by unbiased population-based genetic screening, 2 clarify the mutation spectrum and genotype/phenotype correlations, and 3 summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287. While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions.

  4. Modeling of autosomal-dominant retinitis pigmentosa in Caenorhabditis elegans uncovers a nexus between global impaired functioning of certain splicing factors and cell type-specific apoptosis.

    Science.gov (United States)

    Rubio-Peña, Karinna; Fontrodona, Laura; Aristizábal-Corrales, David; Torres, Silvia; Cornes, Eric; García-Rodríguez, Francisco J; Serrat, Xènia; González-Knowles, David; Foissac, Sylvain; Porta-De-La-Riva, Montserrat; Cerón, Julián

    2015-12-01

    Retinitis pigmentosa (RP) is a rare genetic disease that causes gradual blindness through retinal degeneration. Intriguingly, seven of the 24 genes identified as responsible for the autosomal-dominant form (adRP) are ubiquitous spliceosome components whose impairment causes disease only in the retina. The fact that these proteins are essential in all organisms hampers genetic, genomic, and physiological studies, but we addressed these difficulties by using RNAi in Caenorhabditis elegans. Our study of worm phenotypes produced by RNAi of splicing-related adRP (s-adRP) genes functionally distinguishes between components of U4 and U5 snRNP complexes, because knockdown of U5 proteins produces a stronger phenotype. RNA-seq analyses of worms where s-adRP genes were partially inactivated by RNAi, revealed mild intron retention in developing animals but not in adults, suggesting a positive correlation between intron retention and transcriptional activity. Interestingly, RNAi of s-adRP genes produces an increase in the expression of atl-1 (homolog of human ATR), which is normally activated in response to replicative stress and certain DNA-damaging agents. The up-regulation of atl-1 correlates with the ectopic expression of the pro-apoptotic gene egl-1 and apoptosis in hypodermal cells, which produce the cuticle, but not in other cell types. Our model in C. elegans resembles s-adRP in two aspects: The phenotype caused by global knockdown of s-adRP genes is cell type-specific and associated with high transcriptional activity. Finally, along with a reduced production of mature transcripts, we propose a model in which the retina-specific cell death in s-adRP patients can be induced through genomic instability.

  5. Structure-Function Modeling of Optical Coherence Tomography and Standard Automated Perimetry in the Retina of Patients with Autosomal Dominant Retinitis Pigmentosa.

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    Travis B Smith

    Full Text Available To assess relationships between structural and functional biomarkers, including new topographic measures of visual field sensitivity, in patients with autosomal dominant retinitis pigmentosa.Spectral domain optical coherence tomography line scans and hill of vision (HOV sensitivity surfaces from full-field standard automated perimetry were semi-automatically aligned for 60 eyes of 35 patients. Structural biomarkers were extracted from outer retina b-scans along horizontal and vertical midlines. Functional biomarkers were extracted from local sensitivity profiles along the b-scans and from the full visual field. These included topographic measures of functional transition such as the contour of most rapid sensitivity decline around the HOV, herein called HOV slope for convenience. Biomarker relationships were assessed pairwise by coefficients of determination (R2 from mixed-effects analysis with automatic model selection.Structure-function relationships were accurately modeled (conditional R(2>0.8 in most cases. The best-fit relationship models and correlation patterns for horizontally oriented biomarkers were different than vertically oriented ones. The structural biomarker with the largest number of significant functional correlates was the ellipsoid zone (EZ width, followed by the total photoreceptor layer thickness. The strongest correlation observed was between EZ width and HOV slope distance (marginal R(2 = 0.85, p<10(-10. The mean sensitivity defect at the EZ edge was 7.6 dB. Among all functional biomarkers, the HOV slope mean value, HOV slope mean distance, and maximum sensitivity along the b-scan had the largest number of significant structural correlates.Topographic slope metrics show promise as functional biomarkers relevant to the transition zone. EZ width is strongly associated with the location of most rapid HOV decline.

  6. Identification of Two Disease-causing Genes TJP2 and GJB2 in a Chinese Family with Unconditional Autosomal Dominant Nonsyndromic Hereditary Hearing Impairment

    Institute of Scientific and Technical Information of China (English)

    Hong-Yang Wang; Ya-Li Zhao; Qiong Liu; Hu Yuan; Yun Gao; Lan Lan; Lan Yu

    2015-01-01

    Background: There are more than 300 genetic loci that have been found to be related to hereditary hearing impairment (HHI), including 92 causative genes for nonsyndromic hearing loss, among which 34 genes are related to autosomal dominant nonsyndromic HHI (ADNSHHI).Traditional linkage analysis and candidate gene sequencing are not effective at detecting the ADNSHHI, especially for the unconditional families that may have more than one pathogenic cause.This study identified two disease-causing genes TJP2 and GJB2 in a Chinese family with unconditional ADNSHHI.Methods: To decipher the genetic code of a Chinese family (family 686) with ADNSHHI, different gene screening techniques have been performed, including linkage analysis, candidate genes screening, high-throughput sequencing and Sanger sequencing.These techniques were done on samples obtained from this family over a period of 10 years.Results: We identified a pathogenic missense mutation, c.2081G>A (p.G694E), in TJP2, a gene that plays a crucial role in apoptosis and age-related hearing loss (ARHL).The mutation was co-segregated in this pedigree in all, but not in the two patients who presented with different phenotypes from the other affected family members.In one of the two patients, we confirmed that the compound heterozygosity for p.Y136* and p.G45E in the GJB2 gene may account for the phenotype shown in this patient.Conclusions: We identified the co-occurrence of two genetic causes in family 686.The possible disease-causing missense mutation of TJP2 in family 686 presents an opportunity for further investigation into ARHL.It is necessary to combine various genes screening methods, especially for some unconventional cases.

  7. Recurrent De Novo Mutations Affecting Residue Arg1 38 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

    NARCIS (Netherlands)

    Fischer-Zirnsak, Bjoern; Escande-Beillard, Nathalie; Ganesh, Jaya; Tan, Yu Xuan; Al Bughaili, Mohammed; Lin, Angela E.; Sahai, Inderneel; Bahena, Paulina; Reichert, Sara L.; Loh, Abigail; Wright, Graham D.; Liu, Jaron; Rahikkala, Elisa; Pivnick, Eniko K.; Choudhri, Asim F.; Krueger, Ulrike; Zemojtel, Tomasz; van Ravenswaaij-Arts, Conny; Mostafavi, Roya; Stolte-Dijkstra, Irene; Symoens, Sofie; Pajunen, Leila; Al-Gazali, Lihadh; Meierhofer, David; Robinson, Peter N.; Mundlos, Stefan; Villarroel, Camilo E.; Byers, Peter; Masri, Amira; Robertson, Stephen P.; Schwarze, Ulrike; Callewaert, Bert; Reversade, Bruno; Kornak, Uwe

    2015-01-01

    Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively,

  8. Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys.

    Science.gov (United States)

    Schwiebert, Erik M; Wallace, Darren P; Braunstein, Gavin M; King, Sandi R; Peti-Peterdi, Janos; Hanaoka, Kazushige; Guggino, William B; Guay-Woodford, Lisa M; Bell, P Darwin; Sullivan, Lawrence P; Grantham, Jared J; Taylor, Amanda L

    2002-04-01

    ATP and its metabolites are potent autocrine agonists that act extracellularly within tissues to affect epithelial function. In polycystic kidneys, renal tubules become dilated and/or encapsulated as cysts, creating abnormal microenvironments for autocrine signaling. Previously, our laboratory has shown that high-nanomolar to micromolar quantities of ATP are released from cell monolayers in vitro and detectable in cyst fluids from microdissected human autosomal dominant polycystic kidney (ADPKD) cysts. Here, we show enhanced ATP release from autosomal recessive polycystic kidney (ARPKD) and ADPKD epithelial cell models. RT-PCR and immunoblotting for P2Y G protein-coupled receptors and P2X purinergic receptor channels show expression of mRNA and/or protein for multiple subtypes from both families. Assays of cytosolic Ca(2+) concentration and secretory Cl(-) transport show P2Y and P2X purinergic receptor-mediated stimulation of Cl(-) secretion via cytosolic Ca(2+)-dependent signaling. Therefore, we hypothesize that autocrine purinergic signaling may augment detrimentally cyst volume expansion in ADPKD or tubule dilation in ARPKD, accelerating disease progression.

  9. Tuberous sclerosis complex and polycystic kidney disease contiguous gene syndrome with Moyamoya disease.

    Science.gov (United States)

    Lai, Jonathan; Modi, Lopa; Ramai, Daryl; Tortora, Matthew

    2017-04-01

    Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are two diseases sharing close genetic loci on chromosome 16. Due to contiguous gene syndrome, also known as contiguous gene deletion syndrome, the proximity of TSC2 and PKD1 genes increases the risk of co-deletion resulting in a shared clinical presentation. Furthermore, Moyamoya disease (MMD) is a rare vaso-occlusive disease in the circle of Willis. We present the first case of TSC2/PKD1 contiguous gene syndrome in a patient with MMD along with detailed histopathologic, radiologic, and cytogenetic analyses. We also highlight the clinical presentation and surgical complications in this case.

  10. Aspectos clínicos da doença renal policística autossômica recessiva DRPAR Clinical aspects of autosomal recessive polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Natasha Favoretto Dias

    2010-09-01

    Full Text Available INTRODUÇÃO: A Doença Renal Policística Autossômica Recessiva (DRPAR é uma causa importante de morbidade e mortalidade pediátricas, com um espectro variável de manifestações clínicas. MÉTODOS: A apresentação e evolução clínica de 25 pacientes (Pts foram analisadas através da revisão de prontuários, aplicando-se os formulários propostos por Guay-Woodford et al. As morbidades associadas à doença foram avaliadas quanto à frequência e à idade de manifestação. RESULTADOS: A idade média de diagnóstico foi de 61,45 meses (0 a 336,5 meses, com distribuição similar entre os sexos (52% dos pts do sexo feminino. Houve histórico familiar da doença em 20% dos casos (5/25, com dois casos de consanguinidade. Na análise inicial, diagnosticou-se hipertensão arterial (HAS em 56% dos Pts (14/25; doença renal crônica estágio > 2 (DRC > 2 em 24% (6/25; infecções do trato urinário (ITU em 40% (10/25 e hipertensão portal (HP em 32% dos casos (8/25. Das ultrassonografias abdominais iniciais, 80% demonstraram rins ecogênicos com cistos grosseiros e 64% detectaram fígado e vias biliares normais. Inibidores da ECA foram utilizados em 36% dos Pts, betabloqueadores em 20%, bloqueadores de canais de cálcio em 28% e diuréticos em 36% dos casos. Na análise final, após um tempo de acompanhamento médio de 152,2 meses (29,8 a 274,9 meses, HAS foi diagnosticada em 76% dos Pts, DRC > 2 em 44%, ITU em 52% e HP em 68%. CONCLUSÃO: As altas morbidade e mortalidade associadas à DRPAR justificam a construção de um banco de dados internacional, visando ao estabelecimento de um tratamento de suporte precoce.INTRODUCTION: Autosomal Recessive Polycystic Kidney Disease (ARPKD is an important pediatric cause of morbidity and mortality, with a variable clinical spectrum. METHODS: The clinical presentation and evolution of 25 patients (Pts were analyzed by clinical record review, according to the forms proposed by Guay-Woodford et al

  11. Sex-linked dominant

    Science.gov (United States)

    Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... can be either an autosomal chromosome or a sex chromosome. It also depends on whether the trait ...

  12. Refinement of the OPA1 gene locus on chromosome 3q28-q29 to a region of 2-8 cM, in one Cuban pedigree with autosomal dominant optic atrophy type Kjer

    Energy Technology Data Exchange (ETDEWEB)

    Lunkes, A.; Hartung, U.; Auburger, G. [Univ. Hospital Duesseldorf (Germany)] [and others

    1995-10-01

    Kjer type autosomal dominant optic atrophy was reported to have a prevalence of 1:50,000 and is therefore the most common form of familial optic atrophy. Age at onset and chronic progressive course were used as subclassification criteria by Kjer, Jaeger, and Smith, stating that almost all cases manifested subacutely before 8 years of age. Typically, tritan color defects and small paracentral scotomas are found together with both variable reduction of visual acuity, of approximately 0.3/0.1, and a temporal pallor on fundoscopy. Pathologically the retinal ganglion cells are affected, resulting in a progressive degeneration of the optic nerve. 12 refs., 1 fig., 1 tab.

  13. Refined genetic mapping of autosomal dominant retinitis pigmentosa locus RP18 reduces the critical region to 2 cM between D1S442 and D1S2858 on chromosome 1q.

    Science.gov (United States)

    Xu, S Y; Rosenberg, T; Gal, A

    1998-04-01

    Linkage analysis was performed on a large Danish family to refine the position of RP18, the locus for autosomal dominant retinitis pigmentosa, mapped previously between D1S534 and D1S305 in chromosome 1p13-q21. We genotyped the family members for five microsatellite-type DNA polymorphisms and mapped RP18 between D1S422 and D1S2858 to a region of less than 2 cM. No obvious candidate gene has yet been assigned to the chromosomal interval defined here.

  14. Cilia and polycystic kidney disease, kith and kin.

    Science.gov (United States)

    Huang, Liwei; Lipschutz, Joshua H

    2014-06-01

    In the past decade, cilia have been found to play important roles in renal cystogenesis. Many genes, such as PKD1 and PKD2 which, when mutated, cause autosomal dominant polycystic kidney disease (ADPKD), have been found to localize to primary cilia. The cilium functions as a sensor to transmit extracellular signals into the cell. Abnormal cilia structure and function are associated with the development of polyscystic kidney disease (PKD). Cilia assembly includes centriole migration to the apical surface of the cell, ciliary vesicle docking and fusion with the cell membrane at the intended site of cilium outgrowth, and microtubule growth from the basal body. This review summarizes the most recent advances in cilia and PKD research, with special emphasis on the mechanisms of cytoplasmic and intraciliary protein transport during ciliogenesis.

  15. Autosomal recessive epidermolytic palmoplantar keratoderma.

    Science.gov (United States)

    Alsaleh, Q A; Teebi, A S

    1990-08-01

    Palmoplantar keratoderma (PPK) is a heterogeneous group of disorders. Epidermolytic PPK is a well delineated autosomal dominant entity, but no recessive form is known. Here we report two sons of phenotypically normal, consanguineous, Arab parents with features suggestive of PPK. They presented with patchy eczematous skin lesions followed by PPK and raised serum levels of IgE. Skin biopsy from the keratotic lesions showed the features of epidermolytic hyperkeratosis. Autosomal recessive inheritance is suggested and the differential diagnosis is discussed.

  16. Organic depression and Terson′s syndrome in adult polycystic kidney disease: Case report and review of literature

    Directory of Open Access Journals (Sweden)

    Ranganath R Kulkarni

    2014-01-01

    Full Text Available Depressive symptoms are common in neurological diseases, at times posing dilemma in organic or functional origin. Cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes that resemble primary depressions both clinically and therapeutically in about half of the patients following acute stroke. Terson′s syndrome is the direct occurrence of vitreous hemorrhage following subarachnoid/subdural hemorrhage, often overlooked in the acute setting. Autosomal dominant (adult polycystic kidney disease may be associated with berry aneurysms and hypertension, and may lead to intracranial bleeds. We report an unusual case of organic depression and Terson′s syndrome in a 50-year-old female with polycystic kidney disease and hypertension, following anterior communicating artery aneurysmal subarachnoid bleed with bilateral subdural extension. Management included anti-hypertensives, antiepileptics, neodymium: YAG laser photocoagulation, and aneurysmal clipping.

  17. Síndrome das pernas inquietas com herança autossômica dominante piorada pelo uso de mirtazapina: relato de caso Worsening of autosomal dominant restless legs syndrome after use of mirtazapine: case report

    Directory of Open Access Journals (Sweden)

    Hélio A.G. Teive

    2002-12-01

    Full Text Available Relatamos o caso de uma paciente de 78 anos, com diagnóstico estabelecido de síndrome das pernas inquietas (SPI, de etiologia primária com herança autossômica dominante. A paciente apresentava quadro depressivo associado. Enfatiza-se a piora do quadro clínico da SPI após o uso de anti-depressivo com ação inibidora seletiva da recaptação de serotonina (mirtazapina, com atenuação dos sintomas após a retirada da droga, e a excelente resposta terapêutica com o uso de agonista dopaminérgico (pramipexol em baixa dose.We report the case of a 78 years old female patient with primary restless legs syndrome (RLS with an autosomal dominant pattern of inheritance. In addition, the patient also had depression. We emphasize the worsening of symptoms of RLS after the use of a selective serotonin uptake inhibitor (mirtazapine, with improvement after the drug was discontinued, and an excellent recovery with the use of low dose dopaminergic agonist (pramipexol.

  18. Genetics Home Reference: autosomal dominant hypocalcemia

    Science.gov (United States)

    ... in the hands and feet (carpopedal spasms) and muscle cramping, prickling or tingling sensations (paresthesias), or twitching of ... plays an important role in the control of muscle movement, and a shortage of this molecule can lead to cramping or twitching of the muscles. Impairment of the ...

  19. Mutation Screening for Candidate Genes in a Chinese Pedigree with Autosomal Dominant Hereditary Auditory Neuropathy Spectrum Disorder (ANSD)%常染色体显性遗传性听神经病基因突变筛查

    Institute of Scientific and Technical Information of China (English)

    赵昱; 石力; 王剑; 梁鹏飞; 王淑娟; 邱建华

    2014-01-01

    目的:针对一个常染色体显性遗传性非综合征性听神经病谱系障碍家系进行已知致病基因筛查分析,了解是否存在可能致病的基因突变。方法选择本课题组收集到的一个家系4代24人作为研究对象,采集受试者外周静脉血提取基因组DNA,应用在线引物设计软件Primers进行引物设计,采用直接测序法对已知听神经病相关基因进行测序,使用DNAMan软件对序列进行比对分析。结果该家系遗传方式符合显性遗传特征,患者听力学特征符合非综合征型听神经病谱系障碍,对家系中全部患者及部分听力正常成员完成DIAPH3、OTOF、PJVK、GJB2基因外显子及线粒体DNA12S rRNA1494、1555位点的测序分析,未发现可疑致病突变。结论该家系未检测到已知相关基因致病突变,高度提示新基因突变致病的可能,有待于进一步研究。%Objective To identify possible pathogenic gene mutations in a Chinese pedigree with autosomal dominant hereditary non-syndromic auditory neuropathy spectrum disorder (ANSD) . Methods A pedigree of 4 generations (24 people ) was studied. Genomic DNA was extracted from peripheral blood. Primers were designed using a free internet primer de-sign software. Known auditory neuropathy related genes were analyzed by direct sequencing and gene sequences were ana-lyzed comparatively using the DNAMan software. Results In this pedigree, the mode of inheritance was consistent with autoso-mal dominant genetic diseases, and the characteristics of patients were in accordance with the diagnosis of auditory neuropa-thy spectrum disorder (ANSD). Direct sequencing of exons of the DIAPH3, OTOF, PJVK, GJB2 and GJB3 genes as well as the mitochondrial 12SrRNA gene in all patients and some other members with normal hearing in this pedigree showed no suspi-cious mutation. Conclusion None of the known pathogenic mutations is detected in this Chinese ANSD family, suggesting the

  20. 一中国人家系常染色体显性遗传垂体性尿崩症基因突变研究%Mutation of autosomal dominant neurohypophyseal diabetes insipidus in a Chinese pedigree

    Institute of Scientific and Technical Information of China (English)

    陈育才; 谢文煌; 王柠; 慕容慎行; 黄妙辉; 黄梅芳

    2001-01-01

    Objective To elucidate the molecular mechanism of autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) in Chinese. Methods A Chinese family with ADNDI was studied. Polymerase chain reaction-single strand conformation polymorphisms (PCR-SSCP) of exon 1 and exon 2 of arginine vasopressin neurophysin Ⅱ (AVP-NPII) gene were performed in 4 patients and 4 normal phenotypic members of the pedigree and 1 patient from other family. Direct DNA sequencing of PCR-amplified geomic DNA in exon 2 are carried out. Results In exon 1, the affected patients and unaffected people in same kindred and a nonfamilial insipidus from other family had the same strand in SSCP analysis. But there were differences in SSCP analysis from exon 2 as follows: besides having the same strand as healthy man in same kindred or a nonfamilial affected patient, SSCP analysis showed that affected patients from ADNDI had two new different strands. The results were confirmed by direct DNA sequencing of PCR-amplified geomic DNA. A 3-base pair deletion (GAG) out of two consecutive GAG sequence (nucleotides 1826-1831) was identified in affected individual with ADNDI. This mutation should yield an abnormal AVP precursor lacking Glu47 in its neurophysin-Ⅱ moeity. Since Glu47 is essential for NP molecules to form a salt bridge with AVP, the function of NP as a carrier proetin for AVP would be impaired which leads to acceleration proteolytic degradation. Conclusion The nucleotides deletion in the coding region for neurophysin Ⅱ gene appears to be one of the causes of autosomal dominant neurohypophyseal diabetes insipidus in Chinese.%目的 探讨中国人的常染色体显性遗传垂体性尿崩症(ADNDI)的分子发病机制。方法 对一个家系中4例ADNDI患者、4例未发病者及1例来自其他家庭的患者的精氨酸加压素-运载蛋白Ⅱ(AVP-NPⅡ)基因外显子1和2进行聚合酶链反应-单链构像多态性(PCR-SSCP)分析及基因测序研究。结果 SSCP分

  1. Mapping of Gene Underlying Autosomal Dominant Non-syndromic Hearing Loss(DFNA)%常染色体显性遗传非综合征型耳聋致病基因定位研究

    Institute of Scientific and Technical Information of China (English)

    孙悍军; 袁慧军; 韩东一; 贺林; 陶然; 程静; 杨淑芝; 曹菊阳; 于黎明; 洪梦迪; 冯国鄞; 戴朴

    2006-01-01

    耳聋具有高度的遗传异质性, 迄今已定位了51个常染色体显性遗传非综合征型耳聋(autosomal dominant non-syndromic sensorineural hearing loss, DFNA)基因位点, 20个DFNA相关基因被克隆.文章收集了一个DFNA巨大家系, 家系中有血缘关系的家族成员共170人, 对73名家族成员进行了详细的病史调查、全身检查和耳科学检查, 提示39人有不同程度的迟发性感音神经性听力下降, 未见前庭及其他系统的异常.应用ABI公司382个常染色体微卫星多态标记进行全基因组扫描连锁分析, 将该家系致聋基因定位于14q12-13处D14S1021-D14S70之间约7.6 cM (3.18 Mb)的区域, 最大LOD值为6.69 (D14S1040), 与已知DFNA9位点有4.7 cM (2.57 Mb)的重叠区, DFNA9致病基因COCH位于重叠区域内.下一步拟进行COCH基因的突变筛查, 以揭示该家系耳聋的分子致病机制.

