Arrestin gene mutations in autosomal recessive retinitis pigmentosa.

Science.gov (United States)

Nakazawa, M; Wada, Y; Tamai, M

1998-04-01

To assess the clinical and molecular genetic studies of patients with autosomal recessive retinitis pigmentosa associated with a mutation in the arrestin gene. Results of molecular genetic screening and case reports with DNA analysis and clinical features. University medical center. One hundred twenty anamnestically unrelated patients with autosomal recessive retinitis pigmentosa. DNA analysis was performed by single strand conformation polymorphism followed by nucleotide sequencing to search for a mutation in exon 11 of the arrestin gene. Clinical features were characterized by visual acuity slitlamp biomicroscopy, fundus examinations, fluorescein angiography, kinetic visual field testing, and electroretinography. We identified 3 unrelated patients with retinitis pigmentosa associated with a homozygous 1-base-pair deletion mutation in codon 309 of the arrestin gene designated as 1147delA. All 3 patients showed pigmentary retinal degeneration in the midperipheral area with or without macular involvement. Patient 1 had a sibling with Oguchi disease associated with the same mutation. Patient 2 demonstrated pigmentary retinal degeneration associated with a golden-yellow reflex in the peripheral fundus. Patients 1 and 3 showed features of retinitis pigmentosa without the golden-yellow fundus reflex. Although the arrestin 1147delA has been known as a frequent cause of Oguchi disease, this mutation also may be related to the pathogenesis of autosomal recessive retinitis pigmentosa. This phenomenon may provide evidence of variable expressivity of the mutation in the arrestin gene.

Evidence for nonallelic genetic heterogeneity in autosomal recessive retinitis pigmentosa

NARCIS (Netherlands)

Bleeker-Wagemakers, L. M.; Gal, A.; Kumar-Singh, R.; van den Born, L. I.; Li, Y.; Schwinger, E.; Sandkuijl, L. A.; Bergen, A. A.; Kenna, P.; Humphries, P.

1992-01-01

Recent evidence suggesting the involvement of mutant rhodopsin proteins in the pathogenesis of autosomal recessive retinitis pigmentosa has prompted us to investigate whether this form of the disease shows non-allelic genetic heterogeneity, as has previously been shown to be the case in autosomal

Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

Science.gov (United States)

Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet; Kelsh, Robert N; Hansen, Lars; Levesque, Mitchell P; Vilhelmsen, Kaj; Møllgård, Kjeld; Stemple, Derek L; Rosenberg, Thomas

2013-03-07

Autosomal-recessive albinism is a hypopigmentation disorder with a broad phenotypic range. A substantial fraction of individuals with albinism remain genetically unresolved, and it has been hypothesized that more genes are to be identified. By using homozygosity mapping of an inbred Faroese family, we identified a 3.5 Mb homozygous region (10q22.2-q22.3) on chromosome 10. The region contains five protein-coding genes, and sequencing of one of these, C10orf11, revealed a nonsense mutation that segregated with the disease and showed a recessive inheritance pattern. Investigation of additional albinism-affected individuals from the Faroe Islands revealed that five out of eight unrelated affected persons had the nonsense mutation in C10orf11. Screening of a cohort of autosomal-recessive-albinism-affected individuals residing in Denmark showed a homozygous 1 bp duplication in C10orf11 in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal-recessive albinism in humans. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Genetics of recessive cognitive disorders

OpenAIRE

Musante, Luciana; Ropers, H. Hilger

2014-01-01

Most severe forms of intellectual disability (ID) have specific genetic causes. Numerous X chromosome gene defects and disease-causing copy-number variants have been linked to ID and related disorders, and recent studies have revealed that sporadic cases are often due to dominant de novo mutations with low recurrence risk. For autosomal recessive ID (ARID) the recurrence risk is high and, in populations with frequent parental consanguinity, ARID is the most common form of ID. Even so, its elu...

Hereditary motor and sensory neuropathy-russe: new autosomal recessive neuropathy in Balkan Gypsies.

Science.gov (United States)

Thomas, P K; Kalaydjieva, L; Youl, B; Rogers, T; Angelicheva, D; King, R H; Guergueltcheva, V; Colomer, J; Lupu, C; Corches, A; Popa, G; Merlini, L; Shmarov, A; Muddle, J R; Nourallah, M; Tournev, I

2001-10-01

A novel peripheral neuropathy of autosomal recessive inheritance has been identified in Balkan Gypsies and termed hereditary motor and sensory neuropathy-Russe (HMSN-R). We investigated 21 affected individuals from 10 families. Distal lower limb weakness began between the ages of 8 and 16 years, upper limb involvement beginning between 10 and 43 years, with an average of 22 years. This progressive disorder led to severe weakness of the lower limbs, generalized in the oldest subject (aged 57 years), and marked distal upper limb weakness. Prominent distal sensory loss involved all modalities, resulting in neuropathic joint degeneration in two instances. All patients showed foot deformity, and most showed hand deformity. Motor nerve conduction velocity was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent. There was loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve. HMSN-R is a new form of autosomal recessive inherited HMSN caused by a single founder mutation in a 1 Mb interval on chromosome 10q.

Autosomal recessive osteopetrosis with a unique imaging finding: multiple encephaloceles

Energy Technology Data Exchange (ETDEWEB)

Saglam, Dilek; Bilgici, Meltem Ceyhan; Bekci, Tuemay [Ondokuz Mayis University, Department of Radiology, School of Medicine, Kurupelit, Samsun (Turkey); Albayrak, Canan; Albayrak, Davut [Ondokuz Mayis University, Department of Pediatrics, School of Medicine, Kurupelit, Samsun (Turkey)

2017-05-15

Osteopetrosis is a hereditary form of sclerosing bone dysplasia with various radiological and clinical presentations. The autosomal recessive type, also known as malignant osteopetrosis, is the most severe type, with the early onset of manifestations. A 5-month-old infant was admitted to our hospital with recurrent respiratory tract infections. Chest X-ray and skeletal survey revealed the classic findings of osteopetrosis, including diffuse osteosclerosis and bone within a bone appearance. At follow-up, the patient presented with, thickened calvarium, multiple prominent encephaloceles, and dural calcifications leading to the intracranial clinical manifestations with bilateral hearing and sight loss. Autosomal recessive osteopetrosis is one of the causes of encephaloceles and this finding may become dramatic if untreated. (orig.)

Autosomal recessive osteopetrosis with a unique imaging finding: multiple encephaloceles

International Nuclear Information System (INIS)

Saglam, Dilek; Bilgici, Meltem Ceyhan; Bekci, Tuemay; Albayrak, Canan; Albayrak, Davut

2017-01-01

Osteopetrosis is a hereditary form of sclerosing bone dysplasia with various radiological and clinical presentations. The autosomal recessive type, also known as malignant osteopetrosis, is the most severe type, with the early onset of manifestations. A 5-month-old infant was admitted to our hospital with recurrent respiratory tract infections. Chest X-ray and skeletal survey revealed the classic findings of osteopetrosis, including diffuse osteosclerosis and bone within a bone appearance. At follow-up, the patient presented with, thickened calvarium, multiple prominent encephaloceles, and dural calcifications leading to the intracranial clinical manifestations with bilateral hearing and sight loss. Autosomal recessive osteopetrosis is one of the causes of encephaloceles and this finding may become dramatic if untreated. (orig.)

Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

Energy Technology Data Exchange (ETDEWEB)

Beggs, A.H.; Neumann, P.E.; Anderson, M.S.; Kunkel, L.M. (Harvard Medical School, Boston, MA (United States)); Arahata, Kiichi; Arikawa, Eri; Nonaka, Ikuya (National Inst. of Neuroscience, Tokyo (Japan))

1992-01-15

Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.

Identification of Mutations in SDR9C7 in 6 Families with Autosomal Recessive Congenital Ichthyosis

DEFF Research Database (Denmark)

Hotz, A; Fagerberg, C; Vahlquist, A

2018-01-01

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization. To date, ARCI has been associated with following genes: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, TGM1, PNPLA1 and recently SDR9C7 and SULT2B1.(1-6) Furthermore, seven patients from...

Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

DEFF Research Database (Denmark)

Bultmann-Mellin, Insa; Conradi, Anne; Maul, Alexandra C

2015-01-01

Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been ...

Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum

Science.gov (United States)

2011-01-01

Autosomal Recessive Primary Microcephaly (MCPH) is a rare disorder of neurogenic mitosis characterized by reduced head circumference at birth with variable degree of mental retardation. In MCPH patients, brain size reduced to almost one-third of its original volume due to reduced number of generated cerebral cortical neurons during embryonic neurogensis. So far, seven genetic loci (MCPH1-7) for this condition have been mapped with seven corresponding genes (MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, and STIL) identified from different world populations. Contribution of ASPM and WDR62 gene mutations in MCPH World wide is more than 50%. By and large, primary microcephaly patients are phenotypically indistinguishable, however, recent studies in patients with mutations in MCPH1, WDR62 and ASPM genes showed a broader clinical and/or cellular phenotype. It has been proposed that mutations in MCPH genes can cause the disease phenotype by disturbing: 1) orientation of mitotic spindles, 2) chromosome condensation mechanism during embryonic neurogenesis, 3) DNA damage-response signaling, 4) transcriptional regulations and microtubule dynamics, 5) certain unknown centrosomal mechanisms that control the number of neurons generated by neural precursor cells. Recent discoveries of mammalian models for MCPH have open up horizons for researchers to add more knowledge regarding the etiology and pathophysiology of MCPH. High incidence of MCPH in Pakistani population reflects the most probable involvement of consanguinity. Genetic counseling and clinical management through carrier detection/prenatal diagnosis in MCPH families can help reducing the incidence of this autosomal recessive disorder. PMID:21668957

Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia

NARCIS (Netherlands)

Chassine, T.; Bocquet, B.; Daien, V.; Avila-Fernandez, A.; Ayuso, C.; Collin, R.W.J.; Corton, M.; Hejtmancik, J.F.; Born, L.I. van den; Klevering, B.J.; Riazuddin, S.A.; Sendon, N.; Lacroux, A.; Meunier, I.; Hamel, C.P.

2015-01-01

OBJECTIVE: To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. METHODS: Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1

Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis.

Science.gov (United States)

Ferlazzo, Edoardo; Striano, Pasquale; Italiano, Domenico; Calarese, Tiziana; Gasparini, Sara; Vanni, Nicola; Fruscione, Floriana; Genton, Pierre; Zara, Federico

2016-09-01

Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis is an extremely rare condition, so far reported in a single family of Algerian origin presenting an unusual, severe form of progressive myoclonus epilepsy characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment, with probable autosomal recessive inheritance. Disease onset was between 6 and 16 years of age. Genetic study allowed to identify a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. The mutation decreased C18-ceramide levels. In addition, downregulation of CerS1 in neuroblastoma cell line showed activation of ER stress response and induction of proapoptotic pathways. This observation demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.

A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs.

Directory of Open Access Journals (Sweden)

Margret L Casal

Full Text Available Autosomal recessive congenital ichthyosis in the American bulldog is characterized by generalized scaling and erythema with adherent scale on the glabrous skin. We had previously linked this disorder to NIPAL4, which encodes the protein ichthyin. Sequencing of NIPAL4 revealed a homozygous single base deletion (CanFam3.1 canine reference genome sequence NC_06586.3 g.52737379del, the 157th base (cytosine in exon 6 of NIPAL4 as the most likely causative variant in affected dogs. This frameshift deletion results in a premature stop codon producing a truncated and defective NIPAL4 (ichthyin protein of 248 amino acids instead of the wild-type length of 404. Obligate carriers were confirmed to be heterozygous for this variant, and 150 clinically non-affected dogs of other breeds were homozygous for the wild-type gene. Among 800 American bulldogs tested, 34% of clinically healthy dogs were discovered to be heterozygous for the defective allele. More importantly, the development of this canine model of autosomal recessive congenital ichthyosis will provide insight into the development of new treatments across species.

Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.

Directory of Open Access Journals (Sweden)

Dirk J Lefeber

2011-12-01

Full Text Available Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5-13 years with a predominant presentation of dilated cardiomyopathy (DCM. Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG. Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations.

Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

NARCIS (Netherlands)

Klevering, B.J.; Blankenagel, A.; Maugeri, A.; Cremers, F.P.M.; Hoyng, C.B.; Rohrschneider, K.

2002-01-01

PURPOSE: To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. METHODS: The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were

Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone- shaped epiphyses in hands and hips

NARCIS (Netherlands)

Hellemans, J; Coucke, PJ; Giedion, A; De Paepe, A; Kramer, P; Beemer, F; Mortier, GR

Acrocapitofemoral dysplasia is a recently delineated autosomal recessive skeletal dysplasia, characterized clinically by short stature with short limbs and radiographically by cone-shaped epiphyses, mainly in hands and hips. Genome-wide homozygosity mapping in two consanguineous families linked the

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

NDST1 missense mutations in autosomal recessive intellectual disability.

Science.gov (United States)

Reuter, Miriam S; Musante, Luciana; Hu, Hao; Diederich, Stefan; Sticht, Heinrich; Ekici, Arif B; Uebe, Steffen; Wienker, Thomas F; Bartsch, Oliver; Zechner, Ulrich; Oppitz, Cornelia; Keleman, Krystyna; Jamra, Rami Abou; Najmabadi, Hossein; Schweiger, Susann; Reis, André; Kahrizi, Kimia

2014-11-01

NDST1 was recently proposed as a candidate gene for autosomal recessive intellectual disability in two families. It encodes a bifunctional GlcNAc N-deacetylase/N-sulfotransferase with important functions in heparan sulfate biosynthesis. In mice, Ndst1 is crucial for embryonic development and homozygous null mutations are perinatally lethal. We now report on two additional unrelated families with homozygous missense NDST1 mutations. All mutations described to date predict the substitution of conserved amino acids in the sulfotransferase domain, and mutation modeling predicts drastic alterations in the local protein conformation. Comparing the four families, we noticed significant overlap in the clinical features, including both demonstrated and apparent intellectual disability, muscular hypotonia, epilepsy, and postnatal growth deficiency. Furthermore, in Drosophila, knockdown of sulfateless, the NDST ortholog, impairs long-term memory, highlighting its function in cognition. Our data confirm NDST1 mutations as a cause of autosomal recessive intellectual disability with a distinctive phenotype, and support an important function of NDST1 in human development. © 2014 Wiley Periodicals, Inc.

A Dutch family with autosomal recessively inherited lower motor neuron predominant motor neuron disease due to optineurin mutations

NARCIS (Netherlands)

Beeldman, Emma; van der Kooi, Anneke J.; de Visser, Marianne; van Maarle, Merel C.; van Ruissen, Fred; Baas, Frank

2015-01-01

Approximately 10% of motor neuron disease (MND) patients report a familial predisposition for MND. Autosomal recessively inherited MND is less common and is most often caused by mutations in the superoxide dismutase 1 (SOD1) gene. In 2010, autosomal recessively inherited mutations in the optineurin

Two novel mutations in ILDR1 gene cause autosomal recessive ...

Indian Academy of Sciences (India)

In a recent screening programme on hearing loss (HL), we examined 17 common autosomal recessive nonsyndromic hearing loss (ARNSHL) genes in every consanguineous Ira- nian family with ARNSHL that was referred to our centre. We first screened GJB2 mutations and then utilized a panel of three to four short ...

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.

Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia

DEFF Research Database (Denmark)

Hellström Pigg, Maritta; Bygum, Anette; Gånemo, Agneta

2016-01-01

Autosomal recessive congenital ichthyosis (ARCI) represents a heterogeneous group of rare disorders of cornification with 3 major subtypes: harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A 4th subtype has also been proposed: pleomorphic...... ichthyosis (PI), characterized by marked skin changes at birth and subsequently mild symptoms. In nationwide screenings of suspected cases of ARCI in Denmark and Sweden, we identified 132 patients (age range 0.1-86 years) classified as HI (n = 7), LI (n = 70), CIE (n = 17) and PI (n = 38). At birth......-100%). A scoring (0-4) of ichthyosis/ery-thema past infancy showed widely different mean values in the subgroups: HI (3.2/3.1), LI (2.4/0.6), CIE (1.8/1.6), PI (1.1/0.3). Novel or recurrent mutations were found in 113 patients: TGM1 (n = 56), NIPAL4 (n = 15), ALOX12B (n = 15), ABCA12 (n = 8), ALOXE3 (n = 9), SLC27...

[Investigation of Genetic Aetiology in Neurodegenerative Ataxias: Recommendations from the Group of Neurogenetics of Centro Hospitalar São João, Portugal].

Science.gov (United States)

Gomes, Tiago; Guimaraes, Joana; Leão, Miguel

2017-06-30

In recent decades, a long and increasing list of monogenic neurodegenerative ataxias has been identified, allowing for better characterization of the pathophysiology, phenotype and prognosis of this heterogeneous group of disorders, while also revealing potential new therapeutic targets. However, the heterogeneity and complexity of the genotype-phenotype relationships and the high costs of molecular genetics often make it difficult for clinicians to decide on a molecular investigation based on an unbiased rational plan. Clinical history is essential to guide the diagnostic workup, but often the phenotype does not hold enough specificity to allow for predicting the genotype. The Group of Neurogenetics of the Centro Hospitalar São João, a multidisciplinary team of neurologists and geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic aetiology of neurodegenerative ataxias in clinical practice, based on international consensus documents (currently containing potentially outdated information) and published scientific evidence on this topic. At the time these recommendations were written, there were around 10 well described autosomal recessive loci and more than 27 autosomal dominant loci for neurodegenerative ataxias. This document covers, in a pragmatic way, the rational process used for the genetic diagnosis of neurodegenerative ataxias, with specific recommendations for the various groups of these heterogeneous diseases, per the Portuguese reality.

Genetic Causes of Putative Autosomal Recessive Intellectual Disability Cases in Hamedan Province

Directory of Open Access Journals (Sweden)

Milad Bastami

2012-04-01

Full Text Available Objective: The aim of this study was to investigate the genetic causes of autosomal recessive intellectual disabilities (AR-ID in Hamadan province of Iran. Materials & Methods: In this descriptive-analytical cross-sectional study, 25 families with more than one affected with putative autosomal recessive intellectual disability were chosen with collaboration of Welfare Organization of Hamadan province. Families were included a total of 60 patients (39 male and 21 female whose intellectual disability had been confirmed by Raven IQ test. Each family was asked for clinical examination and getting consent form. Blood sample was collected from each family. One proband from each family was tested for CGG repeat expansion in FMR1 gene, chromosomal abnormalities and inborn errors of metabolism. We also performed homozygosity mapping based on STR markers for seven known MCPH loci in families with primary microcephaly and AR-ID. Results: Five families had full mutation of Fragile X syndrome. No chromosomal abnormalities were identified. Metabolic screening revealed one family with Medium Chain Acyl CoA Dehydrogenase deficiency. None of three families with primary microcephaly and AR-ID showed linkage to any of known seven MCPH loci. Conclusion: The main causes of ID in Hamadan province were Fragile X syndrome and Autosomal Recessive Primary Microcephaly with the frequencies of 20% and 12%, respectively.

Autosomal recessive ichthyosis with hypotrichosis syndrome: further delineation of the phenotype

NARCIS (Netherlands)

Avrahami, L.; Maas, S.; Pasmanik-Chor, M.; Rainshtein, L.; Magal, N.; Smitt, J. H. S.; van Marle, J.; Shohat, M.; Basel-Vanagaite, L.

2008-01-01

Autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome, which is characterized by congenital ichthyosis, abnormal hair and corneal involvement, has recently been shown in one consanguineous Israeli Arab family to be caused by a mutation in the ST14 gene, which encodes serine protease

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Science.gov (United States)

Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A; Pagnamenta, Alistair T; Alswaid, Abdulrahman; Baker, Eva H; Blair, Edward; Borck, Guntram; Brinkmann, Julia; Craigen, William; Dung, Vu Chi; Emrick, Lisa; Everman, David B; van Gassen, Koen L; Gulsuner, Suleyman; Harr, Margaret H; Jain, Mahim; Kuechler, Alma; Leppig, Kathleen A; McDonald-McGinn, Donna M; Can, Ngoc Thi Bich; Peleg, Amir; Roeder, Elizabeth R; Rogers, R Curtis; Sagi-Dain, Lena; Sapp, Julie C; Schäffer, Alejandro A; Schanze, Denny; Stewart, Helen; Taylor, Jenny C; Verbeek, Nienke E; Walkiewicz, Magdalena A; Zackai, Elaine H; Zweier, Christiane; Zenker, Martin; Lee, Brendan; Biesecker, Leslie G

2018-02-22

PurposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.MethodsFamilies underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.ResultsTwelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.ConclusionThese clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249.

Clinical and genetic characteristics of autosomal recessive axonal neuropathy with neuromyotonia in Russian patients

Directory of Open Access Journals (Sweden)

E. L. Dadali

2017-01-01

Full Text Available Introduction. Hereditary motor and sensory neuropathies are genetically heterogeneous group of disorders characterized by a progressive muscle weakness, atrophy of hand and leg muscles often associated with deformations, and mild to moderate sensory loss. Axonal neuropathy with neuromyotonia (AR-ANM is one of the rarest autosomal recessive hereditary neuropathies. Materials and methods. Six (6 patients (4 men, 2 women aged 14–40 years from unrelated families with suspicion of HMSN were examined clinically, neurophysiologically and using DNA analysis. Results. Neurophysiological examination revealed motor and sensory neuropathy with neuromyotonia signs in all patients. In all cases homozygous variant of recessive mutations с.110G/C (р.Arg37Pro in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1 has been revealed. Conclusion. There is the first description of the clinical and neurophysiological features of six patients with AR-ANM in Russia. 

Genetics of recessive cognitive disorders.

Science.gov (United States)

Musante, Luciana; Ropers, H Hilger

2014-01-01

Most severe forms of intellectual disability (ID) have specific genetic causes. Numerous X chromosome gene defects and disease-causing copy-number variants have been linked to ID and related disorders, and recent studies have revealed that sporadic cases are often due to dominant de novo mutations with low recurrence risk. For autosomal recessive ID (ARID) the recurrence risk is high and, in populations with frequent parental consanguinity, ARID is the most common form of ID. Even so, its elucidation has lagged behind. Here we review recent progress in this field, show that ARID is not rare even in outbred Western populations, and discuss the prospects for improving its diagnosis and prevention. Copyright © 2013 Elsevier Ltd. All rights reserved.

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

NARCIS (Netherlands)

Lesage, S.; Drouet, V.; Majounie, E.; Deramecourt, V.; Jacoupy, M.; Nicolas, A.; Cormier-Dequaire, F.; Hassoun, S.M.; Pujol, C.; Ciura, S.; Erpapazoglou, Z.; Usenko, T.; Maurage, C.A.; Sahbatou, M.; Liebau, S.; Ding, J.; Bilgic, B.; Emre, M.; Erginel-Unaltuna, N.; Guven, G.; Tison, F.; Tranchant, C.; Vidailhet, M.; Corvol, J.C.; Krack, P.; Leutenegger, A.L.; Nalls, M.A.; Hernandez, D.G.; Heutink, P.; Gibbs, J.R.; Hardy, J.; Wood, N.W.; Gasser, T.; Durr, A.; Deleuze, J.F.; Tazir, M.; Destee, A.; Lohmann, E.; Kabashi, E.; Singleton, A.; Corti, O.; Brice, A.; Scheffer, H.; Bloem, B.R.; et al.,

2016-01-01

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with

Genetic Counselors' Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels.

Science.gov (United States)

Mets, Sarah; Tryon, Rebecca; Veach, Patricia McCarthy; Zierhut, Heather A

2016-04-01

The development of hereditary cancer genetic testing panels has altered genetic counseling practice. Mutations within certain genes on cancer panels pose not only a cancer risk, but also a reproductive risk for autosomal recessive conditions such as Fanconi anemia, constitutional mismatch repair deficiency syndrome, and ataxia telangiectasia. This study aimed to determine if genetic counselors discuss reproductive risks for autosomal recessive conditions associated with genes included on cancer panels, and if so, under what circumstances these risks are discussed. An on-line survey was emailed through the NSGC list-serv. The survey assessed 189 cancer genetic counselors' experiences discussing reproductive risks with patients at risk to carry a mutation or variant of uncertain significance (VUS) in a gene associated with both an autosomal dominant cancer risk and an autosomal recessive syndrome. Over half (n = 82, 55 %) reported having discussed reproductive risks; the remainder (n = 66, 45 %) had not. Genetic counselors who reported discussing reproductive risks primarily did so when patients had a positive result and were of reproductive age. Reasons for not discussing these risks included when a patient had completed childbearing or when a VUS was identified. Most counselors discussed reproductive risk after obtaining results and not during the informed consent process. There is inconsistency as to if and when the discussion of reproductive risks is taking place. The wide variation in responses suggests a need to develop professional guidelines for when and how discussions of reproductive risk for autosomal recessive conditions identified through cancer panels should occur with patients.

Microcephaly-chorioretinopathy syndrome, autosomal recessive form. A case report

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Rafael Fabiano Machado Rosa

Full Text Available CONTEXT: The autosomal recessive form of microcephaly-chorioretinopathy syndrome is a rare genetic condition that is considered to be an important differential diagnosis with congenital toxoplasmosis.CASE REPORT: Our patient was a seven-year-old white boy who was initially diagnosed with congenital toxoplasmosis. However, his serological tests for congenital infections, including toxoplasmosis, were negative. He was the first child of young, healthy and consanguineous parents (fourth-degree relatives. The parents had normal head circumferences and intelligence. The patient presented microcephaly and specific abnormalities of the retina, with multiple diffuse oval areas of pigmentation and patches of chorioretinal atrophy associated with diffuse pigmentation of the fundus. Ophthalmological evaluations on the parents were normal. A computed tomography scan of the child's head showed slight dilation of lateral ventricles and basal cisterns without evidence of calcifications. We did not find any lymphedema in his hands and feet. He had postnatal growth retardation, severe mental retardation and cerebral palsy.CONCLUSIONS: The finding of chorioretinal lesions in a child with microcephaly should raise suspicions of the autosomal recessive form of microcephaly-chorioretinopathy syndrome, especially in cases with an atypical pattern of eye fundus and consanguinity. A specific diagnosis is essential for an appropriate clinical evaluation and for genetic counseling for the patients and their families.

Autosomal-dominant osteopetrosis: An incidental finding

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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.

A novel NR2E3 gene mutation in autosomal recessive retinitis pigmentosa with cystic maculopathy

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Mahajan, D.; Votruba, Marcela

2017-01-01

NR2E3 is a gene that encodes for photoreceptor cell specific nuclear receptor, which is involved in cone proliferation. The splice site mutation 119-2A>C in NR2E3 (15q23) has been previously reported to underlie recessive enhanced cone S sensitivity syndrome, clumped pigmentary retinal degeneration, Goldman-Favre syndrome and also autosomal dominant and autosomal recessive retinitis pigmentosa (RP). However, the mutation c 571 + 2 T > C in NR2E3 has not been previously reported with retinal d...

Investigation of Genetic Aetiology in Neurodegenerative Ataxias: Recommendations from the Group of Neurogenetics of Centro Hospitalar São João, Portugal

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Tiago Gomes

2017-06-01

Full Text Available In recent decades, a long and increasing list of monogenic neurodegenerative ataxias has been identified, allowing for better characterization of the pathophysiology, phenotype and prognosis of this heterogeneous group of disorders, while also revealing potential new therapeutic targets. However, the heterogeneity and complexity of the genotype-phenotype relationships and the high costs of molecular genetics often make it difficult for clinicians to decide on a molecular investigation based on an unbiased rational plan. Clinical history is essential to guide the diagnostic workup, but often the phenotype does not hold enough specificity to allow for predicting the genotype. The Group of Neurogenetics of the Centro Hospitalar São João, a multidisciplinary team of neurologists and geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic aetiology of neurodegenerative ataxias in clinical practice, based on international consensus documents (currently containing potentially outdated information and published scientific evidence on this topic. At the time these recommendations were written, there were around 10 well described autosomal recessive loci and more than 27 autosomal dominant loci for neurodegenerative ataxias. This document covers, in a pragmatic way, the rational process used for the genetic diagnosis of neurodegenerative ataxias, with specific recommendations for the various groups of these heterogeneous diseases, per the Portuguese reality.

Genotype-phenotype correlation in FMF patients: A "non classic" recessive autosomal or "atypical" dominant autosomal inheritance?

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Procopio, V; Manti, S; Bianco, G; Conti, G; Romeo, A; Maimone, F; Arrigo, T; Cutrupi, M C; Salpietro, C; Cuppari, C

2018-01-30

Uncertainty remains on the pathogenetic mechanisms, model of inheritance as well as genotype-phenotype correlation of FMF disease. To investigate the impact of genetic factors on the FMF phenotype and the disease inheritance model. A total of 107 FMF patients were enrolled. Patients were diagnosed clinically. All patients underwent genetic analysis of the FMF locus on 16p13.3. 9 distinct mutations were detected. Specifically, the 85.98% of patients showed a heterozygous genotype. The most common genotypes were p.Met680Ile/wt and p.Met694Val/wt. The most frequent clinical findings were fever, abdominal pain, joint pain, thoracic pain, and erysipelas-like erythema. Analysis of clinical data did not detect any significant difference in clinical phenotype among heterozygous, homozygous as well as compound homozygous subjects, further supporting the evidence that, contrary to the recessive autosomal inheritance, heterozygous patients fulfilled the criteria of clinical FMF. Moreover, subjects with p.Met694Val/wt and p.Met680Ile/wt genotype reported the most severe clinical phenotype. p.Ala744Ser/wt, p.Glu148Gln/Met680Ile, p.Met680Ile/Met680Ile, p.Met680Ile/Met694Val, p.Pro369Ser/wt, p.Met694Ile/wt, p.Glu148Gln/Glu148Gln, p.Lys695Arg/wt resulted in 100% pathogenicity. The existence of a "non classic" autosomal recessive inheritance as well as of an "atypical" dominant autosomal inheritance with incomplete penetrance and variable expressivity cannot be excluded in FMF. Copyright © 2017 Elsevier B.V. All rights reserved.

New parkin mutations and atypical phenotypes in families with autosomal recessive parkinsonism.

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Rawal, N.; Periquet, M.; Lohmann, E.; Lucking, C.B.; Teive, H.; Ambrosio, G.; Raskin, S.; Lincoln, S.; Hattori, N.; Guimaraes, J.; Horstink, M.W.I.M.; Santos Bele, W. Dos; Brousolle, E.; Destee, A.; Mizuno, Y.; Farrer, M.; Deleuze, J.F.; Michele, G. de; Agid, Y.; Durr, A.; Brice, A.

2003-01-01

The frequency of parkin mutations was evaluated in 30 families of highly diverse geographic origin with early-onset autosomal recessive parkinsonism. Twelve different mutations, six of which were new, were found in 10 families from Europe and Brazil. Patients with parkin mutations had significantly

A novel HSF4 gene mutation (p.R405X causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan

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Cheema Abdul

2008-11-01

Full Text Available Abstract Background Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can also be inherited in an autosomal recessive or X-linked fashion. To date, 12 loci for autosomal recessive cataracts have been mapped including a locus on chromosome 16q22 containing the disease-causing gene HSF4 (Genbank accession number NM_001040667. Here, we describe a family from Pakistan with the first nonsense mutation in HSF4 thus expanding the mutational spectrum of this heat shock transcription factor gene. Methods A large consanguineous Pakistani family with autosomal recessive cataracts was collected from Quetta. Genetic linkage analysis was performed for the common known autosomal recessive cataracts loci and linkage to a locus containing HSF4 (OMIM 602438 was found. All exons and adjacent splice sites of the heat shock transcription factor 4 gene (HSF4 were sequenced. A mutation-specific restriction enzyme digest (HphI was performed for all family members and unrelated controls. Results The disease phenotype perfectly co-segregated with markers flanking the known cataract gene HSF4, whereas other autosomal recessive loci were excluded. A maximum two-point LOD score with a Zmax = 5.6 at θ = 0 was obtained for D16S421. Direct sequencing of HSF4 revealed the nucleotide exchange c.1213C > T in this family predicting an arginine to stop codon exchange (p.R405X. Conclusion We identified the first nonsense mutation (p.R405X in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract.

Congenital myotonic myopathy in the miniature schnauzer: an autosomal recessive trait.

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Vite, C H; Melniczek, J; Patterson, D; Giger, U

1999-01-01

Myotonia is a clinical sign characterized by a delay in skeletal muscle relaxation following electrical or mechanical stimulation. A series of related miniature schnauzer dogs with congenital myotonic myopathy were studied. A composite pedigree of six affected litters and the results of a planned breeding between two affected animals are consistent with an autosomal recessive mode of inheritance.

An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3

OpenAIRE

Bouhouche Ahmed; Benomar Ali; Errguig Leila; Lachhab Lamiae; Bouslam Naima; Aasfara Jehanne; Sefiani Sanaa; Chabraoui Layachi; El Fahime Elmostafa; El Quessar Abdeljalil; Jiddane Mohamed; Yahyaoui Mohamed

2012-01-01

Abstract Background Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. Methods All family members underwent neurologic...

Inhibitory action of chlorophyllin of autosome recessive lethals induced by irradiation

International Nuclear Information System (INIS)

Salceda, V.M.; Pimentel, P.A.E.; Cruces, M.P.

2006-01-01

The chlorophyllin is a sodium salt of the chlorophyll that has a strong protective action of the damage induced by different agents so much physical as chemical. In Drosophila there is reported this effect in somatic cells. In contrast, in germinal cells using tests with the sexual chromosomes has not been found such inhibitory action. For this reason, in this occasion we will refer to the effect of the lethality induced in autosome chromosomes, in particular to the chromosome II of this species. For such effect groups of males of the line Canton-S its were pre-treated for 24h with or without 69 mm of CCS and later on treaties with or without 40 Gy of gamma irradiation. The males were then subjected to the technical Cy L / Pm for the detection of recessive lethals. In the third generation the respective counts of the descendant of each one of them to determine the corresponding categories for each extracted chromosome were made. To be mendelian crosses it is expected for a normal chromosome a proportion 2:1 of individuals with genotype Cy L / +: +/+. The absence of individuals +/+ it is indicative of a lethal gene, until 10% of these individuals of each male's total descendant, it is considered that is carrying of a semi lethal gene. The sum of lethal and semi lethals constitutes the category detrimental. The obtained results indicated that the pre-treatment with CCS reduces in a significant way the frequency of induced lethals by 40 Gy of gamma rays. The fact that an effect inhibitor has not been observed in the test of recessive lethal bound to the sex obtained previously, it contrasts with the effect observed in the chromosome II, results of this study and with the one observed in the chromosome III in somatic cells. The above-mentioned shows a differential action of the CCS between sexual chromosomes and autosomal before the effect of the gamma radiation. At the moment we don't have an explanation to these evidences. To evaluate the action of the chlorophyllin

Autosomal recessive polycystic kidney disorder due to two novel compound heterozygote mutations in PKHD1 gene: case report

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Mohammad Miryounesi

2017-01-01

Full Text Available Background: Autosomal recessive polycystic kidney disorder (ARPCKD is one of the most prevalent hereditary disorders in neonates and children. Its frequency is between 1/6000 to 1/55000 births. In the most severe cases, it can be diagnosed prenatally by the presence of enlarged, echogenic kidneys and oligohydramnios. However, in the milder forms, clinical manifestations are usually detected in neonatal and childhood period. PKHD1 gene located on chromosome 6 is linked with this disorder. About half of detected mutations in this gene are missense ones. The largest protein product of this gene is called the FPC/polyductin complex (FPC. It is a single-membrane spanning protein whose absence leads to abnormal ciliogenesis in the kidneys. Case presentation: Here we present a 5-year-old female patient affected with ARPCKD. She has been born to a non-consanguineous healthy Iranian parents. No similar disorder has been seen in the family. Prenatal history has been normal. In order to find the genetic background, DNA was extracted from patient's peripheral blood lymphocytes. PKHD1 gene exons and exon-intron boundaries were sequenced using next generation sequencing platform. Two novel variants have been detected in compound heterozygote state in the patient (c.6591C>A, c.8222C>A. Bioinformatics tools predicted these variants to be pathogenic. Conclusion: In the present study, we detected two novel variants in PKHD1 gene in a patient with ARPCKD. The relatively mild phenotype of this patient is in accordance with the missense mutations found. Molecular genetic tools can help in accurate risk assessment as well as precise genotype-phenotype correlation establishment in families affected with such disorder to decrease the birth of affected individuals through preimplantation genetic diagnosis or better management of disorder.

Enfermedad poliquística autosómica recesiva Recessive autosomal polycystic disease

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Sandalio Durán Álvarez

2007-06-01

Full Text Available Como enfermedades renales poliquísticas hereditarias se describen clásicamente la autosómica recesiva y la autosómica dominante, mal llamadas enfermedad poliquística de tipo infantily de;tipo adulto, respectivamente, pues ambas pueden verse tanto en una como en otra edad. Los conceptos cambiantes en cuanto a la enfermedad autosómica recesiva, dados por los progresos en el tratamiento de los recién nacidos con la enfermedad, y la localización del gen, que por su mutación la produce, nos motivan hacer esta breve revisión con la finalidad de contribuir a la comprensión de la enfermedad por los estudiantes de medicina y el médico general básico.Recessive autosomal and dominant autosomal polycystic kidney diseases are classically described as hereditary illnesses; they are also called polycystic disease of child type” and of adult typerespectively since both may be seen in any of these two life stages. The changing concepts of recessive autosomal disease, given the advances made in the treatment of newborns with this disease, and the location of the gen, the mutation of which causes it, encouraged us to make a brief literature review to help medical students and general practitioners to understand this disease.

Evidence for autosomal recessive inheritance in cerebral gigantism

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Nevo, S.; Zeltzer, M.; Benderly, A.; Levy, J.

1974-01-01

Three cases of cerebral gigantism, two sibs and their double first cousin, are described in a large inbred family from Israel. Two of the three were observed and diagnosed at birth and two were followed for two years. They all presented the signs and symptoms considered typical of this syndrome, as well as some of the less frequent findings. Generalized oedema and flexion contractures of the feet were observed in two of the three at birth. This has not hitherto been reported in cases of cerebral gigantism, of whom only a few have been observed and diagnosed at birth. Autosomal recessive inheritance is clearly implied in this family. Images PMID:4841084

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

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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.

Autosomal dominant hereditary ataxia in Sri Lanka

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Sumathipala, Dulika S; Abeysekera, Gayan S; Jayasekara, Rohan W; Tallaksen, Chantal ME; Dissanayake, Vajira HW

2013-01-01

Background Spinocerebellar ataxias (SCA) are a group of hereditary neurodegenerative disorders. Prevalence of SCA subtypes differ worldwide. Autosomal dominant ataxias are the commonest types of inherited ataxias seen in Sri Lanka. The aim of the study is to determine the genetic etiology of patients with autosomal dominant ataxia in Sri Lanka and to describe the clinical features of each genetic subtype. Methods ...

The aging brain and neurodegenerative disorders

International Nuclear Information System (INIS)

Braffman, B.H.; Trojanowski, J.Q.; Atlas, S.W.

1991-01-01

Both the aging brain and neurodegenerative disorders are characterized by a lack of vital endurance of affected neurons resulting in their premature death. Neuronal shrinkage or atrophy and death are normal and inevitable aspects of normal or successful aging; this is unexpected, excessive, and premature in neurodegenerative disorders. These histologic changes result in the neuroimaging findings of focal and/or diffuse atrophy with consequent enlargement of cerebrospinal fluid (CSF) spaces. The aging brain and neurodegenerative disorders share other magnetic resonance (MR) changes, i.e., markedly hypointense extrapyramidal nuclei and hyperintense white matter foci. The sequelae of senescent vascular changes result in additional characteristic features of the aging brain. This paper presents the MR and neuropathologic manifestations of both the normal aging brain and the brain affected by neurodegenerative disorders

Novel FAM20A mutation causes autosomal recessive amelogenesis imperfecta.

Science.gov (United States)

Volodarsky, Michael; Zilberman, Uri; Birk, Ohad S

2015-06-01

To relate the peculiar phenotype of amelogenesis imperfecta in a large Bedouin family to the genotype determined by whole genome linkage analysis. Amelogenesis imperfecta (AI) is a broad group of inherited pathologies affecting enamel formation, characterized by variability in phenotypes, causing mutations and modes of inheritance. Autosomal recessive or compound heterozygous mutations in FAM20A, encoding sequence similarity 20, member A, have been shown to cause several AI phenotypes. Five members from a large consanguineous Bedouin family presented with hypoplastic amelogenesis imperfecta with unerupted and resorbed permanent molars. Following Soroka Medical Center IRB approval and informed consent, blood samples were obtained from six affected offspring, five obligatory carriers and two unaffected siblings. Whole genome linkage analysis was performed followed by Sanger sequencing of FAM20A. The sequencing unravelled a novel homozygous deletion mutation in exon 11 (c.1523delC), predicted to insert a premature stop codon (p.Thr508Lysfs*6). We provide an interesting case of novel mutation in this rare disorder, in which the affected kindred is unique in the large number of family members sharing a similar phenotype. Copyright © 2015 Elsevier Ltd. All rights reserved.

Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

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Cornel Martina C

2010-07-01

Full Text Available Abstract Background The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only. Methods/Design This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis. Discussion This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous

Splicing defect in FKBP10 gene causes autosomal recessive osteogenesis imperfecta disease: a case report.

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Maghami, Fatemeh; Tabei, Seyed Mohammad Bagher; Moravej, Hossein; Dastsooz, Hassan; Modarresi, Farzaneh; Silawi, Mohammad; Faghihi, Mohammad Ali

2018-05-25

Osteogenesis imperfecta (OI) is a group of connective tissue disorder caused by mutations of genes involved in the production of collagen and its supporting proteins. Although the majority of reported OI variants are in COL1A1 and COL1A2 genes, recent reports have shown problems in other non-collagenous genes involved in the post translational modifications, folding and transport, transcription and proliferation of osteoblasts, bone mineralization, and cell signaling. Up to now, 17 types of OI have been reported in which types I to IV are the most frequent cases with autosomal dominant pattern of inheritance. Here we report an 8- year- old boy with OI who has had multiple fractures since birth and now he is wheelchair-dependent. To identify genetic cause of OI in our patient, whole exome sequencing (WES) was carried out and it revealed a novel deleterious homozygote splice acceptor site mutation (c.1257-2A > G, IVS7-2A > G) in FKBP10 gene in the patient. Then, the identified mutation was confirmed using Sanger sequencing in the proband as homozygous and in his parents as heterozygous, indicating its autosomal recessive pattern of inheritance. In addition, we performed RT-PCR on RNA transcripts originated from skin fibroblast of the proband to analyze the functional effect of the mutation on splicing pattern of FKBP10 gene and it showed skipping of the exon 8 of this gene. Moreover, Real-Time PCR was carried out to quantify the expression level of FKBP10 in the proband and his family members in which it revealed nearly the full decrease in the level of FKBP10 expression in the proband and around 75% decrease in its level in the carriers of the mutation, strongly suggesting the pathogenicity of the mutation. Our study identified, for the first time, a private pathogenic splice site mutation in FKBP10 gene and further prove the involvement of this gene in the rare cases of autosomal recessive OI type XI with distinguished clinical manifestations.

Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia-Brief Report.

Science.gov (United States)

Thedrez, Aurélie; Sjouke, Barbara; Passard, Maxime; Prampart-Fauvet, Simon; Guédon, Alexis; Croyal, Mikael; Dallinga-Thie, Geesje; Peter, Jorge; Blom, Dirk; Ciccarese, Milco; Cefalù, Angelo B; Pisciotta, Livia; Santos, Raul D; Averna, Maurizio; Raal, Frederick; Pintus, Paolo; Cossu, Maria; Hovingh, Kees; Lambert, Gilles

2016-08-01

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients. © 2016 American Heart Association, Inc.

Molecular genetic analysis of consanguineous Pakistani families with autosomal recessive hypohidrotic ectodermal dysplasia.

Science.gov (United States)

Bibi, Nosheen; Ahmad, Saeed; Ahmad, Wasim; Naeem, Muhammad

2011-02-01

Hypohidrotic ectodermal dysplasia is an inherited disorder characterized by defective development of teeth, hairs and sweat glands. X-linked hypohidrotic ectodermal dysplasia is caused by mutations in the EDA gene, and autosomal forms of hypohidrotic ectodermal dysplasia are caused by mutations in either the EDAR or the EDARADD genes. To study the molecular genetic cause of autosomal recessive hypohidrotic ectodermal dysplasia in three consanguineous Pakistani families (A, B and C), genotyping of 13 individuals was carried out by using polymorphic microsatellite markers that are closely linked to the EDAR gene on chromosome 2q11-q13 and the EDARADD gene on chromosome 1q42.2-q43. The results revealed linkage in the three families to the EDAR locus. Sequence analysis of the coding exons and splice junctions of the EDAR gene revealed two mutations: a novel non-sense mutation (p.E124X) in the probands of families A and B and a missense mutation (p.G382S) in the proband of family C. In addition, two synonymous single-nucleotide polymorphisms were also identified. The finding of mutations in Pakistani families extends the body of evidence that supports the importance of EDAR for the development of hypohidrotic ectodermal dysplasia. © 2010 The Authors. Australasian Journal of Dermatology © 2010 The Australasian College of Dermatologists.

Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X.

Science.gov (United States)

Song, Y; Zhao, D; Xu, X; Lv, F; Li, L; Jiang, Y; Wang, O; Xia, W; Xing, X; Li, M

2018-03-09

We identified novel compound heterozygous mutations in SERPINH1 in a Chinese boy suffering from recurrent fractures, femoral deformities, and growth retardation, which resulted in extremely rare autosomal recessive OI type X. Long-term treatment of BPs was effective in increasing BMD Z-score, reducing fracture incidence and reshaping vertebrae compression. Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by low bone mineral density, recurrent fractures, and progressive bone deformities. Mutation in serpin peptidase inhibitor clade H, member 1 (SERPINH1), which encodes heat shock protein 47 (HSP47), leads to rare autosomal recessive OI type X. We aimed to detect the phenotype and the pathogenic mutation of OI type X in a boy from a non-consanguineous Chinese family. We investigated the pathogenic mutations and analyzed their relationship with the phenotype in the patient using next-generation sequencing (NGS) and Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment in this patient was evaluated. The patient suffered from multiple fractures, low bone mass, and bone deformities in the femur, without dentinogenesis imperfecta or hearing loss. Compound heterozygous variants were found in SERPINH1 as follows: c.149 T>G in exon 2 and c.1214G>A in exon 5. His parents were heterozygous carriers of each of these mutations, respectively. Bisphosphonates could be helpful in increasing BMD Z-score, reducing bone fracture risk and reshaping the compressed vertebral bodies of this patient. We reported novel compound heterozygous mutations in SERPINH1 in a Chinese OI patient for the first time, which expanded the spectrum of phenotype and genotype of extremely rare OI type X.

[Genetic study of the autosomal recessive form of Charcot-Marie-Tooth in an Algerian family].

Science.gov (United States)

Hamadouche, T; Tazir-Melboucy, M; Benhassine, T

1998-01-01

Charcot-Marie-Tooth disease (CMT) is a hereditary neuropathy characterized by muscular atrophy and progressive sensitive alterations that affect limbs. The CMT is one of the most heterogenous diseases, clinically as well as genetically. At least twelve loci are responsible for the CMT phenotype, four of them for the autosomal recessive form. The aim of our work was to determinate the implication/exclusion of these four loci in an Algerian family by linkage analysis using microsatellites markers. We have tested the four loci on 8q13-21.1 (CMT4A), 11q23 (CMT4B), 5q23-33 (CMT4C) 8q24 (CMTAR). The haplotype reconstruction allowed us to exclude all the loci in this family, suggesting that the locus (gene) responsible for this form of CMT is localized elsewhere in the genome, thus providing an other observation of the great heterogeneity of the CMT, particularly autosomal recessive.

Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses

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Carsten Bergmann

2018-02-01

Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is a hepatorenal fibrocystic disorder that is characterized by enlarged kidneys with progressive loss of renal function and biliary duct dilatation and congenital hepatic fibrosis that leads to portal hypertension in some patients. Mutations in the PKHD1 gene are the primary cause of ARPKD; however, the disease is genetically not as homogeneous as long thought and mutations in several other cystogenes can phenocopy ARPKD. The family history usually is negative, both for recessive, but also often for dominant disease genes due to de novo arisen mutations or recessive inheritance of variants in genes that usually follow dominant patterns such as the main ADPKD genes PKD1 and PKD2. Considerable progress has been made in the understanding of polycystic kidney disease (PKD. A reduced dosage of disease proteins leads to the disruption of signaling pathways underlying key mechanisms involved in cellular homeostasis, which may help to explain the accelerated and severe clinical progression of disease course in some PKD patients. A comprehensive knowledge of disease-causing genes is essential for counseling and to avoid genetic misdiagnosis, which is particularly important in the prenatal setting (e.g., preimplantation genetic diagnosis/PGD. For ARPKD, there is a strong demand for early and reliable prenatal diagnosis, which is only feasible by molecular genetic analysis. A clear genetic diagnosis is helpful for many families and improves the clinical management of patients. Unnecessary and invasive measures can be avoided and renal and extrarenal comorbidities early be detected in the clinical course. The increasing number of genes that have to be considered benefit from the advances of next-generation sequencing (NGS which allows simultaneous analysis of a large group of genes in a single test at relatively low cost and has become the mainstay for genetic diagnosis. The broad phenotypic and genetic

Genetic Defects Underlie the Non-syndromic Autosomal Recessive Intellectual Disability (NS-ARID

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Saleha Shamim

2017-05-01

Full Text Available Intellectual disability (ID is a neurodevelopmental disorder which appears frequently as the result of genetic mutations and may be syndromic (S-ID or non-syndromic (NS-ID. ID causes an important economic burden, for patient's family, health systems, and society. Identifying genes that cause S-ID can easily be evaluated due to the clinical symptoms or physical anomalies. However, in the case of NS-ID due to the absence of co-morbid features, the latest molecular genetic techniques can be used to understand the genetic defects that underlie it. Recent studies have shown that non-syndromic autosomal recessive (NS-ARID is extremely heterogeneous and contributes much more than X-linked ID. However, very little is known about the genes and loci involved in NS-ARID relative to X-linked ID, and whose complete genetic etiology remains obscure. In this review article, the known genetic etiology of NS-ARID and possible relationships between genes and the associated molecular pathways of their encoded proteins has been reviewed which will enhance our understanding about the underlying genes and mechanisms in NS-ARID.

[Autosomal-recessive renal cystic disease and congenital hepatic fibrosis: clinico-anatomic case].

Science.gov (United States)

Rostol'tsev, K V; Burenkov, R A; Kuz'micheva, I A

2012-01-01

Clinico-anatomic observation of autosomal-recessive renal cystic disease and congenital hepatic fibrosis at two fetuses from the same family was done. Mutation of His3124Tyr in 58 exon of PKHD1 gene in heterozygous state was found out. The same pathomorphological changes in the epithelium of cystic renal tubules and bile ducts of the liver were noted. We suggest that the autopsy research of fetuses with congenital abnormalities, detected after prenatal ultrasonic screening, has high diagnostic importance.

Molecular and phenotypic analysis of a family with autosomal recessive cone-rod dystrophy and Stargardt disease.

NARCIS (Netherlands)

Ijzer, Suzanne; Born, L.I. van den; Zonneveld, M.N.; Lopez, I.; Ayyagari, R.; Teye-Botchway, L.; Mota-Vieira, L.; Cremers, F.P.M.; Koenekoop, R.K.

2007-01-01

PURPOSE: To identify the causative gene mutations in three siblings with severe progressive autosomal recessive cone-rod dystrophy (arCRD) and their fifth paternal cousin with Stargardt disease (STGD1) and to specify the phenotypes. METHODS: We evaluated eight sibs of one family, three family

Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease-different clinical entities and comparable perinatal renal abnormalities.

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Hackl, Agnes; Mehler, Katrin; Gottschalk, Ingo; Vierzig, Anne; Eydam, Marcus; Hauke, Jan; Beck, Bodo B; Liebau, Max C; Ensenauer, Regina; Weber, Lutz T; Habbig, Sandra

2017-05-01

Differential diagnosis of prenatally detected hyperechogenic and enlarged kidneys can be challenging as there is a broad phenotypic overlap between several rare genetic and non-genetic disorders. Metabolic diseases are among the rarest underlying disorders, but they demand particular attention as their prognosis and postnatal management differ from those of other diseases. We report two cases of cystic, hyperechogenic and enlarged kidneys detected on prenatal ultrasound images, resulting in the suspected diagnosis of autosomal recessive polycystic kidney disease (ARPKD). Postnatal clinical course and work-up, however, revealed early, neonatal forms of disorders of fatty acid oxidation (DFAO) in both cases, namely, glutaric acidemia type II, based on identification of the novel, homozygous splice-site mutation c.1117-2A > G in the ETFDH gene, in one case and carnitine palmitoyltransferase II deficiency in the other case. Review of pre- and postnatal sonographic findings resulted in the identification of some important differences that might help to differentiate DFAO from ARPKD. In DFAO, kidneys are enlarged to a milder degree than in ARPKD, and the cysts are located ubiquitously, including also in the cortex and the subcapsular area. Interestingly, recent studies have pointed to a switch in metabolic homeostasis, referred to as the Warburg effect (aerobic glycolysis), as one of the underlying mechanisms of cell proliferation and cyst formation in cystic kidney disease. DFAO are characterized by the inhibition of oxidative phosphorylation, resulting in aerobic glycolysis, and thus they do resemble the Warburg effect. We therefore speculate that this inhibition might be one of the pathomechanisms of renal hyperproliferation and cyst formation in DFAO analogous to the reported findings in ARPKD. Neonatal forms of DFAO can be differentially diagnosed in neonates with cystic or hyperechogenic kidneys and necessitate immediate biochemical work-up to provide early

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

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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 ...

Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

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Tingaud-Sequeira, Angèle; Raldúa, Demetrio; Lavie, Julie

2017-01-01

ABHD12 mutations have been linked to neurodegenerative PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract), a rare, progressive, autosomal, recessive disease. Although ABHD12 is suspected to play a role in the lysophosphatidylserine and/or endocannabinoid...... and motor skill impairment. A disruption of retina architecture and retinotectal projections was observed, together with an inhibition of lens clarification and a low number of mechanosensory hair cells in the inner ear and lateral line system. The severe phenotypes in abhd12 knockdown morphants were...

Autophagy and neurodegenerative disorders

Institute of Scientific and Technical Information of China (English)

Evangelia Kesidou; Roza Lagoudaki; Olga Touloumi; Kyriaki-Nefeli Poulatsidou; Constantina Simeonidou

2013-01-01

Accumulation of aberrant proteins and inclusion bodies are hallmarks in most neurodegenerative diseases. Consequently, these aggregates within neurons lead to toxic effects, overproduction of reactive oxygen species and oxidative stress. Autophagy is a significant intracel ular mechanism that removes damaged organelles and misfolded proteins in order to maintain cel homeostasis. Excessive or insufficient autophagic activity in neurons leads to altered homeostasis and influences their survival rate, causing neurodegeneration. The review article provides an update of the role of autophagic process in representative chronic and acute neurodegenerative disorders.

Transmission of Neurodegenerative Disorders Through Blood Transfusion

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Edgren, Gustaf; Hjalgrim, Henrik; Rostgaard, Klaus

2016-01-01

BACKGROUND: The aggregation of misfolded proteins in the brain occurs in several neurodegenerative disorders. Aberrant protein aggregation is inducible in rodents and primates by intracerebral inoculation. Possible transfusion transmission of neurodegenerative diseases has important public health...... implications. OBJECTIVE: To investigate possible transfusion transmission of neurodegenerative disorders. DESIGN: Retrospective cohort study. SETTING: Nationwide registers of transfusions in Sweden and Denmark. PARTICIPANTS: 1 465 845 patients who received transfusions between 1968 and 2012. MEASUREMENTS.......9% received a transfusion from a donor diagnosed with one of the studied neurodegenerative diseases. No evidence of transmission of any of these diseases was found, regardless of approach. The hazard ratio for dementia in recipients of blood from donors with dementia versus recipients of blood from healthy...

Autosomal recessive hyper IgM syndrome associated with activation-induced cytidine deaminase gene in three Turkish siblings presented with tuberculosis lymphadenitis - Case report.

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Patiroglu, Turkan; Akar, H Haluk; van der Burg, Mirjam; Unal, Ekrem

2015-09-01

The hyper-immunoglobulin M (HIGM) syndrome is a heterogeneous group of genetic disorders characterized by recurrent infections, decreased serum levels of immunoglobulin G (IgG) and IgA, and normal/increased serum levels of IgM. Herein, we describe three Turkish siblings with HIGM syndrome who had a homozygous missense mutation (c.70C>T, p.Arg24Trp) in the activation-induced cytidine deaminase gene which results in autosomal recessive HIGM syndrome. Two of the siblings, sibling 1 and sibling 3, presented with cervical deep abscess and cervical tuberculosis lymphadenitis, respectively.

Libyan Boy with Autosomal Recessive Trait (P22-phox Defect of Chronic Granulomatous Disease

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Ilka Schulze

2006-09-01

Full Text Available Chronic granulomatous disease (CGD is a primary immune deficiency disorder of the phagocytes. In this disorder, phagocytic cells (polymorphonuclear leukocytes and monocytes cannot produce active oxygen metabolites, and therefore, cannot destroy the ingested intracellular bacteria. Clinically, patients with CGD usually have recurrent bacterial and fungal infections causing abscess and granuloma formation in the skin, lymph nodes and visceral organs.In this report, we present a boy from Libya with a rare autosomal recessive trait of CGD (defect of p22-phox who has chronic lung disease following multiple severe pneumonia attacks. The case we present suffered from bloody diarrhea since the third month of his life. He also had recurrent episodes of fever, and later, developed persistent cervical lymphadenitis and failure to gain weight. CGD is a very rare condition worldwide. It is also not recognized here in Libya, and usually not in the list of differential diagnosis for chronic pulmonary infections. We advise that pediatricians and general practitioners who treat chronic cases of lung diseases (with or without chronic diarrhea should consider primary immunodeficiency disorders in the hope that early diagnosis and treatment may prevent chronic complications especially of the respiratory tract. Furthermore, we state that, to the best of our knowledge, this is the first documented case of CGD from Libya.

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.

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Lesage, Suzanne; Drouet, Valérie; Majounie, Elisa; Deramecourt, Vincent; Jacoupy, Maxime; Nicolas, Aude; Cormier-Dequaire, Florence; Hassoun, Sidi Mohamed; Pujol, Claire; Ciura, Sorana; Erpapazoglou, Zoi; Usenko, Tatiana; Maurage, Claude-Alain; Sahbatou, Mourad; Liebau, Stefan; Ding, Jinhui; Bilgic, Basar; Emre, Murat; Erginel-Unaltuna, Nihan; Guven, Gamze; Tison, François; Tranchant, Christine; Vidailhet, Marie; Corvol, Jean-Christophe; Krack, Paul; Leutenegger, Anne-Louise; Nalls, Michael A; Hernandez, Dena G; Heutink, Peter; Gibbs, J Raphael; Hardy, John; Wood, Nicholas W; Gasser, Thomas; Durr, Alexandra; Deleuze, Jean-François; Tazir, Meriem; Destée, Alain; Lohmann, Ebba; Kabashi, Edor; Singleton, Andrew; Corti, Olga; Brice, Alexis

2016-03-03

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism

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Grønskov, Karen; Ek, Jakob; Sand, Annie

2009-01-01

PURPOSE: The study was initiated to investigate the mutation spectrum of four OCA genes and to calculate the birth prevalence in patients with autosomal recessive albinism. METHODS: Mutation analysis using dHPLC or direct DNA sequencing of TYR, OCA2, TYRP1, and MATP was performed in 62 patients....... Two mutations in one OCA gene explained oculocutaneous albinism (OCA) in 44% of the patients. Mutations in TYR were found in 26% of patients, while OCA2 and MATP caused OCA in 15% and 3%, respectively. No mutations were found in TYRP1. Of the remaining 56% of patients, 29% were heterozygous...... for a mutation in either TYR or OCA2, and 27% were without mutations in any of the four genes. Exclusive expression of the mutant allele was found in four heterozygous patients. A minimum birth prevalence of 1 in 14,000 was calculated, based on register data on 218 patients. The proportion of OCA to autosomal...

CYP7B1

DEFF Research Database (Denmark)

Roos, P; Svenstrup, K; Danielsen, E R

2014-01-01

UNLABELLED: The SPG5A subtype of Hereditary Spastic Paraplegia (HSP) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the CYP7B1 gene, which encodes a steroid cytochrome P450 7α-hydroxylase. This enzyme provides the primary metabolic route for neurosteroids. Clinica......UNLABELLED: The SPG5A subtype of Hereditary Spastic Paraplegia (HSP) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the CYP7B1 gene, which encodes a steroid cytochrome P450 7α-hydroxylase. This enzyme provides the primary metabolic route for neurosteroids.......945_947 dupGGC p.A316AA). CONCLUSION: SPG5A could be characterized as a predominantly pure HSP. MRS showing elevated mI/Cr ratio in the white matter may be indicative of SPG5A....

Autozygosity mapping of a large consanguineous Pakistani family reveals a novel non-syndromic autosomal recessive mental retardation locus on 11p15-tel

DEFF Research Database (Denmark)

Rehman, Shoaib ur; Baig, Shahid Mahmood; Eiberg, Hans

2011-01-01

done in all sampled individuals in the family. The nuclear central loop in the five generation family showed homozygosity for a 6-Mb telomeric region on 11p15, whereas all other linkage regions were excluded by calculation of logarithm of odds (LOD) for the SNP microarray data. A maximum LOD score of Z......Autosomal recessive inherited mental retardation is an extremely heterogeneous disease and accounts for approximately 25% of all non-syndromic mental retardation cases. Autozygosity mapping of a large consanguineous Pakistani family revealed a novel locus for non-syndromic autosomal recessive...

Novel compound heterozygous MYO7A mutations in Moroccan families with autosomal recessive non-syndromic hearing loss.

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Amina Bakhchane

Full Text Available The MYO7A gene encodes a protein belonging to the unconventional myosin super family. Mutations within MYO7A can lead to either non syndromic hearing loss or to the Usher syndrome type 1B (USH1B. Here, we report the results of genetic analyses performed on Moroccan families with autosomal recessive non syndromic hearing loss that identified two families with compound heterozygous MYO7A mutations. Five mutations (c.6025delG, c.6229T>A, c.3500T>A, c.5617C>T and c.4487C>A were identified in these families, the latter presenting two differently affected branches. Multiple bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. In conclusion, the absence of vestibular and retinal symptom in the affected patients suggests that these families have the isolated non-syndromic hearing loss DFNB2 (nonsyndromic autosomal recessive hearing loss presentation, instead of USH1B.

Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders

International Nuclear Information System (INIS)

Agarwal, Swati; Yadav, Anuradha; Chaturvedi, Rajnish Kumar

2017-01-01

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and they serve to be a promising therapeutic target for several neurodegenerative disorders, which includes Parkinson disease, Alzheimer's disease, Huntington disease and Amyotrophic Lateral Sclerosis. PPARs play an important role in the downregulation of mitochondrial dysfunction, proteasomal dysfunction, oxidative stress, and neuroinflammation, which are the major causes of the pathogenesis of neurodegenerative disorders. In this review, we discuss about the role of PPARs as therapeutic targets in neurodegenerative disorders. Several experimental approaches suggest potential application of PPAR agonist as well as antagonist in the treatment of neurodegenerative disorders. Several epidemiological studies found that the regular usage of PPAR activating non-steroidal anti-inflammatory drugs is effective in decreasing the progression of neurodegenerative diseases including PD and AD. We also reviewed the neuroprotective effects of PPAR agonists and associated mechanism of action in several neurodegenerative disorders both in vitro as well as in vivo animal models. - Highlights: • Peroxisome -activated receptors (PPARs) serve to be a promising therapeutic target for several neurodegenerative disorders. • PPAR agonist as well as provides neuroprotection in vitro as well as in vivo animal models of neurodegenerative disorders. • PPAR activating anti-inflammatory drugs use is effective in decreasing progression of neurodegenerative diseases.

Addressing key issues in the consanguinity-related risk of autosomal recessive disorders in consanguineous communities: lessons from a qualitative study of British Pakistanis.

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Darr, A; Small, N; Ahmad, W I U; Atkin, K; Corry, P; Modell, B

2016-01-01

Currently, there is no consensus regarding services required to help families with consanguineous marriages manage their increased genetic reproductive risk. Genetic services for communities with a preference for consanguineous marriage in the UK remain patchy, often poor. Receiving two disparate explanations of the cause of recessive disorders (cousin marriage and recessive inheritance) leads to confusion among families. Further, the realisation that couples in non-consanguineous relationships have affected children leads to mistrust of professional advice. British Pakistani families at-risk for recessive disorders lack an understanding of recessive disorders and their inheritance. Such an understanding is empowering and can be shared within the extended family to enable informed choice. In a three-site qualitative study of British Pakistanis, we explored family and health professional perspectives on recessively inherited conditions. Our findings suggest, firstly, that family networks hold strong potential for cascading genetic information, making the adoption of a family-centred approach an efficient strategy for this community. However, this is dependent on provision of high-quality and timely information from health care providers. Secondly, families' experience was of ill-coordinated and time-starved services, with few having access to specialist provision from Regional Genetics Services; these perspectives were consistent with health professionals' views of services. Thirdly, we confirm previous findings that genetic information is difficult to communicate and comprehend, further complicated by the need to communicate the relationship between cousin marriage and recessive disorders. A communication tool we developed and piloted is described and offered as a useful resource for communicating complex genetic information.

Aquatherapy for neurodegenerative disorders.

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Plecash, Alyson R; Leavitt, Blair R

2014-01-01

Aquatherapy is used for rehabilitation and exercise; water provides a challenging, yet safe exercise environment for many special populations. We have reviewed the use of aquatherapy programs in four neurodegenerative disorders: Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. Results support the use of aquatherapy in Parkinson's disease and multiple sclerosis, however further evidence is required to make specific recommendations in all of the aforementioned disorders.

SNP Analysis and Whole Exome Sequencing: Their Application in the Analysis of a Consanguineous Pedigree Segregating Ataxia

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Sarah L. Nickerson

2015-10-01

Full Text Available Autosomal recessive cerebellar ataxia encompasses a large and heterogeneous group of neurodegenerative disorders. We employed single nucleotide polymorphism (SNP analysis and whole exome sequencing to investigate a consanguineous Maori pedigree segregating ataxia. We identified a novel mutation in exon 10 of the SACS gene: c.7962T>G p.(Tyr2654*, establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS. Our findings expand both the genetic and phenotypic spectrum of this rare disorder, and highlight the value of high-density SNP analysis and whole exome sequencing as powerful and cost-effective tools in the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias.

Implementing Non-Invasive Prenatal Diagnosis (NIPD) in a National Health Service Laboratory; From Dominant to Recessive Disorders.

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Drury, Suzanne; Mason, Sarah; McKay, Fiona; Lo, Kitty; Boustred, Christopher; Jenkins, Lucy; Chitty, Lyn S

2016-01-01

Our UK National Health Service regional genetics laboratory offers NIPD for autosomal dominant and de novo conditions (achondroplasia, thanataphoric dysplasia, Apert syndrome), paternal mutation exclusion for cystic fibrosis and a range of bespoke tests. NIPD avoids the risks associated with invasive testing, making prenatal diagnosis more accessible to families at high genetic risk. However, the challenge remains in offering definitive diagnosis for autosomal recessive diseases, which is complicated by the predominance of the maternal mutant allele in the cell-free DNA sample and thus requires a variety of different approaches. Validation and diagnostic implementation for NIPD of congenital adrenal hyperplasia (CAH) is further complicated by presence of a pseudogene that requires a different approach. We have used an assay targeting approximately 6700 heterozygous SNPs around the CAH gene (CYP21A2) to construct the high-risk parental haplotypes and tested this approach in five cases, showing that inheritance of the parental alleles can be correctly identified using NIPD. We are evaluating various measures of the fetal fraction to help determine inheritance of parental mutations. We are currently exploring the utility of an NIPD multi-disorder panel for autosomal recessive disease, to make testing more widely applicable to families with a variety of serious genetic conditions.

Additional case of Marden-Walker syndrome: support for the autosomal-recessive inheritance adn refinement of phenotype in a surviving patient.

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Orrico, A; Galli, L; Zappella, M; Orsi, A; Hayek, G

2001-02-01

In this report, we present a 14-year-old girl, born to consanguineous parents, who presented with severe mental retardation, hypotonia, short stature, and congenital joint contractures. The craniofacial features were scaphocephaly, thin/long and immobile face, marked hypoplasia of the midface, temporal narrowness, blepharophimosis, palpebral ptosis, and strabismus. The combination of such a distinctive craniofacial appearance and psychomotor retardation allows us to recognize a new case of the Marden-Walker syndrome. Our patient represents one of the rare cases in which consanguineous mating supports the autosomal-recessive pattern of inheritance of this condition. Furthermore, through refining the phenotype of a surviving patient, this report may contribute to a better recognition of this disorder in older affected children.

Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3.

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Klebe, Stephan; Azzedine, Hamid; Durr, Alexandra; Bastien, Patrick; Bouslam, Naima; Elleuch, Nizar; Forlani, Sylvie; Charon, Celine; Koenig, Michel; Melki, Judith; Brice, Alexis; Stevanin, Giovanni

2006-06-01

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity in the lower limbs. Twenty-nine different loci (SPG) have been mapped so far, and 11 responsible genes have been identified. Clinically, one distinguishes between pure and complex HSP forms which are variably associated with numerous combinations of neurological and extra-neurological signs. Less is known about autosomal recessive forms (ARHSP) since the mapped loci have been identified often in single families and account for only a small percentage of patients. We report a new ARHSP locus (SPG30) on chromosome 2q37.3 in a consanguineous family with seven unaffected and four affected members of Algerian origin living in Eastern France with a significant multipoint lod score of 3.8. Ten other families from France (n = 4), Tunisia (n = 2), Algeria (n = 3) and the Czech Republic (n = 1) were not linked to the newly identified locus thus demonstrating further genetic heterogeneity. The phenotype of the linked family consists of spastic paraparesis and peripheral neuropathy associated with slight cerebellar signs confirmed by cerebellar atrophy on one CT scan.

Mismanagement of Wilson's disease as psychotic disorder.

Science.gov (United States)

Bidaki, Reza; Zarei, Mina; Mirhosseini, S M Mahdy; Moghadami, Samar; Hejrati, Maral; Kohnavard, Marjan; Shariati, Behnam

2012-01-01

Wilson's disease (WD) or hepatolenticular degeneration is an inherited neurodegenerative disorder of copper metabolism (autosomal recessive, chromosome13). Psychiatric disorders in WD include dementia, characterized by mental slowness, poor concentration, and memory impairment. Symptoms may progress rapidly, especially in younger patients, but are more often gradual in development with periods of remission and exacerbation. Delusional disorder and schizophrenia-like psychosis are rare forms of psychiatric presentation. In this report, the patient with WD presented by psychosis symptoms and treated mistaken as schizophrenia for almost ten years. Although he has treated with antipsychotics, he had periods of remissions and relapses and never was symptoms free. Since psychosis can be the manifestation of medical diseases such as WD, overall view of these patients is necessary and medical diseases should be considered as a differential diagnosis.

Molecular characterization of WFS1 in patients with Wolfram syndrome

NARCIS (Netherlands)

Van den Ouweland, JMW; Cryns, K; Pennings, RJE; Walraven, [No Value; Janssen, GMC; Maassen, JA; Veldhuijzen, BFE; Arntzenius, AB; Lindhout, D; Cremers, CWRJ; Van Camp, G; Dikkeschei, LD

Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

Processing of mutant N-acetyl-alpha-glucosaminidase in mucopolysaccharidosis type IIIB fibroblasts cultured at low temperature

NARCIS (Netherlands)

Meijer, O. L. M.; te Brinke, H.; Ofman, R.; IJlst, L.; Wijburg, F. A.; van Vlies, N.

2017-01-01

Background: The autosomal recessive, neurodegenerative disorder mucopolysaccharidosis type IIIB (MPSIIIB) is caused by a deficiency of the lysosomal enzyme N-acetyl-alpha-glucosaminidase (NAGLU), resulting in accumulation of heparan sulfate. The disease spectrum comprises a severe, rapidly

Molecular characterization of WFS1 in patients with Wolfram syndrome.

NARCIS (Netherlands)

Ouweland, J.M.W. van den; Cryns, K.; Pennings, R.J.E.; Walraven, I.; Janssen, G.M.; Maassen, J.A.; Veldhuijzen, B.F.; Arntzenius, A.B.; Lindhout, D.; Cremers, C.W.R.J.; Camp, G. van; Dikkeschei, L.D.

2003-01-01

Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

A Novel Homozygous Missense Mutation in HOXC13 Leads to Autosomal Recessive Pure Hair and Nail Ectodermal Dysplasia.

Science.gov (United States)

Li, Xiaoxiao; Orseth, Meredith Lee; Smith, J Michael; Brehm, Mary Abigail; Agim, Nnenna Gebechi; Glass, Donald Alexander

2017-03-01

Pure hair and nail ectodermal dysplasia (PHNED) is a rare disorder that presents with hypotrichosis and nail dystrophy while sparing other ectodermal structures such as teeth and sweat glands. We describe a homozygous novel missense mutation in the HOXC13 gene that resulted in autosomal recessive PHNED in a Hispanic child. The mutation c.812A>G (p.Gln271Arg) is located within the DNA-binding domain of the HOXC13 gene, cosegregates within the family, and is predicted to be maximally damaging. This is the first reported case of a missense HOXC13 mutation resulting in PHNED and the first reported case of PHNED identified in a North American family. Our findings illustrate the critical role of HOXC13 in human hair and nail development. © 2017 Wiley Periodicals, Inc.

A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis.

Science.gov (United States)

Bordbar, Mohammad Reza; Modarresi, Farzaneh; Farazi Fard, Mohammad Ali; Dastsooz, Hassan; Shakib Azad, Nader; Faghihi, Mohammad Ali

2017-05-03

Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis. Therefore, genes involved in these steps play important roles in the pathogenesis of HLH disease which include PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2). Here, we report a novel missense mutation in an 8-year-old boy suffered from hepatosplenomegaly, hepatitis, epilepsy and pancytopenia. The patient was born to a first-cousin parents with no previous documented disease in his parents. To identify mutated gene in the proband, Whole Exome Sequencing (WES) utilizing next generation sequencing was used on an Illumina HiSeq 2000 platform on DNA sample from the patient. Results showed a novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120 T > G, p.W374G) in the patient and then using Sanger sequencing it was confirmed in the proband and his parents. Since his parents were heterozygous for the identified mutation, autosomal recessive pattern of inheritance was confirmed in the family. Our study identified a rare new pathogenic missense mutation in PRF1 gene in patient with HLH disease and it is the first report of mutation in PRF1 in Iranian patients with this disease.

Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.

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Cali E Willet

Full Text Available Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant. Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.

Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.

Science.gov (United States)

Willet, Cali E; Makara, Mariano; Reppas, George; Tsoukalas, George; Malik, Richard; Haase, Bianca; Wade, Claire M

2015-01-01

Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant). Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.