  2. Combination of Whole Genome Sequencing, Linkage and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy with Features of Left Ventricular Non-Compaction

    Science.gov (United States)

    Hooper, Charlotte; Ormondroyd, Liz; Pagnamenta, Alistair; Lise, Stefano; Salatino, Silvia; Knight, Samantha JL; Taylor, Jenny C.; Thomson, Kate L.; Arnold, Linda; Chatziefthimiou, Spyros D.; Konarev, Petr V.; Wilmanns, Matthias; Ehler, Elisabeth; Ghisleni, Andrea; Gautel, Mathias; Blair, Edward; Watkins, Hugh; Gehmlich, Katja

    2016-01-01

    Background High throughput next generation sequencing techniques have made whole genome sequencing accessible in clinical practice, however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging. Methods and Results Here we combine whole genome sequencing with linkage analysis in a three-generation family affected by cardiomyopathy with features of autosomal dominant left-ventricular non-compaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease amongst the eight surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, affecting a conserved residue in the second immunoglobulin-like domain of titin, was introduced in a bacterially expressed recombinant protein fragment and biophysically characterised in comparison to its wild-type counterpart. Multiple experiments, including size exclusion chromatography, small angle X-ray scattering and circular dichroism spectroscopy suggest partial unfolding and domain destabilisation in the presence of the mutation. Moreover, binding experiments in mammalian cells show that the mutation markedly impairs binding to the titin ligand telethonin. Conclusions Here we present genetic and functional evidence implicating the novel A178D missense mutation in titin as the cause of a highly penetrant familial cardiomyopathy with features of left-ventricular non-compaction. This expands the spectrum of titin’s roles in cardiomyopathies. It furthermore highlights that rare titin missense variants, currently often ignored or left un-interpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. PMID:27625337

  3. 广东地区视网膜色素变性两大家系RHO基因突变分析%Analysis of RHO gene mutation for two autosomal dominant retinitis pigmentosa families in Guangdong Province

    Institute of Scientific and Technical Information of China (English)

    徐志勇; 胡玉华; 陈璐; 黄小菊; 张阮章; 王沙燕

    2009-01-01

    目的 分析广东地区两个常染色体显性遗传视网膜色素变性(autosomal dominant retinRis pigmento-sa,ADRP)家系视紫红质(rhodopsin,RHO)基因突变,探讨基因突变与临床表型的关系.方法 收集广东地区两个常染色体显性遗传视网膜色素变性家系的临床资料,对家系成员进行视力、视野、眼底镜检查;应用聚合酶链反应(PCR)和直接测序技术,对两个家系所有现存成员进行RHO基因检测.结果 发现一家系患者为P347S杂合性突变.另一家系患者存在P171L杂合性突变,两家系的临床表现为发病早,病情进展快,表型较严重,该两家系正常成员均未发现RHO基因突变.结论 RHO基因的P347S与P171L突变分别为该两家系视网膜色素变性的病因.该两种突变均导致较严重的临床表型,与分子基础一致.

  4. Relative genes of autosomal dominant congenital cataracts%常染色体显性遗传先天性白内障相关基因的研究进展

    Institute of Scientific and Technical Information of China (English)

    邱靖森; 张铭志

    2012-01-01

    先天性白内障是由于胚胎期晶状体代谢异常而导致的自身透明度下降的致盲性疾病,遗传因素与疾病的发生、发展有很大的联系.目前研究发现先天性白内障的发生至少与22个基因的变异有关,其中以常染色体显性遗传为主,涉及的基因包括晶状体蛋白基因(CRY)、缝隙连接通道蛋白基因(GJA)、膜蛋白基因(MIP)、细胞骨架蛋白基因(BFSP)和转录调节因子基因等.本文对近几年来关于常染色体显性遗传先天性白内障致病基因方面的研究进行综述.%Congenital cataract is developed due to the metabolic disturbance of lens in embryo,which induces the degression of the transparency of lens.Genetic factors are associated with development of this disease.Autosomal dominant congenital cataract (ADCC) is the major type in reported congenital cataract.So far,twenty-two genes associated with ADCC have been found.These genes invole CRY,GJA,MIP,BFSP,transcription factor,and so on.This paper summarizes the genetic researches on ADCC in recent years.

  5. Heterotrimeric G protein signaling in polycystic kidney disease.

    Science.gov (United States)

    Hama, Taketsugu; Park, Frank

    2016-07-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a signalopathy of renal tubular epithelial cells caused by naturally occurring mutations in two distinct genes, polycystic kidney disease 1 (PKD1) and 2 (PKD2). Genetic variants in PKD1, which encodes the polycystin-1 (PC-1) protein, remain the predominant factor associated with the pathogenesis of nearly two-thirds of all patients diagnosed with PKD. Although the relationship between defective PC-1 with renal cystic disease initiation and progression remains to be fully elucidated, there are numerous clinical studies that have focused upon the control of effector systems involving heterotrimeric G protein regulation. A major regulator in the activation state of heterotrimeric G proteins are G protein-coupled receptors (GPCRs), which are defined by their seven transmembrane-spanning regions. PC-1 has been considered to function as an unconventional GPCR, but the mechanisms by which PC-1 controls signal processing, magnitude, or trafficking through heterotrimeric G proteins remains to be fully known. The diversity of heterotrimeric G protein signaling in PKD is further complicated by the presence of non-GPCR proteins in the membrane or cytoplasm that also modulate the functional state of heterotrimeric G proteins within the cell. Moreover, PC-1 abnormalities promote changes in hormonal systems that ultimately interact with distinct GPCRs in the kidney to potentially amplify or antagonize signaling output from PC-1. This review will focus upon the canonical and noncanonical signaling pathways that have been described in PKD with specific emphasis on which heterotrimeric G proteins are involved in the pathological reorganization of the tubular epithelial cell architecture to exacerbate renal cystogenic pathways.

  6. Cyst fluid from a murine model of polycystic kidney disease stimulates fluid secretion, cyclic adenosine monophosphate accumulation, and cell proliferation by Madin-Darby canine kidney cells in vitro.

    Science.gov (United States)

    Yamaguchi, T; Nagao, S; Takahashi, H; Ye, M; Grantham, J J

    1995-03-01

    Cyst fluids from subjects with autosomal dominant polycystic kidney disease (ADPKD) cause polarized monolayers of MDCK cells to secrete fluid toward the apical compartment in vitro. To determine the extent to which secretagogue accumulation may be a general feature of polycystic diseases, cyst fluid from mice with a slowly progressive form of hereditary PKD (DBA/2FG-pcy/pcy) was added to polarized MDCK monolayers. Basolateral application of cyst fluids (diluted with culture medium to 15% final concentration) from 13 different animals 16 to 35 weeks old increased the fluid secretion rate from a baseline of 0.023 +/- 0.003 to 0.111 +/- 0.017 microL/cm2/h (P matricies.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. 多囊肾去顶减压术改善肾功能的临床研究%Clinical study of renal function improvement after cyst decortication operation for patients with autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    唐硕; 柳良仁; 张宗平; 王安果; 魏强

    2007-01-01

    目的 探索去顶减压术是否有益于多囊肾肾功能的恢复及程度.方法 对31例成人型多囊肾患者施行去顶减压术.手术选择传统开放和腹腔镜两种术式.并进行术前术后腰痛、血压、囊肾体积、肾小球滤过率的比较,以了解对肾功能改善的临床意义.随访时间为6个月~5年.结果 术后患者临床症状迅速改善,血压下降,囊肾体积减小,肾小球滤过率(Glomerular filtration rate,GFR)升高.结论 去顶减压术是治疗成人型多囊肾较好的方法,并有助于肾功能的恢复.

  8. Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside

    Directory of Open Access Journals (Sweden)

    Hyun-Jung Kim

    2012-09-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is the most common life-threatening hereditary disease in the USA resulting in chronic kidney disease and the need for dialysis and transplantation. Approximately 85% of cases of ADPKD are caused by a mutation in the Pkd1 gene that encodes polycystin-1, a large membrane receptor. The Pkd1 gene mutation results in abnormal proliferation in tubular epithelial cells, which plays a crucial role in cyst development and/or growth in PKD. Activation of the proliferative mammalian target of rapamycin (mTOR signaling pathway has been demonstrated in polycystic kidneys from rodents and humans. mTOR inhibition with sirolimus or everolimus decreases cysts in most animal models of PKD including Pkd1 and Pkd2 gene deficient orthologous models of human disease. On the basis of animal studies, human studies were undertaken. Two large randomized clinical trials published in the New England Journal of Medicine of everolimus or sirolimus in ADPKD patients were very unimpressive and associated with a high side-effect profile. Possible reasons for the unimpressive nature of the human studies include their short duration, the high drop-out rate, suboptimal dosing, lack of randomization of “fast” and “slow progressors” and the lack of correlation between kidney size and kidney function in ADPKD. The future of mTOR inhibition in ADPKD is discussed.

  9. The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs.

    Science.gov (United States)

    Shen, Peter S; Yang, Xiaoyong; DeCaen, Paul G; Liu, Xiaowen; Bulkley, David; Clapham, David E; Cao, Erhu

    2016-10-20

    The Polycystic Kidney Disease 2 (Pkd2) gene is mutated in autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic disorders. Here, we present the cryo-EM structure of PKD2 in lipid bilayers at 3.0 Å resolution, which establishes PKD2 as a homotetrameric ion channel and provides insight into potential mechanisms for its activation. The PKD2 voltage-sensor domain retains two of four gating charges commonly found in those of voltage-gated ion channels. The PKD2 ion permeation pathway is constricted at the selectivity filter and near the cytoplasmic end of S6, suggesting that two gates regulate ion conduction. The extracellular domain of PKD2, a hotspot for ADPKD pathogenic mutations, contributes to channel assembly and strategically interacts with the transmembrane core, likely serving as a physical substrate for extracellular stimuli to allosterically gate the channel. Finally, our structure establishes the molecular basis for the majority of pathogenic mutations in Pkd2-related ADPKD.

  10. Transplantation of umbilical cord mesenchymal stem cells for treatment of autosomal dominant spinocerebellar ataxias in 12 cases%脐带间充质干细胞治疗脊髓小脑性共济失调12例

    Institute of Scientific and Technical Information of China (English)

    邱云; 汪铮; 路红社; 许鹏; 陈文怡; 路延光; 丁永红

    2012-01-01

    BACKGROUND: There is no study addressing transplantation of umbilical cord mesenchymal stem cells for the treatment of spinocerebellar ataxia.OBJECTIVE: To study the clinical effect of human umbilical cord stem cells transplantation in the treatment of autosomal dominant spinocerebellar ataxias. METHODS: Spinocerebellar ataxias patients selected from Stem Transplantation Center of the 455 Hospital of Chinese PLA were treated with umbilical cord mesenchymal stem cells transplantation via intrathecal injection. The number of umbilical cord mesenchymal stem cells was 107 per transplantation, once per week, for 4 weeks.RESULTS AND CONCLUSION: Both the total score of the International Cooperative Ataxia Rating Scale and Activities of Daily Living score were significantly decreased at 1 month after transplantation compared with before treatment (P < 0.05). The nerve function was significantly improved and the total effective rate was up to 16.7%. Experimental findings indicate that, transplantation of umbilical cord mesenchymal stem cells via intrathecal injection is a feasible and effective treatment to ameliorate the clinical efficacy of spinocerebellar ataxias patients and improve their quality of life.%背景:目前尚未见应用脐带间充质干细胞治疗脊髓小脑性共济失调的报道.目的:观察脐带间充质干细胞治疗脊髓小脑性共济失调的临床效果.方法:选择2010-09/12解放军455医院干细胞移植中心收治的12例脊髓小脑共济失调患者,给予脐带间充质干细胞鞘内注射,每次107个细胞,1次/周,4次为1个疗程.结果与结论:患者治疗后1个月与治疗前比较国际合作共济失调评分量表评分及日常生活量表评分均明显降低(P < 0.05),提示患者的神经功能显著改善,总有效率为16.7%.说明脐带间充质干细胞鞘内注射治疗可以在一定程度上改善脊髓小脑性共济失调患者的临床症状,提高患者生活质量.

  11. Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment.

    Science.gov (United States)

    Perugorria, Maria J; Labiano, Ibone; Esparza-Baquer, Aitor; Marzioni, Marco; Marin, Jose J G; Bujanda, Luis; Banales, Jesús M

    2017-01-01

    Polycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs. However, the discovery of the presence of bile acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD (i.e. polycystic kidney (PCK) rat) suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases. On the other hand, ursodeoxycholic acid (UDCA) has emerged as a new potential therapeutic tool for PLDs by promoting the inhibition of cystic cholangiocyte growth in both PCK rats and highly symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD: most common type of PLD), and improving symptoms. Chronic treatment with UDCA normalizes the decreased intracellular calcium levels in ADPKD human cholangiocytes in vitro, which results in the reduction of their baseline-stimulated proliferation. Moreover, UDCA decreases the liver concentration of cytotoxic bile acids in PCK rats and the bile acid-dependent enhanced proliferation of cystic cholangiocytes. Here, the role of bile acids in the pathogenesis of PLDs and the potential therapeutic value of UDCA for the treatment of these diseases are reviewed and future lines of investigation in this field are proposed.

  12. Dietary citrate treatment of polycystic kidney disease in rats.

    Science.gov (United States)

    Tanner, George A; Tanner, Judith A

    2003-01-01

    Progression of autosomal-dominant polycystic kidney disease (ADPKD) in the heterozygous male Han:SPRD rat is dramatically slowed by ingestion of potassium or sodium citrate. This study examined the efficacy of delayed therapy with sodium citrate, the effect of sodium citrate therapy on kidney cortex levels of transforming growth factor-beta (TGF-beta), and the response to calcium citrate ingestion. Rats were provided with citrate salts in their food, and renal clearance, blood pressure, blood chemistry, and survival determinations were made. Sodium citrate therapy was most effective when started at age 1 month, and delay of therapy until age 3 months produced no benefit. Kidney cortex TGF-beta levels were elevated in 3- and 8-month-old rats with ADPKD, but not in 6-week-old rats. Sodium citrate treatment, started at age 1 month, lowered TGF-beta levels to normal in 3-month-old rats, but this is probably not the primary mechanism of citrate's beneficial effect. Calcium citrate had only a modest effect in preserving glomerular filtration rate. Effective treatment of ADPKD in this rat model requires early administration of a readily absorbed alkalinizing citrate salt. Existing data on ADPKD patients on vegetarian diets or with kidney stones should be studied in light of these findings.

  13. The Molecular Pathogenesis of Autosomal Dominant Optic Atrophy%常染色体显性视神经萎缩的分子遗传学研究进展

    Institute of Scientific and Technical Information of China (English)

    张娟娟; 周翔天; 瞿佳; 管敏鑫

    2008-01-01

    Autosomal dominant optic atrophy (ADOA), also called Kjer optic neuropathy, is the most common form of inherited optic neuropathy with a prevalence between 1: 10 000 and 1 : 50 000. The optic atrophy often occurs in the childhood (the average age-of-onset: 7 years old) and with an insidious onset of variable visual loss, temperal optic nerve pallor, central or caecocentral visual field scotoma and dyschromatopsia (often appears tetartanopia). Histopathological studies suggest that the underlying defect is retinal ganglion cell degeneration. Mutations in OPA1 encoding a conserved mitochondrial dynamin-related GTPase are the major cause of ADOA. 117 OPA1 ADOA-associated mutations consisted of 31.6% of deletions/insertions, 16.2% of nonsense, 25.6% of missense and 28. 8% of splicing mutations. The majority of mutations reside at the ceding sequence of this gene, especially in the GTPase domain. Other ADOA-associated genes were OPA3 (19q13. 2-q13.3), OPA4 (18q12.2-q12.3) and OPA5 (22q12.1-q13.1). The variable phenotypes of vision loss suggest the involvement of other genetic factors, personal factors and environmental factors in the pathogcnesis of ADOA.%常染色体显性视神经萎缩常在儿童期发病,发病率约1:10 000~1:50 000,表现为隐匿性渐进性视力减退,双颞侧视盘苍白,中心或旁中心暗点,色觉障碍(常表现为蓝黄色盲).组织病理学表现为:视网膜神经节细胞退行性变.OPA1编码一种保守的动力相关GTPase,OPA1突变是ADOA发病的主要原因,目前已发现117个ADOA相关OPA1突变,包括:31.6%缺失和插人突变,16.2%无义突变,25.6%错义突变和28.8%剪接突变.这些突变分布于OPA1基因编码区,但多数位于GTPase区.另外,本病还与OPA3(19q13.2-q13.3)、OPA4(18q12.2-q12.3)及OPA5(22q12.1-q13.1)基因突变有关.个体间的表型差异表明:其他遗传因素、个人因素以及环境因素可能与ADOA发病有关.

  14. Polycystic Ovary Syndrome

    Science.gov (United States)

    ... Staff Polycystic ovary syndrome (PCOS) is a common endocrine system disorder among women of reproductive age. Women with PCOS ... and symptoms and then rules out other possible disorders. During this ... An Endocrine Society clinical practice guideline. The Journal of Clinical ...

  15. Polycystic Ovary Syndrome FAQ

    Science.gov (United States)

    ... are common signs and symptoms of polycystic ovary syndrome (PCOS)? • What causes PCOS? • What is insulin resistance? • What can high levels of androgens lead to? • What can irregular menstrual periods lead ...

  16. Polycystic Ovary Syndrome (PCOS)

    Science.gov (United States)

    ... high androgens, such as having excess body or facial hair Cysts (fluid-filled sacs) on one or both ovaries—"polycystic" literally means "having many cysts" Some women diagnosed with PCOS have the first two conditions ...

  17. 先天性非进展性常染色体显性遗传非综合症型耳聋家系临床表型特征分析%Phenotype characteristics of a Chinese family with congenital, stable, autosomal dominant non-syndromic sensorineural hearing loss

    Institute of Scientific and Technical Information of China (English)

    郭亿莲; 赖海彪; 袁慧军; 李征玥; 何琦; 孙一帆; 徐庆文; 周小军; 张丽娟; 王明松; 孔祥廉

    2011-01-01

    目的 一个连续三代的常染色体显性遗传先天性非进展性非综合症型耳聋家系的临床听力学特征及遗传规律.方法 对耳聋家系成员进行病史采集、体格检查、纯音测听、声导抗、听性脑干反应检测,其中一名患者进行颞骨CT扫描检查.绘制遗传图谱并进行遗传学特征分析.结果 该家系成员共计18人,耳聋患者11人,其中一例为氨基糖苷类药物致聋患者.该耳聋家系每代及男女均有发病,非药物致聋患者均表现为语前聋、平稳型、全频中度听力下降,听力曲线呈平坦型.结论 该家系遗传方式符合常染色体显性遗传规律,表现为全频中度感音神经性耳聋.该研究为下一步的致聋基因的定位与鉴定奠定了良好的工作基础.%Objective To study the phenotypes and genetic characteristics of a three-generation Chinese family with autosomal dominant inherited progressive nonsyndromic hearing loss. Methods Pedigree was drawn after the investigation. Eighteen family members were examined including detailed audiology tesing (pure tone assay, acoustic immittance testing and auditory brainstem response audiometry). One patient received temporal bone CT. Results This family was comprised of 18 members, of whom 11 were affected. One patient had a history of using aminoglycosides. The pattern of inheritance of this family was autosomal dominant based on the investigation information. The affected members showed pre-lingual, stable, bilateral moderate sensorineural hearing impairment involving all frequencies. The audiograms showed generally flat hearing loss. Conclusion Pedigree analysis suggests an autosomal dominant hereditary pattern in this family. The information from this study will facilitate linkage analysis and positional cloning for identifying the causative gene in this family.

  18. Dominant cystoid macular dystrophy

    NARCIS (Netherlands)

    Saksens, N.T.M.; Huet, R.A.C. van; Lith-Verhoeven, J.J. van; Hollander, A.I. den; Hoyng, C.B.; Boon, C.J.

    2015-01-01

    OBJECTIVE: To describe the clinical characteristics and long-term follow-up in patients with autosomal dominant cystoid macular dystrophy (DCMD). DESIGN: Retrospective case series. PARTICIPANTS: Ninety-seven patients with DCMD. METHODS: Extensive ophthalmic examination, including visual acuity (VA),

  19. The clinical characteristics of a pedigree with incompletely penetrated autosomal dominant hereditary spastic paraplegia and its exclusion analysis of genetic loci%不完全外显的遗传性痉挛性截瘫一家系临床与致病基因排除定位分析

    Institute of Scientific and Technical Information of China (English)

    赵国华; 任志军; 刘小民; 李书剑; 郭鹏; 沈璐; 夏昆; 唐北沙

    2008-01-01

    Objective To describe the clinical features of a big family with ineompletely penetrated autosomal dominant hereditary spastic paraplegia(SPG) and perform the exclusion analysis of genetic loci.Methods The clinical information of this SPG family was analyzed retmspecfively.Exclusion analysis of the known autosomal dominant SPG loci was performed by using rnltiplex fluorescence PCR, capillary electrophoresis and Linkage package. Results There were eleven affected members available in this SPG family and the age at onset ranged from 2 to 10 years.The first symptoms were a bilateral,symmetrical,progressive lower limb weakness and spasticity.Patients presented with spastieity and hyperrdlexia,positive Babinski sign and scissors gait,and the upper limbs were involved more seveiely than the lower limbs.No urinary inconsistence,sensory impairment,nystagmus and dementia were found.Genetic analyfis showed that this family was consistent with autosomal dominant inheritance.The linkage analysis and mutation analysis revealed this family was not linked to the known autosomal dominant loci.Conclusion This SPG family had typical"pure"clinical symptoms.The age at onset Was early and the signs in the upper limbs were more obvious than those in the lower limbs.The result of linkage analysis shows that this family represents a new SPG subtype.%目的 描述一个遗传了4代的不完全外显的遗传性痉挛性截瘫(hereditary spastic paraplegia,SPG)大家系的临床特征,并进行致病基因排除定位分析.方法 对SPG家系内11例患者的临床资料进行回顾性分析,并采用荧光多重PCR、毛细管凝胶电泳、Linkage软件包,选择对已定位常染色体显性遗传致病基因位点附近微卫星标记进行连锁分析.结果 该SPG家系的11例患者的发病年龄2~10岁,表现为缓慢进展的双下肢僵硬无力,四肢肌张力轻度增高,双上肢为主的腱反射亢进,剪刀步态和病理征阳性,无小便失禁或尿频、感觉障

  20. Polycystic Ovary Syndrome

    OpenAIRE

    Akula Annapurna

    2015-01-01

    Polycystic ovary syndrome is a condition in which a woman has an imbalance of female sex hormones. This may lead to menstrual cycle changes, cysts in the ovaries, trouble getting pregnant, and other health changes. In PCOS, mature eggs are not released from the ovaries. Instead, they can form very small cysts in the ovary. These changes can contribute to infertility. Common symptoms of PCOS include Menstrual disorders, Infertility, High levels of testosterone and Metabolic syndrome. Obesity, ...

  1. Polycystic ovary syndrome and acne.

    Science.gov (United States)

    Chuan, Sandy S; Chang, R Jeffrey

    2010-01-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive aged women. It is typically characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries. Women with PCOS often experience dermatologic manifestations of hyperandrogenism, including hirsutism, acne vulgaris, and androgenic alopecia. This article will review the treatments for acne due to androgen excess in PCOS women.

  2. Effect of inhibition of converting enzyme on renal hemodynamics and sodium management in polycystic kidney disease.

    Science.gov (United States)

    Torres, V E; Wilson, D M; Burnett, J C; Johnson, C M; Offord, K P

    1991-10-01

    We compared the tubular transport of sodium and the erythrocyte sodium-lithium countertransport activity in hypertensive patients with autosomal dominant polycystic kidney disease (ADPKD) and in normotensive control subjects. In addition, we assessed the effects of inhibition of converting enzyme on renal hemodynamics and sodium excretion in hypertensive patients with ADPKD to provide information on mechanisms responsible for the increased renal vascular resistance and filtration fraction and the adjustment of the pressure-natriuresis relationship during saline expansion, observed in patients with ADPKD, hypertension, and preserved renal function. In comparison with normotensive control subjects, the hypertensive patients with ADPKD had lower renal plasma flows, higher renal vascular resistances and filtration fractions, and similar proximal and distal fractional reabsorptions of sodium. The administration of enalapril resulted in significant increases in the renal plasma flow and significant reductions in mean arterial pressure, renal vascular resistance, and filtration fraction, but the glomerular filtration rate remained unchanged. Despite the significant reduction in mean arterial pressure during inhibition of converting enzyme, the distal fractional reabsorption of sodium decreased while the total fractional excretion of sodium remained unchanged or increased slightly. No significant differences were detected between the normotensive control subjects and the hypertensive patients with ADPKD in erythrocyte sodium-lithium countertransport activity, plasma renin activity, plasma aldosterone concentration, or atrial natriuretic factor. These results suggest that the renal renin-angiotensin system plays a central role in the alterations in renal hemodynamics and sodium management associated with the development of hypertension in ADPKD.

  3. Renal histology in polycystic kidney disease with incipient and advanced renal failure.

    Science.gov (United States)

    Zeier, M; Fehrenbach, P; Geberth, S; Möhring, K; Waldherr, R; Ritz, E

    1992-11-01

    Renal specimens were obtained at surgery or postmortem from patients with autosomal dominant polycystic kidney disease (ADPKD). Patients had either serum creatinine (SCr) below 350 mumol/liter (N = 12) or terminal renal failure (N = 50). Specimens were examined by two independent observers using a carefully validated score system. Mean glomerular diameters were similar in ADPKD patients with early renal failure (176 +/- 38 microns) and in victims of traffic accidents (177 +/- 23 microns), while they were significantly greater in diabetics with comparable renal function (205 +/- 16 microns). Glomerular diameters in ADPKD patients with terminal renal failure (191 +/- 45 microns) and with early renal failure were not significantly different. On average, 29% of glomeruli (17 to 62) were globally sclerosed in early renal failure, and 49% (19 to 93) in terminal renal failure. The proportion of glomeruli with segmental sclerosis was less than 4% in both groups. Marked vascular sclerosis, interstitial fibrosis, and tubular atrophy were present in early renal failure, and even more so in terminal renal failure. Interstitial infiltrates were scarce and consisted mainly of CD4 positive lymphocytes and CD68 positive macrophages. Immunestaining with monoclonal renin antibodies showed an increased juxtaglomerular index and expression of renin by arterioles adjacent to cysts, as well as by cyst wall epithelia. The data show more severe vascular and interstitial, but not glomerular, changes in ADPKD with advanced as compared to early renal failure.

  4. Presymptomatic testing for adult onset polycystic kidney disease in at-risk kidney transplant donors.

    Science.gov (United States)

    Hannig, V L; Hopkins, J R; Johnson, H K; Phillips, J A; Reeders, S T

    1991-09-15

    Autosomal dominant adult-onset polycystic kidney disease (ADPKD) is estimated to have an incidence of 1/1,000 and accounts for approximately 10% of all end-stage renal disease in the United States. While relatives are attractive as renal donors due to their availability and the improved transplant success associated with living-related donors, they may coincidentally be at risk for ADPKD. Accurate presymptomatic testing for at-risk potential donors is critical for both the donor and the recipient. We report here 2 families in which presymptomatic testing for ADPKD was accomplished by DNA linkage analysis on several potential renal donors prior to transplant. This resulted in the protection of both donors and recipients by preventing the transplantation of a kidney affected by ADPKD. Thorough counseling prior to DNA analysis (including discussion of accuracy and possible testing outcomes of presymptomatic diagnosis of ADPKD, diagnosis of noncarrier status, false paternity, and non-informative study) was essential to provide informed consent and preserve confidentiality within the family. Confidentiality for potential donors found presymptomatically to be affected (with a 94% or greater probability) was especially difficult to maintain.

  5. A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder?

    Science.gov (United States)

    Aldea, Anna; Campistol, Josep M; Arostegui, Juan I; Rius, Josefa; Maso, Montserrat; Vives, Jordi; Yagüe, Jordi

    2004-01-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring short attacks of fever and serositis. Secondary AA amyloidosis is the worst complication of the disease and often determines the prognosis. The MEFV gene, on chromosome 16p13.3, is responsible for the disease and around 30 mutations have been reported to date. Colchicine is the standard FMF treatment today, and prevents both attacks and amyloid deposition in 95% of patients. Here we describe a three-generation Spanish kindred with five family members affected by a severe periodic inflammatory disorder associated with renal AA amyloidosis and colchicine unresponsiveness. Clinical diagnosis of definite FMF disease was made based on the Tel-Hashomer criteria set. Genetic analyses revealed that all subjects were heterozygous for the new H478Y MEFV variant, segregating with the disease. In addition, mutations in the TNFRSF1A and CIAS1/PYPAF1/NALP3 genes, related to the dominantly inherited autoinflammatory periodic syndromes, were ruled out. However, the dominant inheritance of the disease, the long fever episodes with a predominant joint involvement, and the resistance to colchicine in these patients raise the question of whether the periodic syndrome seen in this kindred is a true FMF disease with unusual manifestations or rather another MEFV-associated periodic syndrome. We conclude that the new H478Y MEFV mutation is the dominant pathological variant causing the inflammatory periodic syndrome in this kindred and that full-length analyses of the MEFV gene are needed to obtain an adequate diagnosis of patients with clinical suspicion of a hereditary periodic fever syndrome, especially those from non-ancestral populations.

  6. [Polycystic ovary syndrome].

    Science.gov (United States)

    Vrbíková, Jana

    2015-10-01

    For diagnosing of polycystic ovary syndrome (PCOS) it is currently recommended to follow the ESHRE criteria. For diagnosis according to them two of the following three symptoms are sufficient: 1. morphology of polycystic ovaria, 2. clinical manifestations of hyperandrogenism or laboratory proof of hyperandrogenemia, and 3. oligo-anovulation. PCOS is a complex disorder in whose pathogenesis genetic and environmental effects interact. It is not a gynecological disorder alone, the syndrome is accompanied by insulin resistance which leads to increased incidence of type 2 diabetes mellitus and impaired glucose tolerance (4 times and twice, independently of BMI). Also gestational DM occurs more frequently. Dyslipidemia, arterial hypertension, elevated CRP and homocysteine levels, endothelial dysfunction and greater intima-media thickness are also more frequent. It is not quite clear, however, whether women with PCOS suffer cardiovascular events more frequently as well. More often than is accidental PCOS is associated with depression, anxiety and eating disorders, further with nonalcoholic steatohepatitis and with the sleep apnoea syndrome - especially in obese women. Therapeutic measures include non-pharmacological methods - lifestyle adjustments focused on weight reduction in obese individuals, cosmetic measures for dermatologic manifestation of hyperandrogenism, in particular laser and pharmacotherapy (combined hormonal contraceptives and antiandrogens). Menstrual irregularities can be treated with contraceptives or cyclical administration of gestagens, also metformin can be used.

  7. Polycystic ovary syndrome.

    Science.gov (United States)

    Azziz, Ricardo; Carmina, Enrico; Chen, ZiJiang; Dunaif, Andrea; Laven, Joop S E; Legro, Richard S; Lizneva, Daria; Natterson-Horowtiz, Barbara; Teede, Helena J; Yildiz, Bulent O

    2016-01-01

    Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.

  8. Polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Aziz, M; Naver, Klara; Wissing, Marie Louise Muff

    2012-01-01

    Objectives: The primary objective of this multicenter study is to evaluate the relative impact of insulin resistance (IR) and body mass index (BMI) in women with polycystic ovary syndrome (PCOS) on (1) Key hemodynamic/thrombogenic variables, (2) Oocyte quality and early embryo development, (3) Fe...... biochemical markers of growth and inflammation and clinical pregnancy complications. Main outcome measures: Metabolic and hemostatic risk-biomarkers, oocyte and embryo quality, adverse pregnancy outcome, fetal growth and placental function in women with PCOS.......Objectives: The primary objective of this multicenter study is to evaluate the relative impact of insulin resistance (IR) and body mass index (BMI) in women with polycystic ovary syndrome (PCOS) on (1) Key hemodynamic/thrombogenic variables, (2) Oocyte quality and early embryo development, (3......) Fetal growth, placental function and adverse obstetric outcome. Secondary objective: To establish a PCOS database and biobank facilitating future basic and interventional research related to PCOS. Design: A cross-sectional and longitudinal cohort study at four University Hospitals in Denmark. Population...

  9. Polycystic Diseases in Visceral Organs

    Directory of Open Access Journals (Sweden)

    Shakila Abdul-Majeed

    2011-01-01

    Full Text Available Primary cilia are nonmotile, microtubule-based, antenna-like organelles projecting from the apical surface of most mammalian cells. Elegant studies have established the importance of ciliary structure and function in signal transduction and the sensory roles of cilia in maintaining healthy cellular state. In particular, dysfunctional cilia have been implicated in a large number of diseases mainly characterized by the presence of fluid-filled cysts in various organs. Aside from polycystic kidney disease (PKD, however, the roles of cilia in polycystic liver disease (PLD, polycystic pancreas disease (PPD, and polycystic ovarian syndrome (PCOS are still very vague. In addition, although gender and sex hormones are known to regulate cyst formation, their roles in regulating physiological functions of cilia need to be further explored.

  10. POLYCYSTIC OVARY SYNDROME IN ADOLESCENCE

    Directory of Open Access Journals (Sweden)

    Diana Baptista

    2017-02-01

    Conclusion: Identification of adolescents at risk for Polycystic Ovary Syndrome is critical, not only for an appropriate therapeutic approach, but also to prevent co-morbidities associated with the syndrome, including obesity, insulin resistance, dyslipidemia and infertility.

  11. Polycystic ovary syndrome and hirsutism

    OpenAIRE

    Evliyaoğlu, Olcay

    2011-01-01

    Polycystic ovary syndrome is a multi factorial heterogenous disorder characterized by chronic anovulation and hyperandrogenism Diagnosis is based on clinical or laboratory evidence of nbsp; hyperandrogenism nbsp; For diagnosis at least two of the three Rotterdam criteria oligo anovulation clinical or biochemical signs of hyperandrogenism polycystic ovaries nbsp; should be ensured Clinical symptoms usually begin around menarche nbsp; Oligomenorrhea amenorrhea hirsutism acne alopecia can be ass...

  12. POLYCYSTIC OVARY SYNDROME IN ADOLESCENCE

    OpenAIRE

    Diana Baptista; Maria João Vieira; Carla Meireles

    2017-01-01

    Introduction:Polycystic Ovary Syndrome is recognized as the most common endocrine disorder of reproductive-age women. The syndrome often presents during adolescence, but the diagnosis in this age group is complicated by the overlap between features of the syndrome and physiologic findings observed during the normal progression of puberty. Objective:To review the diagnosis and treatment of Polycystic Ovary Syndrome in adolescence. Development:There are no consensual diagnostic criteria o...

  13. Genetics Home Reference: autosomal dominant nocturnal frontal lobe epilepsy

    Science.gov (United States)

    ... with ADNFLE have experienced psychiatric disorders (such as schizophrenia), behavioral problems, or intellectual disability. It is unclear ... Changes Mutations in the CHRNA2 , CHRNA4 , and CHRNB2 genes can cause ADNFLE . These genes provide instructions for ...

  14. A CASE OF AUTOSOMAL DOMINANT BILATERAL FAMILIAL ANIRIDIA

    Directory of Open Access Journals (Sweden)

    Srinivas M

    2014-04-01

    Full Text Available Aniridia are rare developmental anomalies present in 1.8/100, 000 live births. Aniridia occurs due to abnormal neuroectodermal development secondary to mutations in paired box gene 6 (PAX6 on band p13 of chromosome 11 which regulates eye development. Aniridia may be congenital or traumatic. It may occur in isolation or be associated with a number of syndromes such as WAGR. Two third of cases are familial and one third is sporadic. We report a family of aniridia with different clinical spectrum of features.

  15. Progeria (Hutchison-Gilford syndrome) in siblings: in an autosomal recessive pattern of inheritance.

    Science.gov (United States)

    Raghu, T Y; Venkatesulu, G A; Kantharaj, G R; Suresh, T; Veeresh, V; Hanumanthappa, Y

    2001-01-01

    Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclerodermatous changes over the extremities, alopecia, beaked nose, prominent veins and bird-like facies. Radiological features were consistent with features of progeria. The present case highlights rarity of progeria in siblings with a possible autosomal recessive pattern.

  16. Progeria (Hutchison - Gilford syndrome in siblings: In an autosomal recessive pattern of inheritance

    Directory of Open Access Journals (Sweden)

    Raghu Tanjore

    2001-09-01

    Full Text Available Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclcrodermatous changes over the extremities, alopecia, beaked nose, prominent veins and bird-like facies. Radiological features were consistent with features of progeria. The present case highlights rarity of progeria in siblings with a possible autosomal recessive pattern.

  17. Polycystic ovarian syndrome

    Directory of Open Access Journals (Sweden)

    Nina Madnani

    2013-01-01

    Full Text Available Polycystic ovarian syndrome (PCOS is a "multispeciality" disorder suspected in patients with irregular menses and clinical signs of hyperandrogenism such as acne, seborrhoea, hirsutism, irregular menses, infertility, and alopecia. Recently, PCOS has been associated with the metabolic syndrome. Patients may develop obesity, insulin resistance, acanthosis nigricans, Type 2 diabetes, dyslipidemias, hypertension, non-alcoholic liver disease, and obstructive sleep apnoea. Good clinical examination with hematological and radiological investigations is required for clinical evaluation. Management is a combined effort involving a dermatologist, endocrinologist, gynecologist, and nutritionist. Morbidity in addition includes a low "self image" and poor quality of life. Long term medications and lifestyle changes are essential for a successful outcome. This article focuses on understanding the normal and abnormal endocrine functions involved in the pathogenesis of PCOS. Proper diagnosis and management of the patient is discussed.