Localization of A Novel Autosomal Recessive Non-Syndromic Hearing Impairment Locus (DFNB38) to 6q26–q27 in a Consanguineous Kindred from Pakistan

OpenAIRE

Ansar, Muhammad; Ramzan, Mohammad; Pham, Thanh L.; Yan, Kai; Jamal, Syed Muhammad; Haque, Sayedul; Ahmad, Wasim; Leal, Suzanne M.

2003-01-01

For autosomal recessive nonsyndromic hearing impairment over 30 loci have been mapped and 19 genes have been identified. DFNB38, a novel locus for autosomal recessive nonsyndromic hearing impairment, was localized in a consanguineous Pakistani kindred to 6q26–q27. The affected family members present with profound prelingual sensorineural hearing impairment and use sign language for communications. Linkage was established to microsatellite markers located on chromosome 6q26–q27 (Multipoint lod...

The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice

Science.gov (United States)

van Huet, Ramon A. C.; Pierrache, Laurence H.M.; Meester-Smoor, Magda A.; Klaver, Caroline C.W.; van den Born, L. Ingeborgh; Hoyng, Carel B.; de Wijs, Ilse J.; Collin, Rob W. J.; Hoefsloot, Lies H.

2015-01-01

Purpose To determine the efficacy of multiple versions of a commercially available arrayed primer extension (APEX) microarray chip for autosomal recessive retinitis pigmentosa (arRP). Methods We included 250 probands suspected of arRP who were genetically analyzed with the APEX microarray between January 2008 and November 2013. The mode of inheritance had to be autosomal recessive according to the pedigree (including isolated cases). If the microarray identified a heterozygous mutation, we performed Sanger sequencing of exons and exon–intron boundaries of that specific gene. The efficacy of this microarray chip with the additional Sanger sequencing approach was determined by the percentage of patients that received a molecular diagnosis. We also collected data from genetic tests other than the APEX analysis for arRP to provide a detailed description of the molecular diagnoses in our study cohort. Results The APEX microarray chip for arRP identified the molecular diagnosis in 21 (8.5%) of the patients in our cohort. Additional Sanger sequencing yielded a second mutation in 17 patients (6.8%), thereby establishing the molecular diagnosis. In total, 38 patients (15.2%) received a molecular diagnosis after analysis using the microarray and additional Sanger sequencing approach. Further genetic analyses after a negative result of the arRP microarray (n = 107) resulted in a molecular diagnosis of arRP (n = 23), autosomal dominant RP (n = 5), X-linked RP (n = 2), and choroideremia (n = 1). Conclusions The efficacy of the commercially available APEX microarray chips for arRP appears to be low, most likely caused by the limitations of this technique and the genetic and allelic heterogeneity of RP. Diagnostic yields up to 40% have been reported for next-generation sequencing (NGS) techniques that, as expected, thereby outperform targeted APEX analysis. PMID:25999674

Pregnancy in autosomal recessive polycystic kidney disease.

Science.gov (United States)

Banks, Nicole; Bryant, Joy; Fischer, Roxanne; Huizing, Marjan; Gahl, William A; Gunay-Aygun, Meral

2015-03-01

Autosomal recessive polycystic kidney disease (ARPKD) is the most common childhood-onset ciliopathy. As treatments improve, more women are reaching reproductive age, but little is known about ARPKD and pregnancy. In our ongoing study on ARPKD and other ciliopathies, 12 females over 18 years of age were identified and systematically evaluated. Six had children; four carried pregnancies and delivered, one used assisted reproductive technology and had a surrogate carry the pregnancy, and one adopted. We report the outcomes of four pregnancies with live birth deliveries and two women who chose alternate family building options. Patient one was diagnosed at 6 months, and at age 21 had a pregnancy complicated by transient worsening of renal function (creatinine increase from 1.15 to 1.78 mg/dL). Patient two was diagnosed with ARPKD at age seven and had an uncomplicated pregnancy at age 23. Patient three was diagnosed incidentally with ARPKD at age 23, 3 months after completion of an uncomplicated pregnancy. Patient four who had an uncomplicated pregnancy at age 33 was diagnosed with ARPKD at age 46. Women with ARPKD face reproductive decisions largely bereft of information about the pregnancies of other ARPKD patients. We report four cases of pregnancy and ARPKD to expand current knowledge and encourage further research.

A Novel Mutation in the Transglutaminase-1 Gene in an Autosomal Recessive Congenital Ichthyosis Patient

Directory of Open Access Journals (Sweden)

D. Vaigundan

2014-01-01

Full Text Available Structure-function implication on a novel homozygous Trp250/Gly mutation of transglutaminase-1 (TGM1 observed in a patient of autosomal recessive congenital ichthyosis is invoked from a bioinformatics analysis. Structural consequences of this mutation are hypothesized in comparison to homologous enzyme human factor XIIIA accepted as valid in similar structural analysis and are projected as guidelines for future studies at an experimental level on TGM1 thus mutated.

Macroepiphyseal dysplasia with symptomatic osteoporosis, wrinkled skin, and aged appearance: A presumed autosomal recessive condition

Energy Technology Data Exchange (ETDEWEB)

McAlister, W.H.; Coe, J.D.; Whyte, M.P.

1986-01-01

We report our detailed investigation of a 7-1/2-year-old girl with short stature, aged appearance, decreased subcutaneous fat and muscle mass, dry coarse hair, foot deformities, macroepiphyses with prominent but lax joints, and osteoporosis with recurrent fractures who is the offspring of first cousins. This constellation of abnormalities differs from previously reported cases where macroepiphyses were a prominent finding. Our patient appears, therefore, to have a new, autosomal recessively inherited, syndrome.

Macroepiphyseal dysplasia with symptomatic osteoporosis, wrinkled skin, and aged appearance: A presumed autosomal recessive condition

International Nuclear Information System (INIS)

McAlister, W.H.; Coe, J.D.; Whyte, M.P.; Shriners Hospital for Crippled Children, St. Louis, MO

1986-01-01

We report our detailed investigation of a 7-1/2-year-old girl with short stature, aged appearance, decreased subcutaneous fat and muscle mass, dry coarse hair, foot deformities, macroepiphyses with prominent but lax joints, and osteoporosis with recurrent fractures who is the offspring of first cousins. This constellation of abnormalities differs from previously reported cases where macroepiphyses were a prominent finding. Our patient appears, therefore, to have a new, autosomal recessively inherited, syndrome. (orig.)

Quantification of free sialic acid in urine by HPLC-electrospray tandem mass spectrometry: A tool for the diagnosis of sialic acid storage disease

NARCIS (Netherlands)

Valianpour, Fredoen; Abeling, Nicolaas G. G. M.; Duran, Marinus; Huijmans, Jan G. M.; Kulik, Willem

2004-01-01

Background: Sialic acid storage diseases (SSDs) are severe autosomal recessive neurodegenerative disorders caused by a transport defect across the lysosomal membrane, which leads to accumulation of sialic acid in tissues, fibroblasts, and urine. Defective free sialic acid transport can be

Health risks for ataxia-telangiectasia mutated heterozygotes : a systematic review, meta-analysis and evidence-based guideline

NARCIS (Netherlands)

van Os, N J H; Roeleveld, N; Weemaes, C M R; Jongmans, M C J; Janssens, G O; Taylor, A M R; Hoogerbrugge, N; Willemsen, Michel A A P

Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers

A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia

DEFF Research Database (Denmark)

Roos, L; Fang, M; Dali, C

2013-01-01

to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where...... three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented...... with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations....

Novel mutation in TSPAN12 leads to autosomal recessive inheritance of congenital vitreoretinal disease with intra-familial phenotypic variability.

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Gal, Moran; Levanon, Erez Y; Hujeirat, Yasir; Khayat, Morad; Pe'er, Jacob; Shalev, Stavit

2014-12-01

Developmental malformations of the vitreoretinal vasculature are a heterogeneous group of conditions with various modes of inheritance, and include familial exudative vitreoretinopathy (FEVR), persistent fetal vasculature (PFV), and Norrie disease. We investigated a large consanguineous kindred with multiple affected individuals exhibiting variable phenotypes of abnormal vitreoretinal vasculature, consistent with the three above-mentioned conditions and compatible with autosomal recessive inheritance. Exome sequencing identified a novel c.542G > T (p.C181F) apparently mutation in the TSPAN12 gene that segregated with the ocular disease in the family. The TSPAN12 gene was previously reported to cause dominant and recessive FEVR, but has not yet been associated with other vitreoretinal manifestations. The intra-familial clinical variability caused by a single mutation in the TSPAN12 gene underscores the complicated phenotype-genotype correlation of mutations in this gene, and suggests that there are additional genetic and environmental factors involved in the complex process of ocular vascularization during embryonic development. Our study supports considering PFV, FEVR, and Norrie disease a spectrum of disorders, with clinical and genetic overlap, caused by mutations in distinct genes acting in the Norrin/β-catenin signaling pathway. © 2014 Wiley Periodicals, Inc.

The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation.

Science.gov (United States)

Basel-Vanagaite, L; Attia, R; Yahav, M; Ferland, R J; Anteki, L; Walsh, C A; Olender, T; Straussberg, R; Magal, N; Taub, E; Drasinover, V; Alkelai, A; Bercovich, D; Rechavi, G; Simon, A J; Shohat, M

2006-03-01

The molecular basis of autosomal recessive non-syndromic mental retardation (NSMR) is poorly understood, mostly owing to heterogeneity and absence of clinical criteria for grouping families for linkage analysis. Only two autosomal genes, the PRSS12 gene on chromosome 4q26 and the CRBN on chromosome 3p26, have been shown to cause autosomal recessive NSMR, each gene in only one family. To identify the gene causing autosomal recessive NSMR on chromosome 19p13.12. The candidate region established by homozygosity mapping was narrowed down from 2.4 Mb to 0.9 Mb on chromosome 19p13.12. A protein truncating mutation was identified in the gene CC2D1A in nine consanguineous families with severe autosomal recessive NSMR. The absence of the wild type protein in the lymphoblastoid cells of the patients was confirmed. CC2D1A is a member of a previously uncharacterised gene family that carries two conserved motifs, a C2 domain and a DM14 domain. The C2 domain is found in proteins which function in calcium dependent phospholipid binding; the DM14 domain is unique to the CC2D1A protein family and its role is unknown. CC2D1A is a putative signal transducer participating in positive regulation of I-kappaB kinase/NFkappaB cascade. Expression of CC2D1A mRNA was shown in the embryonic ventricular zone and developing cortical plate in staged mouse embryos, persisting into adulthood, with highest expression in the cerebral cortex and hippocampus. A previously unknown signal transduction pathway is important in human cognitive development.

A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability

OpenAIRE

Larti, Farzaneh; Kahrizi, Kimia; Musante, Luciana; Hu, Hao; Papari, Elahe; Fattahi, Zohreh; Bazazzadegan, Niloofar; Liu, Zhe; Banan, Mehdi; Garshasbi, Masoud; Wienker, Thomas F; Hilger Ropers, H; Galjart, Niels; Najmabadi, Hossein

2015-01-01

In the context of a comprehensive research project, investigating novel autosomal recessive intellectual disability (ARID) genes, linkage analysis based on autozygosity mapping helped identify an intellectual disability locus on Chr.12q24, in an Iranian family (LOD score=3.7). Next-generation sequencing (NGS) following exon enrichment in this novel interval, detected a nonsense mutation (p.Q1010*) in the CLIP1 gene. CLIP1 encodes a member of microtubule (MT) plus-end tracking proteins, which ...

Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

NARCIS (Netherlands)

Klevering, B.J.; Ijzer, S.; Rohrschneider, K.; Zonneveld-Vrieling, M.N.; Allikmets, R.; Born, L.I. van den; Maugeri, A.; Hoyng, C.B.; Cremers, F.P.M.

2004-01-01

Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or

Malformations among 289,365 Births Attributed to Mutations with Autosomal Dominant and Recessive and X-Linked Inheritance.

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Toufaily, M Hassan; Westgate, Marie-Noel; Nasri, Hanah; Holmes, Lewis B

2018-01-01

The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders. The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well. One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents. It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts.

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Bushra Irum

Full Text Available To identify the molecular basis of non-syndromic autosomal recessive congenital cataracts (arCC in a consanguineous family.All family members participating in the study received a comprehensive ophthalmic examination to determine their ocular phenotype and contributed a blood sample, from which genomic DNA was extracted. Available medical records and interviews with the family were used to compile the medical history of the family. The symptomatic history of the individuals exhibiting cataracts was confirmed by slit-lamp biomicroscopy. A genome-wide linkage analysis was performed to localize the disease interval. The candidate gene, LIM2 (lens intrinsic membrane protein 2, was sequenced bi-directionally to identify the disease-causing mutation. The physical changes caused by the mutation were analyzed in silico through homology modeling, mutation and bioinformatic algorithms, and evolutionary conservation databases. The physiological importance of LIM2 to ocular development was assessed in vivo by real-time expression analysis of Lim2 in a mouse model.Ophthalmic examination confirmed the diagnosis of nuclear cataracts in the affected members of the family; the inheritance pattern and cataract development in early infancy indicated arCC. Genome-wide linkage analysis localized the critical interval to chromosome 19q with a two-point logarithm of odds (LOD score of 3.25. Bidirectional sequencing identified a novel missense mutation, c.233G>A (p.G78D in LIM2. This mutation segregated with the disease phenotype and was absent in 192 ethnically matched control chromosomes. In silico analysis predicted lower hydropathicity and hydrophobicity but higher polarity of the mutant LIM2-encoded protein (MP19 compared to the wild-type. Moreover, these analyses predicted that the mutation would disrupt the secondary structure of a transmembrane domain of MP19. The expression of Lim2, which was detected in the mouse lens as early as embryonic day 15 (E15

Congenital non-syndromal autosomal recessive deafness in Bengkala, an isolated Balinese village.

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Winata, S; Arhya, I N; Moeljopawiro, S; Hinnant, J T; Liang, Y; Friedman, T B; Asher, J H

1995-01-01

Bengkala is an Indonesian village located on the north shore of Bali that has existed for over 700 years. Currently, 2.2% of the 2185 people in this village have profound congenital deafness. In response to the high incidence of deafness, the people of Bengkala have developed a village specific sign language which is used by many of the hearing and deaf people. Deafness in Bengkala is congenital, sensorineural, non-syndromal, and caused by a fully penetrant autosomal recessive mutation at the DFNB3 locus. The frequency of the DFNB3 mutation is estimated to be 9.4% among hearing people who have a 17.2% chance of being heterozygous for DFNB3. PMID:7616538

Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

Science.gov (United States)

Klevering, B Jeroen; Blankenagel, Anita; Maugeri, Alessandra; Cremers, Frans P M; Hoyng, Carel B; Rohrschneider, Klaus

2002-06-01

To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were reviewed after molecular analysis revealed mutations in the ABCA4 gene. In two of the patients both the photopic and scotopic electroretinogram were nonrecordable. In the remainder, the photopic cone b-wave amplitudes appeared to be more seriously affected than the scotopic rod b-wave amplitudes. Although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Fundoscopy revealed evidence of early-onset maculopathy, sometimes accompanied by involvement of the retinal periphery in the later stages of the disease. Mutations in the ABCA4 gene are the pathologic cause of the CRD-like dystrophy in these patients, and the resultant clinical pictures are complex and heterogeneous. Given this wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful.

The Presence of Periodic Limb Movement Disorder in a Patient with Diabetes Mellitus and Optic Atrophy (Wolfram Syndrome

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Bo Seong Kwon

2014-12-01

Full Text Available Wolfram syndrome (WFS is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD, together known as DIDMOAD. This syndrome is a rare autosomal recessive neurodegenerative disorder and typically begins wtih insulin-dependent diabetes mellitus. Periodic limb movement disorder (PLMD is characterized by periodic episodes of repetitive, highly stereotyped, limb movement during sleep, which results in disturbed sleep. Its pathophysiology is unclear. It is associated with many conditions, but we were unable to find a previous report regarding WFS accompanied by PLMD. We therefore report, for the first time, about a patient with WFS presenting with PLMD and discuss its pathomechanism with a literature review.

Novel compound heterozygous mutations in MYO7A gene associated with autosomal recessive sensorineural hearing loss in a Chinese family.

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Ma, Yalin; Xiao, Yun; Zhang, Fengguo; Han, Yuechen; Li, Jianfeng; Xu, Lei; Bai, Xiaohui; Wang, Haibo

2016-04-01

Mutations in MYO7A gene have been reported to be associated with Usher Syndrome type 1B (USH1B) and nonsyndromic hearing loss (DFNB2, DFNA11). Most mutations in MYO7A gene caused USH1B, whereas only a few reported mutations led to DFNB2 and DFNA11. The current study was designed to investigate the mutations among a Chinese family with autosomal recessive hearing loss. In this study, we present the clinical, genetic and molecular characteristics of a Chinese family. Targeted capture of 127 known deafness genes and next-generation sequencing were employed to study the genetic causes of two siblings in the Chinese family. Sanger sequencing was employed to examine those variant mutations in the members of this family and other ethnicity-matched controls. We identified the novel compound heterozygous mutant alleles of MYO7A gene: a novel missense mutation c.3671C>A (p.A1224D) and a reported insert mutation c.390_391insC (p.P131PfsX9). Variants were further confirmed by Sanger sequencing. These two compound heterozygous variants were co-segregated with autosomal recessive hearing loss phenotype. The gene mutation analysis and protein sequence alignment further supported that the novel compound heterozygous mutations were pathogenic. The novel compound heterozygous mutations (c.3671C>A and c.390_391insC) in MYO7A gene identified in this study were responsible for the autosomal recessive sensorineural hearing loss of this Chinese family. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non‐syndromic mental retardation

Science.gov (United States)

Basel‐Vanagaite, L; Attia, R; Yahav, M; Ferland, R J; Anteki, L; Walsh, C A; Olender, T; Straussberg, R; Magal, N; Taub, E; Drasinover, V; Alkelai, A; Bercovich, D; Rechavi, G; Simon, A J; Shohat, M

2006-01-01

Background The molecular basis of autosomal recessive non‐syndromic mental retardation (NSMR) is poorly understood, mostly owing to heterogeneity and absence of clinical criteria for grouping families for linkage analysis. Only two autosomal genes, the PRSS12 gene on chromosome 4q26 and the CRBN on chromosome 3p26, have been shown to cause autosomal recessive NSMR, each gene in only one family. Objective To identify the gene causing autosomal recessive NSMR on chromosome 19p13.12. Results The candidate region established by homozygosity mapping was narrowed down from 2.4 Mb to 0.9 Mb on chromosome 19p13.12. A protein truncating mutation was identified in the gene CC2D1A in nine consanguineous families with severe autosomal recessive NSMR. The absence of the wild type protein in the lymphoblastoid cells of the patients was confirmed. CC2D1A is a member of a previously uncharacterised gene family that carries two conserved motifs, a C2 domain and a DM14 domain. The C2 domain is found in proteins which function in calcium dependent phospholipid binding; the DM14 domain is unique to the CC2D1A protein family and its role is unknown. CC2D1A is a putative signal transducer participating in positive regulation of I‐κB kinase/NFκB cascade. Expression of CC2D1A mRNA was shown in the embryonic ventricular zone and developing cortical plate in staged mouse embryos, persisting into adulthood, with highest expression in the cerebral cortex and hippocampus. Conclusions A previously unknown signal transduction pathway is important in human cognitive development. PMID:16033914

Interdependence of laforin and malin proteins for their stability and ...

Indian Academy of Sciences (India)

https://www.ias.ac.in/article/fulltext/jbsc/040/05/0863-0871. Keywords. Epilepsy; locus heterogeneity; post-translational modification; protein-protein interaction. Abstract. Lafora disease (LD), an autosomal recessive and fatal form of neurodegenerative disorder, is characterized by the presence of polyglucosan inclusions in ...

A Challenging Case of Hepatoblastoma Concomitant with Autosomal Recessive Polycystic Kidney Disease and Caroli Syndrome—Review of the Literature

Directory of Open Access Journals (Sweden)

Nevil Kadakia

2017-06-01

Full Text Available We report a rare case of an 18-month-old female with autosomal recessive polycystic kidney disease, Caroli syndrome, and pure fetal type hepatoblastoma. The liver tumor was surgically resected with no chemotherapy given. Now 9 years post resection she demonstrates no local or distant recurrence and stable renal function.

Interaction between -Synuclein and Other Proteins in Neurodegenerative Disorders

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Kurt A. Jellinger

2011-01-01

Full Text Available Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.

Mutations in DZIP1L, which encodes a ciliary transition zone protein, cause autosomal recessive polycystic kidney disease

Science.gov (United States)

Lu, Hao; Galeano, Maria C. Rondón; Ott, Elisabeth; Kaeslin, Geraldine; Kausalya, P. Jaya; Kramer, Carina; Ortiz-Brüchle, Nadina; Hilger, Nadescha; Metzis, Vicki; Hiersche, Milan; Tay, Shang Yew; Tunningley, Robert; Vij, Shubha; Courtney, Andrew D.; Whittle, Belinda; Wühl, Elke; Vester, Udo; Hartleben, Björn; Neuber, Steffen; Frank, Valeska; Little, Melissa H.; Epting, Daniel; Papathanasiou, Peter; Perkins, Andrew C.; Wright, Graham D.; Hunziker, Walter; Gee, Heon Yung; Otto, Edgar A.; Zerres, Klaus; Hildebrandt, Friedhelm; Roy, Sudipto; Wicking, Carol; Bergmann, Carsten

2017-01-01

Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in the DAZ interacting protein 1-like (DZIP1L) gene in patients with ARPKD, findings we have further validated by loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and at the distal end of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. Consistent with a defect in the diffusion barrier, we found that the ciliary membrane translocation of the PKD proteins, polycystin-1 and −2, is compromised in DZIP1L mutant cells. Together, these data provide the first conclusive evidence that ARPKD is not a homogeneous disorder, and establishes DZIP1L as a second gene involved in its pathogenesis. PMID:28530676

Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease.

Science.gov (United States)

Lu, Hao; Galeano, Maria C Rondón; Ott, Elisabeth; Kaeslin, Geraldine; Kausalya, P Jaya; Kramer, Carina; Ortiz-Brüchle, Nadina; Hilger, Nadescha; Metzis, Vicki; Hiersche, Milan; Tay, Shang Yew; Tunningley, Robert; Vij, Shubha; Courtney, Andrew D; Whittle, Belinda; Wühl, Elke; Vester, Udo; Hartleben, Björn; Neuber, Steffen; Frank, Valeska; Little, Melissa H; Epting, Daniel; Papathanasiou, Peter; Perkins, Andrew C; Wright, Graham D; Hunziker, Walter; Gee, Heon Yung; Otto, Edgar A; Zerres, Klaus; Hildebrandt, Friedhelm; Roy, Sudipto; Wicking, Carol; Bergmann, Carsten

2017-07-01

Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.

The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

Directory of Open Access Journals (Sweden)

Yajin Liao

2017-02-01

Full Text Available The mitochondrial calcium uniporter (MCU—a calcium uniporter on the inner membrane of mitochondria—controls the mitochondrial calcium uptake in normal and abnormal situations. Mitochondrial calcium is essential for the production of adenosine triphosphate (ATP; however, excessive calcium will induce mitochondrial dysfunction. Calcium homeostasis disruption and mitochondrial dysfunction is observed in many neurodegenerative disorders. However, the role and regulatory mechanism of the MCU in the development of these diseases are obscure. In this review, we summarize the role of the MCU in controlling oxidative stress-elevated mitochondrial calcium and its function in neurodegenerative disorders. Inhibition of the MCU signaling pathway might be a new target for the treatment of neurodegenerative disorders.

A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa

NARCIS (Netherlands)

Van Schil, Kristof; Klevering, B. Jeroen; Leroy, Bart P.; Pott, Jan Willem R.; Bandah-Rozenfeld, Dikla; Zonneveld-Vrieling, Marijke N.; Sharon, Dror; den Hollander, Anneke I.; Cremers, Frans P. M.; De Baere, Elfride; Collin, Rob W. J.; van den Born, L. Ingeborgh

PURPOSE. To identify mutations in FAM161A underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch and Belgian populations and to investigate whether common FAM161A-associated phenotypic features could be identified. METHODS. Homozygosity mapping, amplification-refractory mutation

Fine mapping of the autosomal recessive retinitis pigmentosa locus (RP12) on chromosome 1q; exclusion of the phosducin gene (PDC)

NARCIS (Netherlands)

van Soest, S.; te Nijenhuis, S.; van den Born, L. I.; Bleeker-Wagemakers, E. M.; Sharp, E.; Sandkuijl, L. A.; Westerveld, A.; Bergen, A. A.

1996-01-01

In a previous study on a large pedigree from a genetically isolated population in the Netherlands, we localized a gene for autosomal recessive retinitis pigmentosa with paraarteriolar preservation of the retinal pigment epithelium (PPRPE) on the long arm of chromosome 1. In this study, we present an

Molecular diagnostic in two families affected with Autosomic Recessive Pigmentary Retinitis

International Nuclear Information System (INIS)

Leal Esquivel, A.

1996-01-01

This study included two Costa Rican families with members affected by Recessive Pigmentary Autosomic Retinitis (RPAR). The first family (C1) from the province of San Jose, has 10 alive affected members, and 14 obligatory carriers. They present an Early Appearance Degeneration, RPAR tipe1 (cane-cone). The author used polymorphic markers (STRPs) to discard some related regions, with the RP in the literature. He also used the Linkage program, for the analysis of ligaments. The second family (P1), proceeding from Acosta (situated in the province of Alajuela), has 13 alive affected members and 23 obligatory carriers and they present numerous consanguineous unions. This case is a RPAR with Early Appearance (Night Blindness, fat ERG), but with a shower degeneration. The author concludes that, with studies such as this one, there will be a capacity to offer RP molecular diagnostic, and also advance in its knowledge and treatment. (S. Grainger)

Molecular diagnostics of neurodegenerative disorders

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Megha eAgrawal

2015-09-01

Full Text Available Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer’s and Parkinson’s disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease, and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders.

Molecular diagnostics of neurodegenerative disorders.

Science.gov (United States)

Agrawal, Megha; Biswas, Abhijit

2015-01-01

Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer's and Parkinson's disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders.

A novel c.5308_5311delGAGA mutation in Senataxin in a Cypriot family with an autosomal recessive cerebellar ataxia

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Zamba-Papanicolaou Eleni

2008-04-01

Full Text Available Abstract Background Senataxin (chromosome 9q34 was recently identified as the causative gene for an autosomal recessive form of Ataxia (ARCA, termed as Ataxia with Oculomotor Apraxia, type 2 (AOA2 and characterized by generalized incoordination, cerebellar atrophy, peripheral neuropathy, "oculomotor apraxia" and increased alpha-fetoprotein (AFP. Here, we report a novel Senataxin mutation in a Cypriot ARCA family. Methods We studied several Cypriot autosomal recessive cerebellar ataxia (ARCA families for linkage to known ARCA gene loci. We linked one family (909 to the SETX locus on chromosome 9q34 and screened the proband for mutations by direct sequencing. Results Sequence analysis revealed a novel c.5308_5311delGAGA mutation in exon 11 of the SETX gene. The mutation has not been detected in 204 control chromosomes from the Cypriot population, the remaining Cypriot ARCA families and 37 Cypriot sporadic cerebellar ataxia patients. Conclusion We identified a novel SETX homozygous c.5308_5311delGAGA mutation that co-segregates with ARCA with cerebellar atrophy and raised AFP.

Genetic Linkage Analysis of DFNB2 Locus with Autosomal Recessive Hearing Loss in Families Negative for GJB2 Mutations in Khuzestan Province

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Parisa Tahmasebi

2016-09-01

Full Text Available Abstract Background: Hearing loss is a common sensory impairment in humans which half of its causes are genetic reasons. Genetic hearing loss can be divided into the two types of syndromic and non-syndromic, which 80% of non-syndromic cases is Autosomal Recessive Non-Syndromic Hearing Loss. The aim of the present research is to determine the contribution of DFNB2 locus (MYO7A gene in causing an autosomal recessive hearing loss in the one group of the deaf families of Khuzestan province. Materials and Methods: This study was conducted on 26 families with autosomal recessive hearing loss (with 4 patients and negative for GJB2 mutations in Khuzestan province. 22 families suffered from ARNSHL and 4 families suffered from Usher syndrome. Linkage analysis was performed by using STR (Short Tandem Repeat markers related to DFNB2 locus. Each family’s genotype was determined by PCR-PAGE method. Furthermore, haplotypes drawing and LOD score calculations were performed. Results: From 26 families with hearing loss participating in this research, following genetic linkage analysis and haplotypes drawing, two families (7.7% of the families showed linkage to DFNB2 locus. One family (4.5% suffered from ARNSHL and another family suffered from Usher syndrome. Conclusion: The results of the present research show that the contribution of DFNB2 locus in causing hearing loss in the population of Khuzestan province was similar to other studies conducted in Iran and this locus with other important loci should be considered to check in the hearing loss panel.

A rare neurocutaneous syndrome and a rare association | Ali ...

African Journals Online (AJOL)

Among the many causes of ataxia, Ataxia -telangictasia is an autosomal recessive1, multi system disease affecting the skin, nervous system & immune system. It's prevalence has been estimated at 1 to 2 per 100,000 It is a neurodegenerative disorder2 in which there is progressive cerebellar ataxia, occulocutaneous ...

Autosomal recessive retinitis pigmentosa caused by mutations in the MAK gene.

Science.gov (United States)

Stone, Edwin M; Luo, Xunda; Héon, Elise; Lam, Byron L; Weleber, Richard G; Halder, Jennifer A; Affatigato, Louisa M; Goldberg, Jacqueline B; Sumaroka, Alexander; Schwartz, Sharon B; Cideciyan, Artur V; Jacobson, Samuel G

2011-12-28

To determine the disease expression in autosomal recessive (ar) retinitis pigmentosa (RP) caused by mutations in the MAK (male germ cell-associated kinase) gene. Patients with RP and MAK gene mutations (n = 24; age, 32-77 years at first visit) were studied by ocular examination, perimetry, and optical coherence tomography (OCT). All but one MAK patient were homozygous for an identical truncating mutation in exon 9 and had Ashkenazi Jewish heritage. The carrier frequency of this mutation among 1207 unrelated Ashkenazi control subjects was 1 in 55, making it the most common cause of heritable retinal disease in this population and MAK-associated RP the sixth most common Mendelian disease overall in this group. Visual acuities could be normal into the eighth decade of life. Kinetic fields showed early loss in the superior-temporal quadrant. With more advanced disease, superior and midperipheral function was lost, but the nasal field remained. Only a central island was present at late stages. Pigmentary retinopathy was less prominent in the superior nasal quadrant. Rod-mediated vision was abnormal but detectable in the residual field; all patients had rod>cone dysfunction. Photoreceptor layer thickness was normal centrally but decreased with eccentricity. At the stages studied, there was no evidence of photoreceptor ciliary elongation. The patterns of disease expression in the MAK form of arRP showed some resemblance to patterns described in autosomal dominant RP, especially the form caused by RP1 mutations. The similarity in phenotypes is of interest, considering that there is experimental evidence of interaction between Mak and RP1 in the photoreceptor cilium.

Two Cases of Autosomal Recessive Congenital Ichthyosis due to CYP4F22 Mutations: Expanding the Genotype of Self-Healing Collodion Baby

NARCIS (Netherlands)

Noguera-Morel, L.; Feito-Rodriguez, M.; Maldonado-Cid, P.; Garcia-Minaur, S.; Kamsteeg, E.J.; Gonzalez-Sarmiento, R.; Lucas-Laguna, R. De; Hernandez-Martin, A.; Torrelo, A.

2016-01-01

Collodion babies are born with a tight, shiny cast that sheds in a few weeks. After shedding, most patients will display features of autosomal recessive congenital ichthyosis (ARCI) later in life but in up to 10% of cases, the skin eventually becomes normal or only minimally involved, a phenotype

Autosomal dominant syndrome resembling Coffin-Siris syndrome.

Science.gov (United States)

Flynn, Maureen A; Milunsky, Jeff M

2006-06-15

Coffin-Siris syndrome is a multiple congenital anomaly/mental retardation syndrome with phenotypic variability [OMIM 135900]. The diagnosis is based solely on clinical findings, as there is currently no molecular, biochemical, or cytogenetic analysis available to confirm a diagnosis. Although typically described as an autosomal recessive disorder, autosomal dominant inheritance has also been infrequently reported. We describe a mother and her two daughters who all have features that resemble Coffin-Siris syndrome. However, this is not a completely convincing diagnosis given that hypertelorism is not a feature of Coffin-Siris syndrome and the family is relatively mildly affected. Yet, this family provides further evidence of an autosomal dominant mode of inheritance for a likely variant of Coffin-Siris syndrome (at least in some families). In addition, Sibling 1 had premature thelarche. She is the second reported individual within the spectrum of Coffin-Siris syndrome to have premature thelarche, indicating that it may be a rare clinical feature. Copyright 2006 Wiley-Liss, Inc.

Localization of A Novel Autosomal Recessive Non-Syndromic Hearing Impairment Locus (DFNB38) to 6q26–q27 in a Consanguineous Kindred from Pakistan

Science.gov (United States)

Ansar, Muhammad; Ramzan, Mohammad; Pham, Thanh L.; Yan, Kai; Jamal, Syed Muhammad; Haque, Sayedul; Ahmad, Wasim; Leal, Suzanne M.

2010-01-01

For autosomal recessive nonsyndromic hearing impairment over 30 loci have been mapped and 19 genes have been identified. DFNB38, a novel locus for autosomal recessive nonsyndromic hearing impairment, was localized in a consanguineous Pakistani kindred to 6q26–q27. The affected family members present with profound prelingual sensorineural hearing impairment and use sign language for communications. Linkage was established to microsatellite markers located on chromosome 6q26–q27 (Multipoint lod score 3.6). The genetic region for DFNB38 spans 10.1 cM according to the Marshfield genetic map and is bounded by markers D6S980 and D6S1719. This genetic region corresponds to 3.4 MB on the sequence-based physical map. PMID:12890929

Mutations in the ABCA4 (ABCR) Gene Are the Major Cause of Autosomal Recessive Cone-Rod Dystrophy

OpenAIRE

Maugeri, Alessandra; Klevering, B. Jeroen; Rohrschneider, Klaus; Blankenagel, Anita; Brunner, Han G.; Deutman, August F.; Hoyng, Carel B.; Cremers, Frans P. M.

2000-01-01

The photoreceptor cell–specific ATP-binding cassette transporter gene (ABCA4; previously denoted “ABCR”) is mutated in most patients with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients with isolated CRD, all fro...

Ghrelin: a link between ageing, metabolism and neurodegenerative disorders

NARCIS (Netherlands)

Stoyanova, Irina

2014-01-01

Along with the increase in life expectancy over the last century comes the increased risk for development of age-related disorders, including metabolic and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. These chronic disorders share two main characteristics:

New autosomal recessive faciodigitogenital syndrome.

OpenAIRE

Teebi, A S; Naguib, K K; Al-Awadi, S; Al-Saleh, Q A

1988-01-01

Most pedigrees of Aarskog's faciodigitogenital syndrome have suggested X linked inheritance. However, sex influenced autosomal dominant inheritance is also a possibility in some families. We describe an Arab family of normal consanguineous parents with five children (three males and two females) with some features of Aarskog syndrome in addition to some unusual hair changes. The possibility that this family represents a distinct previously unrecognised faciodigitogenital syndrome with short s...

Evidence-based therapy for sleep disorders in neurodegenerative diseases

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LIU Ling

2013-08-01

Full Text Available Objective To evaluate the effectiveness of the treatments for sleep disorders in neurodegenerative diseases so as to provide the best therapeutic regimens for the evidence-based treatment. Methods Search PubMed, MEDLINE, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure (CNKI databases with "sleep disorder or sleep disturbance", "neurodegenerative diseases", "Parkinson's disease or PD", "Alzheimer's disease or AD", "multiple system atrophy or MSA" as retrieval words. The quality of the articles were evaluated with Jadad Scale. Results A total of 35 articles, including 2 systematic reviews, 5 randomized controlled trials, 13 clinical controlled trials, 13 case series and 2 epidemiological investigation studies were included for evaluation, 13 of which were high grade and 22 were low grade articles. Clinical evidences showed that: 1 advice on sleep hygiene, careful use of dopaminergic drugs and hypnotic sedative agents should be considered for PD. Bright light therapy (BLT may improve circadian rhythm sleep disorders and clonazepam may be effective for rapid eye movement sleep behavior disorder (RBD. However, to date, very few controlled studies are available to make a recommendation for the management of sleep disorders in PD; 2 treatments for sleep disorders in AD include drug therapy (e.g. melatonin, acetylcholinesterase inhibitors, antipsychotic drugs, antidepressants and non-drug therapy (e.g. BLT, behavior therapy, but very limited evidence shows the effectiveness of these treatments; 3 the first line treatment for sleep-related breathing disorder in MSA is nasal continuous positive airway pressure (nCPAP, and clonazepam is effective for RBD in MSA; 4 there is rare evidence related to the treatment of sleep disorders in dementia with Lewy body (DLB and amyotrophic lateral sclerosis (ALS. Conclusion Evidence-based medicine can provide the best clinical evidence on sleep disorders' treatment in neurodegenerative

Mutation analysis of 272 Spanish families affected by autosomal recessive retinitis pigmentosa using a genotyping microarray.