  18. Mutations of rhodopsin gene in a family with autosomal dominant retinitis pigmentosa%一个常染色体显性视网膜色素变性家系表型分析和RHO基因突变检测

    Institute of Scientific and Technical Information of China (English)

    章雪敏; 刘铁城; 金鑫; 袁慧军; 张宝全; 王瑛

    2012-01-01

    目的 分析一常染色体显性视网膜色素变性(autosomal dominant retinitis pigmentosa,adRP)家系的临床表型,确定该家系与视紫红质(rhodopsin,RHO)基因的关系.方法 依据RP诊断标准及患者临床表型,确定一连续4代发病的adRP家系遗传的特点;采集家系中13位成员外周血8-10ml,提取基因组DNA;聚合酶链反应(polymerase chain reaction,PCR)扩增RHO基因的第1-5外显子基因片段,产物纯化后直接测序;测序结果与美国国立生物技术信息中心(National Center for Biotechnology Information,NCBI)数据库上公布的核酸标准序列进行比对分析.结果 该家系临床特点为所有患者均于10岁左右出现夜盲,1例22岁出现视野损害,2例40岁左右出现视野损害,并且于50岁左右双眼相继发生急性闭角型青光眼和并发性白内障.该家系5例患者在RHO基因外显子、上下游非编码序列以及内含子及外显子拼接部中均未发现碱基改变.结论 本研究家系患者存在遗传异质性和表型异质性,RHO基因不是该家系的致病基因.%Objective To study the relation between a family with autosomal dominant retinitis pigmentosa(adRP) and rhodopsin (RHO) by analyzing the clinical phenotype of adRP. Methods Genetic characteristics of the family with adRP occurring in 4 consecutive generations were observed according to the RP diagnostic criteria of retinitis pigmentosa(RP) and the clinical phenotype of the adRP family members. Peripheral blood samples(8-10ml) were taken from 13 family members of the family with adRP. Genomic DNA was isolated and the first 5 exons of RHO gene segments were amplified by PCR. The purified PCR products were directly sequenced, which was compared with the standard sequence of nucleic acid from National Center for Biotechnology Information(NCBl). Results Night blindness occurred in all members of the family at the age of about 10 years. Visual field damage was observed in 1 member at the age of

  19. Bicc1 links the regulation of cAMP signaling in polycystic kidneys to microRNA-induced gene silencing

    Institute of Scientific and Technical Information of China (English)

    Nathalie Piazzon; Charlotte Maisonneuve; Isabelle Guilleret; Samuel Rotman; Daniel B. Constam

    2012-01-01

    Genetic defects in autosomal-dominant polycystic kidney disease (ADPKD) promote cystic growth of renal tubules,at least in part by stimulating the accumulation of cAMP.How renal cAMP levels are regulated is incompletely understood.We show that cAMP and the expression of its synthetic enzyme adenylate cyclase-6 (AC6) are up-regulated in cystic kidneys of Bicc1-/-knockout mice.Bicc1,a protein comprising three K homology (KH) domains and a sterile alpha motif (SAM),is expressed in proximal tubules.The KH domains independently bind AC6 mRNA and recruit the miR-125a from Dicer,whereas the SAM domain enables silencing by Argonaute and TNRC6A/GW182.Bicc1 similarly induces silencing of the protein kinase inhibitor PKlα by miR-27a.Thus,Bicc1 is needed on these target mRNAs for silencing by specific miRNAs.The repression of AC6 by Bicc1 might explain why cysts in ADPKD patients preferentially arise from distal tubules.

  20. The effects of antihypertensive agents on the survival rate of polycystic kidney disease in Han:SPRD rats.

    Science.gov (United States)

    Kanno, Yoshihiko; Okada, Hirokazu; Moriwaki, Kenshi; Nagao, Shizuko; Takahashi, Hisahide; Suzuki, Hiromichi

    2002-11-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder in humans. Hypertension is one of the major complications, and its control might affect the renal survival and disease mortality. Suitable antihypertensive agents have been discussed based on clinical and animal studies, but no definitive conclusion has been reached. Generally, therefore, all antihypertensives are indiscriminately treated as if providing the same level of blood pressure control. In this study, the blood pressure control of two antihypertensives was investigated using a rat model of ADPKD in humans. Twenty-four male Hannover-Sprague Dawley (Han:SPRD) rats were divided into three groups: a group receiving amlodipine (6 mg/day), a group receiving benazepril (6 mg/day) and an untreated control group. Blood pressure, body weight, and urinary protein excretion were regularly measured up to week 52. Amlodipine and benazepril significantly decreased blood pressure and urinary protein excretion to the same degree. Moreover, a remarkably prolonged survival rate was observed in both groups (at week 52, the survival rate was 25% in controls, 50% in the amlodipine group, and 50% in the benazepril group). Examination at autopsy revealed that enlarged cysts were prevalent in the renal tissue of both experimental all three groups, suggesting that the cystic disease had reached the end-stage in all the animals. In conclusion, both amlodipine and benazepril significantly improved blood pressure control, urinary protein excretion, and survival rate, possibly due to their enhancement of renal survival.

  1. Gonadal mosaicism as a rare cause of autosomal recessive inheritance.

    Science.gov (United States)

    Anazi, S; Al-Sabban, E; Alkuraya, F S

    2014-03-01

    Autosomal recessive diseases are typically caused by the biparental inheritance of familial mutant alleles. Unusual mechanisms by which the recessiveness of a mutant allele is unmasked include uniparental isodisomy and the occurrence of a de novo chromosomal rearrangement that disrupts the other allele. Gonadal mosaicism is a condition in which a postfertilization mutation is confined to the gamete precursors and is not detected in somatic tissues. Gonadal mosaicism is known to give the impression of autosomal recessive inheritance when recurrence of an autosomal-dominant condition among offspring of phenotypically normal parents is observed. Here, we report an extremely rare event in which maternal gonadal mosaicism for a recessive mutation in COL4A4 caused the recurrence of Alport syndrome within a consanguineous family. Such rare occurrence should be taken into account when analyzing pedigrees both for clinical and research purposes.

  2. 先天性膜性白内障一家系致病基因的遗传分析%Mutation of 22q11.2-q12.1 gene in a family with autosomal dominant congenital membranous cataract

    Institute of Scientific and Technical Information of China (English)

    袁芳; 李飞峰; 刘伟; 刘华; 季健; 马旭

    2009-01-01

    目的 分析一个先天性白内障家系的遗传规律,对其突变基因进行初步研究.方法 选取一先天性膜性白内障家系,对家系成员进行临床检查并采集静脉血.标准饱和酚/氯仿抽提法提取DNA,选取多态性微卫星遗传标记,合成引物,聚合酶链反应,聚丙烯酰胺凝胶电泳,基因分型,等位基因共享分析法对已知候选基因进行排除性定位.结果 该家系为常染色体显性遗传性先天性白内障家系.其致病基因与D22S315联系紧密,重组发生在以D22S303和D22S1167为上下边界的范围内.对该范围内已知的先天性白内障致病基因CRYBB1、CRYBB2、CRYBB3、CRYBA4进行DNA直接测序,未发现突变.结论 该家系致病基因定位于22q11.2~q12.1的2.4 Mbp范围内,其致病基因与已知基因座不同.该范围内可能存在导致先天性膜性白内障的新的致病基因.%Objective Autosomal dominant congenital cataract (ADCC) is a common heredit disease.Some known genes and mutated loci related to ADCC have been found.The present study provides other disease-causing genes in the ADCC family.This study was to identify the genetic defect in four generations of a Chinese family with autosomal dominant congenital membranous cataracts and demonstrate the functional analysis of a candidate gene in the family.MethodsThe family with hereditary cataract was recruited from the Tianjin Medical University Eye Center.The family history was collected and recorded.Clinical and ophthalmologic examinations were performed on 6 affected and 14 unaffected family members and periphery blood samples were collected from all of the subjects for genomic DNA preparation.The members were genotyped with microsatellite markers at loci associated with cataracts.Multiplex polymerase chain reaction (PCR) was carried out with microsatellite markers near to candidated loci related to congenital cataracts.PCR products from each DNA sample were separated on a polyarcylamide gel and

  3. Autosomal recessive hypophosphataemic rickets with hypercalciuria is not caused by mutations in the type II renal sodium/phosphate cotransporter gene.

    NARCIS (Netherlands)

    Heuvel, L.P.W.J. van den; Koul, K. Op de; Knots, E.; Knoers, N.V.A.M.; Monnens, L.A.H.

    2001-01-01

    BACKGROUND: At present the genetic defect for autosomal recessive and autosomal dominant hypophosphataemic rickets with hypercalciuria (HHRH) is unknown. Type II sodium/phosphate cotransporter (NPT2) gene is a serious candidate for being the causative gene in either or both autosomal recessive and a

  4. [Polycystic ovary syndrome (PCOS)].

    Science.gov (United States)

    Torre, A; Fernandez, H

    2007-09-01

    Polycystic ovaries syndrome (PCOS) is one of the most common female hormonal disorders. Its multiple components--reproductive, metabolic, neoplasic and cardiovascular--have a major impact on the public health. Androgen excess and resistance to insulin, probably from genetic origin, are responsible for most of the clinical symptomatology. Resistance to insulin seems to be accompanied by a greater risk of glucose intolerance, type 2 diabetes, lipidic anomalies and can involve the development of cardiovascular diseases. In addition, sleep apnea syndrome is more progressively described in PCOS. Infertility, menses disorders and hirsutism often push these patients to consult their physician. A better understanding of the physiopathological mechanisms led to the emergence of new therapeutic options increasing the sensitivity to insulin. Besides the pregnancy wishes, cares aim to attenuate the marks of the hyper-androgenism (hormonal treatment and cosmetic) and to correct cardiovascular, respiratory and gynaecological risk factors. In case of infertility by anovulation, cares must be performed by trained experts to minimize the risk of ovarian hyper-stimulation syndrome and multiple pregnancies. A gradation from loose weight to clomiphene citrate ovulation induction, ovarian drilling, low dose gonadotropin, in vitro fertilisation, or in vitro maturation of oocytes should bring back good reproduction potential.

  5. POLYCYSTIC OVARY SYNDROME

    Directory of Open Access Journals (Sweden)

    Akula Annapurna

    2013-09-01

    Full Text Available Polycystic ovary syndrome is a condition in which a woman has an imbalance of female sex hormones. This may lead to menstrual cycle changes, cysts in the ovaries, trouble getting pregnant, and other health changes. In PCOS, mature eggs are not released from the ovaries. Instead, they can form very small cysts in the ovary. These changes can contribute to infertility. Common symptoms of PCOS include Menstrual disorders, Infertility, High levels of testosterone and Metabolic syndrome. Obesity, sedentary life style with inadequate physical activity, stress, junk food consumption are thought to be contributing factors in addition to genetic origin. In recent years many of the girls and women are suffering from PCOS because of wrong eating habits, stressful living conditions and lack of physical activity. Weight loss has been the major recommendation by physicians for women with PCOS. Lifestyle modifications including stress reduction, moderate exercise, and group support, along with a decrease in total calorie intake and avoiding junk food consumption have had positive results. A decrease of only 5% of total body weight is associated with decreased insulin levels, increased fertility, reduced hirsutism and acne, and lower testosterone levels. Whole grains, fruits and vegetables with foods containing protein and natural fat along with vitamins and minerals are beneficial.

  6. Value of qualitative research in polycystic ovary syndrome

    Institute of Scientific and Technical Information of China (English)

    Ma Hongxia; Liang Huiling; Gao Jingshu; Ma Hongli; Liu Jianping; Ng Hungyu Ernest; Billhult Annika

    2014-01-01

    Objective This article aims to introduce the benefits of qualitative research and to discuss how such research can be applied to the study of polycystic ovary syndrome (PCOS).Data sources Relevant articles were published in English as of May 2013 from Pubmed.Terms "polycystic ovary syndrome/PCOS,qualitative research and methodology" were used for searching.Study selection Articles studying PCOS with qualitative methods were reviewed.Articles associated with the use of qualitative research in clinical research were cited.Results Six qualitative studies related to PCOS were found in the literature search.These studies addressed different aspects in PCOS women including their womanhood,lived experience,information need,and experience of treatment with acupuncture.Five of these six studies used phenomenology as guiding theory.Conclusion Quantitative research has been the dominant approach in the field so far,qualitative research is relevant to the advancement of PCOS.

  7. 一个迟发性非综合征型常染色体显性遗传性聋家系表型特征及致病基因初步探讨%A Preliminary Study of Phenotypic Characteristics and Causative Genes in a Family with Late-onset Nonsyndromic Autosomal Dominant Hereditary Hearing Loss

    Institute of Scientific and Technical Information of China (English)

    王鸿涵; 刘亚兰; 卢焰梅; 贺楚峰; 冯永; 王行炜; 梅凌云; 陈红胜; 蒋璐; 门美超; 张华; 李海波

    2012-01-01

    Objective To analyze the clinical phenotype of a pedigree with late - onset hereditary hearing loss, and investigate the disease- causing genes of this family. Methods The detailed medical history information of the participants in a large Hunan Province family with hereditary hearing loss were collected. Physical and augdio logical examination were administered.Two individuals were carried out Computed tomography (CT) scan of the temporal bone, The participants' inrormation was sorted, out and the geoalogica tree map was charted. Alter revie wiog the literature, we speculated oo geoes that could lead to desfness sccordiog to pheootype of this family. Some candidate geoes codiog regioo were amplified by polymerase chain reaction (PCR) using geocmic DNA which was extracted from the proband's peripheral blood. PCR products were purified by exopeptidase. Ao ABI 3730XL geoetic soslyzer was used for direct sequeociog, and data was analyzed usiog DNASTAR-Lasergeoe SeqMan Pro software. Results The family tree showed that this was 30 autosomal domioant non-syodromic deafoess pedigree. Clioical fea tures were remarkably similar amoog subjects. All of them were operated oo for "buzz-like" tinnitus between 9 and 25 years old, and then for bilateral hearing loss. Pure tone audiometry examination showed the hearing loss be gan at the higher frequencies,then the lower frequencies with the aggravation of hearing loss. Conclusion Pedigree analysis suggested this family conformed to the characteristics of autosomal dominant hereditary pattern. The causa tive gene of this family needs more exploration.%目的 分析一个迟发性遗传性聋大家系的临床表型,探讨该家系耳聋患者的致病基因.方法 对一个湖南籍耳聋大家系成员进行详细的病史资料采集、体格检查、听力学检查,其中两名患者做了颞骨CT检查.绘制家系图.以先证者外周血基因组DNA为模板对候选致病基因进行涵盖全部编码序列聚

  8. Overweight in polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Ravn, P; Haugen, A G; Glintborg, D

    2013-01-01

    Aim: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal women affecting 5-10%. Nearly 50% are overweight or obese, which result in a more severe phenotype of PCOS. Weight loss is therefore considered the first line treatment in overweight women with PCOS...

  9. Metformin in polycystic ovary syndrome

    NARCIS (Netherlands)

    Moll, E.

    2013-01-01

    The main result of this thesis can be summarized as follows: the addition of metformin to clomifene citrate in therapy-naïve women with polycystic ovary syndrome does not increase their chance of pregnancy except for possibly a subgroup of older women with high waist hip ratio, does hardly lead to i

  10. The population genetics of X-autosome synthetic lethals and steriles.

    Science.gov (United States)

    Lachance, Joseph; Johnson, Norman A; True, John R

    2011-11-01

    Epistatic interactions are widespread, and many of these interactions involve combinations of alleles at different loci that are deleterious when present in the same individual. The average genetic environment of sex-linked genes differs from that of autosomal genes, suggesting that the population genetics of interacting X-linked and autosomal alleles may be complex. Using both analytical theory and computer simulations, we analyzed the evolutionary trajectories and mutation-selection balance conditions for X-autosome synthetic lethals and steriles. Allele frequencies follow a set of fundamental trajectories, and incompatible alleles are able to segregate at much higher frequencies than single-locus expectations. Equilibria exist, and they can involve fixation of either autosomal or X-linked alleles. The exact equilibrium depends on whether synthetic alleles are dominant or recessive and whether fitness effects are seen in males, females, or both sexes. When single-locus fitness effects and synthetic incompatibilities are both present, population dynamics depend on the dominance of alleles and historical contingency (i.e., whether X-linked or autosomal mutations occur first). Recessive synthetic lethality can result in high-frequency X-linked alleles, and dominant synthetic lethality can result in high-frequency autosomal alleles. Many X-autosome incompatibilities in natural populations may be cryptic, appearing to be single-locus effects because one locus is fixed. We also discuss the implications of these findings with respect to standing genetic variation and the origins of Haldane's rule.

  11. 伴听觉症状的家族性颞叶外侧癫痫的临床特点及LGI1基因突变检测%Clinical characteristics and LGII gene mutation analysis on an autosomal dominant lateral temporal lobe epilepsy

    Institute of Scientific and Technical Information of China (English)

    席志芹; 王学峰; 吕洋; 王亮; 肖飞; 关立峰

    2009-01-01

    Objective To report the clinical and genetic study of a new Chinese family with autosomal dominant lateral temporal lobe epilepsy (ADLTE).Methods The living affected members underwent a full clinical,neurophysiological,electroencephalogram (EEG),and magnetic resonance imaging (MRI) study.Genetic analysis was performed by LGI1 DNA sequence analysis.Results The clinical feature of the patients was coincidence well with the definition of ADLTE by International league Against Epilepsy in 2001.The living affected members had an adult or children onset of drug-responsive tonic-clonic seizures or complex partial seizures constantly preceded by auditory or visional aura.Routine EEG revealed no focal abnormalities over both temporal regions.MRI detected no structural abnormality.Analysis of LGI1 gene showed no mutation in all affected members.Conclusion This kindred has typical clinical manifestations of ADLTE.The pathogenesis has no association with mutation of the exons of LGIl gene.%目的 研究伴听觉症状的常染色体显性遗传颞叶外侧癫痫(ADLTE)一家系相关基因富亮氨酸胶质瘤失活基因1(LGll)的突变,探讨该综合征的临床特征及基因基础.方法 对该家系进行详细的病史询问和遗传学调查,采集患者和家属血液,按受累同胞对配对法对LGIl基因的8个外显子分别设计引物,用聚合酶链反应(PCR)结合DNA测序,检测该家系中有无LGIl基因外显子突变.结果 家系中所有患者符合国际抗癫痫联盟2001年新癫痫综合征标准中ADLTE典型表现,头颅MRI正常,PCR结合DNA序列分析LGIl基因8个外显子未发现突变.结论 该家系临床表现与ADLTE相同,但其发病不是由已知的LGIl基因外显子突变所致.

  12. Distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómico dominante por mutación del factor de crecimiento fibroblástico 23 en una familia Different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets caused by a FGF 23 mutation in one family

    Directory of Open Access Journals (Sweden)

    Armando Luis Negri

    2004-04-01

    Full Text Available Describimos distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómico dominante en 4 miembros de una misma familia y su respuesta al tratamiento. Paciente N° 1: de sexo femenino de 60 años que consultó por dolores costales y pélvicos, con osteoporosis densitométrica, hipofosfatemia con bajo umbral renal de fósforo, PTH intacta normal y calcemia normal. Tratada con fósforo neutro y calcitriol logró la normalización bioquímica y una notable mejoría de la densitometría en menos de un año. Paciente N° 2: su nieta, consultó al año y ocho meses de edad por presentar talla en percentil 3 y genu varum. En el laboratorio mostró hipofosfatemia y fosfatasa alcalina total muy elevada y en la Rx de mano, ensanchamiento y deflecamiento epifisario compatible con raquitismo. Tratada con fósforo neutro y calcitriol, normalizó los parámetros bioquímicos y logró un ascenso en el percentil de talla de 3 a 50 a los 20 meses de tratamiento. Paciente N° 3: la madre de la paciente N° 2, quien sin ninguna manifestación clínica y con densitometría ósea normal presentó hipofosfatemia que se normalizó con tratamiento con fosfato neutro. Paciente N° 4: el tío de la paciente N° 2, tuvo raquitismo hipofosfatémico de niño, y luego de los 5 años normalizó el fósforo sin tratamiento. Estudiado a los 29 años presentó fósforo normal y densitometría ósea normal. El análisis del ADN genómico de la paciente N° 3 mostró una mutación con sentido erróneo en el gen del factor de crecimiento fifroblástico 23 (sustitución de arginina por una glutamina en posición 179. Por lo tanto se llegó al diagnóstico de raquitismo/osteomalacia hipofosfatémico autosómico dominante.In this report we describe different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets (ADHR in 4 members of the same family as well as the treatment used in these patients and their response to it. Patient N

  13. Clinical features and gene mutations of Chinese patients with autosomal dominant Charcot-Marie-Tooth disease%常染色体显性遗传腓骨肌萎缩症的临床与基因突变特点

    Institute of Scientific and Technical Information of China (English)

    郭鹏; 宋福聪; 王相斌; 冯文霞; 胡志强; 唐北沙; 夏昆

    2011-01-01

    Objective To analyze the characteristics of the clinical features and the gene mutations between Chinese patients with autosomal dominant Charcot-Marie-Tooth disease. Methods The clinical manifestations, electrophysiological and pathological investigations of patients with autosomal dominant Charcot-Marie-Tooth were analyzed retrospectively. One hundred and six CMT patients underwent mutation analysis of PMP22 duplication and PMP22, MPZ, SIMPLE, EGR2, RAB7,NEFL,MFN2,Hsp27 and Hsp22. Results CMT1A was caused by PMP22 duplication,and CMT1B was caused by MPZ mutation. In those patients,the age of onset were earlier. The most frequently first symptom was weakness and atrophy in lower limbs with hypesthesia. Physical examination showed distal limb weakness and wasting,and taplipes cavus in all of them. Electromyogram and nerve conduction velocity showed slow nerve conduction. Pathological examination showed demye-lination. CMT2A2 was caused by MFN2 mutation,CMT2F wag caused by Hsp27 mutation,and CMT2L was caused by Hsp22 mutation. Compared with CMT1 ,patients of CMT2 were less frequent,the age of onset were later,motor disability was more sever than sensory disability. Electromyogram and nerve conduction velocity was normal. Pathological examination showed axonal denaturation. Conclusions In this study, the results of the mutation screening were consistent with the clinical features. Mutation screening has the character of high accuracy,little harm and can help to diagnosis earlier,so it suggestes to be performed widely in the clinic especially to the patients who has family history or to the lineal relatives.%目的:探讨常染色体显性遗传腓骨肌萎缩症(CMT)患者的临床与基因突变的特点。方法:对43个常染色体显性遗传CMT家系共106例患者的临床表现、电生理和病理特点进行回顾性分析,并进行PMP22的大片段重复突变和PMP22、MPZ、SIMPLE、EGR2、RAB7、NEFL、MFN2、Hsp27及Hsp22

  14. Pregnancy in polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Sadishkumar Kamalanathan

    2013-01-01

    Full Text Available Polycystic ovary syndrome affects 6 to 15% of reproductive age women worldwide. It is associated with increased risk of miscarriage, gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm delivery, and birth of small for gestational age infant. Many studies on issues relating to pathophysiology and management of these complications have been published recently. These issues are being reviewed here using relevant articles retrieved from Pubmed database, especially from those published in recent past.

  15. Metabolic Syndrome: Polycystic Ovary Syndrome.

    Science.gov (United States)

    Mortada, Rami; Williams, Tracy

    2015-08-01

    Polycystic ovary syndrome (PCOS) is a heterogeneous condition characterized by androgen excess, ovulatory dysfunction, and polycystic ovaries. It is the most common endocrinopathy among women of reproductive age, affecting between 6.5% and 8% of women, and is the most common cause of infertility. Insulin resistance is almost always present in women with PCOS, regardless of weight, and they often develop diabetes and metabolic syndrome. The Rotterdam criteria are widely used for diagnosis. These criteria require that patients have at least two of the following conditions: hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The diagnosis of PCOS also requires exclusion of other potential etiologies of hyperandrogenism and ovulatory dysfunction. The approach to PCOS management differs according to the presenting symptoms and treatment goals, particularly the patient's desire for pregnancy. Weight loss through dietary modifications and exercise is recommended for patients with PCOS who are overweight. Oral contraceptives are the first-line treatment for regulating menstrual cycles and reducing manifestations of hyperandrogenism, such as acne and hirsutism. Clomiphene is the first-line drug for management of anovulatory infertility. Metformin is recommended for metabolic abnormalities such as prediabetes, and a statin should be prescribed for cardioprotection if the patient meets standard criteria for statin therapy.

  16. Polycystic Ovarian Syndrome: A Primer.

    Science.gov (United States)

    Thornton, Emily C; Von Wald, Tiffany; Hansen, Keith

    2015-06-01

    Polycystic ovary syndrome (PCOS) affects 8-10 percent of reproductive-aged females, making it the most common state of endocrine dysfunction in women. Patients with PCOS are often treated for the signs and symptoms of the condition without consideration for the underlying syndrome, causing frustration for many affected patients. Abnormal uterine bleeding, endometrial hyperplasia and cancer, hirsutism and other skin changes, obesity, glucose intolerance, hypertension, and hyperlipidemia often accompany the syndrome, making it imperative to address these issues. The keys to diagnosis and treatment are understanding the diagnostic criteria of hyperandrogenism, ovulatory dysfunction, polycystic ovaries and the metabolic syndrome, while aiming treatment at controlling the symptoms and causes of the syndrome. In 2013, the Endocrine Society released its clinical guidelines, Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline. This gives clear diagnostic criteria, and treatment goals aimed at the etiology of the syndrome: to decrease hyperandrogenic symptoms, management of underlying metabolic abnormalities, prevention of endometrial hyperplasia and carcinoma, and improvement of ovulation.

  17. 一个常染色体显性遗传Emery-Dreifuss型肌营养不良家系的基因突变分析%Mutation analysis of a Chinese family with autosomal dominant Emery-Dreifuss muscular dystrophy

    Institute of Scientific and Technical Information of China (English)

    袁军辉; 胡静; 赵哲; 沈宏锐; 李娜; 邴琪

    2010-01-01

    Objective To investigate the clinical, pathological and genetic characteristics in a family with autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD). Methods Clinical data and skeletal muscle specimens were collected from two patients (the proband and her daughter) for pathological analysis. DNA samples of the proband and her family members (7 persons from 3 generations) were obtained for PCR amplification and direct DNA sequencing of the lamin A/C (LMNA) gene. Haplotype analysis was performed after the identification of mutation. Results The proband had typical clinical manifestation of EDMD: joint contracture, progressive muscle weakness and atrophy and cardiac conduction dysfunction. Muscular pathology revealed myopathic changes combined with slight neuropathic changes. A heterozygous missense mutation 1583 (C→G) (T528R) was identified in exon 9 of the LMNA gene in the two patients, but not in other family members. Haplotype analysis indicated that the proband and her daughter shared the same causative haplotype. Conclusion This is the first report of the phenotype and genotype of AD-EDMD in Chinese.%目的 探讨一个常染色体显性遗传Emery-Dreifuss型肌营养不良(Emery-Dreifuss muscular dystrophy,EDMD)家系的临床、病理及遗传学特点.方法 收集家系中2例患者(先证者及女儿)的临床资料及骨骼肌标本,行组织化学染色病理分析;收集先证者及家系成员(3代7人)血液DNA标本,采用聚合酶链反应和DNA直接测序方法 对LMNA基因进行突变检测;明确基因变异位点后对家系行单倍型分析.结果 先证者具有典型的EDMD临床表现:关节挛缩、进行性加重的肌无力和肌萎缩、心脏传导异常;骨骼肌活检病理示肌源性合并轻度神经源性改变;2例患者LMNA基因第9外显子发现杂合错义突变1583(C→G)(T528R),表型正常的其他家系成员未发现该突变;单倍型分析显示先证者及女儿具有相同的致病单倍型.结论

  18. 成人多囊肾病泌尿系感染与肾功能损害的相关性研究%The detrimental effect of urinary tract infection on renal function of adults with autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    陆钫; 叶敏; 朱英坚; 陈建华

    2002-01-01

    目的探讨成人多囊肾病(ADPKD)泌尿系感染对肾功能损害的临床意义.方法分析总结478例ADPKD患者泌尿系感染发生率,及其与肾功能损害的相关性.结果本组ADPKD泌尿系感染的发生率为26.4%.膀胱炎27例、肾盂肾炎89例、囊肿感染积脓11例、肾周脓肿3例、无症状性泌尿系感染9例.感染与性别、泌尿系统器械检查、肾功能不全及尿石症等因素有关.反复泌尿系感染是导致ADPKD肾功能进行性损害的最重要因素.结论避免各种不必要的器械检查,积极消除肾内、肾外梗阻因素,应用有效的抗生素,对控制和预防ADPKD的泌尿系感染,延缓肾功能损害具有十分重要的意义.

  19. A novel approach identifying hybrid sterility QTL on the autosomes of Drosophila simulans and D. mauritiana.

    Science.gov (United States)

    Dickman, Christopher T D; Moehring, Amanda J

    2013-01-01

    When species interbreed, the hybrid offspring that are produced are often sterile. If only one hybrid sex is sterile, it is almost always the heterogametic (XY or ZW) sex. Taking this trend into account, the predominant model used to explain the genetic basis of F1 sterility involves a deleterious interaction between recessive sex-linked loci from one species and dominant autosomal loci from the other species. This model is difficult to evaluate, however, as only a handful of loci influencing interspecies hybrid sterility have been identified, and their autosomal genetic interactors have remained elusive. One hindrance to their identification has been the overwhelming effect of the sex chromosome in mapping studies, which could 'mask' the ability to accurately map autosomal factors. Here, we use a novel approach employing attached-X chromosomes to create reciprocal backcross interspecies hybrid males that have a non-recombinant sex chromosome and recombinant autosomes. The heritable variation in phenotype is thus solely caused by differences in the autosomes, thereby allowing us to accurately identify the number and location of autosomal sterility loci. In one direction of backcross, all males were sterile, indicating that sterility could be entirely induced by the sex chromosome complement in these males. In the other direction, we identified nine quantitative trait loci that account for a surprisingly large amount (56%) of the autosome-induced phenotypic variance in sterility, with a large contribution of autosome-autosome epistatic interactions. These loci are capable of acting dominantly, and thus could contribute to F1 hybrid sterility.

  20. Autosomal recessive hereditary auditory neuropathy

    Institute of Scientific and Technical Information of China (English)

    王秋菊; 顾瑞; 曹菊阳

    2003-01-01

    Objectives: Auditory neuropathy (AN) is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses (ABRs) and normal cochlear outer hair cell function as measured by otoacoustic emissions (OAEs). Many risk factors are thought to be involved in its etiology and pathophysiology. Three Chinese pedigrees with familial AN are presented herein to demonstrate involvement of genetic factors in AN etiology. Methods: Probands of the above - mentioned pedigrees, who had been diagnosed with AN, were evaluated and followed up in the Department of Otolaryngology Head and Neck Surgery, China PLA General Hospital. Their family members were studied and the pedigree diagrams were established. History of illness, physical examination,pure tone audiometry, acoustic reflex, ABRs and transient evoked and distortion- product otoacoustic emissions (TEOAEs and DPOAEs) were obtained from members of these families. DPOAE changes under the influence of contralateral sound stimuli were observed by presenting a set of continuous white noise to the non - recording ear to exam the function of auditory efferent system. Some subjects received vestibular caloric test, computed tomography (CT)scan of the temporal bone and electrocardiography (ECG) to exclude other possible neuropathy disorders. Results: In most affected subjects, hearing loss of various degrees and speech discrimination difficulties started at 10 to16 years of age. Their audiological evaluation showed absence of acoustic reflex and ABRs. As expected in AN, these subjects exhibited near normal cochlear outer hair cell function as shown in TEOAE & DPOAE recordings. Pure- tone audiometry revealed hearing loss ranging from mild to severe in these patients. Autosomal recessive inheritance patterns were observed in the three families. In Pedigree Ⅰ and Ⅱ, two affected brothers were found respectively, while in pedigree Ⅲ, 2 sisters were affected. All the patients were otherwise normal without

  1. STATINS IN POLYCYSTIC OVARY SYNDROME

    Directory of Open Access Journals (Sweden)

    P. S. Patel*, T. D. Goswami, A. D. Sharma and B. S. Arora

    2012-11-01

    Full Text Available Polycystic ovary syndrome (PCOS is the most common endocrine disorder in women. PCOS varies from a mild menstrual disorder to severe disturbance of reproductive and metabolic functions. Statins, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA reductase inhibitors with intrinsic antioxidant properties, exert profound and broad-reaching effects on various types of tissues. By blocking an early step of the mevalonate pathway, statins inhibit proliferation of several cell types including vascular smooth muscles, hepatocytes, and several neoplastic cell lines. The pleiotropic effects of statins may be due to inhibition of cholesterol synthesis. Some common treatments lifestyle changes, insulin-sensitizing agents.

  2. Diagnosis of adolescent polycystic ovary syndrome.

    Science.gov (United States)

    Hardy, Tristan S E; Norman, Robert J

    2013-08-01

    Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age and is increasingly recognized as a disorder manifesting in the peripubertal and adolescent period. Diagnosis in the adolescent is difficult due to the high background rate of menstrual irregularity, the high prevalence of polycystic ovarian morphology and hyperandrogenic features in this population. Recent guidelines suggest that menstrual irregularity for over two years, reduced reliance on ultrasound diagnosis of polycystic ovarian morphology, and accurate assessment of hyperandrogenic and metabolic features are suitable strategies for the diagnosis of PCOS in the adolescent. Accurate diagnosis is important given the long-term implications of the disorder, with increasing emphasis on metabolic sequelae.

  3. 常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病的颅脑MRI表现%The cranial MRI appearance of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in a family

    Institute of Scientific and Technical Information of China (English)

    张金平; 孙冰莲; 余永强; 潘华; 汤永祥; 钱振; 高萍; 刘丰; 李惠芬

    2008-01-01

    目的 提高对常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病(CADASIL)的颅脑MRI表现的认识.方法 对一家系2代5例患者进行头颅常规MR和MR血管成像(MRA)检查.对经Notch3基因检查或皮肤组织活检超微病理检查确诊的3例和经MRI与临床诊断的1例CADASIL的MRI资料进行分析.结果 MR检查的5例中4例CADASIL均获得明确诊断,1例排除诊断.4例CADASIL均见两侧颞叶、额叶和顶叶大致对称性皮层下与侧脑室旁白质病灶,呈长T1、长T2信号,但枕叶累及甚少且皮层不受累;O'Sullivan征阳性4例,皮层下腔隙性损害(SLLs)征阳性2例;3例半卵圆中心可见多发圆形或卵圆形囊性梗死即"黑洞",4例均见多发圆点状血管周间隙即"胡椒罐盖"样征象;4例全部显示胼胝体单发或多发斑片状显著长T1、长T2信号,其中2例伴萎缩;内囊前肢与外囊均受累,呈"人"字征;基底节和脑干可见单发或多发陈旧性腔隙性梗死灶;1例伴右侧小脑小片状梗死灶;4例全部有轻度至中度的脑干、小脑和大脑萎缩;MRA颅内Ⅰ-Ⅲ级较大动脉均未见明显异常.结论 CADASIL的颅脑MRI表现具有一定的特征性,可为CADASIL的初诊和筛选提供重要依据.%Objective To recognize the cranial MRI appearance in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL). Methods Five patients with CADASIL from two generations in a family underwent routine MRI and MRA examinations.Three patients with CADASIL were confirmed by the Notch3 genetic testing and the vascular pathological Results and one was diagnosed on basis of MR and clinical manifestations. The imaging data from 4 patients with CADASIL were analyzed.Results Four cases achieved preliminary diagnosis of CADASIL and one was excluded by MRI.In 4 patients with CADASIL,bilateral symmetrical,confluent white matter lesions in the subcortical and Deriventricular regions were seen frequently

  4. CRYAA gene mutation study in a family with autosomal dominant congenital cataract combined with microcornea%常染色体显性遗传核性白内障合并小角膜的CRYAA基因突变研究

    Institute of Scientific and Technical Information of China (English)

    梁小芳; 肖伟; 石磊; 华芮; 张学

    2011-01-01

    Objective To identify the gene mutation in a four-generation Chinese family with autosomal dominant congenital cataract associated with microcornea. Methods Experimental research.Twelve members in this family (including six affected and six unaffected individuals) were enrolled into this study. They underwent full ophthalmological and clinical examinations to rule out any concomitant disorders.Blood samples were collected and genomic DNA was extracted. Microsatellite markers near the reported loci,which are associated with congenital cataract and microcornea were selected and amplified from DNA samples using polymerase chain reaction. Linkage analysis was performed. The exons and exon/intron junction of candidate gene in the related chromosome were sequenced. The product of the first exon was digested by ApaL Ⅰ restriction enzyme to certify the mutation. Results The phenotype studied in this family was nuclear cataract accompanied with microcornea. At markers D21S1885 and D21S1890 near the locus 21q22. 3, the affected members had the same allele, but the unaffected did not. The Lod scores were 2. 11in both markers, indicating that this locus were linked to the congenital cataract in this family. DNA sequencing of candidate gene CRYAA showed a heterozygous mutation c. 34C > T in exon 1, which led to condon 12 in peptide chain encoding arginine substituted by cysteine. ApaL Ⅰ enzyme digestion certified that all of the affected members had the same mutation c. 34C >T, but the unaffected and normal individuals did not. Conclusion Mutation (p. R12C) of CRYAA is the genetic change that causes the occurrence of congenital cataract with microcornea in this family.%目的 研究一个4代常染色体显性遗传先天性核性白内障伴小角膜家系的致病基因.方法 实验研究.对12例家系成员(6例患者,6例非患者)进行眼部检查并采集静脉血,提取基因组DNA.在已知的与先天性白内障伴小角膜相关致病基因附近选择微

  5. Genetics Home Reference: polycystic kidney disease

    Science.gov (United States)

    ... ED. Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy. Pediatr Res. 2014 Jan; ... healthcare professional . About Genetics Home Reference Site Map Customer Support Selection Criteria for Links USA.gov Copyright ...

  6. Polycystic ovary syndrome: current infertility management.

    Science.gov (United States)

    Aubuchon, Mira; Legro, Richard S

    2011-12-01

    This review summarizes the diagnosis of polycystic ovary syndrome and management of associated infertility. The goal is to guide clinicians through basic evaluation, initial treatment, and briefly describe more complex therapies.

  7. Polycystic ovary syndrome: from phenotype to genetype

    NARCIS (Netherlands)

    Y.V. Louwers (Yvonne)

    2014-01-01

    markdownabstract__Abstract__ oligomenorrhea or amenorrhea, hirsutism or hyperandrogenism and polycystic ovarian morphology. Later in life, adverse metabolic implications, such as obesity, insulin resistance, type 2 diabetes and cardiovascular disease, become more prominent. In this thesis, we aimed

  8. Behavioral Retardation in a Macaque with Autosomal Trisomy and Aging Mother.

    Science.gov (United States)

    Waal, Frans B. M. de; And Others

    1996-01-01

    The social development of a female rhesus monkey was followed from birth until death, age 32 months. The monkey had an extra autosome and was hydrocephalic. The monkey showed serious motor deficiencies, delayed social development, poorly established dominance relationships, and heavy dependence on mother and kin. The monkey was, however, well…

  9. [Psychosocial approach in polycystic ovary syndrome].