Science.gov (United States)

Ávila-Fernández, Almudena; Cantalapiedra, Diego; Aller, Elena; Vallespín, Elena; Aguirre-Lambán, Jana; Blanco-Kelly, Fiona; Corton, M; Riveiro-Álvarez, Rosa; Allikmets, Rando; Trujillo-Tiebas, María José; Millán, José M; Cremers, Frans P M; Ayuso, Carmen

2010-12-03

Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive loss of vision. The aim of this study was to identify the causative mutations in 272 Spanish families using a genotyping microarray. 272 unrelated Spanish families, 107 with autosomal recessive RP (arRP) and 165 with sporadic RP (sRP), were studied using the APEX genotyping microarray. The families were also classified by clinical criteria: 86 juveniles and 186 typical RP families. Haplotype and sequence analysis were performed to identify the second mutated allele. At least one-gene variant was found in 14% and 16% of the juvenile and typical RP groups respectively. Further study identified four new mutations, providing both causative changes in 11% of the families. Retinol Dehydrogenase 12 (RDH12) was the most frequently mutated gene in the juvenile RP group, and Usher Syndrome 2A (USH2A) and Ceramide Kinase-Like (CERKL) were the most frequently mutated genes in the typical RP group. The only variant found in CERKL was p.Arg257Stop, the most frequent mutation. The genotyping microarray combined with segregation and sequence analysis allowed us to identify the causative mutations in 11% of the families. Due to the low number of characterized families, this approach should be used in tandem with other techniques.

Global warming and neurodegenerative disorders: speculations on their linkage.

Science.gov (United States)

Habibi, Laleh; Perry, George; Mahmoudi, Morteza

2014-01-01

Climate change is having considerable impact on biological systems. Eras of ice ages and warming shaped the contemporary earth and origin of creatures including humans. Warming forces stress conditions on cells. Therefore, cells evolved elaborate defense mechanisms, such as creation of heat shock proteins, to combat heat stress. Global warming is becoming a crisis and this process would yield an undefined increasing rate of neurodegenerative disorders in future decades. Since heat stress is known to have a degenerative effects on neurons and, conversely, cold conditions have protective effect on these cells, we hypothesize that persistent heat stress forced by global warming might play a crucial role in increasing neurodegenerative disorders.

Predictive gene testing for Huntington disease and other neurodegenerative disorders.

Science.gov (United States)

Wedderburn, S; Panegyres, P K; Andrew, S; Goldblatt, J; Liebeck, T; McGrath, F; Wiltshire, M; Pestell, C; Lee, J; Beilby, J

2013-12-01

Controversies exist around predictive testing (PT) programmes in neurodegenerative disorders. This study sets out to answer the following questions relating to Huntington disease (HD) and other neurodegenerative disorders: differences between these patients in their PT journeys, why and when individuals withdraw from PT, and decision-making processes regarding reproductive genetic testing. A case series analysis of patients having PT from the multidisciplinary Western Australian centre for PT over the past 20 years was performed using internationally recognised guidelines for predictive gene testing in neurodegenerative disorders. Of 740 at-risk patients, 518 applied for PT: 466 at risk of HD, 52 at risk of other neurodegenerative disorders - spinocerebellar ataxias, hereditary prion disease and familial Alzheimer disease. Thirteen percent withdrew from PT - 80.32% of withdrawals occurred during counselling stages. Major withdrawal reasons related to timing in the patients' lives or unknown as the patient did not disclose the reason. Thirty-eight HD individuals had reproductive genetic testing: 34 initiated prenatal testing (of which eight withdrew from the process) and four initiated pre-implantation genetic diagnosis. There was no recorded or other evidence of major psychological reactions or suicides during PT. People withdrew from PT in relation to life stages and reasons that are unknown. Our findings emphasise the importance of: (i) adherence to internationally recommended guidelines for PT; (ii) the role of the multidisciplinary team in risk minimisation; and (iii) patient selection. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

Science.gov (United States)

Klevering, B Jeroen; Yzer, Suzanne; Rohrschneider, Klaus; Zonneveld, Marijke; Allikmets, Rando; van den Born, L Ingeborgh; Maugeri, Alessandra; Hoyng, Carel B; Cremers, Frans P M

2004-12-01

Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.

Global warming and neurodegenerative disorders: speculations on their linkage

Science.gov (United States)

Habibi, Laleh; Perry, George; Mahmoudi, Morteza

2014-01-01

Climate change is having considerable impact on biological systems. Eras of ice ages and warming shaped the contemporary earth and origin of creatures including humans. Warming forces stress conditions on cells. Therefore, cells evolved elaborate defense mechanisms, such as creation of heat shock proteins, to combat heat stress. Global warming is becoming a crisis and this process would yield an undefined increasing rate of neurodegenerative disorders in future decades. Since heat stress is known to have a degenerative effects on neurons and, conversely, cold conditions have protective effect on these cells, we hypothesize that persistent heat stress forced by global warming might play a crucial role in increasing neurodegenerative disorders. PMID:25671171

A familial disorder with low bone density and renal phosphate wasting.

NARCIS (Netherlands)

Grondel, I.M.; Deure, J. van der; Zanen, A.L.; Dogger, M.; Heuvel, L.P.W.J. van den

2009-01-01

Hereditary forms of renal phosphate wasting have been studied thoroughly in the past years. X-linked Hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and autosomal recessive hypophosphatemic rickets (ARHR) are known genetic disorders in which a

Autosomal recessive Oliver-McFarlane syndrome: retinitis pigmentosa, short stature (GH deficiency), trichomegaly, and hair anomalies or CPD syndrome (chorioretinopathy-pituitary dysfunction).

Science.gov (United States)

Haimi, Motti; Gershoni-Baruch, Ruth

2005-10-15

We describe a brother and sister with retinitis pigmentosa (RP), growth failure, long eyelashes, and sparse hair. They were born to young healthy consanguineous parents and presented at birth with IUGR. Evolving pigmentary retinopathy was diagnosed at the age of 5 years. A similar condition (Oliver-McFarlane) syndrome was reported previously. Our two sibs confirm the existence of this autosomal recessive syndrome.

Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.

Science.gov (United States)

Rohena, Luis; Kuehn, Devon; Marchegiani, Shannon; Higginson, Jason D

2011-04-01

Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant skin, abnormal genitalia, and developmental delay in two-thirds of the reported patients. Additional anomalies include dry skin, growth retardation, hearing loss, camptodactyly, hypertelorism, absent zygomatic arches, and umbilical abnormalities. We present the second familial case of ablepharon-macrostomia syndrome in a newborn female and her 22-year-old father making autosomal dominant inheritance more likely than the previously proposed autosomal recessive transmission for this disorder. These cases likely represent the 16th and 17th reported cases of AMS and the first case suspected on prenatal ultrasound. Additionally, the child shows more prominent features of the disorder when compared to her father documenting variable expression and possible anticipation. This article is a US Government work and, as such, is in the public domain in the United States of America. Published 2011 Wiley-Liss, Inc.

EDAR mutation in autosomal dominant hypohidrotic ectodermal dysplasia in two Swedish families

Directory of Open Access Journals (Sweden)

Schmitt-Egenolf Marcus

2006-11-01

Full Text Available Abstract Background Hypohidrotic ectodermal dysplasia (HED is a genetic disorder characterized by defective development of teeth, hair, nails and eccrine sweat glands. Both autosomal dominant and autosomal recessive forms of HED have previously been linked to mutations in the ectodysplasin 1 anhidrotic receptor (EDAR protein that plays an important role during embryogenesis. Methods The coding DNA sequence of the EDAR gene was analyzed in two large Swedish three-generational families with autosomal dominant HED. Results A non-sense C to T mutation in exon 12 was identified in both families. This disease-specific mutation changes an arginine amino acid in position 358 of the EDAR protein into a stop codon (p.Arg358X, thereby truncating the protein. In addition to the causative mutation two polymorphisms, not associated with the HED disorder, were also found in the EDAR gene. Conclusion The finding of the p.Arg358X mutation in the Swedish families is the first corroboration of a previously described observation in an American family. Thus, our study strengthens the role of this particular mutation in the aetiology of autosomal dominant HED and confirms the importance of EDAR for the development of HED.

A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFbeta signaling and cause autosomal dominant spondylocarpotarsal synostosis

NARCIS (Netherlands)

Zieba, J.; Zhang, W.; Chong, J.X.; Forlenza, K.N.; Martin, J.H.; Heard, K.; Grange, D.K.; Butler, M.G.; Kleefstra, T.; Lachman, R.S.; Nickerson, D.; Regnier, M.; Cohn, D.H.; Bamshad, M.; Krakow, D.

2017-01-01

Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in

Otologic Manifestations of Autosomal Recessive Congenital Ichthyosis in Children.

Science.gov (United States)

Martín-Santiago, A; Rodríguez-Pascual, M; Knöpfel, N; Hernández-Martín, Á

2015-11-01

Few studies have investigated ear involvement in nonsyndromic autosomal recessive congenital ichthyosis (ARCI). To assess the type and frequency of otologic manifestations of ARCI in patients under follow-up at the pediatric dermatology department of our hospital. We prospectively studied the presence of ear pain, ear itching, tinnitus, otitis, cerumen impaction, accumulation of epithelial debris, and hearing loss. Daily hygiene measures, topical treatments, medical-surgical interventions, and frequency of visits to an ear, nose, and throat (ENT) specialist were noted in the patients' medical records. Ear examination and hearing tests were performed in all cases. Ten patients were studied: 2 had a self-healing collodion baby phenotype and 8 had ichthyosis. There was mention of otologic manifestations in the records of all 8 patients with ichthyosis (100%); 6 of these patients (75%) had abnormalities in the external auditory canal examination and 2 (25%) had conductive hearing loss. Our findings are limited by the small number of patients studied, all of whom were younger than 19 years. The involvement of both dermatologists and ENT specialists in the management of patients with ichthyosis is crucial to ensure the application of the best therapeutic and preventive measures. More studies are needed to assess the prevalence and impact on quality of life of ear involvement in patients with ichthyosis and to determine the optimal interval between ENT visits for these patients. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

Trends in the Molecular Pathogenesis and Clinical Therapeutics of Common Neurodegenerative Disorders

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Sibongile R. Sibambo

2009-06-01

Full Text Available The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders’ in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions.

Students with Attention Deficit Hyperactivity Disorder Participating in Recess

Science.gov (United States)

Lucas, Matthew D.; Justice, Michael J.; Rosko, Kelly M.

2014-01-01

The participation of a student with Attention Deficit Hyperactivity Disorder (ADHD) in recess can often be both challenging and rewarding for the student and teacher. This paper will address common characteristics of children with ADHD and present basic solutions to improve the experience of these children in the recess setting. Initially, the…

A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

Directory of Open Access Journals (Sweden)

Jinglan Zhang

2016-04-01

Full Text Available Genetic leukoencephalopathies (gLEs are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS. The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES, we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G, as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026. VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting and CORVET (class C core vacuole/endosome tethering protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

Inhibitory action of chlorophyllin of autosome recessive lethals induced by irradiation; Accion inhibidora de la clorofilina de letales recesivos autosonicos inducidos por irradiacion

Energy Technology Data Exchange (ETDEWEB)

Salceda, V.M.; Pimentel, P.A.E.; Cruces, M.P. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)]. e-mail: vmss@nuclear.inin.mx

2006-07-01

The chlorolin is a sodium salt of the chlorophyll that has a strong protective action of the damage induced by different agents so much physical as chemical. In Drosophila there is reported this effect in somatic cells. In contrast, in germinal cells using tests with the sexual chromosomes has not been found such inhibitory action. For this reason, in this occasion we will refer to the effect of the lethality induced in autosome chromosomes, in particular to the chromosome II of this species. For such effect groups of males of the line Canton-S its were pre-treated for 24h with or without 69 mm of CCS and later on treaties with or without 40 Gy of gamma irradiation. The males were then subjected to the technical Cy L / Pm for the detection of recessive lethals. In the third generation the respective counts of the descendant of each one of them to determine the corresponding categories for each extracted chromosome were made. To be mendelian crosses it is expected for a normal chromosome a proportion 2:1 of individuals with genotype Cy L / +: +/+. The absence of individuals +/+ it is indicative of a lethal gene, until 10% of these individuals of each male's total descendant, it is considered that is carrying of a semi lethal gene. The sum of lethal and semi lethals constitutes the category detrimental. The obtained results indicated that the pre-treatment with CCS reduces in a significant way the frequency of induced lethals by 40 Gy of gamma rays. The fact that an effect inhibitor has not been observed in the test of recessive lethal bound to the sex obtained previously, it contrasts with the effect observed in the chromosome II, results of this study and with the one observed in the chromosome III in somatic cells. The above-mentioned shows a differential action of the CCS between sexual chromosomes and autosomal before the effect of the gamma radiation. At the moment we don't have an explanation to these evidences. To evaluate the action of the

Inhibitory action of chlorophyllin of autosome recessive lethals induced by irradiation; Accion inhibidora de la clorofilina de letales recesivos autosonicos inducidos por irradiacion

Energy Technology Data Exchange (ETDEWEB)

Salceda, V M; Pimentel, P A.E.; Cruces, M P [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

2006-07-01

The chlorolin is a sodium salt of the chlorophyll that has a strong protective action of the damage induced by different agents so much physical as chemical. In Drosophila there is reported this effect in somatic cells. In contrast, in germinal cells using tests with the sexual chromosomes has not been found such inhibitory action. For this reason, in this occasion we will refer to the effect of the lethality induced in autosome chromosomes, in particular to the chromosome II of this species. For such effect groups of males of the line Canton-S its were pre-treated for 24h with or without 69 mm of CCS and later on treaties with or without 40 Gy of gamma irradiation. The males were then subjected to the technical Cy L / Pm for the detection of recessive lethals. In the third generation the respective counts of the descendant of each one of them to determine the corresponding categories for each extracted chromosome were made. To be mendelian crosses it is expected for a normal chromosome a proportion 2:1 of individuals with genotype Cy L / +: +/+. The absence of individuals +/+ it is indicative of a lethal gene, until 10% of these individuals of each male's total descendant, it is considered that is carrying of a semi lethal gene. The sum of lethal and semi lethals constitutes the category detrimental. The obtained results indicated that the pre-treatment with CCS reduces in a significant way the frequency of induced lethals by 40 Gy of gamma rays. The fact that an effect inhibitor has not been observed in the test of recessive lethal bound to the sex obtained previously, it contrasts with the effect observed in the chromosome II, results of this study and with the one observed in the chromosome III in somatic cells. The above-mentioned shows a differential action of the CCS between sexual chromosomes and autosomal before the effect of the gamma radiation. At the moment we don't have an explanation to these evidences. To evaluate the action of the chlorophyllin on

An intronic deletion in the PROM1 gene leads to autosomal recessive cone-rod dystrophy.

Science.gov (United States)

Eidinger, Osnat; Leibu, Rina; Newman, Hadas; Rizel, Leah; Perlman, Ido; Ben-Yosef, Tamar

2015-01-01

To investigate the genetic basis for autosomal recessive cone-rod dystrophy (CRD) in a consanguineous Israeli Jewish family. Patients underwent a detailed ophthalmic evaluation, including eye examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potential (VEP). Genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array was performed to identify homozygous regions shared among two of the affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico and in vitro analyses were used to predict the effect of the identified mutation on splicing. The affected family members are three siblings who have various degrees of progressive visual deterioration, glare, color vision abnormalities, and night vision difficulties. Visual field tests revealed central scotomas of different extension. Cone and rod ERG responses were reduced, with cones more severely affected. Homozygosity mapping revealed several homozygous intervals shared among two of the affected individuals. One included the PROM1 gene. Sequence analysis of the 26 coding exons of PROM1 in one affected individual revealed no mutations in the coding sequence or in intronic splice sites. However, in intron 21, proximate to the intron-exon junction, we observed a homozygous 10 bp deletion between positions -26 and -17 (c.2281-26_-17del). The deletion was linked to a known SNP, c.2281-6C>G. The deletion cosegregated with the disease in the family, and was not detected in public databases or in 101 ethnically-matched control individuals. In silico analysis predicted that this deletion would lead to altered intron 21 splicing. Bioinformatic analysis predicted that a recognition site for the SRSF2 splicing factor is located within the deleted sequence. The in vitro splicing assay demonstrated that c.2281-26_-17del leads to complete exon 22 skipping. A novel

Recessive omodysplasia: five new cases and review of the literature

International Nuclear Information System (INIS)

Elcioglu, Nursel H.; Gustavson, Karl H.; Wilkie, Andrew O.M.; Yueksel-Apak, Memune; Spranger, Juergen W.

2004-01-01

Autosomal recessive omodysplasia (MIM 258315) is a rare skeletal dysplasia characterized by severe congenital micromelia with shortening and distal tapering of the humeri and femora to give a club-like appearance. Fewer than 20 cases have been reported in the literature so far. The purpose of this study was to more clearly describe the clinical and radiographic phenotypes and their changes with age. Five new patients, including two sibs, with autosomal recessive omodysplasia are presented. Clinical features are rhizomelic dwarfism with limited extension of elbows and knees and a distinct face with a short nose, depressed nasal bridge, long philtrum, midline haemangiomas in infants and cryptorchidism in males. Radiological findings are distal hypoplasia of the short humerus and femur with characteristic radial dislocation and radioulnar diastasis. Based on a review of these and 16 previously reported patients, the regressive nature of the humerofemoral changes and the obvious male predominance are stressed. Phenotypic similarities with the atelosteogenesis group of disorders and with diastrophic dysplasia suggest common pathogenetic mechanisms. (orig.)

Ghrelin and Neurodegenerative Disorders-a Review.

Science.gov (United States)

Shi, Limin; Du, Xixun; Jiang, Hong; Xie, Junxia

2017-03-01

Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor 1a (GHS-R1a), is a gut-derived, orexigenic peptide hormone that primarily regulates growth hormone secretion, food intake, and energy homeostasis. With the wide expression of GHS-R1a in extra-hypothalamic regions, the physiological role of ghrelin is more extensive than solely its involvement in metabolic function. Ghrelin has been shown to be involved in numerous higher brain functions, such as memory, reward, mood, and sleep. Some of these functions are disrupted in neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). This link between ghrelin and these neurodegenerative diseases is supported by numerous studies. This review aims to provide a comprehensive overview of the most recent evidence of the novel neuromodulatory role of ghrelin in PD, AD, and HD. Moreover, the changes in circulating and/or central ghrelin levels that are associated with disease progression are also postulated to be a biomarker for clinical diagnosis and therapy.

Enamelin/ameloblastin gene polymorphisms in autosomal amelogenesis imperfecta among Syrian families.

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Dashash, Mayssoon; Bazrafshani, Mohamed Riza; Poulton, Kay; Jaber, Saaed; Naeem, Emad; Blinkhorn, Anthony Stevenson

2011-02-01

  This study was undertaken to investigate whether a single G deletion within a series of seven G residues (codon 196) at the exon 9-intron 9 boundary of the enamelin gene ENAM and a tri-nucleotide deletion at codon 180 in exon 7 (GGA vs deletion) of ameloblastin gene AMBN could have a role in autosomal amelogenesis imperfecta among affected Syrian families.   A new technique - size-dependent, deletion screening - was developed to detect nucleotide deletion in ENAM and AMBN genes. Twelve Syrian families with autosomal-dominant or -recessive amelogenesis imperfecta were included.   A homozygous/heterozygous mutation in the ENAM gene (152/152, 152/153) was identified in affected members of three families with autosomal-dominant amelogenesis imperfecta and one family with autosomal-recessive amelogenesis imperfecta. A heterozygous mutation (222/225) in the AMBN gene was identified. However, no disease causing mutations was found. The present findings provide useful information for the implication of ENAM gene polymorphism in autosomal-dominant/-recessive amelogenesis imperfecta.   Further investigations are required to identify other genes responsible for the various clinical phenotypes. © 2010 Blackwell Publishing Asia Pty Ltd.

Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia.

Science.gov (United States)

Chassine, Thomas; Bocquet, Béatrice; Daien, Vincent; Avila-Fernandez, Almudena; Ayuso, Carmen; Collin, Rob Wj; Corton, Marta; Hejtmancik, J Fielding; van den Born, L Ingeborgh; Klevering, B Jeroen; Riazuddin, S Amer; Sendon, Nathacha; Lacroux, Annie; Meunier, Isabelle; Hamel, Christian P

2015-10-01

To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1 mutation, 8 and 33 had X-linked RP (xlRP) with RP2 and RPGR mutations, respectively, 198 and 93 had Usher syndrome and arRP without RP1 mutations, respectively. The median of the spherical equivalent (SE) and the IQR (Q25-Q75) was determined and multiple comparisons were performed. arRP patients with RP1 mutations had SE median at -4.0 dioptres (D) OD (Ocula Dextra); -3.88 D OS (Ocula Sinistra), whereas arRP patients without RP1 mutations (-0.50 D OD; -0.75 D OS) and Usher syndrome patients (-0.50 D OD; -0.38 D OS) were significantly less myopic (pUsher syndrome and adRP with RP1 mutation had a narrow IQR (-9.06 to -1.13 D), whereas arRP with RP1 mutations and xlRP with RP2 or RPGR mutations had a larger range (-9.06; -1.13 D). arRP patients with RP1 mutations have myopia not different from patients with xlRP with RP2 or RPGR mutations, while RP patients from other genetic subgroups were emmetropic or mildly myopic. We suggest that arRP patients with high myopic refractive error should be preferentially analysed for RP1 mutations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Mutation analysis of 272 Spanish families affected by autosomal recessive retinitis pigmentosa using a genotyping microarray.

NARCIS (Netherlands)

Avila-Fernandez, A.; Cantalapiedra, D.; Aller, E.; Vallespin, E.; Aguirre-Lamban, J.; Blanco-Kelly, F.; Corton, M.; Riveiro-Alvarez, R.; Allikmets, R.; Trujillo-Tiebas, M.J.; Millan, J.M.; Cremers, F.P.M.; Ayuso, C.

2010-01-01

PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive loss of vision. The aim of this study was to identify the causative mutations in 272 Spanish families using a genotyping microarray. METHODS: 272 unrelated Spanish families, 107 with autosomal

Distribution of skeletal muscle involvement in autosomal recessive distal muscular dystrophy

International Nuclear Information System (INIS)

Mizusawa, Hidehiro; Nakanishi, Takao; Kobayashi, Fumie.

1987-01-01

Distribution of skeletal muscle involvement in 5 cases with autosomal recessive distal muscular dystrophy was studied clinically and by computed tomography (CT). Manual muscle test showed muscle involvement with a predilection for flexors in the lower leg and adductors in the thigh. Flexion and extension of the thigh and the lower leg was impaired to similar degree. In progressed cases, neck flexors and trunk muscles were also affected mildly. CT disclosed more clearly the preferential involvement of flexors in the lower leg, and involvement of both hamstrings · adductors group and extensors group of the thigh to similar degree. However, m. popliteus was curiously well preserved. In addition, there was a stage showing high density and hypertrophy of m. sartorius, m. gracilis, m. adductor, m. biceps femoris, m. semimenbranosus, m. semitendinosus or m. rectus femoris, which in thought to be compensatory hypertrophy. M. gluteus minimus in the pelvic girdle and m. dorsi proprii in the trunk were also liable to be affected. The CT findings are regarded as characteristic features noted clearly before muscle weakness and atrophy become apparent clinically. CT is very useful for distinguishing distal muscular dystrophy from rimmed vacuolar distal myopathy in which m. quadriceps femoris and flexors of the lower leg are usually well preserved without compensatory hypertrophy on CT. (author)

A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers

Directory of Open Access Journals (Sweden)

Yonatan Perez

2017-01-01

Full Text Available Mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI anchor cause autosomal recessive glycosylation defects, with a wide phenotypic spectrum of intellectual disability, seizures, minor facial dysmorphism, hypotonia, and elevated serum alkaline phosphatase. We now describe consanguineous Bedouin kindred presenting with an autosomal recessive syndrome of intellectual disability and elevated serum alkaline phosphatase. Genome-wide linkage analysis identified 6 possible disease-associated loci. Whole-exome sequencing followed by Sanger sequencing validation identified a single variant in PGAP2 as the disease-causing mutation (C.554G>A; p.185(R>Q, segregating as expected within the kindred and not found in 150 Bedouin controls. The mutation replaces a highly conserved arginine residue with glutamine within the Frag1 (FGF receptor activating domain of PGAP2. Interestingly, this mutation is a known dbSNP variant (rs745521288, build 147 with a very low allele frequency (0.00000824 in dbSNP, no homozygotes reported, highlighting the fact that dbSNP variants should not be automatically ruled out as disease-causing mutations. We further showed that PGAP2 is ubiquitously expressed, but in line with the disease phenotype, it is highly transcribed in human brain, skeletal muscle, and liver. Interestingly, a mild phenotype of slightly elevated serum levels of alkaline phosphatase and significant learning disabilities was observed in heterozygous carriers.

Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8

Science.gov (United States)

Boycott, Kym M.; Beaulieu, Chandree L.; Kernohan, Kristin D.; Gebril, Ola H.; Mhanni, Aziz; Chudley, Albert E.; Redl, David; Qin, Wen; Hampson, Sarah; Küry, Sébastien; Tetreault, Martine; Puffenberger, Erik G.; Scott, James N.; Bezieau, Stéphane; Reis, André; Uebe, Steffen; Schumacher, Johannes; Hegele, Robert A.; McLeod, D. Ross; Gálvez-Peralta, Marina; Majewski, Jacek; Ramaekers, Vincent T.; Nebert, Daniel W.; Innes, A. Micheil; Parboosingh, Jillian S.; Abou Jamra, Rami

2015-01-01

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development. PMID:26637978

Neurodegenerative Disorders Treatment: The MicroRNA Role.

Science.gov (United States)

Ridolfi, Barbara; Abdel-Haq, Hanin

2017-01-01

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and prion disease are not timely and effectively treated using conventional therapies. This emphasizes the need for alternative therapeutic approaches. In this respect, gene-based therapies have been adopted as potentially feasible alternative therapies, where the microRNA (miRNA) approach has experienced a great explosion in recent years. Because miRNAs have been shown to be implicated in the pathogenesis of several diseases including neurodegenerative diseases, they are intensely studied as candidates for diagnostic and prognostic biomarkers, as predictors of drug response and as therapeutic agents. In this review, we evaluate the feasibility of both direct and indirect miRNA mimics and inhibitors toward the regulation of neurodegenerative-related genes both in vivo and in vitro models, highlight the advantages and drawbacks associated with miRNA-based therapy, and summarize the relevant techniques and approaches attempted to deliver miRNAs to the central nervous system for therapeutic purposes, with particular regard to the exosomes. Additionally, we describe a new approach that holds great promise for the treatment of a wide range of diseases including neurodegenerative disorders. This approach is based on addressing the incorporation of miRNAs into exosomes to increase the quantity and quality of miRNA packed and delivered to the central nervous system and other sites of action. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Identification of a Novel Dentin Matrix Protein-1 (DMP-1) Mutation and Dental Anomalies in a Kindred with Autosomal Recessive Hypophosphatemia

OpenAIRE

Turan, Serap; Aydin, Cumhur; Bereket, Abdullah; Akcay, Teoman; Güran, Tülay; Yaralioglu, Betul Akmen; Bastepe, Murat; Jüppner, Harald

2009-01-01

An autosomal recessive form of hypophosphatemia (ARHP) was recently shown to be caused by homozygous mutations in DMP1, the gene encoding dentin matrix protein-1 (DMP-1), a non-collagenous bone matrix protein with an important role in the development and mineralization of bone and teeth. Here, we report a previously not reported consanguineous ARHP kindred in which the three affected individuals carry a novel homozygous DMP-1 mutation. The index case presented at the age of 3 years with bowin...

Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach

Science.gov (United States)

Zimoń, Magdalena; Battaloǧlu, Esra; Parman, Yesim; Erdem, Sevim; Baets, Jonathan; De Vriendt, Els; Atkinson, Derek; Almeida-Souza, Leonardo; Deconinck, Tine; Ozes, Burcak; Goossens, Dirk; Cirak, Sebahattin; Van Damme, Philip; Shboul, Mohammad; Voit, Thomas; Van Maldergem, Lionel; Dan, Bernard; El-Khateeb, Mohammed S.; Guergueltcheva, Velina; Lopez-Laso, Eduardo; Goemans, Nathalie; Masri, Amira; Züchner, Stephan; Timmerman, Vincent; Topaloǧlu, Haluk; De Jonghe, Peter

2016-01-01

Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1—GDAP1, SH3 domain and tetratricopeptide repeats-containing protein 2—SH3TC2, histidine-triad nucleotide binding protein 1—HINT1) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22 % of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3 % patients. Apart from a newly described founder mutation in GDAP1, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the SH3TC2 gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies. PMID:25231362

Nanomedicine and neurodegenerative disorders: so close yet so far.

Science.gov (United States)

Tosi, Giovanni; Vandelli, Maria Angela; Forni, Flavio; Ruozi, Barbara

2015-07-01

This editorial provides an overview of the main advantages of the use of nanomedicine-based approach for innovation in the treatment of neurodegenerative diseases. Besides these aspects, a critical analysis on the main causes that slow the application of nanomedicine to brain disorders is given along with the identification of possible solutions and possible interventions. Better communication between the main players of research in this field and a detailed understanding of the most critical issues to be addressed should help in defining future directions towards the improvement and, finally, the clinical application of nanomedicine to neurodegenerative diseases.

Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome.

Science.gov (United States)

Yoo, Da Hye; Choi, Young-Chul; Nam, Da Eun; Choi, Sun Seong; Kim, Ji Won; Choi, Byung-Ok; Chung, Ki Wha

2017-07-01

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many parts of the body, particularly the brain and muscles. This study examined a Korean MELAS-like syndrome patient with seizure, stroke-like episode, and optic atrophy. Target sequencing of whole mtDNA and 73 nuclear genes identified compound heterozygous mutations p.R205X and p.L255P in the FASTKD2. Each of his unaffected parents has one of the two mutations, and both mutations were not found in 302 controls. FASTKD2 encodes a FAS-activated serine-threonine (FAST) kinase domain 2 which locates in the mitochondrial inner compartment. A FASTKD2 nonsense mutation was once reported as the cause of a recessive infantile mitochondrial encephalomyopathy. The present case showed relatively mild symptoms with a late onset age, compared to a previous patient with FASTKD2 mutation, implicating an inter-allelic clinical heterogeneity. Because this study is the second report of an autosomal recessive mitochondrial encephalomyopathy patient with a FASTKD2 mutation, it will extend the phenotypic spectrum of the FASTKD2 mutation. Copyright © 2017. Published by Elsevier B.V.

Recent Updates in the Treatment of Neurodegenerative Disorders Using Natural Compounds

Directory of Open Access Journals (Sweden)

Mahmood Rasool

2014-01-01

Full Text Available Neurodegenerative diseases are characterized by protein aggregates and inflammation as well as oxidative stress in the central nervous system (CNS. Multiple biological processes are linked to neurodegenerative diseases such as depletion or insufficient synthesis of neurotransmitters, oxidative stress, abnormal ubiquitination. Furthermore, damaging of blood brain barrier (BBB in the CNS also leads to various CNS-related diseases. Even though synthetic drugs are used for the management of Alzheimer’s disease, Parkinson’s disease, autism, and many other chronic illnesses, they are not without side effects. The attentions of researchers have been inclined towards the phytochemicals, many of which have minimal side effects. Phytochemicals are promising therapeutic agents because many phytochemicals have anti-inflammatory, antioxidative as well as anticholinesterase activities. Various drugs of either synthetic or natural origin applied in the treatment of brain disorders need to cross the BBB before they can be used. This paper covers various researches related to phytochemicals used in the management of neurodegenerative disorders.

The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders.

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Eira, Jessica; Silva, Catarina Santos; Sousa, Mónica Mendes; Liz, Márcia Almeida

2016-06-01

Cytoskeleton defects, including alterations in microtubule stability, in axonal transport as well as in actin dynamics, have been characterized in several unrelated neurodegenerative conditions. These observations suggest that defects of cytoskeleton organization may be a common feature contributing to neurodegeneration. In line with this hypothesis, drugs targeting the cytoskeleton are currently being tested in animal models and in human clinical trials, showing promising effects. Drugs that modulate microtubule stability, inhibitors of posttranslational modifications of cytoskeletal components, specifically compounds affecting the levels of tubulin acetylation, and compounds targeting signaling molecules which regulate cytoskeleton dynamics, constitute the mostly addressed therapeutic interventions aiming at preventing cytoskeleton damage in neurodegenerative disorders. In this review, we will discuss in a critical perspective the current knowledge on cytoskeleton damage pathways as well as therapeutic strategies designed to revert cytoskeleton-related defects mainly focusing on the following neurodegenerative disorders: Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth Disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa.

Science.gov (United States)

Arno, Gavin; Agrawal, Smriti A; Eblimit, Aiden; Bellingham, James; Xu, Mingchu; Wang, Feng; Chakarova, Christina; Parfitt, David A; Lane, Amelia; Burgoyne, Thomas; Hull, Sarah; Carss, Keren J; Fiorentino, Alessia; Hayes, Matthew J; Munro, Peter M; Nicols, Ralph; Pontikos, Nikolas; Holder, Graham E; Asomugha, Chinwe; Raymond, F Lucy; Moore, Anthony T; Plagnol, Vincent; Michaelides, Michel; Hardcastle, Alison J; Li, Yumei; Cukras, Catherine; Webster, Andrew R; Cheetham, Michael E; Chen, Rui

2016-12-01

Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Lower urinary tract dysfunction in patients with parkinsonism and other neurodegenerative disorders

DEFF Research Database (Denmark)

Winge, Kristian

2015-01-01

of incontinence in Alzheimer's disease, but higher cognitive function including attention and self-management may play a role. Incontinence is a major risk factor for loss of independence. The complex pathophysiologic mechanisms of neurodegenerative disorders and hence complex symptoms play important roles......Progressive neurodegenerative disorders are devastating diseases with often fatal outcomes. Lower urinary tract symptoms (LUTS) add to morbidity and increase the risk of becoming dependent on the help of others (e.g., nursing-home referral). In Parkinson's disease (PD), the specific loss...... in LUTS and patient quality of life. Nocturia, incontinence, and urgency as well as poor bladder emptying are the most common symptoms. These symptoms may interact with the core symptoms of the disorders, increasing the risk of incontinence and infection. In rarer neurogenerative disorder LUTS may...

Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability

DEFF Research Database (Denmark)

Hansen, Lars; Tawamie, Hasan; Murakami, Yoshiko

2013-01-01

PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline...... mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated...... alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous...

Krabbe Disease: Report of a Rare Lipid Storage and Neurodegenerative Disorder.

Science.gov (United States)

Pavuluri, Pratyusha; Vadakedath, Sabitha; Gundu, Rajkumar; Uppulety, Sushmitha; Kandi, Venkataramana

2017-01-01

Krabbe disease is a rare (one in 100,000 births) autosomal recessive condition, usually noticed among children. It causes sphingolipidosis (dysfunctional metabolism of sphingolipids) and leads to fatal degenerative changes affecting the myelin sheath of the nervous system. We report a case of a six-year-old male child who presented with symptoms of muscle spasticity and irritability. Diagnosis of this disease can only be made with clinical suspicion. Laboratory diagnosis includes brain magnetic resonance imaging (MRI), magnetic resonance (MR) spectroscopy, biochemical analysis of cerebrospinal fluid, and genetic analysis for detecting mutation in genes coding for galactosyl cerebroside (GALC). We report a case of late infantile Krabbe disease.

The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region

DEFF Research Database (Denmark)

Kozyraki, R; Kristiansen, M; Silahtaroglu, A

1998-01-01

-5445 on the short arm of chromosome 10. This is within the autosomal recessive megaloblastic anemia (MGA1) 6-cM region harboring the unknown recessive-gene locus of juvenile megaloblastic anemia caused by intestinal malabsorption of cobalamin (Imerslund-Gräsbeck's disease). In conclusion, the present...... molecular and genetic information on human cubilin now provides circumstantial evidence that an impaired synthesis, processing, or ligand binding of cubilin is the molecular background of this hereditary form of megaloblastic anemia. Udgivelsesdato: 1998-May-15...

Transposable elements in TDP-43-mediated neurodegenerative disorders.

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Wanhe Li

Full Text Available Elevated expression of specific transposable elements (TEs has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration (FTLD. Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases.

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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son.

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Arcot Sadagopan, Karthikeyan; Battista, Robert; Keep, Rosanne B; Capasso, Jenina E; Levin, Alex V

2015-06-01

Leber congenital amaurosis (LCA) is most often an autosomal recessive disorder. We report a father and son with autosomal dominant LCA due to a mutation in the CRX gene. DNA screening using an allele specific assay of 90 of the most common LCA-causing variations in the coding sequences of AIPL1, CEP290, CRB1, CRX, GUCY2D, RDH12 and RPE65 was performed on the father. Automated DNA sequencing of his son examining exon 3 of the CRX gene was subsequently performed. Both father and son have a heterozygous single base pair deletion of an adenine at codon 153 in the coding sequence of the CRX gene resulting in a frameshift mutation. Mutations involving the CRX gene may demonstrate an autosomal dominant inheritance pattern for LCA.

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, Björn; 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.; Krüger, 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,

Consanguinity and genetic disorders: Profile from Jordan

International Nuclear Information System (INIS)

Hamamy, Hanan A.; Ajlouni, Kamel M.; Masri, Amira T.; Al-Hadidy, Azmy M.

2007-01-01

With 20-30% of all marriages occurring between first cousins, increasing attention in Jordan is now given to role of consanguinity in the occurrence of genetic diseases. The objective of this study is to define the specific categories of genetic disorders associated with consanguineous marriages. Etiological categories and consanguinity rates were studied among 623 families with genetic syndromes, congenital anomalies or mental retardation, or both, seen at the National Center for Diabetes, Endocrinology and Genetics for the period August 2002 to August 2006. Comparisons were made for first cousin marriage rates in the study group and that for the general population. First cousin marriages constituted 69%, 22% and 41.7% of marriages among families with autosomal recessive conditions (group 1), dominant, X-linked and chromosomal conditions (group 2) and sporadic undiagnosed conditions (group 3) respectively. The differences in the rates of the first cousin matings were highly significant when comparing known figures in the general population with group 1 and 3, but not significant with group 2. Two messages to the public and health care personnel regarding consanguinity can be derived from this study. The first message is that among genetic disorders, only autosomal recessive disorders are strongly associated with consanguinity. The second message is that approximately 30% of sporadic undiagnosed cases of mental retardation, congenital anomalies and dimorphism may have an autosomal recessive etiology with risks of recurrence in future pregnancies. (author)

Integration-free induced pluripotent stem cells derived from a patient with autosomal recessive Alport syndrome (ARAS).

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Kuebler, Bernd; Aran, Begoña; Miquel-Serra, Laia; Muñoz, Yolanda; Ars, Elisabet; Bullich, Gemma; Furlano, Monica; Torra, Roser; Marti, Merce; Veiga, Anna; Raya, Angel

2017-12-01

A skin biopsy was obtained from a 25-year-old female patient with autosomal recessive Alport syndrome (ARAS) with the homozygous COL4A3 mutation c.345delG, p.(P166Lfs*37). Dermal fibroblasts were derived and reprogrammed by nucleofection with episomal plasmids carrying OCT3/4, SOX2, KLF4 LIN28, L-MYC and p53shRNA. The generated induced Pluripotent Stem Cell (iPSC) clone AS FiPS1 Ep6F-2 was free of genomically integrated reprogramming genes, had the specific homozygous mutation, a stable karyotype, expressed pluripotency markers and generated embryoid bodies which were differentiated towards the three germ layers in vitro. This iPSC line offers a useful resource to study Alport syndrome pathomechanisms and drug testing. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE AND CONGENITAL HEPATIC FIBROSIS: SUMMARY STATEMENT OF A FIRST NATIONAL INSTITUTES OF HEALTH/OFFICE OF RARE DISEASES CONFERENCE

Science.gov (United States)

Gunay-Aygun, Meral; Avner, Ellis D.; Bacallo, Robert L.; Choyke, Peter L.; Flynn, Joseph T.; Germino, Gregory G.; Guay-Woodford, Lisa; Harris, Peter; Heller, Theo; Ingelfinger, Julie; Kaskel, Frederick; Kleta, Robert; LaRusso, Nicholas F.; Mohan, Parvathi; Pazour, Gregory J.; Shneider, Benjamin L.; Torres, Vicente E.; Wilson, Patricia; Zak, Colleen; Zhou, Jing; Gahl, William A.

2010-01-01

Researchers and clinicians with expertise in autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF) and related fields met on May 5-6, 2005, on the National Institutes of Health (NIH) campus for a 1.5-day symposium sponsored by the NIH Office of Rare Diseases, the National Human Genome Research Institute (NHGRI), and in part by the ARPKD/CHF Alliance. The meeting addressed the present status and the future of ARPKD/CHF research. PMID:16887426

Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene.

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Shaibani, Aziz; Wong, Lee-Jun; Wei Zhang, Victor; Lewis, Richard Alan; Shinawi, Marwan

2015-01-01

Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.

Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia

DEFF Research Database (Denmark)

Grau, Tanja; Artemyev, Nikolai O; Rosenberg, Thomas

2011-01-01

study on PDE6C mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins. Twelve affected patients from seven independent families segregating PDE6C mutations were......Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive...... identified in our total patient cohort of 492 independent families. Eleven different PDE6C mutations were found including two nonsense mutations, three mutations affecting transcript splicing as shown by minigene assays, one 1 bp-insertion and five missense mutations. We also performed a detailed functional...

Homozygosity mapping in autosomal recessive retinitis pigmentosa families detects novel mutations

Science.gov (United States)

Marzouka, Nour al Dain; Hebrard, Maxime; Manes, Gaël; Sénéchal, Audrey; Meunier, Isabelle; Hamel, Christian P.

2013-01-01

Purpose Autosomal recessive retinitis pigmentosa (arRP) is a genetically heterogeneous disease resulting in progressive loss of photoreceptors that leads to blindness. To date, 36 genes are known to cause arRP, rendering the molecular diagnosis a challenge. The aim of this study was to use homozygosity mapping to identify the causative mutation in a series of inbred families with arRP. Methods arRP patients underwent standard ophthalmic examination, Goldman perimetry, fundus examination, retinal OCT, autofluorescence measurement, and full-field electroretinogram. Fifteen consanguineous families with arRP excluded for USH2A and EYS were genotyped on 250 K SNP arrays. Homozygous regions were listed, and known genes within these regions were PCR sequenced. Familial segregation and mutation analyzes were performed. Results We found ten mutations, seven of which were novel mutations in eight known genes, including RP1, IMPG2, NR2E3, PDE6A, PDE6B, RLBP1, CNGB1, and C2ORF71, in ten out of 15 families. The patients carrying RP1, C2ORF71, and IMPG2 mutations presented with severe RP, while those with PDE6A, PDE6B, and CNGB1 mutations were less severely affected. The five families without mutations in known genes could be a source of identification of novel genes. Conclusions Homozygosity mapping combined with systematic screening of known genes results in a positive molecular diagnosis in 66.7% of families. PMID:24339724

Motor Phenotype in Neurodegenerative Disorders: Gait and Balance Platform Study Design Protocol for the Ontario Neurodegenerative Research Initiative (ONDRI).

Science.gov (United States)

Montero-Odasso, Manuel; Pieruccini-Faria, Frederico; Bartha, Robert; Black, Sandra E; Finger, Elizabeth; Freedman, Morris; Greenberg, Barry; Grimes, David A; Hegele, Robert A; Hudson, Christopher; Kleinstiver, Peter W; Lang, Anthony E; Masellis, Mario; McLaughlin, Paula M; Munoz, Douglas P; Strother, Stephen; Swartz, Richard H; Symons, Sean; Tartaglia, Maria Carmela; Zinman, Lorne; Strong, Michael J; McIlroy, William

2017-01-01

The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled. To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients. Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm. Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics. As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality.

Research progress on the pathogenesis of rapid eye movement sleep behavior disorder and neurodegenerative diseases

Directory of Open Access Journals (Sweden)

Hai-yang JIANG

2017-10-01

Full Text Available Rapid eye movement sleep behavior disorder (RBD is a sleep disorder characterized by the disappearance of muscle relaxation and enacting one's dreams during rapid eye movement (REM, with most of the dreams being violent or aggressive. Prevalence of RBD, based on population, is 0.38%-2.01%, but it becomes much higher in patients with neurodegenerative diseases, especially α - synucleinopathies. RBD may herald the emergence of α-synucleinopathies by decades, thus it may be used as an effective early marker of neurodegenerative diseases. In this review, we summarized the progress on the pathogenesis of RBD and its relationship with neurodegenerative diseases. DOI: 10.3969/j.issn.1672-6731.2017.10.003

Current concepts in the treatment of hereditary ataxias

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Pedro Braga Neto

2016-03-01

Full Text Available ABSTRACT Hereditary ataxias (HA represents an extensive group of clinically and genetically heterogeneous neurodegenerative diseases, characterized by progressive ataxia combined with extra-cerebellar and multi-systemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. There is no effective treatment for HA, and management remains supportive and symptomatic. In this review, we will focus on the symptomatic treatment of the main autosomal recessive ataxias, autosomal dominant ataxias, X-linked cerebellar ataxias and mitochondrial ataxias. We describe management for different clinical symptoms, mechanism-based approaches, rehabilitation therapy, disease modifying therapy, future clinical trials and perspectives, genetic counseling and preimplantation genetic diagnosis.

Autosomal-recessive and X-linked forms of hereditary motor and sensory neuropathy in childhood.

Science.gov (United States)

Ouvrier, Robert; Geevasingha, Nimeshan; Ryan, Monique M

2007-08-01

The hereditary motor and sensory neuropathies (HMSNs, Charcot-Marie-Tooth neuropathies) are the most common degenerative disorders of the peripheral nervous system. In recent years a dramatic expansion has occurred in our understanding of the molecular basis and cell biology of the recessively inherited demyelinating and axonal neuropathies, with delineation of a number of new neuropathies. Mutations in some genes cause a wide variety of clinical, neurophysiologic, and pathologic phenotypes, rendering diagnosis difficult. The X-linked forms of HMSN represent at least 10%-15% of all HMSNs and have an expanded disease spectrum including demyelinating, intermediate, and axonal neuropathies, transient central nervous system (CNS) dysfunction, mental retardation, and hearing loss. This review presents an overview of the recessive and X-linked forms of HMSN observed in childhood, with particular reference to disease phenotype and neurophysiologic and pathologic abnormalities suggestive of specific diagnoses. These findings can be used by the clinician to formulate a differential diagnosis and guide targeted genetic testing.

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.

Iron in neurodegenerative disorders: being in the wrong place at the wrong time?

Science.gov (United States)

Apostolakis, Sotirios; Kypraiou, Anna-Maria

2017-11-27

Brain iron deposits have been reported consistently in imaging and histologic examinations of patients with neurodegenerative disorders. While the origins of this finding have not been clarified yet, it is speculated that impaired iron homeostasis or deficient transport mechanisms result in the accumulation of this highly toxic metal ultimately leading to formation of reactive oxygen species and cell death. On the other hand, there are also those who support that iron is just an incidental finding, a by product of neuronal loss. A literature review has been performed in order to present the key findings in support of the iron hypothesis of neurodegeneration, as well as to identify conditions causing or resulting from iron overload and compare and contrast their features with the most prominent neurodegenerative disorders. There is an abundance of experimental and observational findings in support of the hypothesis in question; however, as neurodegeneration is a rare incident of commonly encountered iron-associated disorders of the nervous system, and this metal is found in non-neurodegenerative disorders as well, it is possible that iron is the result or even an incidental finding in neurodegeneration. Understanding the underlying processes of iron metabolism in the brain and particularly its release during cell damage is expected to provide a deeper understanding of the origins of neurodegeneration in the years to come.

Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts.

Science.gov (United States)

Irum, Bushra; Khan, Shahid Y; Ali, Muhammad; Daud, Muhammad; Kabir, Firoz; Rauf, Bushra; Fatima, Fareeha; Iqbal, Hira; Khan, Arif O; Al Obaisi, Saif; Naeem, Muhammad Asif; Nasir, Idrees A; Khan, Shaheen N; Husnain, Tayyab; Riazuddin, Sheikh; Akram, Javed; Eghrari, Allen O; Riazuddin, S Amer

2016-01-01

The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. All participating individuals underwent a detailed ophthalmic examination. Each patient's medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequencing libraries were prepared and paired-end sequenced. A large deletion was found that segregated with arCC in the family, and chromosome walking was conducted to estimate the proximal and distal boundaries of the deletion mutation. Exclusion and linkage analysis suggested linkage to a region of chromosome 6p24 harboring GCNT2 (glucosaminyl (N-acetyl) transferase 2) with a two-point logarithm of odds score of 5.78. PCR amplifications of the coding exons of GCNT2 failed in individuals with arCC, and whole-exome data analysis revealed a large deletion on chromosome 6p in the region harboring GCNT2. Chromosomal walking using multiple primer pairs delineated the extent of the deletion to approximately 190 kb. Interestingly, a failure to amplify a junctional fragment of the deletion break strongly suggests an insertion in addition to the large deletion. Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family.

Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

DEFF Research Database (Denmark)

Gal, Andreas; Rau, Isabella; El Matri, Leila

2011-01-01

Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we...... the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced....... heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603...

Gene therapy in animal models of autosomal dominant retinitis pigmentosa

Science.gov (United States)

Rossmiller, Brian; Mao, Haoyu

2012-01-01

Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success. PMID:23077406

Genetic spectrum of autosomal recessive non-syndromic hearing loss in Pakistani families.

Directory of Open Access Journals (Sweden)

Sobia Shafique

Full Text Available The frequency of inherited bilateral autosomal recessive non-syndromic hearing loss (ARNSHL in Pakistan is 1.6/1000 individuals. More than 50% of the families carry mutations in GJB2 while mutations in MYO15A account for about 5% of recessive deafness. In the present study a cohort of 30 ARNSHL families was initially screened for mutations in GJB2 and MYO15A. Homozygosity mapping was performed by employing whole genome single nucleotide polymorphism (SNP genotyping in the families that did not carry mutations in GJB2 or MYO15A. Mutation analysis was performed for the known ARNSHL genes present in the homozygous regions to determine the causative mutations. This allowed the identification of a causative mutation in all the 30 families including 9 novel mutations, which were identified in 9 different families (GJB2 (c.598G>A, p.Gly200Arg; MYO15A (c.9948G>A, p.Gln3316Gln; c.3866+1G>A; c.8767C>T, p.Arg2923* and c.8222T>C, p.Phe2741Ser, TMC1 (c.362+18A>G, BSND (c.97G>C, p.Val33Leu, TMPRSS3 (c.726C>G, p.Cys242Trp and MSRB3 (c.20T>G, p.Leu7Arg. Furthermore, 12 recurrent mutations were detected in 21 other families. The 21 identified mutations included 10 (48% missense changes, 4 (19% nonsense mutations, 3 (14% intronic mutations, 2 (9% splice site mutations and 2 (9% frameshift mutations. GJB2 accounted for 53% of the families, while mutations in MYO15A were the second most frequent (13% cause of ARNSHL in these 30 families. The identification of novel as well as recurrent mutations in the present study increases the spectrum of mutations in known deafness genes which could lead to the identification of novel founder mutations and population specific mutated deafness genes causative of ARNSHL. These results provide detailed genetic information that has potential diagnostic implication in the establishment of cost-efficient allele-specific analysis of frequently occurring variants in combination with other reported mutations in Pakistani populations.

Computational analysis of TRAPPC9: candidate gene for autosomal recessive non-syndromic mental retardation.

Science.gov (United States)

Khattak, Naureen Aslam; Mir, Asif

2014-01-01

Mental retardation (MR)/ intellectual disability (ID) is a neuro-developmental disorder characterized by a low intellectual quotient (IQ) and deficits in adaptive behavior related to everyday life tasks such as delayed language acquisition, social skills or self-help skills with onset before age 18. To date, a few genes (PRSS12, CRBN, CC2D1A, GRIK2, TUSC3, TRAPPC9, TECR, ST3GAL3, MED23, MAN1B1, NSUN1) for autosomal-recessive forms of non syndromic MR (NS-ARMR) have been identified and established in various families with ID. The recently reported candidate gene TRAPPC9 was selected for computational analysis to explore its potentially important role in pathology as it is the only gene for ID reported in more than five different familial cases worldwide. YASARA (12.4.1) was utilized to generate three dimensional structures of the candidate gene TRAPPC9. Hybrid structure prediction was employed. Crystal Structure of a Conserved Metalloprotein From Bacillus Cereus (3D19-C) was selected as best suitable template using position-specific iteration-BLAST. Template (3D19-C) parameters were based on E-value, Z-score and resolution and quality score of 0.32, -1.152, 2.30°A and 0.684 respectively. Model reliability showed 93.1% residues placed in the most favored region with 96.684 quality factor, and overall 0.20 G-factor (dihedrals 0.06 and covalent 0.39 respectively). Protein-Protein docking analysis demonstrated that TRAPPC9 showed strong interactions of the amino acid residues S(253), S(251), Y(256), G(243), D(131) with R(105), Q(425), W(226), N(255), S(233), its functional partner 1KBKB. Protein-protein interacting residues could facilitate the exploration of structural and functional outcomes of wild type and mutated TRAPCC9 protein. Actively involved residues can be used to elucidate the binding properties of the protein, and to develop drug therapy for NS-ARMR patients.

Al-Aqeel Sewairi Syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy. The first genetic defect of matrix metalloproteinase 2 gene

International Nuclear Information System (INIS)

Al-Aqeel, Aida I.

2005-01-01

We report a distinctive autosomal recessive multicentric osteolysis in Saudi Arabian families with distal arthropathy of the metacarpal, metatarsal and interphalangeal joints, with ultimate progression to the proximal joints with decreased range of movements and deformities with ankylosis and generalized osteopenia. In addition, they had large, painful to touch palmar and plantar pads. Hirsutism and mild dysmorphic facial features including proptosis, a narrow nasal bridge, bulbous nose and micrognathia. Using a genome-wide search for microsatellite markers from 11 members of the family from the Armed Forces Hospital and King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia, localized the disease gene to chromosome 16q12-21. Haplotype analysis with additional markers narrowed the critical region to 1.2cM and identified the matrix metalloproteinase 2 (MMP-2), (gelatinase A, collagenase type IV, EC 3.4, 24,24) gene as a disease candidate at Mount Sinai School of Medicine, New York, United States of America in April 2000. Some affected individuals were homoallelic for a nonsense mutation (TCA>TAA) in codon 244 of exon 5, predicting the replacement of a tyrosine residue by a stop codon in the first fibronectin type II domain (Y244X). Other affected members had a missense mutation in exon 2 arginine 101-histidine (R101H) leading to no MMP-2 enzyme activity in serum or fibroblast or both of affected individuals. In other affected members, a non-pathogenic homoallelic GT transversion resulted in the substitution of an aspartate with a tyrosine residue in codon 210 of exon 4 (D210Y). The MMP-2-null mouse has no developmental defects, but are small, which may reflect genetic redundancy. The discovery that deficiency of this well-characterized gelatinase/collagenase results in an inherited form of an osteolytic and arthritic disorder provides an invaluable insights for the understanding of osteolysis and arthritis and is the first genetic

A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family.

Science.gov (United States)

Uzak, Asli Subasioglu; Tokgoz, Bulent; Dundar, Munis; Tekin, Mustafa

2013-03-01

Alport syndrome (AS) is a genetically heterogeneous disorder that is characterized by hematuria, progressive renal failure typically resulting in end-stage renal disease, sensorineural hearing loss, and variable ocular abnormalities. Only 15% of cases with AS are autosomal recessive and are caused by mutations in the COL4A3 or COL4A4 genes, encoding type IV collagen. Clinical data in a large consanguineous family with four affected members were reviewed, and genomic DNA was extracted. For mapping, 15 microsatellite markers flanking COL4A3, COL4A4, and COL4A5 in 16 family members were typed. For mutation screening, all coding exons of COL4A3 were polymerase chain reaction- amplified and Sanger-sequenced from genomic DNA. The disease locus was mapped to chromosome 2q36.3, where COL4A3 and COL4A4 reside. Sanger sequencing revealed a novel mis-sense mutation (c.2T>C; p.M1T) in exon 1 of COL4A3. The identified nucleotide change was not found in 100 healthy ethnicity-matched controls via Sanger sequencing. We present a large consanguineous Turkish family with AS that was found to have a COL4A3 mutation as the cause of the disease. Although the relationship between the various genotypes and phenotypes in AS has not been fully elucidated, detailed clinical and molecular analyses are helpful for providing data to be used in genetic counseling. It is important to identify new mutations to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy for final diagnosis.

Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

Directory of Open Access Journals (Sweden)

Ana Cotta

2014-09-01

Full Text Available Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype.

REM behaviour disorder detection associated with neurodegenerative diseases

DEFF Research Database (Denmark)

Kempfner, Jacob; Sorensen, Gertrud; Zoetmulder, Marielle

2010-01-01

Abnormal skeleton muscle activity during REM sleep is characterized as REM Behaviour Disorder (RBD), and may be an early marker for different neurodegenerative diseases. Early detection of RBD is therefore highly important, and in this ongoing study a semi-automatic method for RBD detection......, a computerized algorithm has been attempted implemented. By analysing the REM and non-REM EMG activity, using advanced signal processing tools combined with a statistical classifier, it is possible to discriminate normal and abnormal EMG activity. Due to the small number of patients, the overall performance...

Kidney Versus Combined Kidney and Liver Transplantation in Young People With Autosomal Recessive Polycystic Kidney Disease: Data From the European Society for Pediatric Nephrology/European Renal Association-European Dialysis and Transplant (ESPN/ERA-EDTA) Registry

NARCIS (Netherlands)

Mekahli, Djalila; van Stralen, Karlijn J.; Bonthuis, Marjolein; Jager, Kitty J.; Balat, Ayşe; Benetti, Elisa; Godefroid, Nathalie; Edvardsson, Vidar O.; Heaf, James G.; Jankauskiene, Augustina; Kerecuk, Larissa; Marinova, Svetlana; Puteo, Flora; Seeman, Tomas; Zurowska, Aleksandra; Pirenne, Jacques; Schaefer, Franz; Groothoff, Jaap W.; Levtchenko, E.; Haffner, D.; Bjerre, A.; Massy, Z.; Shtiza, D.; Kramar, R.; Oberbauer, R.; Baiko, S.; Sukalo, A.; van Hoeck, K.; Collart, F.; des Grottes, J. M.; Pokrajac, D.; Roussinov, D.; Batinić , D.; Lemac, M.; Slavicek, J.; Seeman, T.; Vondrak, K.; Heaf, J. G.; Toots, U.; Finne, P.; Grö nhagen-Riska, C.; Couchoud, C.; Lasalle, M.; Sahpazova, E.; Abazi, N.; Ristoka Bojkovska, N.; von Gersdorff, G.; Scholz, C.; Tö nshoff, B.; Krupka, K.

2016-01-01

The choice for either kidney or combined liver-kidney transplantation in young people with kidney failure and liver fibrosis due to autosomal recessive polycystic kidney disease (ARPKD) can be challenging. We aimed to analyze the characteristics and outcomes of transplantation type in these

Kidney Versus Combined Kidney and Liver Transplantation in Young People With Autosomal Recessive Polycystic Kidney Disease: Data From the European Society for Pediatric Nephrology/European Renal Association-European Dialysis and Transplant (ESPN/ERA-EDTA) Registry

NARCIS (Netherlands)

Mekahli, D.; Stralen, K.J. van; Bonthuis, M.; Jager, K.J.; Balat, A.; Benetti, E.; Godefroid, N.; Edvardsson, V.O.; Heaf, J.G.; Jankauskiene, A.; Kerecuk, L.; Marinova, S.; Puteo, F.; Seeman, T.; Zurowska, A.; Pirenne, J.; Schaefer, F.; Groothoff, J.W.; Hoitsma, A.J.; et al.,

2016-01-01

BACKGROUND: The choice for either kidney or combined liver-kidney transplantation in young people with kidney failure and liver fibrosis due to autosomal recessive polycystic kidney disease (ARPKD) can be challenging. We aimed to analyze the characteristics and outcomes of transplantation type in

A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability.

Science.gov (United States)

Larti, Farzaneh; Kahrizi, Kimia; Musante, Luciana; Hu, Hao; Papari, Elahe; Fattahi, Zohreh; Bazazzadegan, Niloofar; Liu, Zhe; Banan, Mehdi; Garshasbi, Masoud; Wienker, Thomas F; Ropers, H Hilger; Galjart, Niels; Najmabadi, Hossein

2015-03-01

In the context of a comprehensive research project, investigating novel autosomal recessive intellectual disability (ARID) genes, linkage analysis based on autozygosity mapping helped identify an intellectual disability locus on Chr.12q24, in an Iranian family (LOD score = 3.7). Next-generation sequencing (NGS) following exon enrichment in this novel interval, detected a nonsense mutation (p.Q1010*) in the CLIP1 gene. CLIP1 encodes a member of microtubule (MT) plus-end tracking proteins, which specifically associates with the ends of growing MTs. These proteins regulate MT dynamic behavior and are important for MT-mediated transport over the length of axons and dendrites. As such, CLIP1 may have a role in neuronal development. We studied lymphoblastoid and skin fibroblast cell lines established from healthy and affected patients. RT-PCR and western blot analyses showed the absence of CLIP1 transcript and protein in lymphoblastoid cells derived from affected patients. Furthermore, immunofluorescence analyses showed MT plus-end staining only in fibroblasts containing the wild-type (and not the mutant) CLIP1 protein. Collectively, our data suggest that defects in CLIP1 may lead to ARID.

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

Science.gov (United States)

Morgan, Neil V; Westaway, Shawn K; Morton, Jenny E V; Gregory, Allison; Gissen, Paul; Sonek, Scott; Cangul, Hakan; Coryell, Jason; Canham, Natalie; Nardocci, Nardo; Zorzi, Giovanna; Pasha, Shanaz; Rodriguez, Diana; Desguerre, Isabelle; Mubaidin, Amar; Bertini, Enrico; Trembath, Richard C; Simonati, Alessandro; Schanen, Carolyn; Johnson, Colin A; Levinson, Barbara; Woods, C Geoffrey; Wilmot, Beth; Kramer, Patricia; Gitschier, Jane; Maher, Eamonn R; Hayflick, Susan J

2007-01-01

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis. PMID:16783378

X-Linked and Autosomal Recessive Alport Syndrome

DEFF Research Database (Denmark)

Savige, Judith; Storey, Helen; Il Cheong, Hae

2016-01-01

Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published...... COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss...

Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia

OpenAIRE

Risacher, Shannon L.; Saykin, Andrew J.

2013-01-01

Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer’s disease (AD) and prodromal stages, famili...

Estimation of the frequency of occult mutations for an autosomal recessive disease in the presence of genetic heterogeneity: application to genetic hearing loss disorders.

Science.gov (United States)

Kimberling, William J

2005-11-01

The routine testing for pathologic mutation(s) in a patient's DNA has become the foundation of modern molecular genetic diagnosis. It is especially valuable when the phenotype shows genetic heterogeneity, and its importance will grow as treatments become genotype specific. However, the technology of mutation detection is imperfect and mutations are often missed. This can be especially troublesome when dealing with a recessive disorder where the combination of genetic heterogeneity and missed mutation creates an imprecision in the genotypic assessment of individuals who do not appear to have the expected complement of two pathologic mutations. This article describes a statistical approach to the estimation of the likelihood of a genetic diagnosis under these conditions. In addition to providing a means of testing for missed mutations, it also provides a method of estimating and testing for the presence of genetic heterogeneity in the absence of linkage data. Gene frequencies as well as estimates of sensitivity and specificity can be obtained as well. The test is applied to GJB2 recessive nonsyndromic deafness, Usher syndrome types Ib and IIa, and Pendred-enlarged vestibular aqueduct syndrome. Copyright 2005 Wiley-Liss, Inc.

The acrocallosal syndrome in first cousins: widening of the spectrum of clinical features and further support for autosomal recessive inheritance.

Science.gov (United States)

Schinzel, A

1988-01-01

First cousins, related through their mothers, showed a pattern of craniofacial, brain, and limb anomalies consistent with the acrocallosal syndrome. Both patients had a defect of the corpus callosum, macrocephaly with a protruding forehead and occiput, hypertelorism, non-horizontal palpebral fissures, a small nose, notched ear lobes, and postaxial polydactyly of the hands. The boy, in addition, had hypospadias, cryptorchidism, inguinal hernias, duplication with syndactyly of the phalanges of the big toe, and a bipartite right clavicle. The girl had an arachnoidal cyst, a calvarian defect, and digitalisation of the thumbs. Motor and mental development was retarded in both patients. This observation provides further evidence of probable autosomal recessive inheritance of the acrocallosal syndrome and widens the spectrum of clinical findings and the variability of features in this rare malformation syndrome. Images PMID:3385741

Hippocampal-Prefrontal Circuit and Disrupted Functional Connectivity in Psychiatric and Neurodegenerative Disorders

Directory of Open Access Journals (Sweden)

Ming Li

2015-01-01

Full Text Available In rodents, the hippocampus has been studied extensively as part of a brain system responsible for learning and memory, and the prefrontal cortex (PFC participates in numerous cognitive functions including working memory, flexibility, decision making, and rewarding learning. The neuronal projections from the hippocampus, either directly or indirectly, to the PFC, referred to as the hippocampal-prefrontal cortex (Hip-PFC circuit, play a critical role in cognitive and emotional regulation and memory consolidation. Although in certain psychiatric and neurodegenerative diseases, structural connectivity viewed by imaging techniques has been consistently found to be associated with clinical phenotype and disease severity, the focus has moved towards the investigation of connectivity correlates of molecular pathology and coupling of oscillation. Moreover, functional and structural connectivity measures have been emerging as potential intermediate biomarkers for neuronal disorders. In this review, we summarize progress on the anatomic, molecular, and electrophysiological characters of the Hip-PFC circuit in cognition and emotion processes with an emphasis on oscillation and functional connectivity, revealing a disrupted Hip-PFC connectivity and electrical activity in psychiatric and neurodegenerative disorders as a promising candidate of neural marker for neuronal disorders.

Therapeutic Role and Drug Delivery Potential of Neuroinflammation as a Target in Neurodegenerative Disorders.

Science.gov (United States)

Singh, Abhijeet; Chokriwal, Ankit; Sharma, Madan Mohan; Jain, Devendra; Saxena, Juhi; Stephen, Bjorn John

2017-08-16

Neuroinflammation, the condition associated with the hyperactivity of immune cells within the CNS (central nervous system), has recently been linked to a host range of neurodegenerative disorders. Targeting neuroinflammation could be of prime importance as recent research highlights the beneficial aspects associated with modulating the inflammatory mediators associated with the CNS. One of the main obstructions in neuroinflammatory treatments is the hindrance posed by the blood-brain barrier for the delivery of drugs. Hence, research has focused on novel modes of transport for drugs to cross the barrier through drug delivery and nanotechnology approaches. In this Review, we highlight the therapeutic advancement made in the field of neurodegenerative disorders by focusing on the effect neuroinflammation treatment has on these conditions.

Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome.

Science.gov (United States)

Xavier, Jean; Bourvis, Nadège; Tanet, Antoine; Ramos, Tatiana; Perisse, Didier; Marey, Isabelle; Cohen, David; Consoli, Angèle

2016-10-01

Wolfram syndrome (WS, MIM 222300) is a rare autosomal, recessive neurodegenerative disorder associated with mutations in WFS1, a gene that has been associated with bipolar disorder (BD). WS, characterized by the association of juvenile-onset diabetes mellitus (DM) and bilateral progressive optic atrophy (BPOA), encompasses several other clinical features, including cognitive impairments and psychiatric disorders. Detailed data on the psychiatric phenotype are still scarce, and how WS relates to BD is still unknown. A 17-year-old girl with WS was hospitalized for early-onset BD. A multidisciplinary and developmental assessment was carried out to control mood symptoms and address how BD could be related to WS. Besides DM and BPOA, the patient had several risk factors for BD/mood disorders as follows: (1) a history of abuse and maltreatment; (2) a history of specific language disorder and borderline intelligence associated with academic failure; and (3) a comorbid hypothyroidism. Treatment encompassed all aspects of the adolescent's conditions, such as the use of mood stabilizers, addressing psychosocial and scholastic problems, and treating hypothyroid dysfunction. Given the complexity of WS, this case suggests that the possible association between WS and BD should not only be merely limited to a possible statistical association with WFS1 polymorphism but also to developmental, cognitive, and endocrine risk factors for BD.

Recessive Epidermolysis Bullosa simplex- A case report

African Journals Online (AJOL)

Ademu

Abstract: Background:Epidermolysis bullosa simplex (EBS) is characterized by intraepidermal blister formation, most commonly appearing in early infancy. Many variants of EBS exist; the four most common variants are inherited in an autosomal dominant fashion. The recessive forms are rare and less reported in our ...

Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

DEFF Research Database (Denmark)

Gal, Andreas; Rau, Isabella; El Matri, Leila

2011-01-01

heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603......Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we...... amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both...

Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability

Science.gov (United States)

Heidari, Abolfazl; Tongsook, Chanakan; Najafipour, Reza; Musante, Luciana; Vasli, Nasim; Garshasbi, Masoud; Hu, Hao; Mittal, Kirti; McNaughton, Amy J. M.; Sritharan, Kumudesh; Hudson, Melissa; Stehr, Henning; Talebi, Saeid; Moradi, Mohammad; Darvish, Hossein; Arshad Rafiq, Muhammad; Mozhdehipanah, Hossein; Rashidinejad, Ali; Samiei, Shahram; Ghadami, Mohsen; Windpassinger, Christian; Gillessen-Kaesbach, Gabriele; Tzschach, Andreas; Ahmed, Iltaf; Mikhailov, Anna; Stavropoulos, D. James; Carter, Melissa T.; Keshavarz, Soraya; Ayub, Muhammad; Najmabadi, Hossein; Liu, Xudong; Ropers, Hans Hilger; Macheroux, Peter; Vincent, John B.

2015-01-01

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability. PMID:26206890

Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family.

Science.gov (United States)

Zobor, Ditta; Balousha, Ghassan; Baumann, Britta; Wissinger, Bernd

2014-01-01

Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 45 genes. Recently, the FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. We performed a clinical and molecular genetic study of a consanguineous Palestinian family with two three siblings affected with retinitis pigmentosa. DNA samples were collected from the index patient, his father, his affected sister, and two non-affected brothers. DNA sample from the index was subjected to high resolution genome-wide SNP array. Assuming identity-by-descent in this consanguineous family we applied homozygosity mapping to identify disease causing genes. The index patient reported night blindness since the age of 20 years, followed by moderate disease progression with decrease of peripheral vision, the development of photophobia and later on reduced central vision. At the age of 40 his visual acuity was counting fingers (CF) for both eyes, color discrimination was not possible and his visual fields were severely constricted. Funduscopic examination revealed a typical appearance of advanced RP with optic disc pallor, narrowed retinal vessels, bone-spicule like pigmentary changes in the mid-periphery and atrophic changes in the macula. His younger affected brother (37 years) was reported with overall milder symptoms, while the youngest sister (21 years) reported problems only with night vision. Applying high-density SNP arrays we identified several homozygous genomic regions one of which included the recently identified FAM161A gene mutated in RP28-linked autosomal recessive RP. Sequencing analysis revealed the presence of a novel homozygous nonsense mutation, c.1003C>T/p.R335X in the index patient and the affected sister. We identified an RP28-linked RP family in the Palestinian population caused by a novel nonsense mutation in FAM161A. RP in this family shows a typical disease onset with moderate to rapid progression

Prevalence of GJB2 Mutations in Affected Individuals from United Arab Emirates with Autosomal Recessive Nonsyndromic Hearing Loss.

Science.gov (United States)

Tlili, Abdelaziz; Al Mutery, Abdullah; Kamal Eddine Ahmad Mohamed, Walaa; Mahfood, Mona; Hadj Kacem, Hassen

2017-11-01

Mutations in the gap junction protein beta 2 (GJB2) gene are responsible for more cases of nonsyndromic recessive hearing loss than any other gene. The purpose of our study was to evaluate the prevalence of GJB2 mutations among affected individuals from United Arab Emirates (UAE). There were 50 individuals diagnosed with hereditary hearing loss and 120 healthy individuals enrolled in the study. The Sanger sequencing method was used to screen the GJB2 coding region in all affected individuals. The c.-1G>A variant was determined by the polymerase chain reaction-restriction fragment length polymorphism method in normal individuals. Nine cases with bi-allelic mutations and three cases with mono-allelic mutations were detected in 12 out of 50 patients (24%). The homozygous mutation c.35delG was identified as the cause of hearing loss in six participants (12%). The mutation c.506G>A was identified in three affected individuals (6%). The allelic frequency (14%) and low percentage of individuals that were homozygous (2%) for the c.35delG mutation suggest that there are other genes responsible for nonsyndromic deafness in the UAE population. The results reported here are a preliminary step in collecting epidemiological data regarding autosomal recessive nonsyndromic hearing loss related to GJB2 gene mutations among the UAE population. The c.35delG mutation of the GJB2 gene is the most frequently seen causative mutation in the UAE and is followed by the p.Cys169Tyr mutation.

Dominant versus recessive traits conveyed by allelic mutations - to what extent is nonsense-mediated decay involved?

NARCIS (Netherlands)

Ben-Shachar, S.; Khajavi, M.; Withers, M.A.; Shaw, C.A.; Bokhoven, J.H.L.M. van; Brunner, H.G.; Lupski, J.R.

2009-01-01

Mutations in ROR2, encoding a receptor tyrosine kinase, can cause autosomal recessive Robinow syndrome (RRS), a severe skeletal dysplasia with limb shortening, brachydactyly, and a dysmorphic facial appearance. Other mutations in ROR2 result in the autosomal dominant disease, brachydactyly type B

Meier-Gorlin syndrome: Growth and secondary sexual development of a microcephalic primordial dwarfism disorder

NARCIS (Netherlands)

de Munnik, Sonja A.; Otten, Barto J.; Schoots, Jeroen; Bicknell, Louise S.; Aftimos, Salim; Al-Aama, Jumana Y.; van Bever, Yolande; Bober, Michael B.; Borm, George F.; Clayton-Smith, Jill; Deal, Cheri L.; Edrees, Alaa Y.; Feingold, Murray; Fryer, Alan; van Hagen, Johanna M.; Hennekam, Raoul C.; Jansweijer, Maaike C. E.; Johnson, Diana; Kant, Sarina G.; Opitz, John M.; Ramadevi, A. Radha; Reardon, Willie; Ross, Alison; Sarda, Pierre; Schrander-Stumpel, Constance T. R. M.; Sluiter, A. Erik; Temple, I. Karen; Terhal, Paulien A.; Toutain, Annick; Wise, Carol A.; Wright, Michael; Skidmore, David L.; Samuels, Mark E.; Hoefsloot, Lies H.; Knoers, Nine V. A. M.; Brunner, Han G.; Jackson, Andrew P.; Bongers, Ernie M. H. F.