    Science.gov (United States)

    Kohlné Papp, Ildikó

    2014-11-23

    Polycystic ovary syndrome is the most frequent endocrine disease among women of reproductive age. It is associated with increased risks of various metabolic disorders and complications. most recent data suggest that women suffering from polycystic ovary syndrome are most exposed to several psychological problems. It has been shown that polycystic ovary syndrome exerts a negative impact on female identity and it contributes to the deterioration of quality of life and, eventually, to development of psychiatric problems. The mental consequences of the disease can be as depressing as physiological symptoms. This draws attention on the importance of the disease from the aspect of therapy as well and, therefore, it may be justified to involve a psychologist or psychiatrist in the process for a more effective treatment. The aim of the paper is to summarize the most frequent psychological symptoms associated with the disease.

  10. Polycystic kidney disease gene in the Lewis polycystic kidney rat is mapped to chromosome 10q21–q26

    Directory of Open Access Journals (Sweden)

    Yengkopiong JP

    2012-08-01

    Full Text Available Jada Pasquale YengkopiongDr John Garang Memorial University of Science and Technology, Faculty of Science and Technology, Bor, Republic of South SudanBackground: Polycystic kidney disease (PKD is a life-threatening disorder that affects the kidneys of millions of people across the world. The disease is normally inherited, but it can also be acquired, and leads to development of many cysts in the renal nephrons. In this study, the aim was to characterize PKD in the Lewis polycystic kidney (LPK rat, the newest model for human PKD.Methods: Mating experiments were performed between male LPK rats with PKD and female Brown Norway and Wistar Kyoto rats without PKD to raise second filial (F2 and backcross 1 (BC1 progeny, respectively. Rats that developed PKD were identified. Histological examination of the kidneys and liver was performed. Liver tissue samples were collected from each rat and used to extract DNA. The extracted DNA was amplified, and mapping and linkage analyses were performed to identify the quantitative trait locus that controlled the disease phenotypes.Results: It was established that the disease was controlled by a recessive mutation in a single gene (F2: PKD = 42, non-PKD = 110, χ2 = 0.53; BC1: PKD = 67, non-PKD = 72, χ2 = 0.18, P > 0.05 and that the disease was inherited as autosomal recessive polycystic kidney disease (ARPKD. The rats with PKD developed larger fluid-filled cystic kidneys, higher systolic blood pressure, and anemia. However, there were no extrarenal cysts and no pup deaths. Mapping studies and linkage analyses associated the disease phenotypes in both the F2 and BC1 rats to chromosome 10q21–q26, giving a maximum LOD score of 7.9 (P = 0.00001 between peak markers D10Rat180 and D10Rat26.Conclusion: The quantitative trait locus on chromosome 10q21–q26 does not contain the Pkhd-1 gene, and it is different from quantitative trait loci that control ARPKD in other murine models. The candidate genes located in the

  11. Diagnosis and Treatment of Polycystic Ovary Syndrome.

    Science.gov (United States)

    Williams, Tracy; Mortada, Rami; Porter, Samuel

    2016-07-15

    Polycystic ovary syndrome is the most common endocrinopathy among reproductive-aged women in the United States, affecting approximately 7% of female patients. Although the pathophysiology of the syndrome is complex and there is no single defect from which it is known to result, it is hypothesized that insulin resistance is a key factor. Metabolic syndrome is twice as common in patients with polycystic ovary syndrome compared with the general population, and patients with polycystic ovary syndrome are four times more likely than the general population to develop type 2 diabetes mellitus. Patient presentation is variable, ranging from asymptomatic to having multiple gynecologic, dermatologic, or metabolic manifestations. Guidelines from the Endocrine Society recommend using the Rotterdam criteria for diagnosis, which mandate the presence of two of the following three findings- hyperandrogenism, ovulatory dysfunction, and polycystic ovaries-plus the exclusion of other diagnoses that could result in hyperandrogenism or ovulatory dysfunction. It is reasonable to delay evaluation for polycystic ovary syndrome in adolescent patients until two years after menarche. For this age group, it is also recommended that all three Rotterdam criteria be met before the diagnosis is made. Patients who have marked virilization or rapid onset of symptoms require immediate evaluation for a potential androgen-secreting tumor. Treatment of polycystic ovary syndrome is individualized based on the patient's presentation and desire for pregnancy. For patients who are overweight, weight loss is recommended. Clomiphene and letrozole are first-line medications for infertility. Metformin is the first-line medication for metabolic manifestations, such as hyperglycemia. Hormonal contraceptives are first-line therapy for irregular menses and dermatologic manifestations.

  12. Fine genetic mapping of a gene for autosomal recessive retinitis pigmentosa on chromosome 6p21

    Energy Technology Data Exchange (ETDEWEB)

    Shugart, Yin Y.; Banerjee, P.; Knowles, J.A. [Columbia Univ., New York, NY (United States)] [and others

    1995-08-01

    The inherited retinal degenerations known as retinitis pigmentosa (RP) can be caused by mutations at many different loci and can be inherited as an autosomal recessive, autosomal dominant, or X-linked recessive trait. Two forms of autosomal recessive (arRP) have been reported to cosegregate with mutations in the rhodopsin gene and the beta-subunit of rod phosphodiesterase on chromosome 4p. Genetic linkage has been reported on chromosomes 6p and 1q. In a large Dominican family, we reported an arRp gene near the region of the peripherin/RDS gene. Four recombinations were detected between the disease locus and an intragenic marker derived from peripherin/RDS. 26 refs., 2 figs., 1 tab.

  13. Case Report: Whole-exome analysis of a child with polycystic kidney disease and ventriculomegaly.

    Science.gov (United States)

    Nabhan, M M; Abdelaziz, H; Xu, Y; El Sayed, R; Santibanez-Koref, M; Soliman, N A; Sayer, J A

    2015-04-17

    Autosomal recessive polycystic kidney disease (ARPKD) is an inherited ciliopathy leading to progressive kidney and liver disease. Biallelic mutations in the PKHD1 gene underlie this condition. We describe a child with bilaterally enlarged cystic kidneys, portal hypertension, and cerebral ventriculomegaly. Molecular genetic investigations using whole-exome sequencing and confirmation using Sanger sequencing revealed a homozygous pathogenic mutation in PKHD1 underlying the clinical phenotype of ARPKD. Whole-exome data analysis was used to search for additional rare variants in additional ciliopathy genes that may have contributed to the unusual brain phenotype. Aside from a rare hypomorphic allele in MKS1, no other pathogenic variants were detected. We conclude that the homozygous pathogenic mutation in PKHD1 underlies the ciliopathy phenotype in this patient.

  14. Polycystic ovary syndrome in adolescence.

    Science.gov (United States)

    Driscoll, Deborah A

    2003-08-01

    Polycystic ovary syndrome (PCOS) is a relatively common disorder among adolescent women. The typical clinical features including menstrual irregularities and hirsutism are usually not apparent until middle to late adolescence. Yet studies suggest that PCOS may begin in early puberty. Young women with premature pubarche, a family history of PCOS, Caribbean Hispanic and African American ancestry, and/or obesity are more likely to develop PCOS. Adolescents with PCOS may have elevated total or free testosterone, androstenedione, and luteinizing hormone levels; insulin resistance; and hyperinsulinemia. The laboratory evaluation and management of the adolescent with suspected PCOS should be individualized on the basis of the clinical features and symptoms. The cornerstone of most treatment strategies includes either a combination oral contraceptive or progestin to decrease testosterone levels and regulate the menstrual cycle. Consideration of insulin-sensitizing agents, antiandrogens, topical treatments for acne and excess facial hair, and hair removal is dependent on the patient's symptoms and concerns. A healthy approach to eating, in some cases weight loss, and exercise is encouraged to reduce the risk of cardiovascular disease and type 2 diabetes mellitus. Management of the adolescent with PCOS is challenging and often requires a supportive, multidisciplinary team approach for optimal results.

  15. FOXE3 plays a significant role in autosomal recessive microphthalmia.

    Science.gov (United States)

    Reis, Linda M; Tyler, Rebecca C; Schneider, Adele; Bardakjian, Tanya; Stoler, Joan M; Melancon, Serge B; Semina, Elena V

    2010-03-01

    FOXE3 forkhead transcription factor is essential to lens development in vertebrates. The eyes of Foxe3/foxe3-deficient mice and zebrafish fail to develop normally. In humans, autosomal dominant and recessive mutations in FOXE3 have been associated with variable phenotypes including anterior segment anomalies, cataract, and microphthalmia. We undertook sequencing of FOXE3 in 116 probands with a spectrum of ocular defects ranging from anterior segment dysgenesis and cataract to anophthalmia/microphthalmia. Recessive mutations in FOXE3 were found in four of 26 probands affected with bilateral microphthalmia (15% of all bilateral microphthalmia and 100% of consanguineous families with this phenotype). FOXE3-positive microphthalmia was accompanied by aphakia and/or corneal defects; no other associated systemic anomalies were observed in FOXE3-positive families. The previously reported c.720C > A (p.C240X) nonsense mutation was identified in two additional families in our sample and therefore appears to be recurrent, now reported in three independent microphthalmia families of varied ethnic backgrounds. Several missense variants were identified at varying frequencies in patient and control groups with some apparently being race-specific, which underscores the importance of utilizing race/ethnicity-matched control populations in evaluating the relevance of genetic screening results. In conclusion, FOXE3 mutations represent an important cause of nonsyndromic autosomal recessive bilateral microphthalmia.

  16. Polycystic kidneys and GM2 gangliosidosis-like disease in neonatal springboks (Antidorcas marsupialis).

    Science.gov (United States)

    Herder, V; Kummrow, M; Leeb, T; Sewell, A C; Hansmann, F; Lehmbecker, A; Wohlsein, P; Baumgärtner, W

    2015-05-01

    Clinical, gross, histopathologic, electron microscopic findings and enzymatic analysis of 4 captive, juvenile springboks (Antidorcas marsupialis) showing both polycystic kidneys and a storage disease are described. Springbok offspring (4 of 34; 12%) were affected by either one or both disorders in a German zoo within a period of 5 years (2008-2013). Macroscopic findings included bilaterally severely enlarged kidneys displaying numerous cysts in 4 animals and superior brachygnathism in 2 animals. Histopathologically, kidneys of 4 animals displayed cystic dilation of the renal tubules. In addition, abundant cytoplasmic vacuoles with a diameter ranging from 2 to 10 μm in neurons of the central and peripheral nervous system, hepatocytes, thyroid follicular epithelial cells, pancreatic islets of Langerhans and renal tubular cells were found in 2 springbok neonates indicative of an additional storage disease. Ultrastructurally, round electron-lucent vacuoles, up to 4 μm in diameter, were present in neurons. Enzymatic analysis of liver and kidney tissue of 1 affected springbok revealed a reduced activity of total hexosaminidase (Hex) with relatively increased HexA activity at the same level of total Hex, suggesting a hexosaminidase defect. Pedigree analysis suggested a monogenic autosomal recessive inheritance for both diseases. In summary, related springboks showed 2 different changes resembling both polycystic kidney and a GM2 gangliosidosis similar to the human Sandhoff disease. Whether the simultaneous occurrence of these 2 entities represents an incidental finding or has a genetic link needs to be investigated in future studies.

  17. Additivity dominance

    Directory of Open Access Journals (Sweden)

    Paul Rozin

    2009-10-01

    Full Text Available Judgments of naturalness of foods tend to be more influenced by the process history of a food, rather than its actual constituents. Two types of processing of a ``natural'' food are to add something or to remove something. We report in this study, based on a large random sample of individuals from six countries (France, Germany, Italy, Switzerland, UK and USA that additives are considered defining features of what makes a food not natural, whereas ``subtractives'' are almost never mentioned. In support of this, skim milk (with major subtraction of fat is rated as more natural than whole milk with a small amount of natural vitamin D added. It is also noted that ``additives'' is a common word, with a synonym reported by a native speaker in 17 of 18 languages, whereas ``subtractive'' is lexicalized in only 1 of the 18 languages. We consider reasons for additivity dominance, relating it to omission bias, feature positive bias, and notions of purity.

  18. Oncological repercussions of polycystic ovary syndrome

    DEFF Research Database (Denmark)

    de França Neto, Antônio H; Rogatto, Silvia; Do Amorim, Melania M R

    2010-01-01

    Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder that has been associated with insulin resistance and metabolic syndrome. Evidence has suggested that PCOS may be associated with the appearance of certain types of cancer, particularly endometrial, ovarian and breast cancer...

  19. Women's Health Implications of Polycystic Ovary Syndrome

    NARCIS (Netherlands)

    Veltman-Verhulst, S.M.

    2012-01-01

    Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder of unknown etiology which affects approximately 12% of women. Principal features of PCOS are anovulation resulting in irregular or absent menstruation, excessive androgens (male sex hormones) and ovaries with multiple follicles (polycy

  20. A bovine model for polycystic ovary syndrome

    Science.gov (United States)

    Polycystic ovary syndrome (PCOS) results in the greatest single cause of anovulatory infertility in reproductive age women (affecting 5-10%). Previously, research groups have created animal models utilizing non-human primates and sheep to better understand the mechanisms involved in PCOS. However, c...

  1. Polycystic echinococcosis in Pacas, Amazon region, Peru.

    Science.gov (United States)

    Mayor, Pedro; Baquedano, Laura E; Sanchez, Elisabeth; Aramburu, Javier; Gomez-Puerta, Luis A; Mamani, Victor J; Gavidia, Cesar M

    2015-03-01

    In the Peruvian Amazon, paca meat is consumed by humans. To determine human risk for polycystic echinococcosis, we examined wild pacas from 2 villages; 15 (11.7%) of 128 were infected with Echinococcus vogeli tapeworms. High E. vogeli prevalence among pacas indicates potential risk for humans living in E. vogeli-contaminated areas.

  2. Complementary Therapy in Polycystic Ovary Syndrome

    OpenAIRE

    Aquino, Carmen Imma; Nori, Stefania Lucia

    2014-01-01

    Polycystic Ovary Syndrome (PCOS) is an endocrine disease. PCOS afflicts 5 to 10 % of women of reproductive age. The symptoms are: amenorrhea, oligomenorrhea, hirsutism, obesity, infertility, chronic hyperandrogenic anovulation and acne. Other risk factors aggravate this condition: insulin resistance, obesity, hypertension, dyslipidemia, inflammation and subclinical cardiovascular disease. Anxiety, depression and reduced quality of life are also common. This review highlights the mechanisms an...

  3. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    Science.gov (United States)

    ... Genetics Home Health Conditions ARCA1 autosomal recessive cerebellar ataxia type 1 Enable Javascript to view the expand/ ... Open All Close All Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by ...

  4. Optimal management of subfertility in polycystic ovary syndrome

    OpenAIRE

    Berger JJ; Bates Jr GW

    2014-01-01

    Joshua J Berger, G Wright Bates JrUniversity of Alabama at Birmingham, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Birmingham, AL, USAAbstract: The purpose of this paper is to provide a stepwise approach to treating the infertility/subfertility associated with polycystic ovary syndrome. Defining polycystic ovary syndrome in a patient requires first investigating other possible causes for polycystic ovary morphology, acne, hirsutism, obesity...

  5. Polycystic ovary syndrome: a dermatologic approach.

    Science.gov (United States)

    Moura, Heloisa Helena Gonçalves de; Costa, Dailana Louvain Marinho; Bagatin, Ediléia; Sodré, Celso Tavares; Manela-Azulay, Mônica

    2011-01-01

    Polycystic ovary syndrome (POS) is one of the most common endocrine abnormalities affecting women of reproductive age. It is a cause of significant social embarrassment and emotional distress. The pathogenesis of the disease is not yet fully understood, but it is thought to be a complex multigenic disorder, including abnormalities in the hypothalamic-pituitary axis, steroidogenesis, and insulin resistance. The main diagnostic findings of the syndrome are: hyperandrogenism, chronic anovulation and polycystic ovarian morphology seen on ultrasound. Hyperandrogenism is generally manifested as hirsutism, acne, seborrhea, androgenic alopecia and, in severe cases, signs of virilization. Treatment may improve the clinical manifestations of excess androgen production, normalize menses and ameliorate metabolic syndrome and cardiovascular complications. This article reviews the diagnosis, clinical manifestations, metabolic complications, and treatment of the syndrome. Early diagnosis and the consequent early treatment may prevent metabolic complications and emotional distress that negatively impact the patients' quality of life.

  6. Ovulation induction in polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Ali İrfan Güzel

    2014-12-01

    Full Text Available Polycystic ovary syndrome (PCOS is the most common reason of anovulatory infertility in reproductive age women. To make ovulation in these patients, from simple approach like life style changes to complicated therapies like assisted reproductive techniques are used. In this review, we aimed to emphasize different ovulation induction techniques that can be used in cases with PCOS. J Clin Exp Invest 2014; 5 (4: 626-631

  7. Polycystic ovary syndrome: clinical implication in perimenopause

    OpenAIRE

    Monika Lenart-Lipińska; Beata Matyjaszek-Matuszek; Ewa Woźniakowska; Janusz Solski; Tarach, Jerzy S.; Tomasz Paszkowski

    2014-01-01

    Polycystic ovary syndrome (PCOS), a hyperandrogenic disorder, is the commonest endocrinopathy in premenopausal women. This syndrome is associated with fertility problems, clinical manifestations of hyperandrogenism and metabolic disturbances, particularly insulin resistance and obesity. There is a great body of evidence that patients with PCOS present multiple cardiovascular risk factors and cluster components of metabolic syndrome from early ages. The presence of comorbidities such as abdomi...

  8. Features of Polycystic Ovary Syndrome in adolescence

    OpenAIRE

    Tsikouras, P.; Spyros, L; Manav, B; Zervoudis, S.; Poiana, C; Nikolaos, T.; Petros, P; Dimitraki, M; Koukouli, C; Galazios, G; von Tempelhoff, GF

    2015-01-01

    Rationale: To elucidate the prepubertal risk factors associated with the development of Polycystic Ovary Syndrome (PCOS) and determine the special clinical manifestations of the syndrome in this transitional time of a woman’s life. Objective: To propose therapeutic targets and regimens, not only to prevent the long-term complications of the syndrome, but also to improve the self-esteem of a young girl who matures into womanhood. Methods and Results: A systematic review of literature was perfo...

  9. Polycystic ovary syndrome: clinical and laboratory evaluation

    OpenAIRE

    Marcos Yorghi Khoury; Edmund Chada Baracat; Dolores Perovano Pardini; Mauro Abi Haidar; Eduardo Leme Alves da Motta; Geraldo Rodrigues de Lima

    1996-01-01

    OBJECTIVE: To evaluate clinically, and with laboratory, tests, women with polycystic ovary syndrome (PCO). PATIENTS: One hundred and twelve women with PCO were studied. METHODS: The following data was recorded: Current age; age at menarche; menstrual irregularity, occurrence of similar cases in the family; fertility, obstetric history; body mass index (BMI); and presence of hirsutism. Serum measurements of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, free testoster...

  10. Nonhuman primate models of polycystic ovary syndrome

    OpenAIRE

    David H Abbott; Nicol, Lindsey E.; Levine, Jon E; Xu, Ning; Goodarzi, Mark O.; Dumesic, Daniel A.

    2013-01-01

    With close genomic and phenotypic similarity to humans, nonhuman primate models provide comprehensive epigenetic mimics of polycystic ovary syndrome (PCOS), suggesting early life targeting for prevention. Fetal exposure to testosterone (T), of all nonhuman primate emulations, provides the closest PCOS-like phenotypes, with early-to-mid gestation T-exposed female rhesus monkeys exhibiting adult reproductive, endocrinological and metabolic dysfunctional traits that are co-pathologies of PCOS. L...

  11. Sheep models of polycystic ovary syndrome phenotype

    OpenAIRE

    Padmanabhan, Vasantha; Veiga-Lopez, Almudena

    2012-01-01

    Polycystic ovary syndrome (PCOS) is a fertility disorder affecting 5–7% of reproductive-aged women. Women with PCOS manifest both reproductive and metabolic defects. Several animal models have evolved, which implicate excess steroid exposure during fetal life in the development of the PCOS phenotype. This review addresses the fetal and adult reproductive and metabolic consequences of prenatal steroid excess in sheep and the translational relevance of these findings to PCOS. By comparing findi...

  12. The inositols and polycystic ovary syndrome

    OpenAIRE

    Bharti Kalra; Sanjay Kalra; Sharma, J. B.