2012-01-01

MeierGorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex

Meier-Gorlin syndrome: Growth and secondary sexual development of a microcephalic primordial dwarfism disorder

NARCIS (Netherlands)

de Munnik, S.A.; Otten, B.J.; Schoots, J.; Bicknell, L.S.; Aftimos, S.; Al-Aama, J.Y.; van Bever, Y.; Bober, M.B.; Borm, G.F.; Clayton-Smith, J.; Deal, C.L.; Edrees, A.Y.; Feingold, M.; Fryer, A.; van Hagen, J.M.; Hennekam, R.C.M.; Jansweijer, M.C.E.; Johnson, D.; Kant, S.G.; Opitz, J.M.; Ramadevi, A.R.; Reardon, W.; Ross, A.; Sarda, P.; Schrander-Stumpel, C.T.R.M.; Sluiter, A.E.; Temple, I.K.; Terhal, P.A.; Toutain, A.; Wise, C.A.; Wright, M.; Skidmore, D.L.; Samuels, M.E.; Hoefsloot, L.H.; Knoers, N.V.A.M.; Brunner, H.G.; Jackson, A.P.; Bongers, M.H.F.

2012-01-01

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This

[Sense of smell, physiological ageing and neurodegenerative diseases: II. Ageing and neurodegenerative diseases].

Science.gov (United States)

Fusari, A; Molina, J A

The sense of smell, which was once studied because of its biological and evolutionary significance, is today one of the centres of interest in research on normal and pathological ageing. The latest scientific developments point to an inversely proportional relationship between age and olfactory sensitivity. In certain neurodegenerative diseases this sensory decline is one of the first symptoms of the disorder and is correlated with the progression of the disease. In this work we are going to review the scientific knowledge on loss of sense of smell in ageing and in neurodegenerative diseases, with special attention given to Alzheimer's and Parkinson's diseases. A survey of studies that have examined the olfactory deficits in ageing and in some neurodegenerative diseases offers conclusive results about the presence of these impairments in the early stages of these disorders and even among healthy elderly persons. Although a number of causes contribute to these sensory losses in physiological ageing, a common neurological foundation has been proposed for Alzheimer's and Parkinson's diseases. Nevertheless, despite certain initial similarities, the olfactory deficits shown in these disorders seem to be qualitatively different.

Naturally- and experimentally-designed restorations of the Parkin gene deficit in autosomal recessive juvenile parkinsonism

International Nuclear Information System (INIS)

Asai, Hirohide; Hirano, Makito; Kiriyama, Takao; Ikeda, Masanori; Ueno, Satoshi

2010-01-01

Intranuclear events due to mutations in the Parkin gene remain elusive in autosomal recessive juvenile parkinsonism (ARJP). We identified a mutant PARKIN protein in fibroblast cultures from a pair of siblings with ARJP who were homozygous for the exon 4-deleted Parkin gene. Disease was mild in one patient and debilitating in the other. The detected mutant, encoded by a transcript lacking exon 3 as well as exon 4, is an in-frame deletion that removes 121 aa, resulting in a 344-aa protein (PaDel3,4). Cell culture and transfection studies revealed negative correlations between expression levels of PaDel3,4 and those of cell cycle proteins, including cyclin E, CDK2, ppRb, and E2F-1, and demonstrated that GFP-PaDel3,4 entered nucleus and ubiquitinated cyclin E as a part of SCF hSel-10 ligase complex in the patient cells. In addition, nuclear localization signal-tagged PaDel3,4 expressed in the transfected patient cells most effectively ubiquitinated cyclin E and reduced DNA damage, protecting cells from oxidative stress. Antisense-oligonucleotide treatment promoted skipping of exon 3 and thus generated PaDel3,4, increasing cell survival. Collectively, we propose that naturally- and experimentally-induced exon skipping at least partly restores the mutant Parkin gene deficit, providing a molecular basis for the development of therapeutic exon skipping.

Schwartz–jampel syndrome: Clinical and diagnostic phenotype of a rare genetic disorder

Directory of Open Access Journals (Sweden)

Bhaskara P Shelley

2016-01-01

Full Text Available The distinctive phenotypic, clinical, skeletal characteristics with the typical electrophysiological features of an 11-year-old male child who presented to the neurology outpatient service are described, with the objective of emphasizing the diagnostic awareness of chondrodystrophic myotonia or Schwartz–Jampel syndrome, a very rare genetic disorder. This autosomal recessive disorder due to mutations in the gene Perlecan leads to abnormal cartilage development and anomalous neuromuscular activity.

Like father, like son: periventricular nodular heterotopia and nonverbal learning disorder.

Science.gov (United States)

McCann, Marcia V; Pongonis, Stephen J; Golomb, Meredith R; Edwards-Brown, Mary; Christensen, Celanie K; Sokol, Deborah K

2008-08-01

Periventricular nodular heterotopia is a common malformation of cortical development in which the migration of developing neurons destined for the cerebral cortex is abbreviated. Bilateral periventricular nodular heterotopia is most commonly an X-linked disorder that involves mutations in the filamin A (FLNA) gene, but an autosomal recessive form and sporadic forms have been identified. To our knowledge, autosomal dominant transmission of isolated periventricular nodular heterotopia has not been reported. Periventricular nodular heterotopia has a heterogeneous phenotype, associated commonly with seizure disorder, and more recently with reading deficits and visual-spatial deficits in some patients. We present a father and son with bilateral periventricular nodular heterotopia and similar visual-spatial learning deficits, consistent with nonverbal learning disability.

Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

Science.gov (United States)

Heidari, Abolfazl; Tongsook, Chanakan; Najafipour, Reza; Musante, Luciana; Vasli, Nasim; Garshasbi, Masoud; Hu, Hao; Mittal, Kirti; McNaughton, Amy J M; Sritharan, Kumudesh; Hudson, Melissa; Stehr, Henning; Talebi, Saeid; Moradi, Mohammad; Darvish, Hossein; Arshad Rafiq, Muhammad; Mozhdehipanah, Hossein; Rashidinejad, Ali; Samiei, Shahram; Ghadami, Mohsen; Windpassinger, Christian; Gillessen-Kaesbach, Gabriele; Tzschach, Andreas; Ahmed, Iltaf; Mikhailov, Anna; Stavropoulos, D James; Carter, Melissa T; Keshavarz, Soraya; Ayub, Muhammad; Najmabadi, Hossein; Liu, Xudong; Ropers, Hans Hilger; Macheroux, Peter; Vincent, John B

2015-10-15

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3

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Bouhouche Ahmed

2012-03-01

Full Text Available Abstract Background Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. Methods All family members underwent neurological and radiological examinations. A genome wide search was conducted in this family using the ABI PRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate genes within the region linked to the disease were screened for mutations by direct sequencing. Results Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis of recombination events and LOD score calculation suggests linkage of the responsible gene in a genetic interval of 11 Mb located between D17S789 and D17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven candidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and GRIN2C, identified three missense mutations in the FDXR gene which were also found in a homozygous state in three healthy controls, suggesting that these variants are not disease-causing mutations in the family. Conclusion A novel locus for leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome 17q24.2-25.3 in a consanguineous Moroccan family.

Hereditary sensory and autosomal peripheral neuropathy-type IV: case series and review of literature.

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Ashwin, D P; Chandan, G D; Jasleen, Handa Kaur; Rajkumar, G C; Rudresh, K B; Prashanth, R

2015-06-01

Hereditary sensory and autonomic neuropathy (HSAN) IV is a rare autosomal recessive disorder which is characterized by a decrease in the number of myelinated and non-myelinated nerve fibers of peripheral nerves which causes diminished or absent pain sensation leading to increase in self-mutilative habits. A retrospective study of eight cases ranging from age group of 4 to 17 years for oral and digital signs and symptoms is presented. All the patients showed congenital insensitivity to pain and anhidrosis. Oral self-mutilations, such as autoextraction of teeth and severe bite injuries (with resultant scarring) of the finger tips and oral soft tissues (tongue, lip, and buccal mucosa) were found in most patients. Our study suggests that early diagnosis and specific treatment plan are important for prevention of characteristic of the oral as well as digital trauma associated with this disorder.

Primary diagnosis of Wolfram syndrome in an adult patient--case report and description of a novel pathogenic mutation.

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Waschbisch, Anne; Volbers, Bastian; Struffert, Tobias; Hoyer, Juliane; Schwab, Stefan; Bardutzky, Juergen

2011-01-15

Wolfram syndrome is a rare, autosomal recessive, neurodegenerative disorder presenting with the main clinical symptoms of childhood-onset diabetes mellitus, optic atrophy, diabetes insipidus and deafness (DIDMOAD). Later stages of the disease are dominated by neurological complications and death occurs early in life with a median life expectancy of 30 years. Here we present a 44 year old patient who presented to our hospital with central respiratory failure, cognitive impairment, ataxia and parkinsonism and was first diagnosed with Wolfram syndrome. DNA sequence analysis revealed a novel pathogenic mutation within the WFS1 gene. Advanced clinical and imaging studies performed in this patient highlight the neurodegenerative process in Wolfram syndrome and expand our knowledge on the mutational spectrum of the disease. Copyright © 2010 Elsevier B.V. All rights reserved.

Birth of a healthy infant following preimplantation PKHD1 haplotyping for autosomal recessive polycystic kidney disease using multiple displacement amplification

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Janson, Marleen M.; Roesler, Mark R.; Avner, Ellis D.; Strawn, Estil Y.; Bick, David P.

2010-01-01

Purpose To develop a reliable preimplantation genetic diagnosis protocol for couples who both carry a mutant PKHD1 gene wishing to conceive children unaffected with autosomal recessive polycystic kidney disease (ARPKD). Methods Development of a unique protocol for preimplantation genetic testing using whole genome amplification of single blastomeres by multiple displacement amplification (MDA), and haplotype analysis with novel short tandem repeat (STR) markers from the PKHD1 gene and flanking sequences, and a case report of successful utilization of the protocol followed by successful IVF resulting in the birth of an infant unaffected with ARPKD. Results We have developed 20 polymorphic STR markers suitable for linkage analysis of ARPKD. These linked STR markers have enabled unambiguous identification of the PKHD1 haplotypes of embryos produced by at-risk couples. Conclusions We have developed a reliable protocol for preimplantation genetic diagnosis of ARPKD using single-cell MDA products for PKHD1 haplotyping. PMID:20490649

Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases.

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Mallaret, Martial; Renaud, Mathilde; Redin, Claire; Drouot, Nathalie; Muller, Jean; Severac, Francois; Mandel, Jean Louis; Hamza, Wahiba; Benhassine, Traki; Ali-Pacha, Lamia; Tazir, Meriem; Durr, Alexandra; Monin, Marie-Lorraine; Mignot, Cyril; Charles, Perrine; Van Maldergem, Lionel; Chamard, Ludivine; Thauvin-Robinet, Christel; Laugel, Vincent; Burglen, Lydie; Calvas, Patrick; Fleury, Marie-Céline; Tranchant, Christine; Anheim, Mathieu; Koenig, Michel

2016-07-01

Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.

Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11)

NARCIS (Netherlands)

Luijendijk, M.W.J.; Wijk, E. van; Bischoff, A.M.L.C.; Krieger, E.; Huygen, P.L.M.; Pennings, R.J.E.; Brunner, H.G.; Cremers, C.W.R.J.; Cremers, F.P.M.; Kremer, J.M.J.

2004-01-01

Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant

Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11).

NARCIS (Netherlands)

Luijendijk, M.W.J.; Wijk, E. van; Bischoff, A.M.L.C.; Krieger, E.; Huygen, P.L.M.; Pennings, R.J.E.; Brunner, H.G.; Cremers, C.W.R.J.; Cremers, F.P.M.; Kremer, J.M.J.

2004-01-01

Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

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Taghavi, Shaghayegh; Chaouni, Rita; Tafakhori, Abbas; Azcona, Luis J; Firouzabadi, Saghar Ghasemi; Omrani, Mir Davood; Jamshidi, Javad; Emamalizadeh, Babak; Shahidi, Gholam Ali; Ahmadi, Mona; Habibi, Seyed Amir Hassan; Ahmadifard, Azadeh; Fazeli, Atena; Motallebi, Marzieh; Petramfar, Peyman; Askarpour, Saeed; Askarpour, Shiva; Shahmohammadibeni, Hossein Ali; Shahmohammadibeni, Neda; Eftekhari, Hajar; Shafiei Zarneh, Amir Ehtesham; Mohammadihosseinabad, Saeed; Khorrami, Mehdi; Najmi, Safa; Chitsaz, Ahmad; Shokraeian, Parasto; Ehsanbakhsh, Hossein; Rezaeidian, Jalal; Ebrahimi Rad, Reza; Madadi, Faranak; Andarva, Monavvar; Alehabib, Elham; Atakhorrami, Minoo; Mortazavi, Seyed Erfan; Azimzadeh, Zahra; Bayat, Mahdis; Besharati, Amir Mohammad; Harati-Ghavi, Mohammad Ali; Omidvari, Samareh; Dehghani-Tafti, Zahra; Mohammadi, Faraz; Mohammad Hossein Pour, Banafsheh; Noorollahi Moghaddam, Hamid; Esmaili Shandiz, Ehsan; Habibi, Arman; Taherian-Esfahani, Zahra; Darvish, Hossein; Paisán-Ruiz, Coro

2018-04-01

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

DNA damage in neurodegenerative diseases

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Coppedè, Fabio, E-mail: fabio.coppede@med.unipi.it; Migliore, Lucia, E-mail: lucia.migliore@med.unipi.it

2015-06-15

Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

DNA damage in neurodegenerative diseases

International Nuclear Information System (INIS)

Coppedè, Fabio; Migliore, Lucia

2015-01-01

Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

AUTOSOMAL RECESSIVE PERIPHERAL NEUROPATHY WITH NEUROMYOTONIA (ARAN-NM: DESCRIPTION OF A CLINICAL CASE CONFIRMED BY A MUTATION IN THE HINT1 GENE

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Olga A. Klochkova

2017-01-01

Full Text Available Autosomal recessive  peripheral neuropathy with neuromyotonia  (ARAN-NM  is a relatively newly described  disease associated  with mutations  in the HINT1 gene.  It accounts  for a significant  part of the poorly  differentiated  forms  of axonal polyneuropathies.  We present the first in Russia description of the genetically confirmed case of ARAN-NM in a boy aged 14 years and 11 months without the hereditary-tainted anamnesis. On presentation,  the patient experienced  progressive  distal muscular weakness, asymmetric foot deformity,  gait disorders  and minimal manifestations  of neuromyotonia  (stiffness  in the fingers.  During examination,  we detected an increase in the level of creatine phosphokinase up to 635 U/l, a disturbance of conduction of motor and, to a lesser extent, sensory fibers  of  the  peripheral  nerves  (according  to  the  stimulation  electromyography,  EMG,  denervation-reinnervation  changes,  single positive acute waves, fibrillation potentials, complex repeated discharge (according to the data of needle EMG. In the study of exome, a homozygous mutation c.110G>C, p.R37P was determined in exon 01 of the HINT1 gene, which confirmed the presence of ARAN-NM. A molecular-genetic  examination of the patient's immediate relatives was carried out. The described case is compared with literature data. An overview of currently available information on ARAN-NM is provided. Diagnostic criteria of the disease are presented.

Comparative Incidence of Conformational, Neurodegenerative Disorders.

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Jesús de Pedro-Cuesta

Full Text Available The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs.We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD. We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD forms, amyotrophic lateral sclerosis (ALS, and sporadic rapidly progressing neurodegenerative dementia (sRPNDd. For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined.Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD, to 1589 and 2589 for AMD and Alzheimer's disease (AD respectively. Age-specific profiles varied from (a symmetrical, inverted V-shaped curves for low incidences to (b those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20-24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration.These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to incidence magnitude and survival might

Comparative Incidence of Conformational, Neurodegenerative Disorders

Science.gov (United States)

de Pedro-Cuesta, Jesús; Rábano, Alberto; Martínez-Martín, Pablo; Ruiz-Tovar, María; Alcalde-Cabero, Enrique; Almazán-Isla, Javier; Avellanal, Fuencisla; Calero, Miguel

2015-01-01

Background The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs). Methods We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD). We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD) forms, amyotrophic lateral sclerosis (ALS), and sporadic rapidly progressing neurodegenerative dementia (sRPNDd). For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined. Findings Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD), to 1589 and 2589 for AMD and Alzheimer's disease (AD) respectively. Age-specific profiles varied from (a) symmetrical, inverted V-shaped curves for low incidences to (b) those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c) a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20–24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration. Interpretation These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to

Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis

Science.gov (United States)

Ullah, Rahim; Ansar, Muhammad; Durrani, Zaka Ullah; Lee, Kwanghyuk; Santos-Cortez, Regie Lyn P.; Muhammad, Dost; Ali, Mahboob; Zia, Muhammad; Ayub, Muhammad; Khan, Suliman; Smith, Josh D.; Nickerson, Deborah A.; Shendure, Jay; Bamshad, Michael; Leal, Suzanne M.; Ahmad, Wasim

2016-01-01

Background Ichthyoses are clinically characterized by scaling or hyperkeratosis of the skin or both. It can be an isolated condition limited to the skin or appear secondarily with involvement of other cutaneous or systemic abnormalities. Methods The present study investigated clinical and molecular characterization of three consanguineous families (A, B, C) segregating two different forms of autosomal recessive congenital ichthyosis (ARCI). Linkage in three consanguineous families (A, B, C) segregating two different forms of ARCI was searched by typing microsatellite and single nucleotide polymorphism marker analysis. Sequencing of the two genes TGM1 and ALOXE3 was performed by the dideoxy chain termination method. Results Genome-wide linkage analysis established linkage in family A to TGM1 gene on chromosome 14q11 and in families B and C to ALOXE3 gene on chromosome 17p13. Subsequently, sequencing of these genes using samples from affected family members led to the identification of three novel mutations: a missense variant p.Trp455Arg in TGM1 (family A); a nonsense variant p.Arg140* in ALOXE3 (family B); and a complex rearrangement in ALOXE3 (family C). Conclusion The present study further extends the spectrum of mutations in the two genes involved in causing ARCI. Characterizing the clinical spectrum resulting from mutations in the TGM1 and ALOXE3 genes will improve diagnosis and may direct clinical care of the family members. PMID:26578203

EYS Mutations Causing Autosomal Recessive Retinitis Pigmentosa: Changes of Retinal Structure and Function with Disease Progression

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David B. McGuigan

2017-07-01

Full Text Available Mutations in the EYS (eyes shut homolog gene are a common cause of autosomal recessive (ar retinitis pigmentosa (RP. Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT, and en face autofluoresence imaging, a cohort of 15 patients (ages 12–51 at first visit, some of whom had longitudinal data of function and structure. Rod sensitivity was able to be measured by chromatic perimetry in most patients at their earliest visits and some patients retained patchy rod function into the fifth decade of life. As expected from RP, cone sensitivity persisted after rod function was no longer measurable. The photoreceptor nuclear layer of the central retina was abnormal except at the fovea in most patients at first visit. Perifoveal disease measured over a period of years indicated that photoreceptor structural loss was followed by dysmorphology of the inner retina and loss of retinal pigment epithelial integrity. Although there could be variability in severity, preliminary analyses of the rates of vision loss suggested that EYS is a more rapidly progressive disease than other ciliopathies causing arRP, such as USH2A and MAK.

Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.

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Satoshi Katagiri

Full Text Available OBJECTIVE: The purpose of this study was to investigate frequent disease-causing gene mutations in autosomal recessive retinitis pigmentosa (arRP in the Japanese population. METHODS: In total, 99 Japanese patients with non-syndromic and unrelated arRP or sporadic RP (spRP were recruited in this study and ophthalmic examinations were conducted for the diagnosis of RP. Among these patients, whole exome sequencing analysis of 30 RP patients and direct sequencing screening of all CNGA1 exons of the other 69 RP patients were performed. RESULTS: Whole exome sequencing of 30 arRP/spRP patients identified disease-causing gene mutations of CNGA1 (four patients, EYS (three patients and SAG (one patient in eight patients and potential disease-causing gene variants of USH2A (two patients, EYS (one patient, TULP1 (one patient and C2orf71 (one patient in five patients. Screening of an additional 69 arRP/spRP patients for the CNGA1 gene mutation revealed one patient with a homozygous mutation. CONCLUSIONS: This is the first identification of CNGA1 mutations in arRP Japanese patients. The frequency of CNGA1 gene mutation was 5.1% (5/99 patients. CNGA1 mutations are one of the most frequent arRP-causing mutations in Japanese patients.

Distribution of skeletal muscle involvement in autosomal recessive distal muscular dystrophy. A clinical and computed tomographic study

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Mizusawa, Hidehiro; Nakanishi, Takao; Kobayashi, Fumie

1987-02-01

Distribution of skeletal muscle involvement in 5 cases with autosomal recessive distal muscular dystrophy was studied clinically and by computed tomography (CT). Manual muscle test showed muscle involvement with a predilection for flexors in the lower leg and adductors in the thigh. Flexion and extension of the thigh and the lower leg was impaired to similar degree. In progressed cases, neck flexors and trunk muscles were also affected mildly. CT disclosed more clearly the preferential involvement of flexors in the lower leg, and involvement of both hamstrings center dot adductors group and extensors group of the thigh to similar degree. However, m. popliteus was curiously well preserved. In addition, there was a stage showing high density and hypertrophy of m. sartorius, m. gracilis, m. adductor, m. biceps femoris, m. semimenbranosus, m. semitendinosus or m. rectus femoris, which in thought to be compensatory hypertrophy. M. gluteus minimus in the pelvic girdle and m. dorsi proprii in the trunk were also liable to be affected. The CT findings are regarded as characteristic features noted clearly before muscle weakness and atrophy become apparent clinically. CT is very useful for distinguishing distal muscular dystrophy from rimmed vacuolar distal myopathy in which m. quadriceps femoris and flexors of the lower leg are usually well preserved without compensatory hypertrophy on CT.

The effect of piracetam on ataxia: clinical observations in a group of autosomal dominant cerebellar ataxia patients.

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Ince Gunal, D; Agan, K; Afsar, N; Borucu, D; Us, O

2008-04-01

Autosomal dominant cerebellar ataxias are clinically and genetically heterogeneous neurodegenerative disorders. There is no known treatment to prevent neuronal cell death in these disorders. Current treatment is purely symptomatic; ataxia is one of the most disabling symptoms and represents the main therapeutic challenge. A previous case report suggesting benefit from administration of high dose piracetam inspired the present study of the efficacy of this agent in patients with cerebellar ataxia. Piracetam is a low molecular weight derivative of gamma-aminobutyric acid. Although little is known of its mode of action, its efficacy has been documented in a wide range of clinical indications, such as cognitive disorders, dementia, vertigo and dyslexia, as well as cortical myoclonus. The present report investigated the role of high dose piracetam in patients with cerebellar ataxia. Eight patients with autosomal dominant cerebellar ataxia were given intravenous piracetam 60 g/day by a structured protocol for 14 days. The baseline and end-of-the study evaluations were based on the International Cooperative Ataxia Rating Scale. Statistical analysis demonstrated a significant improvement in the patients' total score (P = 0.018) and a subscale analysis showed statistical significance for only the posture and gait disturbances item (P = 0.018). This study is providing good clinical observation in favour of high dose piracetam infusion to reduce the disability of the patients by improving their gait ataxia.

A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome.

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Bicknell, Louise S; Pitt, James; Aftimos, Salim; Ramadas, Ram; Maw, Marion A; Robertson, Stephen P

2008-10-01

There are several rare syndromes combining wrinkled, redundant skin and neurological abnormalities. Although phenotypic overlap between conditions has suggested that some might be allelic to one another, the aetiology for many of them remains unknown. A consanguineous New Zealand Maori family has been characterised that segregates an autosomal recessive connective tissue disorder (joint dislocations, lax skin) associated with neurological abnormalities (severe global developmental delay, choreoathetosis) without metabolic abnormalities in four affected children. A genome-screen performed under a hypothesis of homozygosity by descent for an ancestral mutation, identified a locus at 10q23 (Z = 3.63). One gene within the candidate interval, ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), was considered a plausible disease gene since a missense mutation had previously been shown to cause progressive neurodegeneration, cataracts, skin laxity, joint dislocations and metabolic derangement in a consanguineous Algerian family. A missense mutation, 2350C>T, was identified in ALDH18A1, which predicts the substitution H784Y. H784 is invariant across all phyla and lies within a previously unrecognised, conserved C-terminal motif in P5CS. In an in vivo assay of flux through this metabolic pathway using dermal fibroblasts obtained from an affected individual, proline and ornithine biosynthetic activity of P5CS was not affected by the H784Y substitution. These data suggest that P5CS may possess additional uncharacterised functions that affect connective tissue and central nervous system function.

Mass spectrometry-based metabolomics: Targeting the crosstalk between gut microbiota and brain in neurodegenerative disorders.

Science.gov (United States)

Luan, Hemi; Wang, Xian; Cai, Zongwei

2017-11-12

Metabolomics seeks to take a "snapshot" in a time of the levels, activities, regulation and interactions of all small molecule metabolites in response to a biological system with genetic or environmental changes. The emerging development in mass spectrometry technologies has shown promise in the discovery and quantitation of neuroactive small molecule metabolites associated with gut microbiota and brain. Significant progress has been made recently in the characterization of intermediate role of small molecule metabolites linked to neural development and neurodegenerative disorder, showing its potential in understanding the crosstalk between gut microbiota and the host brain. More evidence reveals that small molecule metabolites may play a critical role in mediating microbial effects on neurotransmission and disease development. Mass spectrometry-based metabolomics is uniquely suitable for obtaining the metabolic signals in bidirectional communication between gut microbiota and brain. In this review, we summarized major mass spectrometry technologies including liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and imaging mass spectrometry for metabolomics studies of neurodegenerative disorders. We also reviewed the recent advances in the identification of new metabolites by mass spectrometry and metabolic pathways involved in the connection of intestinal microbiota and brain. These metabolic pathways allowed the microbiota to impact the regular function of the brain, which can in turn affect the composition of microbiota via the neurotransmitter substances. The dysfunctional interaction of this crosstalk connects neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. The mass spectrometry-based metabolomics analysis provides information for targeting dysfunctional pathways of small molecule metabolites in the development of the neurodegenerative diseases, which may be valuable for the

Support system and method for detecting neurodegenerative disorder

DEFF Research Database (Denmark)

2013-01-01

The present invention relates to a system and a method for detection of abnormal motor activity during REM sleep, and further to systems and method for assisting in detecting neurodegenerative disorders such as Parkinson's. One embodiment relates to a method for detection of abnormal motor activity...... during REM sleep comprising the steps of: performing polysomnographic recordings of a sleeping subject, thereby obtaining one or more electromyography (EMG) derivations, preferably surface EMG recordings, and one or more EEG derivations, and/or one or more electrooculargraphy (EOG) derivations, detecting...... one or more REM sleep stages, preferably based on the one or more EEG and/or EOG derivations, determining the level of muscle activity during the one or more REM sleep stages based on the one or more EMG derivations, wherein a subject having an increased level of muscle activity during REM sleep...

A defect in the TUSC3 gene is associated with autosomal recessive mental retardation.

Science.gov (United States)

Garshasbi, Masoud; Hadavi, Valeh; Habibi, Haleh; Kahrizi, Kimia; Kariminejad, Roxana; Behjati, Farkhondeh; Tzschach, Andreas; Najmabadi, Hossein; Ropers, Hans Hilger; Kuss, Andreas Walter

2008-05-01

Recent studies have shown that autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to believe that the number of underlying gene defects goes into the thousands. To date, however, only four genes have been implicated in nonsyndromic ARMR (NS-ARMR): PRSS12 (neurotrypsin), CRBN (cereblon), CC2D1A, and GRIK2. As part of an ongoing systematic study aiming to identify ARMR genes, we investigated a large consanguineous family comprising seven patients with nonsyndromic ARMR in four sibships. Genome-wide SNP typing enabled us to map the relevant genetic defect to a 4.6 Mbp interval on chromosome 8. Haplotype analyses and copy-number studies led to the identification of a homozygous deletion partly removing TUSC3 (N33) in all patients. All obligate carriers of this family were heterozygous, but none of 192 unrelated healthy individuals from the same population carried this deletion. We excluded other disease-causing mutations in the coding regions of all genes within the linkage interval by sequencing; moreover, we verified the complete absence of a functional TUSC3 transcript in all patients through RT-PCR. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltransferase complex that catalyzes a pivotal step in the protein N-glycosylation process. Our data suggest that in contrast to other genetic defects of glycosylation, inactivation of TUSC3 causes nonsyndromic MR, a conclusion that is supported by a separate report in this issue of AJHG. TUSC3 is only the fifth gene implicated in NS-ARMR and the first for which mutations have been reported in more than one family.

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

Science.gov (United States)

2017-09-28

-epilepsy-intellectual Disability Syndrome Due to TUD Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to KIAA0226 Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome; Autosomal Recessive Cerebellar Ataxia With Late-onset Spasticity; Autosomal Recessive Cerebellar Ataxia Due to STUB1 Deficiency; Autosomal Recessive Cerebellar Ataxia Due to a DNA Repair Defect; Autosomal Recessive Cerebellar Ataxia - Saccadic Intrusion; Autosomal Recessive Cerebellar Ataxia - Psychomotor Retardation; Autosomal Recessive Cerebellar Ataxia - Blindness - Deafness; Autosomal Recessive Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to a Polyglutamine Anomaly; Autosomal Dominant Spinocerebellar Ataxia Due to a Point Mutation; Autosomal Dominant Spinocerebellar Ataxia Due to a Channelopathy; Autosomal Dominant Spastic Ataxia Type 1; Autosomal Dominant Spastic Ataxia; Autosomal Dominant Optic Atrophy; Ataxia-telangiectasia Variant; Ataxia-telangiectasia; Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy; Autosomal Dominant Cerebellar Ataxia Type 4; Autosomal Dominant Cerebellar Ataxia Type 3; Autosomal Dominant Cerebellar Ataxia Type 2; Autosomal Dominant Cerebellar Ataxia Type 1; Autosomal Dominant Cerebellar Ataxia; Ataxia-telangiectasia-like Disorder; Ataxia-intellectual Disability-oculomotor Apraxia-cerebellar Cysts Syndrome; Ataxia-deafness-intellectual Disability Syndrome; Ataxia With Vitamin E Deficiency; Ataxia With Dementia; Ataxia Neuropathy Spectrum; Ataxia - Tapetoretinal Degeneration; Ataxia - Photosensitivity - Short Stature; Ataxia - Pancytopenia; Ataxia - Oculomotor Apraxia Type 1; Ataxia - Hypogonadism - Choroidal Dystrophy; Ataxia - Other; Ataxia - Genetic Diagnosis - Unknown; Acquired Ataxia; Adult-onset Autosomal Recessive Cerebellar Ataxia; Alcohol Related Ataxia; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type II; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine

Fatty acid oxidation disorders as primary cause of sudden and unexpected death in infants and young children

DEFF Research Database (Denmark)

Banner, Jytte; Kølvraa, S; Gregersen, N

1997-01-01

Disorders of fatty acid metabolism are known to be responsible for cases of sudden and unexpected death in infancy. At least 14 disorders are known at present. 120 cases of sudden infant death syndrome (SIDS) had been examined for a prevalent mutation (G985) causing medium chain acyl Co......A dehydrogenase deficiency, which is inherited in an autosomal recessive mode. No over-representation of either homozygous or heterozygous cases was found....

Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support.

Science.gov (United States)

Marsh, Samuel E; Blurton-Jones, Mathew

2017-06-01

Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease currently affect tens of millions of people worldwide. Unfortunately, as the world's population ages, the incidence of many of these diseases will continue to rise and is expected to more than double by 2050. Despite significant research and a growing understanding of disease pathogenesis, only a handful of therapies are currently available and all of them provide only transient benefits. Thus, there is an urgent need to develop novel disease-modifying therapies to prevent the development or slow the progression of these debilitating disorders. A growing number of pre-clinical studies have suggested that transplantation of neural stem cells (NSCs) could offer a promising new therapeutic approach for neurodegeneration. While much of the initial excitement about this strategy focused on the use of NSCs to replace degenerating neurons, more recent studies have implicated NSC-mediated changes in neurotrophins as a major mechanism of therapeutic efficacy. In this mini-review we will discuss recent work that examines the ability of NSCs to provide trophic support to disease-effected neuronal populations and synapses in models of neurodegeneration. We will then also discuss some of key challenges that remain before NSC-based therapies for neurodegenerative diseases can be translated toward potential clinical testing. Copyright © 2017 Elsevier Ltd. All rights reserved.

Biology and genetics of oculocutaneous albinism and vitiligo ...

African Journals Online (AJOL)

Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism (OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of disorders that result in hypopigmented skin due to ...

Clinical neurogenetics: friedreich ataxia.

Science.gov (United States)

Collins, Abigail

2013-11-01

Friedreich ataxia is the most common autosomal recessive ataxia. It is a progressive neurodegenerative disorder, typically with onset before 20 years of age. Signs and symptoms include progressive ataxia, ascending weakness and ascending loss of vibration and joint position senses, pes cavus, scoliosis, cardiomyopathy, and arrhythmias. There are no disease-modifying medications to either slow or halt the progression of the disease, but research investigating therapies to increase endogenous frataxin production and decrease the downstream consequences of disrupted iron homeostasis is ongoing. Clinical trials of promising medications are underway, and the treatment era of Friedreich ataxia is beginning. Copyright © 2013 Elsevier Inc. All rights reserved.

A novel nonsense mutation in the WFS1 gene causes the Wolfram syndrome.

Science.gov (United States)

Noorian, Shahab; Savad, Shahram; Mohammadi, Davood Shah

2016-05-01

Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder, which is mostly caused by mutations in the WFS1 gene. The WFS1 gene product, which is called wolframin, is thought to regulate the function of endoplasmic reticulum. The endoplasmic reticulum has a critical role in protein folding and material transportation within the cell or to the surface of the cell. Identification of new mutations in WFS1 gene will unravel the molecular pathology of WS. The aim of this case report study is to describe a novel mutation in exon 4 of the WFS1 gene (c.330C>A) in a 9-year-old boy with WS.

Skeletal muscle, but not cardiovascular function, is altered in a mouse model of autosomal recessive hypophosphatemic rickets

Directory of Open Access Journals (Sweden)

Michael J. Wacker

2016-05-01

Full Text Available Autosomal recessive hypophosphatemic rickets (ARHR is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL- fast-twitch muscle, soleus (SOL- slow-twitch muscle, heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2a or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In

Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders.

Science.gov (United States)

Fagherazzi, Elen V; Garcia, Vanessa A; Maurmann, Natasha; Bervanger, Thielly; Halmenschlager, Luis H; Busato, Stefano B; Hallak, Jaime E; Zuardi, Antônio W; Crippa, José A; Schröder, Nadja

2012-02-01

Cannabidiol, the main nonpsychotropic constituent of Cannabis sativa, possesses a large number of pharmacological effects including anticonvulsive, sedative, hypnotic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective, as demonstrated in clinical and preclinical studies. Many neurodegenerative disorders involve cognitive deficits, and this has led to interest in whether cannabidiol could be useful in the treatment of memory impairment associated to these diseases. We used an animal model of cognitive impairment induced by iron overload in order to test the effects of cannabidiol in memory-impaired rats. Rats received vehicle or iron at postnatal days 12-14. At the age of 2 months, they received an acute intraperitoneal injection of vehicle or cannabidiol (5.0 or 10.0 mg/kg) immediately after the training session of the novel object recognition task. In order to investigate the effects of chronic cannabidiol, iron-treated rats received daily intraperitoneal injections of cannabidiol for 14 days. Twenty-four hours after the last injection, they were submitted to object recognition training. Retention tests were performed 24 h after training. A single acute injection of cannabidiol at the highest dose was able to recover memory in iron-treated rats. Chronic cannabidiol improved recognition memory in iron-treated rats. Acute or chronic cannabidiol does not affect memory in control rats. The present findings provide evidence suggesting the potential use of cannabidiol for the treatment of cognitive decline associated with neurodegenerative disorders. Further studies, including clinical trials, are warranted to determine the usefulness of cannabidiol in humans suffering from neurodegenerative disorders.

Cerebrotendinous xanthomatosis (a rare lipid storage disorder): a case report

OpenAIRE

Razi, Syed Mohd; Gupta, Abhinav Kumar; Gupta, Deepak Chand; Gutch, Manish; Gupta, Keshav Kumar; Usman, Syeda Iqra

2016-01-01

Background Cerebrotendinous xanthomatosis is a very rare autosomal recessive lipid storage disorder affecting bile acid biosynthesis. It is manifested by subtle neurological and non-neurological symptoms due to abnormal tissue lipid deposition. Diagnosis is usually delayed but early diagnosis and replacement therapy can prevent devastating neurological sequelae. Case presentation We present a case of a 25-year-old Asian Indian woman who presented with gait difficulty, fusiform swellings of bi...

Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia.

Science.gov (United States)

Adaimy, Lynn; Chouery, Eliane; Megarbane, Hala; Mroueh, Salman; Delague, Valerie; Nicolas, Elsa; Belguith, Hanen; de Mazancourt, Philippe; Megarbane, Andre

2007-10-01

Odonto-onycho-dermal dysplasia is a rare autosomal recessive syndrome in which the presenting phenotype is dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin. We studied three consanguineous Lebanese Muslim Shiite families that included six individuals affected with odonto-onycho-dermal dysplasia. Using a homozygosity-mapping strategy, we assigned the disease locus to an ~9-cM region at chromosome 2q35-q36.2, located between markers rs16853834 and D2S353, with a maximum multipoint LOD score of 5.7. Screening of candidate genes in this region led us to identify the same c.697G-->T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients. At the protein level, the mutation is predicted to result in a premature truncated protein of 232 aa instead of 417 aa. This is the first report to our knowledge of a human phenotype resulting from a mutation in WNT10A, and it is the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, expanding the list of WNT-related diseases.

Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.