    2016-01-01

    This review describes the rationale, biochemical, and clinical data related to the use of inositols in polycystic ovary syndrome (PCOS). It covers studies related to the mechanism of action of myo-inositol and D-chiro-inositol (MDI), with randomized controlled trials conducted in women with PCOS, and utilizes these data to suggest pragmatic indications and methods for using MDI combination in PCOS. Rationally crafted inositol combinations have a potential role to play in maintaining metabolic...

  13. Metabolic consequences of polycystic ovary syndrome.

    Science.gov (United States)

    Churchill, S J; Wang, E T; Pisarska, M D

    2015-12-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women and the leading cause of anovulatory infertility. The prevalence of the syndrome ranges between 6 to 15% based on broader Rotterdam diagnostic criteria verses strict NIH diagnostic criteria.1 The condition is characterized by a combination of ovulatory dysfunction, hyperandrogenism and the presence of polycystic ovaries. PCOS has been associated with multiple metabolic alterations and consequences including impaired glucose tolerance, insulin resistance, hyperinsulinemia, type II diabetes, dyslipidemia, metabolic syndrome, obesity and subclinical cardiovascular disease. It remains unclear however if these associations lead to an increased risk of clinically significant long-term cardiovascular disease. Large prospective studies to date have not detected significant differences in overall cardiovascular morbidity and mortality in PCOS. The phenotypical variability in PCOS has made researching each of these associations challenging as different aspects of the syndrome may be contributing, opposing or confounding factors. The ability to detect significant differences in long-term cardiovascular outcomes may also be due to the variable nature of the syndrome. In this review, we attempt to describe a summary of the current literature concerning the metabolic alterations and cardiovascular consequences of polycystic ovary syndrome.

  14. Adipose expression of adipocytokines in women with polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Fog Svendsen, Pernille; Christiansen, Michael; Hedley, Paula Louise;

    2012-01-01

    To investigate the role of adipocytokines in the pathophysiology of polycystic ovary syndrome (PCOS) by analyzing the messenger RNA (mRNA) expression and plasma levels of adipocytokines.......To investigate the role of adipocytokines in the pathophysiology of polycystic ovary syndrome (PCOS) by analyzing the messenger RNA (mRNA) expression and plasma levels of adipocytokines....

  15. Cardiometabolic abnormalities in the polycystic ovary syndrome : Pharmacotherapeutic insights

    NARCIS (Netherlands)

    Westerveld, H. E.; Hoogendoorn, M.; de Jong, A. W. F.; Goverde, A. J.; Fauser, B. C. J. M.; Dallinga-Thie, G. M.

    2008-01-01

    The polycystic ovary syndrome (PCOS) affects 5-10% of all premenopausal women. It is diagnosed by a combination of oligo-amenorrhea and hyperandrogenism (NIH criteria) or by the presence of two out of three of: oligo-amenorrhea, hyperandrogenism, polycystic ovaries on ultrasound (Rotterdam criteria)

  16. Bone morphogenetic proteins and the polycystic ovary syndrome

    NARCIS (Netherlands)

    E.L.A.F. van Houten (Leonie); J.S.E. Laven (Joop); Y.V. Louwers (Yvonne); A. McLuskey; A.P.N. Themmen (Axel); J.A. Visser (Jenny)

    2013-01-01

    textabstractBackground: Polycystic Ovary Syndrome (PCOS) is defined by two out of the following three criteria being met: oligo- or anovulation, hyperandrogenism, and polycystic ovaries. Affected women are often obese and insulin resistant. Although the etiology is still unknown, members of the Tran

  17. Polycystic Ovary Syndrome : Genetic determinants of the phenotype

    NARCIS (Netherlands)

    O. Valkenburg (Olivier)

    2015-01-01

    markdownabstract__Abstract__ The polycystic ovary syndrome (PCOS) was first described in 1935 by Stein and Leventhal as an association of amenorrhoea, obesity and a typical, polycystically enlarged, appearance of the ovaries at laparatomy1. Taking into account the absence of advanced imaging techni

  18. HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.

    Science.gov (United States)

    Brown, Kerry K; Viana, Lucas M; Helwig, Cecilia C; Artunduaga, Maria A; Quintanilla-Dieck, Lourdes; Jarrin, Patricia; Osorno, Gabriel; McDonough, Barbara; DePalma, Steven R; Eavey, Roland D; Seidman, Jonathan G; Seidman, Christine E

    2013-10-01

    Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia.

  19. Domination, Eternal Domination, and Clique Covering

    Directory of Open Access Journals (Sweden)

    Klostermeyer William F.

    2015-05-01

    Full Text Available Eternal and m-eternal domination are concerned with using mobile guards to protect a graph against infinite sequences of attacks at vertices. Eternal domination allows one guard to move per attack, whereas more than one guard may move per attack in the m-eternal domination model. Inequality chains consisting of the domination, eternal domination, m-eternal domination, independence, and clique covering numbers of graph are explored in this paper.

  20. Mutation rate analysis at 19 autosomal microsatellites.

    Science.gov (United States)

    Qian, Xiao-Qin; Yin, Cai-Yong; Ji, Qiang; Li, Kai; Fan, Han-Ting; Yu, Yan-Fang; Bu, Fan-Li; Hu, Ling-Li; Wang, Jian-Wen; Mu, Hao-Fang; Haigh, Steven; Chen, Feng

    2015-07-01

    Previous studies have demonstrated that a large sample size is needed to reliably estimate population- and locus-specific microsatellite mutation rates. Therefore, we conducted a long-term collaboration study and performed a comprehensive analysis on the mutation characteristics of 19 autosomal short tandem repeat (STR) loci. The STR loci located on 15 of 22 autosomal chromosomes were analyzed in a total of 21,106 samples (11,468 parent-child meioses) in a Chinese population. This provided 217,892 allele transfers at 19 STR loci. An overall mutation rate of 1.20 × 10(-3) (95% CI, 1.06-1.36 × 10(-3) ) was observed in the populations across 18 of 19 STR loci, except for the TH01 locus with no mutation found. Most STR mutations (97.7%) were single-step mutations, and only a few mutations (2.30%) comprised two and multiple steps. Interestingly, approximately 93% of mutation events occur in the male germline. The mutation ratios increased with the paternal age at child birth (r = 0.99, ptesting, kinship analysis, and population genetics.

  1. A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss.

    Science.gov (United States)

    Wasano, Koichiro; Mutai, Hideki; Obuchi, Chie; Masuda, Sawako; Matsunaga, Tatsuo

    2015-08-01

    Mutation of KCNQ4 has been reported to cause autosomal dominant non-syndromic hearing loss (DFNA2A) that usually presents as progressive hearing loss starting from mild to moderate hearing loss during childhood. Here, we identified a novel KCNQ4 mutation, c.1044_1051del8, in a family with autosomal recessive non-syndromic hearing loss. The proband was homozygous for the mutation and was born to consanguineous parents; she showed severe hearing loss that was either congenital or of early childhood onset. The proband had a sister who was heterozygous for the mutation but showed normal hearing. The mutation caused a frameshift that eliminated most of the cytoplasmic C-terminus, including the A-domain, which has an important role for protein tetramerization, and the B-segment, which is a binding site for calmodulin (CaM) that regulates channel function via Ca ions. The fact that the heterozygote had normal hearing indicates that sufficient tetramerization and CaM binding sites were present to preserve a normal phenotype even when only half the proteins contained an A-domain and B-segment. On the other hand, the severe hearing loss in the homozygote suggests that complete loss of the A-domain and B-segment in the protein caused loss of function due to the failure of tetramer formation and CaM binding. This family suggests that some KCNQ4 mutations can cause autosomal recessive hearing loss with more severe phenotype in addition to autosomal dominant hearing loss with milder phenotype. This genotype-phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype due to deletion of the cytoplasmic C-terminus of the potassium channel.

  2. Prevalence of Polycystic Ovary Syndrome Phenotypes Using Updated Criteria for Polycystic Ovarian Morphology: An Assessment of Over 100 Consecutive Women Self-reporting Features of Polycystic Ovary Syndrome

    OpenAIRE

    Clark, Nina M.; Podolski, Amanda J.; Brooks, Eric D; Chizen, Donna R.; Pierson, Roger A.; Lehotay, Denis C; Lujan, Marla E.

    2014-01-01

    The prevalence of polycystic ovary syndrome (PCOS) and its distinct clinical phenotypes were assessed using 3 sets of international diagnostic criteria in women self-reporting concerns over outward features of PCOS. Revised ultrasonographic criteria for polycystic ovaries (PCO) based on modern ultrasound technology were used. Of the participants, 53%, 62%, and 70% were diagnosed with PCOS using National Institutes of Health, Androgen Excess and PCOS Society, and Rotterdam criteria, respective...

  3. Analysis of autosomal dominant spinocerebellar ataxia type 1 in an extended family of central India

    Directory of Open Access Journals (Sweden)

    Shashikant Sharma

    2012-01-01

    Full Text Available Background: Spinocerebeller ataxia type 1 (SCA1 is a specific type of ataxia among a group of inherited diseases of the central nervous system. In SCA1, genetic defects lead to impairment of specific nerve fibers carrying messages to and from the brain, resulting in the degeneration of the cerebellum, the coordination center of the brain. We investigated 24 members of an extended family in Gwalior city, India, some of which were earlier clinically diagnosed to be suffering from yet unconfirmed type of SCA neurodegenerative disorder. Materials and Methods: All the family members from each age group were screened clinically and the characteristics of those resembling with ataxia were recorded for diagnosis by MRI. The confirmed patients of the family were genetically tested by PCR based molecular testing to identify the type of SCA (i.e., SCA 1, 2, 3, 4, 6 or 7. Family tree of the disease inheritance was constructed by pedigree based method. Result and Conclusion: We found the clinical (symptoms and MRI and genetic (Pedigree and PCR results to be correlated. The PCR result revealed the disease to be of SCA 1 type being inherited in the family.

  4. The autosomal dominant spinocerebellar ataxias: emerging mechanistic themes suggest pervasive Purkinje cell vulnerability.

    Science.gov (United States)

    Hekman, Katherine E; Gomez, Christopher M

    2015-05-01

    The spinocerebellar ataxias are a genetically heterogeneous group of disorders with clinically overlapping phenotypes arising from Purkinje cell degeneration, cerebellar atrophy and varying degrees of degeneration of other grey matter regions. For 22 of the 32 subtypes, a genetic cause has been identified. While recurring themes are emerging, there is no clear correlation between the clinical phenotype or penetrance, the type of genetic defect or the category of the disease mechanism, or the neuronal types involved beyond Purkinje cells. These phenomena suggest that cerebellar Purkinje cells may be a uniquely vulnerable neuronal cell type, more susceptible to a wider variety of genetic/cellular insults than most other neuron types.

  5. LMNA-Associated Cardiocutaneous Progeria: a Novel Autosomal Dominant Premature Aging Syndrome with Late Onset

    Science.gov (United States)

    Kane, Megan S.; Lindsay, Mark E.; Judge, Daniel P.; Barrowman, Jemima; Rhys, Colette Ap; Simonson, Lisa; Dietz, Harry C.; Michaelis, Susan

    2013-01-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a well-characterized premature aging disorder caused by mutations in LMNA, the gene encoding the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. Emerging evidence indicates that LMNA-linked progerias can be grouped into two classes: 1) the processing-deficient, early onset “typical” progerias (e.g. HGPS), and 2) the processing-proficient “atypical” progeria syndromes (APS) that are later in onset. Here we describe a novel progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that causes LCPS is a heterozygous missense mutation resulting in an amino acid substitution (D300G) in the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors (FTIs), as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease. PMID:23666920

  6. Ultrabiomicroscopic-Histopathologic Correlations in Individuals with Autosomal Dominant Congenital Microcoria: Three-Generation Family Report

    Directory of Open Access Journals (Sweden)

    Arturo Ramirez-Miranda

    2011-05-01

    Full Text Available Background: Congenital microcoria (CMC is due to a maldevelopment of the dilator pupillae muscle of the iris, with a pupil diameter of less than 2 mm. It is associated with juvenile open angle glaucoma and myopia. We report on a three-generation Mexican-Mestizo family with CMC. The eldest member’s iris biopsy proved muscle anomalies. Further, we analyzed novel ultrasound biomicroscopy findings in the family members who did not require surgery. Patients and Methods: A 62-year-old woman, her 41-year-old son and her 9-year-old grandson affected with microcoria since birth, documented by clinical examination and ultrasound biomicroscopy. The eldest member underwent phacoemulsification, and a biopsy of the iris and the anterior capsule of the lens was taken. Results: Ultrasound biomicroscopy confirmed the CMC diagnosis showing iris thinning and a pupil diameter of less than 2 mm. Histopathology of the iris showed a significant reduction of smooth muscle cells, but no alterations of the anterior lens capsule. Discussion: Although CMC is a rare disorder, which is due to a maldevelopment of the dilator pupillae muscle of the iris, it could be associated with juvenile open angle glaucoma and myopia; therefore, precise diagnosis is required. Ultrasound biomicroscopy could be a great option to confirm the disorder.

  7. A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia.

    Science.gov (United States)

    Choquet, Karine; La Piana, Roberta; Brais, Bernard

    2015-07-01

    Episodic ataxias (EAs) are a heterogeneous group of neurological disorders characterized by recurrent attacks of ataxia. Mutations in KCNA1 and CACNA1A account for the majority of EA cases worldwide. We recruited a two-generation family affected with EA of unknown subtype and performed whole-exome sequencing on two affected members. This revealed a novel heterozygous mutation c.211_212insA (p.I71NfsX27) leading to a premature stop codon in FGF14. Mutations in FGF14 are known to cause spinocerebellar ataxia type 27 (SCA27). Sanger sequencing confirmed segregation within the family. Our findings expand the phenotypic spectrum of SCA27 by underlining the possible episodic nature of this ataxia.

  8. The myosin chaperone UNC45B is involved in lens development and autosomal dominant juvenile cataract

    DEFF Research Database (Denmark)

    Hansen, Lars; Comyn, Sophie; Mang, Yuan;

    2014-01-01

    Genome-wide linkage analysis, followed by targeted deep sequencing, in a Danish multigeneration family with juvenile cataract revealed a region of chromosome 17 co-segregating with the disease trait. Affected individuals were heterozygous for two potentially protein-disrupting alleles in this reg......Genome-wide linkage analysis, followed by targeted deep sequencing, in a Danish multigeneration family with juvenile cataract revealed a region of chromosome 17 co-segregating with the disease trait. Affected individuals were heterozygous for two potentially protein-disrupting alleles......-type embryos resulted in development of a phenotype similar to the steif mutant. The p.Arg805Trp alteration in the mammalian UNC45B gene suggests that developmental cataract may be caused by a defect in non-muscle myosin assembly during maturation of the lens fiber cells.European Journal of Human Genetics...

  9. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome

    NARCIS (Netherlands)

    Burrage, L.C.; Charng, W.L.; Eldomery, M.K.; Willer, J.R.; Davis, E.E.; Lugtenberg, D.; Zhu, W.; Leduc, M.S.; Akdemir, Z.C.; Azamian, M.; Zapata, G.; Hernandez, P.P.; Schoots, J.; Munnik, S.A. de; Roepman, R.; Pearring, J.N.; Jhangiani, S.; Katsanis, N.; Vissers, L.E.L.M.; Brunner, H.G.; Beaudet, A.L.; Rosenfeld, J.A.; Muzny, D.M.; Gibbs, R.A.; Eng, C.M.; Xia, F.; Lalani, S.R.; Lupski, J.R.; Bongers, E.M.H.F.; Yang, Y

    2015-01-01

    Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin

  10. LMNA-associated cardiocutaneous progeria: an inherited autosomal dominant premature aging syndrome with late onset.

    Science.gov (United States)

    Kane, Megan S; Lindsay, Mark E; Judge, Daniel P; Barrowman, Jemima; Ap Rhys, Colette; Simonson, Lisa; Dietz, Harry C; Michaelis, Susan

    2013-07-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease.

  11. The role of the IRE1/Xbp1 pathway in a Drosophila model for autosomal dominant

    OpenAIRE

    Costa, Rita Esperto, 1987-

    2011-01-01

    Tese de mestrado. Biologia (Biologia Molecular e genética). Universidade de Lisboa, Faculdade de Ciências, 2011 Neurodegenerative disorders are a major medical problem for society. Growing evidence indicates that endoplasmic reticulum (ER) stress is an important common pathological event in a variety of neurodegenerative diseases. The unfolded protein response (UPR) is triggered by the accumulation of misfolded proteins provoked by ER stress conditions, to restore homeostasis. We are parti...

  12. Medical therapy for polycystic liver disease.

    Science.gov (United States)

    Khan, S; Dennison, A; Garcea, G

    2016-01-01

    Introduction Somatostatin analogues and rapamycin inhibitors are two classes of drugs available for the management of polycystic liver disease but their overall impact is not clearly established. This article systematically reviews the literature on the medical management of polycystic liver disease. The outcomes assessed include reduction in liver volume and the impact on quality of life. Methods The English language literature published between 1966 and August 2014 was reviewed from a MEDLINE(®), PubMed, Embase™ and Cochrane Library search. Search terms included 'polycystic', 'liver', 'sirolimus', 'everolimus', 'PCLD', 'somatostatin', 'octreotide', 'lanreotide' and 'rapamycin'. Both randomised trials and controlled studies were included. References of the articles retrieved were also searched to identify any further eligible publications. The studies included were appraised using the Jadad score. Results Seven studies were included in the final review. Five studies, of which three were randomised trials, investigated the role of somatostatin analogues and the results showed a mean reduction in liver volume ranging from 2.9% at six months to 4.95 ±6.77% at one year. Only one randomised study examined the influence of rapamycin inhibitors. This trial compared dual therapy with everolimus and octreotide versus octreotide monotherapy. Liver volume reduced by 3.5% and 3.8% in the control and intervention groups respectively but no statistical difference was found between the two groups (p=0.73). Two randomised trials investigating somatostatin analogues assessed quality of life using SF-36(®). Only one subdomain score improved in one of the trials while two subdomain scores improved in the other with somatostatin analogue therapy. Conclusions Somatostatin analogues significantly reduce liver volumes after six months of therapy but have only a modest improvement on quality of life. Rapamycin inhibitors do not confer any additional advantage.

  13. [Blood pressure and polycystic ovary syndrome (PCOS)].

    Science.gov (United States)

    Kiałka, Marta; Milewicz, Tomasz; Klocek, Marek

    2015-01-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder occurring in women of childbearing age. The literature describes the relationship between PCOS and high blood pressure levels and increased risk of arterial hypertension development, which is an important and strong risk factor for adverse cardiovascular events in the future. Among the main causes of hypertension in PCOS women insulin resistance, hyperandrogenism, greater sympathetic nerve activity and concomitance of obesity are stressed. Because PCOS may contribute to earlier development of hypertension, as well as pre-hypertension, therefore it is advisable to monitor blood pressure systematically, to control known risk factors, and to initiate the treatment of hypertension when the disease occur.

  14. Drug discovery for polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    Ying SUN; Hong ZHOU; Bao-xue YANG

    2011-01-01

    In polycystic kidney disease (PKD), a most common human genetic diseases, fluid-filled cysts displace normal renal tubules and cause end-stage renal failure. PKD is a serious and costly disorder. There is no available therapy that prevents or slows down the cystogenesis and cyst expansion in PKD. Numerous efforts have been made to find drug targets and the candidate drugs to treat PKD. Recent studies have defined the mechanisms underlying PKD and new therapies directed toward them. In this review article, we summarize the pathogenesis of PKD, possible drug targets, available PKD models for screening and evaluating new drugs as well as candidate drugs that are being developed.

  15. Psychiatric disorders related to polycystic ovary syndrome.

    Science.gov (United States)

    Krępuła, Katarzyna; Bidzińska-Speichert, Bożena; Lenarcik, Agnieszka; Tworowska-Bardzińska, Urszula

    2012-01-01

    Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The psychiatric disorders accompanying the clinical symptoms and hormonal abnormalities are important, but underestimated, aspects in PCOS. Obesity, hirsutism, acne, menstrual disturbances and infertility play important roles in lowering the quality of life in women with PCOS. Depression and anxiety are more often observed in patients with PCOS than in healthy women. Some authors consider that there is a relationship between valproic acid treatment of bipolar disease and PCOS. There have been reports that in women with PCOS anorexia nervosa, bulimia nervosa and other unspecified eating disorders are found more often than in the general population.

  16. The inositols and polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Bharti Kalra

    2016-01-01

    Full Text Available This review describes the rationale, biochemical, and clinical data related to the use of inositols in polycystic ovary syndrome (PCOS. It covers studies related to the mechanism of action of myo-inositol and D-chiro-inositol (MDI, with randomized controlled trials conducted in women with PCOS, and utilizes these data to suggest pragmatic indications and methods for using MDI combination in PCOS. Rationally crafted inositol combinations have a potential role to play in maintaining metabolic, endocrine, and reproductive health in women with PCOS.

  17. Adipocyte biology in polycystic ovary syndrome.

    Science.gov (United States)

    Barber, T M; Franks, S

    2013-07-05

    Polycystic Ovary Syndrome (PCOS) is a common endocrinopathy that is associated with an adverse metabolic profile including insulin resistance. There is a clear association between obesity, the development of PCOS and the severity of its phenotypic, biochemical and metabolic features. Evidence to support this link includes data from epidemiological, pathophysiological and genetic studies. Given the importance of obesity in the development and manifestation of PCOS, ongoing research into the many facets of adipocyte biology in women with the condition is important and should continue to be a priority. In this review article, we discuss the existing literature on fat distribution, adipokines, adipocyte hypertrophy and adipocyte steroid metabolism in women with PCOS.

  18. The inositols and polycystic ovary syndrome

    Science.gov (United States)

    Kalra, Bharti; Kalra, Sanjay; Sharma, J. B.

    2016-01-01

    This review describes the rationale, biochemical, and clinical data related to the use of inositols in polycystic ovary syndrome (PCOS). It covers studies related to the mechanism of action of myo-inositol and D-chiro-inositol (MDI), with randomized controlled trials conducted in women with PCOS, and utilizes these data to suggest pragmatic indications and methods for using MDI combination in PCOS. Rationally crafted inositol combinations have a potential role to play in maintaining metabolic, endocrine, and reproductive health in women with PCOS. PMID:27730087

  19. Dangerous triplet: Polycystic ovary syndrome, oral contraceptives and Kounis syndrome

    Institute of Scientific and Technical Information of China (English)

    Nurdan; Erol; Aysu; Turkmen; Karaagac; Nicholas; G; Kounis

    2014-01-01

    Polycystic ovary syndrome is characterized by ovulatory dysfunction, androgen excess and polycystic ovaries and is associated with hypertension, diabetes, metabolic syndrome and cardiovascular events. Oral contraceptives constitute first-line treatment, particularly when symptomatic hyperandrogenism is present. However, these drugs are associated with cardiovascular events and hypersensitivity reactions that pose problem in differential diagnosis and therapy. We present a 14 year-old female with polycystic ovary syndrome taking oral contraceptive and suffering from recurrent coronary ischemic attacks with increased eosinophils, and troponin levels suggesting Kounis syndrome.

  20. Seasonal palmar keratoderma in erythropoietic protoporphyria indicates autosomal recessive inheritance.

    Science.gov (United States)

    Holme, S Alexander; Whatley, Sharon D; Roberts, Andrew G; Anstey, Alexander V; Elder, George H; Ead, Russell D; Stewart, M Felicity; Farr, Peter M; Lewis, Helen M; Davies, Nicholas; White, Marion I; Ackroyd, R Simon; Badminton, Michael N

    2009-03-01

    Erythropoietic protoporphyria (EPP) is an inherited disorder that results from partial deficiency of ferrochelatase (FECH). It is characterized clinically by acute photosensitivity and, in 2% of patients, liver disease. Inheritance is usually autosomal dominant with low penetrance but is recessive in about 4% of families. A cross-sectional study of 223 patients with EPP in the United Kingdom identified six individuals with palmar keratoderma. We now show that these and three additional patients, from six families, have an inherited subtype of EPP which is characterized by seasonal palmar keratoderma, relatively low erythrocyte protoporphyrin concentrations, and recessive inheritance. No patient had evidence of liver dysfunction; four patients had neurological abnormalities. Patients were hetero- or homoallelic for nine different FECH mutations; four of which were previously unreported. Prokaryotic expression predicted that FECH activities were 2.7-25% (mean 10.6%) of normal. Neither mutation type nor FECH activity provided an explanation for the unusual phenotype. Our findings show that palmar keratoderma is a clinical indicator of recessive EPP, identify a phenotype that occurs in 38% of reported families with recessive EPP that to our knowledge is previously unreported, and suggest that patients with this phenotype may carry a lower risk of liver disease than other patients with recessive EPP.

  1. ECE1 gene variant shows tendency toward chronic kidney disease advancement among autosomal polycystic kidney disease patients

    Directory of Open Access Journals (Sweden)

    Shiva Nagendra Reddy Annapareddy

    2016-04-01

    結論: 我們觀察到,在 ADPKD 患者間,高血壓是 CKD 病情發展的一個明顯的干擾因素。以上結果意味著,在 ADPKD 患者間,ECE1 基因變體可影響 CKD 的病情發展。

  2. Current aspects of polycystic ovary syndrome: A literature review

    Directory of Open Access Journals (Sweden)

    VICTOR HUGO LOPES DE ANDRADE

    Full Text Available SUMMARY Polycystic ovary syndrome (PCOS is a heterogeneous endocrine disorder with variable prevalence, affecting about one in every 15 women worldwide. The diagnosis of polycystic ovary syndrome requires at least two of the following criteria: oligoovulation and/or anovulation, clinical and/or biochemical evidence of hyperandrogenism and morphology of polycystic ovaries. Women with PCOS appear to have a higher risk of developing metabolic disorders, hypertension and cardiovascular disorders. The aim of this article was to present a review of the literature by searching the databases Pubmed and Scielo, focusing on publications related to polycystic ovaries, including its pathogenesis, clinical manifestations, diagnosis and therapeutic aspects, as well as its association with cardiovascular and arterial hypertensive disorders.

  3. Polycystic ovary syndrome [PCOS]: comprehensive management in primary care.

    Science.gov (United States)

    Samraj, George P N; Kuritzky, Louis

    2002-01-01

    Polycystic ovary syndrome is a common premenopausal endocrino-metabolic disorder. In addition to hyperandrogenism, menstrual abnormalities, ovulatory disturbances and infertility, insulin resistance, dyslipidemia, and obesity may eventuate in long-term cardiovascular consequences.

  4. Polycystic Ovary Syndrome (PCOS): A Guide for Teens

    Science.gov (United States)

    ... of 10 women has PCOS. What is PCOS? Polycystic ovary syndrome (PCOS) is a hormone imbalance that can cause irregular periods, unwanted hair growth, and acne. PCOS begins during a girl’s teen years and ...

  5. Marked hyperandrogenemia and acne associated with polycystic ovaries in Greek women with polycystic ovary syndrome.

    Science.gov (United States)

    Skampardonis, N; Kouskoukis, A; Karpouzis, A; Maroulis, G

    2011-01-01

    PCOS represents the commonest endocrinopathy among women of reproductive age. We conducted this study to evaluate the association between polycystic ovaries and clinical and biochemical features of the syndrome. TVS was performed in 74 women with the clinical diagnosis of PCOS. The findings were compared to biochemical, hormonal and clinical features of the syndrome. Statistical analysis revealed a significantly higher prevalence of acne, LH/FSH ratios and testosterone levels in women with PCO compared to those with normal ovarian morphology. In the subgroup analysis, total ovarian volume correlated significantly with hirsutism scores. Our study revealed a great prevalence of polycystic ovaries in Greek women with PCOS, and emphasizes the significance of transvaginal ultrasound in establishment of the diagnosis of the syndrome. The presence of PCO may not be clinically important when present alone without clinical manifestations but reflects the underlying hyperandrogenemia in PCOS women, representing a useful tool in the management of these patients.

  6. Epidemiology, diagnosis, and management of polycystic ovary syndrome

    OpenAIRE

    Sirmans SM; Pate KA

    2013-01-01

    Susan M Sirmans, Kristen A PateDepartment of Clinical and Administrative Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USAAbstract: Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder characterized by irregular menses, hyperandrogenism, and polycystic ovaries. The prevalence of PCOS varies depending on which criteria are used to make the diagnosis, but is as high as 15%–20% when the European Society for Human Reproduction and...

  7. New markers of insulin resistance in polycystic ovary syndrome

    OpenAIRE

    Polak, K.; Czyzyk, A.; Simoncini, T.; Meczekalski, B.

    2016-01-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder in women of reproductive age. The diagnostic criteria include two out of three features: hyperandrogenism, polycystic ovaries on ultrasound and menstrual irregularities (Rotterdam Criteria 2003). PCOS patients are more vulnerable to develop diabetes, cardiovascular diseases and metabolic syndrome. Insulin resistance (IR) is prevalent in women with PCOS independently of obesity and is critically involved in reprod...

  8. Dangerous triplet: Polycystic ovary syndrome, oral contraceptives and Kounis syndrome

    OpenAIRE

    Erol, Nurdan; Karaagac, Aysu Turkmen; Kounis, Nicholas G.

    2014-01-01

    Polycystic ovary syndrome is characterized by ovulatory dysfunction, androgen excess and polycystic ovaries and is associated with hypertension, diabetes, metabolic syndrome and cardiovascular events. Oral contraceptives constitute first-line treatment, particularly when symptomatic hyperandrogenism is present. However, these drugs are associated with cardiovascular events and hypersensitivity reactions that pose problem in differential diagnosis and therapy. We present a 14 year-old female wi...

  9. MicroRNAs related to androgen metabolism and polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Sørensen, Anja Elaine; Udesen, Pernille Bækgaard; Wissing, Marie Louise

    2016-01-01

    Polycystic ovary syndrome (PCOS) is a frequent endocrine disorder in women. PCOS is associated with altered features of androgen metabolism, increased insulin resistance and impaired fertility. Furthermore, PCOS, being a syndrome diagnosis, is heterogeneous and characterized by polycystic ovaries...

  10. Autosomal recessive transmission of MYBPC3 mutation results in malignant phenotype of hypertrophic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Yilu Wang

    Full Text Available BACKGROUND: Hypertrophic cardiomyopathy (HCM due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved. METHODS: A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls. RESULTS: A novel missense mutation (c.1469G>T, p.Gly490Val in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM. CONCLUSIONS: Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.

  11. Polycystic kidney disease in a Chartreux cat.

    Science.gov (United States)

    Volta, Antonella; Manfredi, Sabrina; Gnudi, Giacomo; Gelati, Aldo; Bertoni, Giorgio

    2010-02-01

    Polycystic kidney disease (PKD) is one of the most common genetic diseases in cats. It has been widely described in Persians and Persian-related cats and sporadically in other breeds. The purpose of the present paper is to describe the first reported case of PKD in a 12-year-old female Chartreux cat. The cat was referred with polyuria and polydipsia and enlarged and irregular kidneys at palpation. Multiple renal cysts and a single liver cyst were identified by ultrasound and the inherited pattern was confirmed by genetic test (polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) assay). Chartreux cats should be included in the screening programme of PKD, and PKD should be always considered as a possible cause of chronic renal failure in this breed.

  12. Treating polycystic ovary syndrome and infertility.

    Science.gov (United States)

    McFarland, Cameron

    2012-01-01

    Between 4% and 18% of women worldwide are affected by polycystic ovary syndrome (PCOS) and have the hormonal imbalances that lead to the cascade of symptoms, including weight gain and obesity. One of the first suggested treatments for infertility associated with PCOS is weight reduction, which has been shown to increase the chance of spontaneous ovulation and menstruation. Pharmacologic treatment usually includes metformin alone or in conjunction with clomiphene; both have been shown to increase conception rates and decrease risk of preeclampsia once pregnancy is achieved. Limited research has been published about the efficacy of oral contraceptives in producing conception. If pregnancy still eludes women with PCOS after initial pharmacologic treatments, gonadotropin therapy by itself or in conjunction with assisted reproductive therapy is considered. These treatments come with higher expense, and increased risk, and require extensive counseling prior to implementation. Additional research is needed to better understand what risks exist for pregnant women with PCOS and for their newborns.

  13. Basic infertility including polycystic ovary syndrome.

    Science.gov (United States)

    Brassard, Maryse; AinMelk, Youssef; Baillargeon, Jean-Patrice

    2008-09-01

    Infertility in women has many possible causes and must be approached systematically. The most common cause of medically treatable infertility is the polycystic ovary syndrome (PCOS). This syndrome is common in young women and is the cause of anovulatory infertility in 70% of cases. It is therefore an important condition to screen and manage in primary care medical settings. In the past 10 years, insulin sensitization with weight loss or metformin has been shown to be a safe and effective treatment for PCOS infertility that eliminates the risk of multiple pregnancy and may reduce the risk of early pregnancy loss as compared with ovulation-inductor drugs. The authors believe metformin should be considered as first-line therapy because it has the advantage to allow for normal single ovulation, for reduced early pregnancy loss, and, most importantly, lifestyle modifications and weight loss before pregnancy. Losing weight not only improves fertility but also reduces adverse pregnancy outcomes associated with obesity.

  14. Psychological aspects of the polycystic ovary syndrome.

    Science.gov (United States)

    Farkas, Judit; Rigó, Adrien; Demetrovics, Zsolt

    2014-02-01

    An overwhelming majority of scientific literature on the polycystic ovary syndrome has utilized a medical approach to analyse the disorder and only few studies have investigated its predisposing psychological factors. This literature review sheds light on the fact that this gynaecological disorder of endocrine origin, which is becoming more frequent, can be associated with a great number of psychological symptoms (e.g. depression, anxiety, body image dissatisfaction, eating and sexual disorders, and low life satisfaction). Thus, the syndrome is significant from a therapeutic point of view as well. Authors review the psychological correlates of specific symptoms, their relationships with other psychological syndromes and analyse the psychosocial background of the disorder as well as the possibilities of psychotherapy.

  15. Coexistence of asthma and polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Zierau, Louise; Gade, Elisabeth Juul; Lindenberg, Svend;

    2016-01-01

    Asthma may be associated with polycystic ovary syndrome (PCOS), and possibly patients with PCOS have a more severe type of asthma. The purpose of this systematic literature review is to summarize evidence of a coexistense of PCOS and asthma using the available literature. The search was completed...... on 01.01.2016. English language articles were retrieved using the search terms 'Asthma' AND 'PCOS', 'Asthma' AND 'systemic inflammation', 'Asthma' AND 'metabolic syndrome', 'asthma' AND 'gynaecology', 'PCOS' AND 'systemic inflammation', 'PCOS' AND 'metabolic syndrome', 'PCOS' AND 'allergy'. Five papers...... meeting prespecified search criteria were found of which two were registry studies of relevance. The current literature supports a coexistense of PCOS and asthma and gives us an indication of the causes for the possible link between PCOS and asthma. Further research in the area must be conducted...

  16. Sheep models of polycystic ovary syndrome phenotype.

    Science.gov (United States)

    Padmanabhan, Vasantha; Veiga-Lopez, Almudena

    2013-07-01

    Polycystic ovary syndrome (PCOS) is a fertility disorder affecting 5-7% of reproductive-aged women. Women with PCOS manifest both reproductive and metabolic defects. Several animal models have evolved, which implicate excess steroid exposure during fetal life in the development of the PCOS phenotype. This review addresses the fetal and adult reproductive and metabolic consequences of prenatal steroid excess in sheep and the translational relevance of these findings to PCOS. By comparing findings in various breeds of sheep, the review targets the role of genetic susceptibility to fetal insults. Disruptions induced by prenatal testosterone excess are evident at both the reproductive and metabolic level with each influencing the other thus creating a self-perpetuating vicious cycle. The review highlights the need for identifying a common mediator of the dysfunctions at the reproductive and metabolic levels and developing prevention and treatment interventions targeting all sites of disruption in unison for achieving optimal success.

  17. Nonhuman primate models of polycystic ovary syndrome.

    Science.gov (United States)

    Abbott, David H; Nicol, Lindsey E; Levine, Jon E; Xu, Ning; Goodarzi, Mark O; Dumesic, Daniel A

    2013-07-01

    With close genomic and phenotypic similarity to humans, nonhuman primate models provide comprehensive epigenetic mimics of polycystic ovary syndrome (PCOS), suggesting early life targeting for prevention. Fetal exposure to testosterone (T), of all nonhuman primate emulations, provides the closest PCOS-like phenotypes, with early-to-mid gestation T-exposed female rhesus monkeys exhibiting adult reproductive, endocrinological and metabolic dysfunctional traits that are co-pathologies of PCOS. Late gestational T exposure, while inducing adult ovarian hyperandrogenism and menstrual abnormalities, has less dysfunctional metabolic accompaniment. Fetal exposures to dihydrotestosterone (DHT) or diethylstilbestrol (DES) suggest androgenic and estrogenic aspects of fetal programming. Neonatal exposure to T produces no PCOS-like outcome, while continuous T treatment of juvenile females causes precocious weight gain and early menarche (high T), or high LH and weight gain (moderate T). Acute T exposure of adult females generates polyfollicular ovaries, while chronic T exposure induces subtle menstrual irregularities without metabolic dysfunction.

  18. Endogenous thrombin potential in polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Aziz, Mubeena; Sidelmann, Johannes Jakobsen; Wissing, Marie Louise Muff;

    2015-01-01

    : Endogenous thrombin potential (ETP). RESULTS: PCOS women with phenotype BMI > 25 + IR have increased potential of thrombin generation. ETP is associated with total body fat mass, IR, and CRP. CONCLUSIONS: Obese and insulin resistant women with PCOS have elevated level of ETP corresponding to increased risk......OBJECTIVES: The objective of this study is to investigate plasma endogenous thrombin generation in four different phenotypes of polycystic ovary syndrome (PCOS) defined by Body Mass Index (BMI) and insulin resistance (IR). PCOS is diagnosed according to the Rotterdam criteria. DESIGN: Multicenter...... cross-sectional study. SETTING: Two major University Hospitals in the Capital region of Denmark. PATIENTS: Hundred forty-eight European women with PCOS were consecutively recruited during April 2010-February 2012. Clinical examination, blood sampling, and DEXA scan were performed. MAIN OUTCOME MEASURES...

  19. Liver transplantation in polycystic liver disease

    DEFF Research Database (Denmark)

    Krohn, Paul S; Hillingsø, Jens; Kirkegaard, Preben

    2008-01-01

    OBJECTIVE: Polycystic liver disease (PLD) is a rare, hereditary, benign disorder. Hepatic failure is uncommon and symptoms are caused by mass effects leading to abdominal distension and pain. Liver transplantation (LTX) offers fully curative treatment, but there is still some controversy about...... whether it is a relevant modality considering the absence of liver failure, relative organ shortage, perioperative risks and lifelong immunosuppression. The purpose of this study was to review our experience of LTX for PLD and to compare the survival with the overall survival of patients who underwent LTX....../kidney transplantation. One patient had undergone kidney transplantation 10 years earlier. RESULTS: Median follow-up was 55 months. One patient who underwent combined transplantation died after 5.4 months because of multiorgan failure after re-LTX, and one patient, with well-functioning grafts, died of lymphoma after 7...

  20. Hirsutism and acne in polycystic ovary syndrome.

    Science.gov (United States)

    Archer, Johanna S; Chang, R Jeffrey

    2004-10-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality affecting reproductive age women. Population-based studies estimate a prevalence of 5-10% [Obstet Gynecol 101 (2003) 995; Aust N Z J Obstet Gynaecol 41 (2001) 202]. The clinical characteristics of PCOS include hyperandrogenism, chronic anovulation, insulin resistance and infertility. Hyperandrogenism is generally manifested as hirsutism and acne. Both these clinical symptoms are treated with similar drug therapies, including oral contraceptive pills (OCPs), topical medications or antiandrogens such as spironolactone, flutamide and finasteride, as well as topical medications. Recent studies have shown that lower doses of these medications are as efficacious as high doses and have the advantage of decreased cost and an improved side-effect profile. Although hirsutism and acne can be considered cosmetic in nature, they cause significant social embarrassment and emotional distress. Physicians should be sensitive to these issues and approach patients in a caring and sympathetic manner.