Science.gov (United States)

Maugeri, A; Klevering, B J; Rohrschneider, K; Blankenagel, A; Brunner, H G; Deutman, A F; Hoyng, C B; Cremers, F P

2000-10-01

The photoreceptor cell-specific ATP-binding cassette transporter gene (ABCA4; previously denoted "ABCR") is mutated, in most patients, with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients from Germany and The Netherlands with isolated CRD. Single-strand conformation-polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans.

Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders.

Science.gov (United States)

Saniotis, Arthur; Henneberg, Maciej; Sawalma, Abdul-Rahman

2018-01-01

Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an "Endomyccorhizae like interface" (ELI) nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

Sleep disturbance in mental health problems and neurodegenerative disease

Directory of Open Access Journals (Sweden)

Anderson KN

2013-05-01

Full Text Available Kirstie N Anderson1 Andrew J Bradley2,3 1Department of Neurology, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK; 2Eli Lilly and Company Limited, Lilly House, Basingstoke, UK; 3Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK Abstract: Sleep has been described as being of the brain, by the brain, and for the brain. This fundamental neurobiological behavior is controlled by homeostatic and circadian (24-hour processes and is vital for normal brain function. This review will outline the normal sleep–wake cycle, the changes that occur during aging, and the specific patterns of sleep disturbance that occur in association with both mental health disorders and neurodegenerative disorders. The role of primary sleep disorders such as insomnia, obstructive sleep apnea, and REM sleep behavior disorder as potential causes or risk factors for particular mental health or neurodegenerative problems will also be discussed. Keywords: sleep, mental health, neurodegenerative disorders, cognition

Glutamate and Neurodegenerative Disease

Science.gov (United States)

Schaeffer, Eric; Duplantier, Allen

As the main excitatory neurotransmitter in the mammalian central nervous system, glutamate is critically involved in most aspects of CNS function. Given this critical role, it is not surprising that glutamatergic dysfunction is associated with many CNS disorders. In this chapter, we review the literature that links aberrant glutamate neurotransmission with CNS pathology, with a focus on neurodegenerative diseases. The biology and pharmacology of the various glutamate receptor families are discussed, along with data which links these receptors with neurodegenerative conditions. In addition, we review progress that has been made in developing small molecule modulators of glutamate receptors and transporters, and describe how these compounds have helped us understand the complex pharmacology of glutamate in normal CNS function, as well as their potential for the treatment of neurodegenerative diseases.

Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe).

Science.gov (United States)

Finsterer, Josef; Stöllberger, Claudia; Wollmann, Eva; Dertinger, Susanne; Laccone, Franco

2016-09-01

Carvajal syndrome is an autosomal dominant or autosomal recessive disorder, manifesting with dilated cardiomyopathy, woolly hair, and palmoplantar keratoma. Additional manifestations can be occasionally found. Carvajal syndrome may be due to mutations in the desmocollin-2, desmoplakin, or plakophilin-2 gene. We report a family with Carvajal syndrome which additionally presented with hypoacusis, noncompaction, recurrent pharyngeal infections, oligodontia, and recurrent diarrhoea. Father and brother were also affected and had died suddenly, the father despite implantation of a cardioverter defibrillator (ICD). Genetic studies revealed the novel pathogenic mutation c.1678A > T in the desmoplakin gene resulting in the amino acid change Ile to Phe at position 560 in the index case and her brother. The index case underwent ICD implantation recently. Phenotypic manifestations of Carvajal syndrome are even broader than so far anticipated, the number of mutations in the desmoplakin gene responsible for Carvajal syndrome is still increasing, and these patients require implantation of an ICD as soon as their diagnosis is established.

Essential Tremor: A Neurodegenerative Disease?

Directory of Open Access Journals (Sweden)

Julian Benito-Leon

2014-07-01

Full Text Available Background: Essential tremor (ET is one of the most common neurological disorders among adults, and is the most common of the many tremor disorders. It has classically been viewed as a benign monosymptomatic condition, yet over the past decade, a growing body of evidence indicates that ET is a progressive condition that is clinically heterogeneous, as it may be associated with a spectrum of clinical features, with both motor and non‐motor elements. In this review, I will describe the most significant emerging milestones in research which, when taken together, suggest that ET is a neurodegenerative condition.Methods: A PubMed search conducted in June 2014 crossing the terms “essential tremor” (ET and “neurodegenerative” yielded 122 entries, 20 of which included the term “neurodegenerative” in the article title. This was supplemented by articles in the author's files that pertained to this topic.Results/Discussion: There is an open and active dialogue in the medical community as to whether ET is a neurodegenerative disease, with considerable evidence in favor of this. Specifically, ET is a progressive disorder of aging associated with neuronal loss (reduction in Purkinje cells as well as other post‐mortem changes that occur in traditional neurodegenerative disorders. Along with this, advanced neuroimaging techniques are now demonstrating distinct structural changes, several of which are consistent with neuronal loss, in patients with ET. However, further longitudinal clinical and neuroimaging longitudinal studies to assess progression are required.

Coenzyme Q10 effects in neurodegenerative disease

Directory of Open Access Journals (Sweden)

Meredith Spindler

2009-11-01

Full Text Available Meredith Spindler1, M Flint Beal1,2, Claire Henchcliffe1,21Department of Neurology, 2Department of Neuroscience, Weill Medical College of Cornell University, New York, NY, USAAbstract: Coenzyme Q10 (CoQ10 is an essential cofactor in the mitochondrial respiratory chain, and as a dietary supplement it has recently gained attention for its potential role in the treatment of neurodegenerative disease. Evidence for mitochondrial dysfunction in neurodegenerative disorders derives from animal models, studies of mitochondria from patients, identification of genetic defects in patients with neurodegenerative disease, and measurements of markers of oxidative stress. Studies of in vitro models of neuronal toxicity and animal models of neurodegenerative disorders have demonstrated potential neuroprotective effects of CoQ10. With this data in mind, several clinical trials of CoQ10 have been performed in Parkinson’s disease and atypical Parkinson’s syndromes, Huntington’s disease, Alzheimer disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis, with equivocal findings. CoQ10 is widely available in multiple formulations and is very well tolerated with minimal adverse effects, making it an attractive potential therapy. Phase III trials of high-dose CoQ10 in large sample sizes are needed to further ascertain the effects of CoQ10 in neurodegenerative diseases.Keywords: coenzyme Q10, neurodegenerative disease, Parkinson’s disease, Huntington’s disease, mitochondrial dysfunction

The incidence of genetic disorders in children and young adults

International Nuclear Information System (INIS)

Anderson, T.W.; Baird, P.A.; Lowry, R.B.; Newcombe, H.B.

1987-11-01

Current estimates of the genetic risks from exposure to ionizing radiation are based on two kinds of data: a) incidence rates in humans for the genetic diseases that are believed to be present in the population due to mutations of natural origin, and b) radiation induced mutation rates. One necessary prerequisite before any possible increase in genetic load from mutagens can be estimated is baseline information on the magnitude of genetically-caused ill health already present in the population. The present study utilizes the data base of an ongoing population-based Registry with multiple sources of ascertainment to estimate the present population load from genetic disease. It was found that 4.9% of liveborn individuals below 25 can be expected to have genetic or partly genetic diseases. This was composed of single-gene disorders (autosomal dominant, autosomal recessive and X-linked recessive), chromosomal anomalies and multifactorial disorders (including those present at birth and those later in onset). Since previous studies have usually considered all congenital anomalies (ICD 740-759) as part of the genetic load, data are also presented separately for this category to facilitate comparison with earlier studies. These new data should represent a better estimate of the genetic load in the population than previous studies

Glucose 6 phosphatase dehydrogenase (G6PD and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities

Directory of Open Access Journals (Sweden)

Manju Tiwari

2017-12-01

Full Text Available Glucose 6 phosphate dehydrogenase (G6PD is a key and rate limiting enzyme in the pentose phosphate pathway (PPP. The physiological significance of enzyme is providing reduced energy to specific cells like erythrocyte by maintaining co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH. There are preponderance research findings that demonstrate the enzyme (G6PD role in the energy balance, and it is associated with blood-related diseases and disorders, primarily the anemia resulted from G6PD deficiency. The X-linked genetic deficiency of G6PD and associated non-immune hemolytic anemia have been studied widely across the globe. Recent advancement in biology, more precisely neuroscience has revealed that G6PD is centrally involved in many neurological and neurodegenerative disorders. The neuroprotective role of the enzyme (G6PD has also been established, as well as the potential of G6PD in oxidative damage and the Reactive Oxygen Species (ROS produced in cerebral ischemia. Though G6PD deficiency remains a global health issue, however, a paradigm shift in research focusing the potential of the enzyme in neurological and neurodegenerative disorders will surely open a new avenue in diagnostics and enzyme therapeutics. Here, in this study, more emphasis was made on exploring the role of G6PD in neurological and inflammatory disorders as well as non-immune hemolytic anemia, thus providing diagnostic and therapeutic opportunities.

A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance

Directory of Open Access Journals (Sweden)

Ali Bassam R

2012-05-01

Full Text Available Abstract Background We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26. Methods In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation. Results Our analysis resulted in the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently found to be causing Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. The phenotype in our patients partially overlaps with the phenotypes associated with those syndromes but they also exhibit some distinctive features including multiple epiphyseal dysplasia. Conclusions We report the first missense homozygous disease-causing mutation in KIF7 and expand the clinical spectrum associated with mutations in this gene to include multiple epiphyseal dysplasia. The missense nature of the mutation might account for the unique presentation in our patients.

Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

DEFF Research Database (Denmark)

2017-01-01

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients...... with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient-parent trios that were generally...... not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population....

Four siblings with distal renal tubular acidosis and nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial appearance: a possible new autosomal recessive syndrome.

Science.gov (United States)

Faqeih, Eissa; Al-Akash, Samhar I; Sakati, Nadia; Teebi, Prof Ahmad S

2007-09-01

We report on four siblings (three males, one female) born to first cousin Arab parents with the constellation of distal renal tubular acidosis (RTA), small kidneys, nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial features. They presented with early developmental delay with subsequent severe mental, behavioral and social impairment and autistic-like features. Their facial features are unique with prominent cheeks, well-defined philtrum, large bulbous nose, V-shaped upper lip border, full lower lip, open mouth with protruded tongue, and pits on the ear lobule. All had proteinuria, hypercalciuria, hypercalcemia, and normal anion-gap metabolic acidosis. Renal ultrasound examinations revealed small kidneys, with varying degrees of hyperechogenicity and nephrocalcinosis. Additional findings included dilated ventricles and cerebral demyelination on brain imaging studies. Other than distal RTA, common causes of nephrocalcinosis were excluded. The constellation of features in this family currently likely represents a possibly new autosomal recessive syndrome providing further evidence of heterogeneity of nephrocalcinosis syndromes. Copyright 2007 Wiley-Liss, Inc.

Identification of IFRD1 variant in a Han Chinese family with autosomal dominant hereditary spastic paraplegia associated with peripheral neuropathy and ataxia.

Science.gov (United States)

Lin, Pengfei; Zhang, Dong; Xu, Guangrun; Yan, Chuanzhu

2018-04-01

Spinocerebellar ataxias (SCAs) are a group of autosomal dominant, clinically heterogeneous neurodegenerative disorders. SCA18 is a rare autosomal dominant sensory/motor neuropathy with ataxia (OMIM#607458) associated with a single missense variant c.514 A>G in the interferon related developmental regulator 1 (IFRD1) gene previously reported in a five-generation American family of Irish origin. However, to date, there have been no other reports of the IFRD1 mutation to confirm its role in SCA. Here, we report a Han Chinese family with SCA18; the family members presented with a slowly progressing gait ataxia, pyramidal tract signs, and peripheral neuropathy. We identified a missense variant (c.514 A>G, p.I172V) in IFRD1 gene in the family using targeted next-generation sequencing and Sanger direct sequencing with specific primers. Our results suggest that the IFRD1 gene may be the causative allele for SCA18.

Fetal brain disruption sequence versus fetal brain arrest: A distinct autosomal recessive developmental brain malformation phenotype.

Science.gov (United States)

Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; El-Khayat, Hamed A; Eid, Ola M; Saba, Soliman; Farag, Mona K; Saleem, Sahar N; Gaber, Khaled R

2015-05-01

The term fetal brain disruption sequence (FBDS) was coined to describe a number of sporadic conditions caused by numerous external disruptive events presenting with variable imaging findings. However, rare familial occurrences have been reported. We describe five patients (two sib pairs and one sporadic) with congenital severe microcephaly, seizures, and profound intellectual disability. Brain magnetic resonance imaging (MRI) revealed unique and uniform picture of underdeveloped cerebral hemispheres with increased extraxial CSF, abnormal gyral pattern (polymicrogyria-like lesions in two sibs and lissencephaly in the others), loss of white matter, dysplastic ventricles, hypogenesis of corpus callosum, and hypoplasia of the brainstem, but hypoplastic cerebellum in one. Fetal magnetic resonance imaging (FMRI) of two patients showed the same developmental brain malformations in utero. These imaging findings are in accordance with arrested brain development rather than disruption. Molecular analysis excluded mutations in potentially related genes such as NDE1, MKL2, OCLN, and JAM3. These unique clinical and imaging findings were described before among familial reports with FBDS. However, our patients represent a recognizable phenotype of developmental brain malformations, that is, apparently distinguishable from either familial microhydranencephaly or microlissencephaly that were collectively termed FBDS. Thus, the use of the umbrella term FBDS is no longer helpful. Accordingly, we propose the term fetal brain arrest to distinguish them from other familial patients diagnosed as FBDS. The presence of five affected patients from three unrelated consanguineous families suggests an autosomal-recessive mode of inheritance. The spectrum of fetal brain disruption sequence is reviewed. © 2015 Wiley Periodicals, Inc.

Autosomal recessive atrial dilated cardiomyopathy with standstill evolution associated with mutation of Natriuretic Peptide Precursor A.

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Disertori, Marcello; Quintarelli, Silvia; Grasso, Maurizia; Pilotto, Andrea; Narula, Nupoor; Favalli, Valentina; Canclini, Camilla; Diegoli, Marta; Mazzola, Silvia; Marini, Massimiliano; Del Greco, Maurizio; Bonmassari, Roberto; Masè, Michela; Ravelli, Flavia; Specchia, Claudia; Arbustini, Eloisa

2013-02-01

Atrial dilatation and atrial standstill are etiologically heterogeneous phenotypes with poorly defined nosology. In 1983, we described 8-years follow-up of atrial dilatation with standstill evolution in 8 patients from 3 families. We later identified 5 additional patients with identical phenotypes: 1 member of the largest original family and 4 unrelated to the 3 original families. All families are from the same geographic area in Northeast Italy. We followed up the 13 patients for up to 37 years, extended the clinical investigation and monitoring to living relatives, and investigated the genetic basis of the disease. The disease was characterized by: (1) clinical onset in adulthood; (2) biatrial dilatation up to giant size; (3) early supraventricular arrhythmias with progressive loss of atrial electric activity to atrial standstill; (4) thromboembolic complications; and (5) stable, normal left ventricular function and New York Heart Association functional class during the long-term course of the disease. By linkage analysis, we mapped a locus at 1p36.22 containing the Natriuretic Peptide Precursor A gene. By sequencing Natriuretic Peptide Precursor A, we identified a homozygous missense mutation (p.Arg150Gln) in all living affected individuals of the 6 families. All patients showed low serum levels of atrial natriuretic peptide. Heterozygous mutation carriers were healthy and demonstrated normal levels of atrial natriuretic peptide. Autosomal recessive atrial dilated cardiomyopathy is a rare disease associated with homozygous mutation of the Natriuretic Peptide Precursor A gene and characterized by extreme atrial dilatation with standstill evolution, thromboembolic risk, preserved left ventricular function, and severely decreased levels of atrial natriuretic peptide.

Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders.

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Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E

2017-03-01

Traumatic brain injury (TBI), advanced age, and cerebral vascular disease are factors conferring increased risk for late onset Alzheimer's disease (AD). These conditions are also related pathologically through multiple interacting mechanisms. The hallmark pathology of AD consists of pathological aggregates of amyloid-β (Aβ) peptides and tau proteins. These molecules are also involved in neuropathology of several other chronic neurodegenerative diseases, and are under intense investigation in the aftermath of TBI as potential contributors to the risk for developing AD and chronic traumatic encephalopathy (CTE). The pathology of TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health. In this regard, dysfunction of the aging neurovascular system could be an important link between TBI and chronic neurodegenerative diseases, either as a precipitating event or related to accumulation of AD-like pathology which is amplified in the context of aging. Thus with advanced age and vascular dysfunction, TBI can trigger self-propagating cycles of neuronal injury, pathological protein aggregation, and synaptic loss resulting in chronic neurodegenerative disease. In this review we discuss evidence supporting TBI and aging as dual, interacting risk factors for AD, and the role of Aβ and cerebral vascular dysfunction in this relationship. Evidence is discussed that Aβ is involved in cyto- and synapto-toxicity after severe TBI, and that its chronic effects are potentiated by aging and impaired cerebral vascular function. From a therapeutic perspective, we emphasize that in the fields of TBI- and aging-related neurodegeneration protective strategies should include preservation of

Genetic Linkage Analysis of the DFNB21 Locus in Autosomal Recessive Hearing Loss in Large Families from Khuzestan Province

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Mahtab Khosrofar

2017-06-01

Full Text Available Abstract Background: Hearing loss (HL is the most common congenital defect in humans. One or two in thousand newborn babies have prelingual hearing loss. Autosomal recessive non-syndromic hearing loss (ARNSHL is the most common form of hereditary deafness. Hearing loss is more common in the developing countries which is due to genetic and environmental (cultural -health factors reasons. HL has a wide range of clinical demonstrations including: congenital or late onset, conductive or sensory-neural, syndromic or non-syndromic hearing loss. The goal of this project is to determine the portion of the DFNB21 (TECTA in ARNSHL in families with negative GJB2 gene in Khuzestan province. Materials and Methods: We studied 21 families with ARNSHL with at least 4 patients and negative for GJB2 mutations from Khuzestan province. Genetic linkage analysis was performed using STR markers linked to DFNB21 locus. Results: Following genetic linkage analysis and haplotyping, out of 21 families with ARNSHL, one family showed linkage to the DFNB21 (TECTA locus. Conclusion: The results of this project confirm other studies in Iran and give insight into the most common loci causing ARNSHL in Iran which could be helpful in research and clinic.

Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders

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Arthur Saniotis

2018-03-01

Full Text Available Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an “Endomyccorhizae like interface” (ELI nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

Preimplantation genetic diagnosis for a Chinese family with autosomal recessive Meckel-Gruber syndrome type 3 (MKS3.

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Yanping Lu

Full Text Available Meckel-Gruber syndrome type 3 is an autosomal recessive genetic defect caused by mutations in TMEM67 gene. In our previous study, we have identified a homozygous TMEM67 mutation in a Chinese family exhibiting clinical characteristics of MKS3, which provided a ground for further PGD procedure. Here we report the development and the first clinical application of the PGD for this MKS3 family. Molecular analysis protocol for clinical PGD procedure was established using 50 single cells in pre-clinical set-up. After whole genomic amplification by multiple displacement amplification with the DNA from single cells, three techniques were applied simultaneously to increase the accuracy and reliability of genetic diagnosis in single blastomere, including real-time PCR with Taq Man-MGB probe, haplotype analysis with polymorphic STR markers and Sanger sequencing. In the clinical PGD cycle, nine embryos at cleavage-stage were biopsied and subjected to genetic diagnosis. Two embryos diagnosed as free of TMEM67 mutation were transferred and one achieving normal pregnancy. Non-invasive prenatal assessment of trisomy 13, 18 and 21 by multiplex DNA sequencing at 18 weeks' gestation excluded the aneuploidy of the analyzed chromosomes. A healthy boy was delivered by cesarean section at 39 weeks' gestation. DNA sequencing from his cord blood confirmed the result of genetic analysis in the PGD cycle. The protocol developed in this study was proved to be rapid and safe for the detection of monogenic mutations in clinical PGD cycle.

SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system.

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Brons, A-K; Henthorn, P S; Raj, K; Fitzgerald, C A; Liu, J; Sewell, A C; Giger, U

2013-01-01

Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds. To determine urinary cystine concentrations, inheritance, and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds. Mixed and purebred Labrador Retrievers (n = 6), Australian Cattle Dogs (6), Miniature Pinschers (4), and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs. Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA. In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed-specific DNA tests were developed, but the prevalence of each mutation remains unknown. These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds. Copyright © 2013 by the American College of Veterinary Internal Medicine.

Pain in Neurodegenerative Disease : Current Knowledge and Future Perspectives

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de Tommaso, Marina; Arendt-Nielsen, Lars; Defrin, Ruth; Kunz, Miriam; Pickering, Gisele; Valeriani, Massimiliano

2016-01-01

Neurodegenerative diseases are going to increase as the life expectancy is getting longer. The management of neurodegenerative diseases such as Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD related disorders, motor neuron diseases (MND), Huntington's disease (HD),

Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders?

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Luchowska-Kocot, Dorota; Kiełczykowska, Małgorzata; Musik, Irena; Kurzepa, Jacek

2017-01-01

Vitamin C (Vit C) is considered to be a vital antioxidant molecule in the brain. Intracellular Vit C helps maintain integrity and function of several processes in the central nervous system (CNS), including neuronal maturation and differentiation, myelin formation, synthesis of catecholamine, modulation of neurotransmission and antioxidant protection. The importance of Vit C for CNS function has been proven by the fact that targeted deletion of the sodium-vitamin C co-transporter in mice results in widespread cerebral hemorrhage and death on post-natal day one. Since neurological diseases are characterized by increased free radical generation and the highest concentrations of Vit C in the body are found in the brain and neuroendocrine tissues, it is suggested that Vit C may change the course of neurological diseases and display potential therapeutic roles. The aim of this review is to update the current state of knowledge of the role of vitamin C on neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis and amyotrophic sclerosis, as well as psychiatric disorders including depression, anxiety and schizophrenia. The particular attention is attributed to understanding of the mechanisms underlying possible therapeutic properties of ascorbic acid in the presented disorders. PMID:28654017

Skeletal muscle training for spinal muscular atrophy type 3 (Protocol).

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Bartels, B.; Montes, J.; Pol, W.L. van der; Groot, J.F. de

2016-01-01

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by a genetic mutation in the survival motor neuron 1 (SMN1) gene (5q11.2-q13.3) (Lefebvre 1995). With an incidence of one in 10,000 live births, it is the leading genetic cause of infant death (Lunn 2008;

Development and validation of brain and spinal cord vector and cell-delivery techniques in pre-clinical minipig models of neurodegenerative disorders

Czech Academy of Sciences Publication Activity Database

Juhás, Štefan; Juhásová, Jana; Klíma, Jiří; Maršala, M.; Maršala, S.; Atsushi, Y.; Johe, K.; Motlík, Jan

2015-01-01

Roč. 78, Suppl 2 (2015), s. 9-10 ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk(CZ) 7F14308 Institutional support: RVO:67985904 Keywords : minipig models of neurodegenerative disorders * brin and spinal cord cell delivery techniques Subject RIV: EB - Genetics ; Molecular Biology

Early Infantile Leigh-like Gene Defects Have a Poor Prognosis: Report and Review

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Majid Alfadhel

2017-10-01

Full Text Available Solute carrier family 19 (thiamine transporter, member 3 ( SCL19A3 gene defect produces an autosomal recessive neurodegenerative disorder associated with different phenotypes and acronyms. One of the common presentations is early infantile lethal Leigh-like syndrome. We report a case of early infantile Leigh-like SLC19A3 gene defects of patients who died at 4 months of age with no response to a high dose of biotin and thiamine. In addition, we report a novel mutation that was not reported previously. Finally, we review the literature regarding early infantile Leigh-like SLC19A3 gene defects and compare the literature with our patient.

Infantile Type Sandhoff Disease with Striking Brain MRI Findings and a Novel Mutation

International Nuclear Information System (INIS)

Beker-Acay, Mehtap; Elmas, Muhsin; Koken, Resit; Unlu, Ebru; Bukulmez, Aysegul

2016-01-01

Sandhoff disease is an autosomal recessive disorder caused by β-hexosaminidase deficiency in which the ganglioside GM2 and other glycolipids accumulate intracellularly within lysosomes. This process results in progressive motor neuron manifestations, death from respiratory failure and infections in infantiles. This report presents a 22-month-old girl with infantile type Sandhoff disease that was hospitalized for generalized seizures and psychomotor retardation. She was diagnosed with a genetically proven novel mutation and by demonstrating it’s specific imaging findings. Determination of spesific changes in neuroimaging which are initial findings for GM2 gangliosidosis is important from the point of diagnosis and follow-up in infants suspected of having a neurodegenerative disease

Severe steatohepatitis in a patient with a rare neutral lipid storage disorder due to ABHD5 mutation.

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Ronchetti, Anna; Prati, Daniele; Pezzotta, Maria Grazia; Tavian, Daniela; Colombo, Roberto; Callea, Francesco; Colli, Agostino

2008-09-01

Fatty liver disease is mainly caused by alcohol consumption, excessive body weight, dyslipidemia and impaired glucose tolerance, but inherited disorders can sometimes be involved. We report the case of a 40-year-old woman with steatohepatitis and severe portal hypertension, associated with ichthyosis, cataract and hypoacusia. The clinical, pathological and genetic findings were consistent with a diagnosis of Chanarin-Dorfman syndrome (CDS), a rare autosomal recessive inherited neutral lipid storage disorder, and genetic analysis showed that a novel ABHD5 mutation is responsible.

Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders.

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Han, Chanshuai; Chaineau, Mathilde; Chen, Carol X-Q; Beitel, Lenore K; Durcan, Thomas M

2018-01-01

Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop "first-of-their-kind" disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an "Open Science" model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders

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Chanshuai Han

2018-02-01

Full Text Available Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop “first-of-their-kind” disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI and its partners are piloting an “Open Science” model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools.

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Silva, Juliana; Monge-Fuentes, Victoria; Gomes, Flávia; Lopes, Kamila; dos Anjos, Lilian; Campos, Gabriel; Arenas, Claudia; Biolchi, Andréia; Gonçalves, Jacqueline; Galante, Priscilla; Campos, Leandro; Mortari, Márcia

2015-08-18

Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer's Disease, Parkinson's Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

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Paulo Victor Sgobbi de Souza

2015-03-01

Full Text Available Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant.

Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome.

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Cabral, Rita M; Kurban, Mazen; Wajid, Muhammad; Shimomura, Yutaka; Petukhova, Lynn; Christiano, Angela M

2012-04-01

Generalized peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by lifelong, continuous shedding of the upper epidermis. Using whole-genome homozygozity mapping and whole-exome sequencing, we identified a novel homozygous missense mutation (c.229C>T, R77W) within the CHST8 gene, in a large consanguineous family with non-inflammatory PSS type A. CHST8 encodes a Golgi transmembrane N-acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1), which we show by immunofluorescence staining to be expressed throughout normal epidermis. A colorimetric assay for total sulfated glycosaminoglycan (GAG) quantification, comparing human keratinocytes (CCD1106 KERTr) expressing wild type and mutant recombinant GalNAc4-ST1, revealed decreased levels of total sulfated GAGs in cells expressing mutant GalNAc4-ST1, suggesting loss of function. Western blotting revealed lower expression levels of mutant recombinant GalNAc4-ST1 compared to wild type, suggesting that accelerated degradation may result in loss of function, leading to PSS type A. This is the first report describing a mutation as the cause of PSS type A. Copyright © 2012 Elsevier Inc. All rights reserved.

Clinical effects of non-ablative and ablative fractional lasers on various hair disorders: a case series of 17 patients.

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Cho, Suhyun; Choi, Min Ju; Zheng, Zhenlong; Goo, Boncheol; Kim, Do-Young; Cho, Sung Bin

2013-04-01

Both ablative and non-ablative fractional lasers have been applied to various uncommon hair disorders. The purpose of this study was to demonstrate the clinical effects of fractional laser therapy on the course of primary follicular and perifollicular pathologies and subsequent hair regrowth. A retrospective review of 17 patients with uncommon hair disorders - including ophiasis, autosomal recessive woolly hair/hypotrichosis, various secondary cicatricial alopecias, pubic hypotrichosis, frontal fibrosing alopecia, and perifolliculitis abscedens et suffodiens - was conducted. All patients had been treated with non-ablative and/or ablative fractional laser therapies. The mean clinical improvement score in these 17 patients was 2.2, while the mean patient satisfaction score was 2.5. Of the 17 subjects, 12 (70.6%) demonstrated a clinical response to non-ablative and/or ablative fractional laser treatments, including individuals with ophiasis, autosomal recessive woolly hair/hypotrichosis, secondary cicatricial alopecia (scleroderma and pressure-induced alopecia), frontal fibrosing alopecia, and perifolliculitis abscedens et suffodiens. Conversely, patients with long-standing ophiasis, surgical scar-induced secondary cicatricial alopecia, and pubic hypotrichosis did not respond to fractional laser therapy. Our findings demonstrate that the use of non-ablative and/or ablative fractional lasers promoted hair growth in certain cases of uncommon hair disorders without any remarkable side effects.

The First Survey of Distribution of Inherited Deafness Patterns in Individuals Referred to Genetic Center of Ahvaz Welfare Organization, Southern Iran

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Gholamreza Mohammadian

2011-09-01

Full Text Available Background and Aim: Deafness is a heterogeneous disorder induced by genetic and environmental factors. It is the most common hereditary sensory-neural disorder that affects 1/1000 to 1/2000 of the newborns. More than 70% of hearing loss cases are caused by genetic disorders, 85% of which result from nonsyndromic autosomal recessive sensory-neural hearing loss. Up to now, more than 100 genes contributing in hearing loss have been determined. Alteration of these genes may result in hearing loss.This study was performed to identify the inheritance patterns of deafness and its relation with ethnicity, gender and consanguineous marriages.Methods: In this survey, data from 356 families affected by hearing loss and referred to welfare organization of Ahvaz during the time were collected based on sex, ethnic groups and relativeness.Results: The results state a high frequency of autosomal recessive deafness caused by consanguineous marriages within Arab and non-Arab ethnic groups (p<0.05. But no significant difference in gender."nConclusion: In conclusion, the high frequency of autosomal recessive deafness among the population with a high frequency of consanguineous marriages is considerable. The dominant pattern of deafness observed in this population was autosomal recessive.

Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis

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Rossi, Massimiliano; Edery, Patrick [Hospices Civils de Lyon, Genetic Department, Referral Centre for Developmental Abnormalities, Femme-Mere-Enfant Hospital, Bron (France); INSERM U1028 UMR CNRS 5,292, UCBL, CRNL TIGER Team, CH le Vinater, Bron (France); Hall, Christine M. [Retired from Department of Radiology, Great Ormond Street Hospital, London (United Kingdom); Bouvier, Raymonde; Collardeau-Frachon, Sophie [Hospices Civils de Lyon, Department of Pathology, CBPE, Bron (France); Le Breton, Frederique [Hospices Civils de Lyon, Department of Pathology, Croix-Rousse Hospital, Lyon (France); Bucourt, Martine [AP-HP, Foetopathology Unit, Jean Verdier Hospital, Bondy (France); Cordier, Marie Pierre [Hospices Civils de Lyon, Genetic Department, Referral Centre for Developmental Abnormalities, Femme-Mere-Enfant Hospital, Bron (France); Vianey-Saban, Christine [Hospices Civils de Lyon, Department of Inborn Errors of Metabolism and Neonatal Screening, CBPE, Bron (France); Parenti, Giancarlo; Andria, Generoso [Federico II University, Department of Translational Medical Sciences, Section of Pediatrics, Naples (Italy); Le Merrer, Martine [AP-HP, Genetic Department, Referal Centre for Skeletal Dysplasias, Institut Imagine, Necker-Enfants Malades Hospital, Paris (United Kingdom); Offiah, Amaka C. [Stephenson Wing Sheffield Children' s NHS Foundation Trust Western Bank, Radiology Department, Children' s Hospital, Academic Unit of Child Health Room C4, Sheffield (United Kingdom)

2015-07-15

Disorders of post-squalene cholesterol biosynthesis are inborn errors of metabolism characterised by multiple congenital abnormalities, including significant skeletal involvement. The most frequent and best-characterised example is the Smith-Lemli-Opitz syndrome. Nine other disorders are known, namely autosomal-recessive Antley-Bixler syndrome, Greenberg dysplasia, X-linked dominant chondrodysplasia punctata, X-linked recessive male emopamil-binding protein deficiency, CHILD syndrome, CK syndrome, sterol C4 methyloxidase-like deficiency, desmosterolosis and lathosterolosis. This study provides an overview of the radiologic features observed in these diseases. A common pattern of limb abnormalities is recognisable, including polydactyly, which is typically post-axial and rarely interdigital and can involve all four limbs, and syndactyly of the toes. Chondrodysplasia punctata is specifically associated with a subgroup of disorders of cholesterol biosynthesis (Greenberg dysplasia, CHILD syndrome, X-linked dominant chondrodysplasia punctata, male emopamil-binding protein deficiency). The possible occurrence of epiphyseal stippling in the Smith-Lemli-Opitz syndrome, initially reported, does not appear to be confirmed. Stippling is also associated with other congenital disorders such as chromosomal abnormalities, brachytelephalangic chondrodysplasia punctata (X-linked recessive chondrodysplasia punctata, disruptions of vitamin K metabolism, maternal autoimmune diseases), rhizomelic chondrodysplasia punctata (peroxisomal disorders) and lysosomal storage disorders. In the differential diagnosis of epiphyseal stippling, a moth-eaten appearance of bones, asymmetry, or presence of a common pattern of limb abnormalities indicate inborn errors of cholesterol biosynthesis. We highlight the specific differentiating radiologic features of disorders of post-squalene cholesterol biosynthesis. (orig.)

Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis

International Nuclear Information System (INIS)

Rossi, Massimiliano; Edery, Patrick; Hall, Christine M.; Bouvier, Raymonde; Collardeau-Frachon, Sophie; Le Breton, Frederique; Bucourt, Martine; Cordier, Marie Pierre; Vianey-Saban, Christine; Parenti, Giancarlo; Andria, Generoso; Le Merrer, Martine; Offiah, Amaka C.

2015-01-01

Disorders of post-squalene cholesterol biosynthesis are inborn errors of metabolism characterised by multiple congenital abnormalities, including significant skeletal involvement. The most frequent and best-characterised example is the Smith-Lemli-Opitz syndrome. Nine other disorders are known, namely autosomal-recessive Antley-Bixler syndrome, Greenberg dysplasia, X-linked dominant chondrodysplasia punctata, X-linked recessive male emopamil-binding protein deficiency, CHILD syndrome, CK syndrome, sterol C4 methyloxidase-like deficiency, desmosterolosis and lathosterolosis. This study provides an overview of the radiologic features observed in these diseases. A common pattern of limb abnormalities is recognisable, including polydactyly, which is typically post-axial and rarely interdigital and can involve all four limbs, and syndactyly of the toes. Chondrodysplasia punctata is specifically associated with a subgroup of disorders of cholesterol biosynthesis (Greenberg dysplasia, CHILD syndrome, X-linked dominant chondrodysplasia punctata, male emopamil-binding protein deficiency). The possible occurrence of epiphyseal stippling in the Smith-Lemli-Opitz syndrome, initially reported, does not appear to be confirmed. Stippling is also associated with other congenital disorders such as chromosomal abnormalities, brachytelephalangic chondrodysplasia punctata (X-linked recessive chondrodysplasia punctata, disruptions of vitamin K metabolism, maternal autoimmune diseases), rhizomelic chondrodysplasia punctata (peroxisomal disorders) and lysosomal storage disorders. In the differential diagnosis of epiphyseal stippling, a moth-eaten appearance of bones, asymmetry, or presence of a common pattern of limb abnormalities indicate inborn errors of cholesterol biosynthesis. We highlight the specific differentiating radiologic features of disorders of post-squalene cholesterol biosynthesis. (orig.)

Correlation of auditory brain stem response and the MRI measurements in neuro-degenerative disorders

International Nuclear Information System (INIS)

Kamei, Hidekazu

1989-01-01

The purpose of this study is to elucidate correlations of several MRI measurements of the cranium and brain, functioning as a volume conductor, to the auditory brain stem response (ABR) in neuro-degenerative disorders. The subjects included forty-seven patients with spinocerebellar degeneration (SCD) and sixteen of amyotrophic lateral sclerosis (ALS). Statistically significant positive correlations were found between I-V and III-V interpeak latencies (IPLs) and the area of cranium and brain in the longitudinal section of SCD patients, and between I-III and III-V IPLs and the area in the longitudinal section of those with ALS. And, also there were statistically significant correlations between the amplitude of the V wave and the area of brain stem as well as that of the cranium in the longitudinal section of SCD patients, and between the amplitude of the V wave and the area of the cerebrum in the longitudinal section of ALS. In conclusion, in the ABR, the IPLs were prolonged and the amplitude of the V wave was decreased while the MRI size of the cranium and brain increased. When the ABR is applied to neuro-degenerative disorders, it might be important to consider not only the conduction of the auditory tracts in the brain stem, but also the correlations of the size of the cranium and brain which act as a volume conductor. (author)

Correlation of auditory brain stem response and the MRI measurements in neuro-degenerative disorders

Energy Technology Data Exchange (ETDEWEB)

Kamei, Hidekazu (Tokyo Women' s Medical Coll. (Japan))

1989-06-01

The purpose of this study is to elucidate correlations of several MRI measurements of the cranium and brain, functioning as a volume conductor, to the auditory brain stem response (ABR) in neuro-degenerative disorders. The subjects included forty-seven patients with spinocerebellar degeneration (SCD) and sixteen of amyotrophic lateral sclerosis (ALS). Statistically significant positive correlations were found between I-V and III-V interpeak latencies (IPLs) and the area of cranium and brain in the longitudinal section of SCD patients, and between I-III and III-V IPLs and the area in the longitudinal section of those with ALS. And, also there were statistically significant correlations between the amplitude of the V wave and the area of brain stem as well as that of the cranium in the longitudinal section of SCD patients, and between the amplitude of the V wave and the area of the cerebrum in the longitudinal section of ALS. In conclusion, in the ABR, the IPLs were prolonged and the amplitude of the V wave was decreased while the MRI size of the cranium and brain increased. When the ABR is applied to neuro-degenerative disorders, it might be important to consider not only the conduction of the auditory tracts in the brain stem, but also the correlations of the size of the cranium and brain which act as a volume conductor. (author).

Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes

DEFF Research Database (Denmark)

Duchatelet, Sabine; Ostergaard, Elsebet; Cortes, Dina

2005-01-01

Eiken syndrome is a rare autosomal recessive skeletal dysplasia. We identified a truncation mutation in the C-terminal cytoplasmic tail of the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) type 1 receptor (PTHR1) gene as the cause of this syndrome. Eiken syndrome differs from Jansen...

Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population.

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Katsuhiro Hosono

Full Text Available Retinitis pigmentosa (RP is a highly heterogeneous genetic disease including autosomal recessive (ar, autosomal dominant (ad, and X-linked inheritance. Recently, arRP has been associated with mutations in EYS (Eyes shut homolog, which is a major causative gene for this disease. This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese arRP patients. To determine the prevalence of EYS mutations, all EYS exons were screened for mutations by polymerase chain reaction amplification, and sequence analysis was performed. We detected 67 sequence alterations in EYS, of which 21 were novel. Of these, 7 were very likely pathogenic mutations, 6 were possible pathogenic mutations, and 54 were predicted non-pathogenic sequence alterations. The minimum observed prevalence of distinct EYS mutations in our study was 18% (18/100, comprising 9 patients with 2 very likely pathogenic mutations and the remaining 9 with only one such mutation. Among these mutations, 2 novel truncating mutations, c.4957_4958insA (p.S1653KfsX2 and c.8868C>A (p.Y2956X, were identified in 16 patients and accounted for 57.1% (20/35 alleles of the mutated alleles. Although these 2 truncating mutations were not detected in Japanese patients with adRP or Leber's congenital amaurosis, we detected them in Korean arRP patients. Similar to Japanese arRP results, the c.4957_4958insA mutation was more frequently detected than the c.8868C>A mutation. The 18% estimated prevalence of very likely pathogenic mutations in our study suggests a major involvement of EYS in the pathogenesis of arRP in the Japanese population. Mutation spectrum of EYS in 100 Japanese patients, including 13 distinct very likely and possible pathogenic mutations, was largely different from the previously reported spectrum in patients from non-Asian populations. Screening for c.4957_4958insA and c.8868C>A mutations in the EYS gene may therefore be very effective for the genetic testing

Profile of Egyptian Patients with Mucopolysaccharidosis | Shawky ...

African Journals Online (AJOL)

Background: Mucopolysaccharidoses (MPS) are chronic progressive lysosomal disorders (Six distinct types) which are inherited as autosomal recessive except MPS II which is inherited as X-linked recessive disorder. Patients and Methods: This study is designed to investigate a group of Egyptian patients with MPS ...

Synthetic prions and other human neurodegenerative proteinopathies.

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Le, Nhat Tran Thanh; Narkiewicz, Joanna; Aulić, Suzana; Salzano, Giulia; Tran, Hoa Thanh; Scaini, Denis; Moda, Fabio; Giachin, Gabriele; Legname, Giuseppe

2015-09-02

Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau. Copyright © 2014 Elsevier B.V. All rights reserved.

Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy

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Shamseldin, Hanan E.; Faqeih, Eissa; Alasmari, Ali; Zaki, Maha S.; Gleeson, Joseph G.; Alkuraya, Fowzan S.

2016-01-01

Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex. PMID:26708753

The first USH2A mutation analysis of Japanese autosomal recessive retinitis pigmentosa patients: a totally different mutation profile with the lack of frequent mutations found in Caucasian patients.

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Zhao, Yang; Hosono, Katsuhiro; Suto, Kimiko; Ishigami, Chie; Arai, Yuuki; Hikoya, Akiko; Hirami, Yasuhiko; Ohtsubo, Masafumi; Ueno, Shinji; Terasaki, Hiroko; Sato, Miho; Nakanishi, Hiroshi; Endo, Shiori; Mizuta, Kunihiro; Mineta, Hiroyuki; Kondo, Mineo; Takahashi, Masayo; Minoshima, Shinsei; Hotta, Yoshihiro

2014-09-01

Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease. The USH2A gene, which accounts for approximately 74-90% of Usher syndrome type 2 (USH2) cases, is also one of the major autosomal recessive RP (arRP) causative genes among Caucasian populations. To identify disease-causing USH2A gene mutations in Japanese RP patients, all 73 exons were screened for mutations by direct sequencing. In total, 100 unrelated Japanese RP patients with no systemic manifestations were identified, excluding families with obvious autosomal dominant inheritance. Of these 100 patients, 82 were included in this present study after 18 RP patients with very likely pathogenic EYS (eyes shut homolog) mutations were excluded. The mutation analysis of the USH2A revealed five very likely pathogenic mutations in four patients. A patient had only one very likely pathogenic mutation and the others had two of them. Caucasian frequent mutations p.C759F in arRP and p.E767fs in USH2 were not found. All the four patients exhibited typical clinical features of RP. The observed prevalence of USH2A gene mutations was approximately 4% among Japanese arRP patients, and the profile of the USH2A gene mutations differed largely between Japanese patients and previously reported Caucasian populations.

Simultaneous Occurence of an Autosomal Dominant Inherited MSX1 Mutation and an X-linked Recessive Inherited EDA Mutation in One Chinese Family with Non-syndromic Oligodontia.

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Zhang, Xiao Xia; Wong, Sing Wai; Han, Dong; Feng, Hai Lan

2015-01-01

To describe the simultaneous occurence of an autosomal dominant inherited MSX1 mutation and an X-linked recessive inherited EDA mutation in one Chinese family with nonsyndromic oligodontia. Clinical data of characteristics of tooth agenesis were collected. MSX1 and EDA gene mutations were detected in a Chinese family of non-syndromic oligodontia. Mild hypodontia in the parents and severe oligodontia in the son was recorded. A novel missense heterozygous mutation c.517C>A (p.Arg173Ser) was detected in the MSX1 gene in the boy and the father. A homozygous missense mutation c.1001G>A (p.Arg334His) was detected in the EDA gene in the boy and the same mutant occurred heterozygously in the mother. Simultaneous occurence of two different gene mutations with different inheritence patterns, which both caused oligodontia, which occurred in one subject and in one family, was reported.

Role of sigma-1 receptors in neurodegenerative diseases

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Linda Nguyen

2015-01-01

Full Text Available Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.

Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families.

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Riveiro-Alvarez, Rosa; Lopez-Martinez, Miguel-Angel; Zernant, Jana; Aguirre-Lamban, Jana; Cantalapiedra, Diego; Avila-Fernandez, Almudena; Gimenez, Ascension; Lopez-Molina, Maria-Isabel; Garcia-Sandoval, Blanca; Blanco-Kelly, Fiona; Corton, Marta; Tatu, Sorina; Fernandez-San Jose, Patricia; Trujillo-Tiebas, Maria-Jose; Ramos, Carmen; Allikmets, Rando; Ayuso, Carmen

2013-11-01

To provide a comprehensive overview of all detected mutations in the ABCA4 gene in Spanish families with autosomal recessive retinal disorders, including Stargardt's disease (arSTGD), cone-rod dystrophy (arCRD), and retinitis pigmentosa (arRP), and to assess genotype-phenotype correlation and disease progression in 10 years by considering the type of variants and age at onset. Case series. A total of 420 unrelated Spanish families: 259 arSTGD, 86 arCRD, and 75 arRP. Spanish families were analyzed through a combination of ABCR400 genotyping microarray, denaturing high-performance liquid chromatography, and high-resolution melting scanning. Direct sequencing was used as a confirmation technique for the identified variants. Screening by multiple ligation probe analysis was used to detect possible large deletions or insertions in the ABCA4 gene. Selected families were analyzed further by next generation sequencing. DNA sequence variants, mutation detection rates, haplotypes, age at onset, central or peripheral vision loss, and night blindness. Overall, we detected 70.5% and 36.6% of all expected ABCA4 mutations in arSTGD and arCRD patient cohorts, respectively. In the fraction of the cohort where the ABCA4 gene was sequenced completely, the detection rates reached 73.6% for arSTGD and 66.7% for arCRD. However, the frequency of possibly pathogenic ABCA4 alleles in arRP families was only slightly higher than that in the general population. Moreover, in some families, mutations in other known arRP genes segregated with the disease phenotype. An increasing understanding of causal ABCA4 alleles in arSTGD and arCRD facilitates disease diagnosis and prognosis and also is paramount in selecting patients for emerging clinical trials of therapeutic interventions. Because ABCA4-associated diseases are evolving retinal dystrophies, assessment of age at onset, accurate clinical diagnosis, and genetic testing are crucial. We suggest that ABCA4 mutations may be associated with a

Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene.

Science.gov (United States)

Sandberg, Michael A; Rosner, Bernard; Weigel-DiFranco, Carol; McGee, Terri L; Dryja, Thaddeus P; Berson, Eliot L

2008-12-01

To estimate the mean rates of ocular function loss in patients with autosomal recessive retinitis pigmentosa due to USH2A mutations. In 125 patients with USH2A mutations, longitudinal regression was used to estimate mean rates of change in Snellen visual acuity, Goldmann visual field area (V4e white test light), and 30-Hz (cone) full-field electroretinogram amplitude. These rates were compared with those of previously studied cohorts with dominant retinitis pigmentosa due to RHO mutations and with X-linked retinitis pigmentosa due to RPGR mutations. Rates of change in patients with the Cys759Phe mutation, the USH2A mutation associated with nonsyndromic disease, were compared with rates of change in patients with the Glu767fs mutation, the most common USH2A mutation associated with Usher syndrome type II (i.e., retinitis pigmentosa and hearing loss). Mean annual exponential rates of decline for the USH2A patients were 2.6% for visual acuity, 7.0% for visual field area, and 13.2% for electroretinogram amplitude. The rate of acuity loss fell between the corresponding rates for the RHO and RPGR patients, whereas the rates for field and ERG amplitude loss were faster than those for the RHO and RPGR patients. No significant differences were found for patients with the Cys759Phe mutation versus patients with the Glu767fs mutation. On average, USH2A patients lose visual acuity faster than RHO patients and slower than RPGR patients. USH2A patients lose visual field and cone electroretinogram amplitude faster than patients with RHO or RPGR mutations. Patients with a nonsyndromic USH2A mutation have the same retinal disease course as patients with syndromic USH2A disease.

Non-coding RNA and pseudogenes in neurodegenerative diseases: "The (unUsual Suspects"

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Valerio eCosta

2012-10-01

Full Text Available Neurodegenerative disorders and cancer are severe diseases threatening human health. The glaring differences between neurons and cancer cells mask the processes involved in their pathogenesis. Defects in cell cycle, DNA repair and cell differentiation can determine unlimited proliferation in cancer, or conversely, compromise neuronal plasticity, leading to cell death and neurodegeneration.Alteration in regulatory networks affecting gene expression contribute to human diseases' onset, including neurodegenerative disorders, and deregulation of non-coding RNAs - particularly microRNAs - is supposed to have a significant impact.Recently, competitive endogenous RNAs - acting as sponges - have been identified in cancer, indicating a new and intricate regulatory network. Given that neurodegenerative disorders and cancer share altered genes and pathways, and considering the emerging role of microRNAs in neurogenesis, we hypothesize competitive endogenous RNAs may be implicated in neurodegenerative diseases. Here we propose, and computationally predict, such regulatory mechanism may be shared between the diseases. It is predictable that similar regulation occurs in other complex diseases, and further investigation is needed.

Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

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Iturria-Medina, Yasser; Sotero, Roberto C; Toussaint, Paule J; Evans, Alan C

2014-11-01

Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

Directory of Open Access Journals (Sweden)

Yasser Iturria-Medina

2014-11-01

Full Text Available Misfolded proteins (MP are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database. Furthermore, this model strongly supports a the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease.

Science.gov (United States)

Ancliff, P J; Gale, R E; Liesner, R; Hann, I M; Linch, D C

2001-11-01

Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Subsequently, autosomal dominant and sporadic forms of the disease have been recognized. All forms are manifest by persistent severe neutropenia and recurrent bacterial infection. In contrast, cyclical hematopoiesis is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, linkage analysis on 13 affected pedigrees identified chromosome 19p13.3 as the likely position for mutations in cyclical hematopoiesis. Heterozygous mutations in the ELA2 gene encoding neutrophil elastase were detected in all families studied. Further work also demonstrated mutations in ELA2 in sporadic and autosomal dominant SCN. However, all mutations described to date are heterozygous and thus appear to act in a dominant fashion, which is inconsistent with an autosomal recessive disease. Therefore, the current study investigated whether mutations in ELA2 could account for the disease phenotype in classical autosomal recessive SCN and in the sporadic and autosomal dominant types. All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing. No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, though 1 was subsequently shown to be a low-frequency polymorphism. These results suggest that mutations in ELA2 are not responsible for classical autosomal recessive Kostmann syndrome but provide further evidence for the role of ELA2 in SCN.

Olfactory memory impairment in neurodegenerative diseases.

Science.gov (United States)

Bahuleyan, Biju; Singh, Satendra

2012-10-01

Olfactory disorders are noted in a majority of neurodegenerative diseases, but they are often misjudged and are rarely rated in the clinical setting. Severe changes in the olfactory tests are observed in Parkinson's disease. Olfactory deficits are an early feature in Alzheimer's disease and they worsen with the disease progression. Alterations in the olfactory function are also noted after severe head injuries, temporal lobe epilepsy, multiple sclerosis, and migraine. The purpose of the present review was to discuss the available scientific knowledge on the olfactory memory and to relate its impairment with neurodegenerative diseases.

Genetics Home Reference: autosomal dominant hypocalcemia

Science.gov (United States)

... individuals have features of a kidney disorder called Bartter syndrome in addition to hypocalcemia. These features can include ... sometimes referred to as autosomal dominant hypocalcemia with Bartter syndrome or Bartter syndrome type V. There are two ...

Clinical Application of Screening for GJB2 Mutations before Cochlear Implantation in a Heterogeneous Population with High Rate of Autosomal Recessive Nonsyndromic Hearing Loss

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Masoud Motasaddi Zarandy

2011-01-01

Full Text Available Clinical application of mutation screening and its effect on the outcome of cochlear implantation is widely debated. We investigated the effect of mutations in GJB2 gene on the outcome of cochlear implantation in a population with a high rate of consanguineous marriage and autosomal recessive nonsyndromic hearing loss. Two hundred and one children with profound prelingual sensorineural hearing loss were included. Forty-six patients had 35delG in GJB2. Speech awareness thresholds (SATs and speech recognition thresholds (SRTs improved following implantation, but there was no difference in performance between patients with GJB2-related deafness versus control (all >0.10. Both groups had produced their first comprehensible words within the same period of time following implantation (2.27 months in GJB2-related deaf versus 2.62 months in controls, =0.22. Although our findings demonstrate the need to uncover unidentified genetic causes of hereditary deafness, they do not support the current policy for genetic screening before cochlear implantation, nor prove a prognostic value.

Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

Science.gov (United States)

Iqbal, Zafar; Willemsen, Marjolein H.; Papon, Marie-Amélie; Musante, Luciana; Benevento, Marco; Hu, Hao; Venselaar, Hanka; Wissink-Lindhout, Willemijn M.; Vulto-van Silfhout, Anneke T.; Vissers, Lisenka E.L.M.; de Brouwer, Arjan P.M.; Marouillat, Sylviane; Wienker, Thomas F.; Ropers, Hans Hilger; Kahrizi, Kimia; Nadif Kasri, Nael; Najmabadi, Hossein; Laumonnier, Frédéric; Kleefstra, Tjitske; van Bokhoven, Hans

2015-01-01

We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. PMID:25704603

Single Nucleotide Polymorphisms of the GJB2 and GJB6 Genes Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss

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Ana Paula Grillo

2015-01-01

Full Text Available Single nucleotide polymorphisms (SNPs are important markers in many studies that link DNA sequence variations to phenotypic changes; such studies are expected to advance the understanding of human physiology and elucidate the molecular basis of diseases. The DFNB1 locus, which contains the GJB2 and GJB6 genes, plays a key role in nonsyndromic hearing loss. Previous studies have identified important mutations in this locus, but the contribution of SNPs in the genes has not yet been much investigated. The aim of this study was to investigate the association of nine polymorphisms located within the DFNB1 locus with the occurrence of autosomal recessive nonsyndromic hearing loss (ARNSHL. The SNPs rs3751385 (C/T, rs7994748 (C/T, rs7329857 (C/T, rs7987302 (G/A, rs7322538 (G/A, rs9315400 (C/T, rs877098 (C/T, rs945369 (A/C, and rs7333214 (T/G were genotyped in 122 deaf patients and 132 healthy controls using allele-specific PCR. There were statistically significant differences between patients and controls, in terms of allelic frequencies in the SNPs rs3751385, rs7994748, rs7329857, rs7987302, rs945369, and rs7333214 (P<0.05. No significant differences between the two groups were observed for rs7322538, rs9315400, and rs877098. Our results suggest that SNPs present in the GJB2 and GJB6 genes may have an influence on ARNSHL in humans.

Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development.

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Stefano Lise

Full Text Available β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5, an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1. In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.

Autosomal male determination in a spinosad-resistant housefly strain from Denmark

DEFF Research Database (Denmark)

Højland, Dorte H; Scott, Jeffrey G; Vagn Jensen, Karl-Martin

2014-01-01

males in this strain. The factor responsible for spinosad resistance in the strain is unknown, but previous studies suggest a role of cytochrome P450s for detoxification of spinosad. Sex determination in the housefly is controlled by a male-determining factor (M), either located on the Y chromosome......BACKGROUND The housefly, Musca domestica L., is a global pest and has developed resistance to most insecticides applied for its control. The insecticide spinosad plays an important role in housefly control. Females of the Danish housefly strain 791spin are threefold more resistant to spinosad than...... of resistance to spinosad. Sex determination in 791spin is due to a male factor on autosome 3. CONCLUSIONS The most likely explanation for the differentiation of spinosad resistance between males and females is a recessive spinosad resistance factor on autosome III. © 2013 Society of Chemical Industry...

Integration of technology-based outcome measures in clinical trials of Parkinson and other neurodegenerative diseases.

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Artusi, Carlo Alberto; Mishra, Murli; Latimer, Patricia; Vizcarra, Joaquin A; Lopiano, Leonardo; Maetzler, Walter; Merola, Aristide; Espay, Alberto J

2018-01-01

We sought to review the landscape of past, present, and future use of technology-based outcome measures (TOMs) in clinical trials of neurodegenerative disorders. We systematically reviewed PubMed and ClinicalTrials.gov for published and ongoing clinical trials in neurodegenerative disorders employing TOMs. In addition, medical directors of selected pharmaceutical companies were surveyed on their companies' ongoing efforts and future plans to integrate TOMs in clinical trials as primary, secondary, or exploratory endpoints. We identified 164 published clinical trials indexed in PubMed that used TOMs as outcome measures in Parkinson disease (n = 132) or other neurodegenerative disorders (n = 32). The ClinicalTrials.gov search yielded 42 clinical trials using TOMs, representing 2.7% of ongoing trials. Sensor-based technology accounted for over 75% of TOMs applied. Gait and physical activity were the most common targeted domains. Within the next 5 years, 83% of surveyed pharmaceutical companies engaged in neurodegenerative disorders plan to deploy TOMs in clinical trials. Although promising, TOMs are underutilized in clinical trials of neurodegenerative disorders. Validating relevant endpoints, standardizing measures and procedures, establishing a single platform for integration of data and algorithms from different devices, and facilitating regulatory approvals should advance TOMs integration into clinical trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism

KAUST Repository

Alsemari, Abdulaziz

2017-11-14

Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency.A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic.These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.

Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism

KAUST Repository

Alsemari, Abdulaziz; Al-Younes, Banan; Goljan, Ewa; Jaroudi, Dyala; BinHumaid, Faisal; Meyer, Brian F.; Arold, Stefan T.; Monies, Dorota

2017-01-01

Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency.A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic.These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.

Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

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Manuel E. Lopez

2013-09-01

Full Text Available Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

A novel approach identifying hybrid sterility QTL on the autosomes of Drosophila simulans and D. mauritiana.

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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.

A novel approach identifying hybrid sterility QTL on the autosomes of Drosophila simulans and D. mauritiana.

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Christopher T D Dickman

Full Text Available 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.

Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation

OpenAIRE

McDermott, David H.; Gammon, Bryan; Snijders, Peter J.; Mbata, Ihunanya; Phifer, Beth; Hartley, A. Howland; Lee, Chyi-Chia Richard; Murphy, Philip M.; Hwang, Sam T.

2009-01-01

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to infection with specific human papillomavirus (HPV) serotypes. EV is a genetically heterogeneous disease, and autosomal recessive and X-linked inheritance patterns have been reported. Nonsense mutations in the genes EVER1 and EVER2 have been identified in over 75% of cases. We present EV in a father and son with typical histologic and clinical findings that occur in the absence of mutation...

Digenic inheritance in autosomal recessive non-syndromic hearing loss cases carrying GJB2 heterozygote mutations: assessment of GJB4, GJA1, and GJC3.

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Kooshavar, Daniz; Tabatabaiefar, Mohammad Amin; Farrokhi, Effat; Abolhasani, Marziye; Noori-Daloii, Mohammad-Reza; Hashemzadeh-Chaleshtori, Morteza

2013-02-01

Autosomal recessive non-syndromic hearing loss (ARNSHL) can be caused by many genes. However, mutations in the GJB2 gene, which encodes the gap-junction (GJ) protein connexin (Cx) 26, constitute a considerable proportion differing among population. Between 10 and 42 percent of patients with recessive GJB2 mutations carry only one mutant allele. Mutations in GJB4, GJA1, and GJC3 encoding Cx30.3, Cx43, and Cx29, respectively, can lead to HL. Combination of different connexins in heteromeric and heterotypic GJ assemblies is possible. This study aims to determine whether variations in any of the genes GJB4, GJA1 or GJC3 can be the second mutant allele causing the disease in the digenic mode of inheritance in the studied GJB2 heterozygous cases. We examined 34 unrelated GJB2 heterozygous ARNSHL subjects from different geographic and ethnic areas in Iran, using polymerase chain reaction (PCR) followed by direct DNA sequencing to identify any sequence variations in these genes. Restriction fragment length polymorphism (RFLP) assays were performed on 400 normal hearing individuals. Sequence analysis of GJB4 showed five heterozygous variations including c.451C>A, c.219C>T, c.507C>G, c.155_158delTCTG and c.542C>T, with only the latter variation not being detected in any of control samples. There were three heterozygous variations including c.758C>T, c.717G>A and c.3*dupA in GJA1 in four cases. We found no variations in GJC3 gene sequence. Our data suggest that GJB4 c.542C>T variant and less likely some variations of GJB4 and GJA1, but not possibly GJC3, can be assigned to ARNSHL in GJB2 heterozygous mutation carriers providing clues of the digenic pattern. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems.

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Iqbal, Zafar; Willemsen, Marjolein H; Papon, Marie-Amélie; Musante, Luciana; Benevento, Marco; Hu, Hao; Venselaar, Hanka; Wissink-Lindhout, Willemijn M; Vulto-van Silfhout, Anneke T; Vissers, Lisenka E L M; de Brouwer, Arjan P M; Marouillat, Sylviane; Wienker, Thomas F; Ropers, Hans Hilger; Kahrizi, Kimia; Nadif Kasri, Nael; Najmabadi, Hossein; Laumonnier, Frédéric; Kleefstra, Tjitske; van Bokhoven, Hans

2015-03-05

We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis.

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Bochner, Ron; Samuelov, Liat; Sarig, Ofer; Li, Qiaoli; Adase, Christopher A; Isakov, Ofer; Malchin, Natalia; Vodo, Dan; Shayevitch, Ronna; Peled, Alon; Yu, Benjamin D; Fainberg, Gilad; Warshauer, Emily; Adir, Noam; Erez, Noam; Gat, Andrea; Gottlieb, Yehonatan; Rogers, Tova; Pavlovsky, Mor; Goldberg, Ilan; Shomron, Noam; Sandilands, Aileen; Campbell, Linda E; MacCallum, Stephanie; McLean, W H Irwin; Ast, Gil; Gallo, Richard L; Uitto, Jouni; Sprecher, Eli

2017-02-01

Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patient's skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that

Disease: H00155 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available H00155 Familial hypercholesterolemia; Autosomal dominant hypercholesterolaemia Fam...n receptor. Other forms of this disorder include hypercholesterolemia caused by mutation of APOB or PCSK9 ge...amilial autosomal recessive hypercholesterolemia. ICD-10: E78.0 MeSH: D006937 OMI

Harlequin Ichthyosis

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Hashemzadeh Ahmad

2009-04-01

Full Text Available It is an autosomal recessive, and occasionally autosomal dominant mutant extremely rare disorder with only 100 reported case in literature. This fatal disorder occur in both sexes and all races. In most circumstances the newborn die soon after birth Also it is known as harlequin fetus, alligator baby or keratosis diffusa fatalis."nBecause of its rarity, we report 2 cases of this disorder, here.

Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant

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2017-07-12

Adenosine Deaminase Deficiency; Autosomal Recessive Disorder; Immune System Disorder; Purine-Nucleoside Phosphorylase Deficiency; Severe Combined Immunodeficiency; Severe Combined Immunodeficiency With Absence of T and B Cells; X-Linked Severe Combined Immunodeficiency

A case Report of Wolfram Syndrome

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Zahra Razavi

2007-01-01

Full Text Available Wolfram syndrome is the association of diabetes mellitus, optic atrophy, diabetes insipidus and sensorineural deafness and is sometimes called DIDMOAD (Diabetes Insipidus, Diabets Mellitus, Optic Atrophy, and Deafness. It is a rare autosomal recessive disease with prevalence of one per 770,000. Natural history of Wolfram syndrome suggests that most patients will eventually develop most complications of this progressive neurodegenerative disorder. Juvenile–onset diabetes mellitus and optic atrophy are the best available diagnostic criteria for Wolfram syndrome. In this report clinical features of a patient with DIDMOAD syndrome is presented. A 12 year old male presented with short standing diabetes mellitus and diabetes insipidus. Further investigations showed bilateral optic atrophy, mild hearing loss and short stature. His parents were relative and he is first case in his family.

Relationships between Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: Clinical Assessments, Biomarkers, and Treatment

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Li, Min; Wang, Li; Liu, Jiang-Hong; Zhan, Shu-Qin

2018-01-01

Objective: Rapid eye movement sleep behavior disorder (RBD) is characterized by dream enactment and loss of muscle atonia during rapid eye movement sleep. RBD is closely related to α-synucleinopathies including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Many studies have investigated the markers of imaging and neurophysiological, genetic, cognitive, autonomic function of RBD and their predictive value for neurodegenerative diseases. This report reviewed the progress of these studies and discussed their limitations and future research directions. Data Sources: Using the combined keywords: “RBD”, “neurodegenerative disease”, “Parkinson disease”, and “magnetic resonance imaging”, the PubMed/MEDLINE literature search was conducted up to January 1, 2018. Study Selection: A total of 150 published articles were initially identified citations. Of the 150 articles, 92 articles were selected after further detailed review. This study referred to all the important English literature in full. Results: Single-nucleotide polymorphisms in SCARB2 (rs6812193) and MAPT (rs12185268) were significantly associated with RBD. The olfactory loss, autonomic dysfunction, marked electroencephalogram slowing during both wakefulness and rapid eye movement sleep, and cognitive impairments were potential predictive markers for RBD conversion to neurodegenerative diseases. Traditional structural imaging studies reported relatively inconsistent results, whereas reduced functional connectivity between the left putamen and substantia nigra and dopamine transporter uptake demonstrated by functional imaging techniques were relatively consistent findings. Conclusions: More longitudinal studies should be conducted to evaluate the predictive value of biomarkers of RBD. Moreover, because the glucose and dopamine metabolisms are not specific for assessing cognitive cognition, the molecular metabolism directly related to cognition should be investigated

Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases.

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Lanza, Valeria; Milardi, Danilo; Di Natale, Giuseppe; Pappalardo, Giuseppe

2018-02-12

There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration. Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs. Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease. In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since

Cell based-gene delivery approaches for the treatment of spinal cord injury and neurodegenerative disorders.

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Taha, Masoumeh Fakhr

2010-03-01

Cell based-gene delivery has provided an important therapeutic strategy for different disorders in the recent years. This strategy is based on the transplantation of genetically modified cells to express specific genes and to target the delivery of therapeutic factors, especially for the treatment of cancers and neurological, immunological, cardiovascular and heamatopoietic disorders. Although, preliminary reports are encouraging, and experimental studies indicate functionally and structurally improvements in the animal models of different disorders, universal application of this strategy for human diseases requires more evidence. There are a number of parameters that need to be evaluated, including the optimal cell source, the most effective gene/genes to be delivered, the optimal vector and method of gene delivery into the cells and the most efficient route for the delivery of genetically modified cells into the patient. Also, some obstacles have to be overcome, including the safety and usefulness of the approaches and the stability of the improvements. Here, recent studies concerning with the cell-based gene delivery for spinal cord injury and some neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease are briefly reviewed, and their exciting consequences are discussed.

Amino acids as dietary excitotoxins: a contribution to understanding neurodegenerative disorders.

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Meldrum, B

1993-01-01

The possibility that some acidic amino acids occurring naturally or as additives in the diet can act as excitotoxins producing central nervous system pathology has been the subject of extensive debate in the last 20 years and is here reviewed. High doses of glutamate, aspartate or related excitatory amino acids given in isolation to neonatal rodents produce acute degeneration organs. Neuropathology resulting from consumption of glutamate or aspartate has not been described in man. Various unusual amino acids of plant origin can produce acute excitotoxic syndromes. In man domoate (consumed in mussels that have fed on (Nitschia pungens) can produce an acute syndrome associated with limbic system lesions and anterograde amnesia. Kainate and domoate produce similar syndromes in rodents; acromelate produces spinal pathology. The mechanisms and manifestations of chronic excitotoxicity are less clearly established. A combination of impaired energy metabolism or impaired buffering of calcium and free radicals and endogenous or exogenous excitotoxins may contribute to neuronal loss in human neurodegenerative disorders.

Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect.

Science.gov (United States)

Barashkov, Nikolay A; Dzhemileva, Lilya U; Fedorova, Sardana A; Teryutin, Fedor M; Posukh, Olga L; Fedotova, Elvira E; Lobov, Simeon L; Khusnutdinova, Elza K

2011-09-01

Hereditary forms of hearing impairment (HI) caused by GJB2 (Cx26) mutations are the frequent sensory disorders registered among newborns in various human populations. In this study, we present data on the molecular, audiological and population features of autosomal recessive deafness 1A (DFNB1A) associated with the donor splicing site IVS1+1G>A mutation of GJB2 gene in Yakut population isolate of the Sakha Republic (Yakutia) located in Eastern Siberia (Russian Federation). The Yakut population exhibits high frequency of some Mendelian disorders, which are rare in other populations worldwide. Mutational analysis of GJB2 gene in 86 unrelated Yakut patients with congenital HI without other clinical features has been performed. In this study, we registered a large cohort of Yakut patients homozygous for the IVS1+1G>A mutation (70 unrelated deaf subjects in total). Detailed audiological analysis of 40 deaf subjects with genotype IVS1+1G>A/IVS1+1G>A revealed significant association of this genotype with mostly symmetrical bilateral severe to profound HI (85% severe-to-profound HI versus 15% mild-to-moderate HI, PA mutation (11.7%) has been found in Yakut population. Reconstruction of 140 haplotypes with IVS1+1G>A mutation demonstrates the common origin of all mutant chromosomes found in Yakuts. The age of mutation was estimated to be approximately 800 years. These findings characterize Eastern Siberia as the region with the most extensive accumulation of the IVS1+1G>A mutation in the world as a result of founder effect.

Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients

NARCIS (Netherlands)

Ebberink, Merel S.; Kofster, Janet; Wanders, Ronald J. A.; Waterham, Hans R.

2010-01-01

The autosomal recessive Zellweger syndrome spectrum (ZSS) disorders comprise a main subgroup of the peroxisome biogenesis disorders. The ZSS disorders can be caused by mutations in any of 12 different currently identified PEX genes resulting in severe, often lethal, multi-systemic disorders. Defects

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes.

Science.gov (United States)

Krasovec, Marc; Nevado, Bruno; Filatov, Dmitry A

2018-05-03

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (π x = 0.016; π aut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex.

Disease: H01478 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. Minor...distributed worldwide. MJD is an autosomal dominant neurodegenerative disorder, involving predominantly the

Ehlers-Danlos syndrome

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Farhana Tahseen Taj

2014-01-01

Full Text Available Ehlers-Danlos syndrome (EDS is a generalized disorder of one element of connective tissue manifesting clinically by fragility and hyperelasticity of the skin and joint laxity. It is a hereditary disorder, the inheritance being usually autosomal dominant with low penetrance. Autosomal recessive and X-linked recessive varieties are also known. First described by Hippocrates in 4 th century B.C., the various clinical types with variable penetrance have been described lately. The number of cases EDS reported in the literature is very meagre. With the available information only about six publications of classic EDS in siblings had been reported in Indian literature.

Cerebral correlates of psychotic syndromes in neurodegenerative diseases.

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Jellinger, Kurt A

2012-05-01

Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer's disease, synucleinopathies (Parkinson's disease, dementia with Lewy bodies), Huntington's disease, frontotemporal degenerations, motoneuron and prion diseases. Many of these psychiatric manifestations may be early expressions of cognitive impairment, but often there is a dissociation between psychotic/behavioural symptoms and the rather linear decline in cognitive function, suggesting independent pathophysiological mechanisms. Strictly neuropathological explanations are likely to be insufficient to explain them, and a large group of heterogeneous factors (environmental, neurochemical changes, genetic factors, etc.) may influence their pathogenesis. Clinico-pathological evaluation of behavioural and psychotic symptoms (PS) in the setting of neurodegenerative and dementing disorders presents a significant challenge for modern neurosciences. Recognition and understanding of these manifestations may lead to the development of more effective preventive and therapeutic options that can serve to delay long-term progression of these devastating disorders and improve the patients' quality of life. A better understanding of the pathophysiology and distinctive pathological features underlying the development of PS in neurodegenerative diseases may provide important insights into psychotic processes in general. © 2011 The Author Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

The emergence of designed multiple ligands for neurodegenerative disorders.

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Geldenhuys, Werner J; Youdim, Moussa B H; Carroll, Richard T; Van der Schyf, Cornelis J

2011-09-01

The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline. Copyright © 2011. Published by Elsevier Ltd.

Terminal phalangeal accessory ossification center of the thumb: an additional radiographic finding in Larsen syndrome

International Nuclear Information System (INIS)

Alanay, Yasemin; Utine, Gulen E.; Tuncbilek, Ergul; Lachman, Ralph S.; Krakow, Deborah

2006-01-01

Larsen syndrome is an autosomal-dominant disorder characterized by multiple joint dislocations, vertebral anomalies and dysmorphic facies. Both autosomal-dominant and autosomal-recessive forms of the disorder have been proposed. Individuals with autosomal-dominant Larsen syndrome have characteristic ''cylindrical-shape'' thumbs caused by broad, shortened phalanges. Autosomal-dominant Larsen syndrome results from heterozygosity for mutations in filamin B, a cytoskeletal protein involved in multicellular processes. We report here a patient with a duplicated or accessory distal thumb phalanx and multiple large joint dislocations who was shown to be heterozygous for a filamin B mutation predicting the amino acid substitution G1691S. This adds a new radiographic finding, duplicated or accessory distal phalanx, to the radiographic abnormalities seen in this rare dominant disorder. (orig.)

Microbiota-Brain-Gut Axis and Neurodegenerative Diseases.

Science.gov (United States)

Quigley, Eamonn M M

2017-10-17

The purposes of this review were as follows: first, to provide an overview of the gut microbiota and its interactions with the gut and the central nervous system (the microbiota-gut-brain axis) in health, second, to review the relevance of this axis to the pathogenesis of neurodegenerative diseases, such as Parkinson's disease, and, finally, to assess the potential for microbiota-targeted therapies. Work on animal models has established the microbiota-gut-brain axis as a real phenomenon; to date, the evidence for its operation in man has been limited and has been confronted by considerable logistical challenges. Animal and translational models have incriminated a disturbed gut microbiota in a number of CNS disorders, including Parkinson's disease; data from human studies is scanty. While a theoretical basis can be developed for the use of microbiota-directed therapies in neurodegenerative disorders, support is yet to come from high-quality clinical trials. In theory, a role for the microbiota-gut-brain axis is highly plausible; clinical confirmation is awaited.

A late-diagnosed phenylketonuria case presenting with autism spectrum disorder in early childhood.

Science.gov (United States)

Mazlum, Betül; Anlar, Banu; Kalkanoğlu-Sivri, H Serap; Karlı-Oğuz, Kader; Özusta, Şeniz; Ünal, Fatih

2016-01-01

Phenylketonuria is one of the most prevalent autosomal recessive hereditary disorders in Turkey. If untreated, it results in severe brain damage and can also be associated with autism in certain patients. We present a three-year old boy who exhibited the symptoms of autism and was subsequently diagnosed with phenylketonuria. This case illustrates that because the majority of autism cases are idiopathic, an occasional patient with a metabolic disorder might be overlooked especially in the era of newborn screening. We also discuss the possible pathogenetic processes leading to autistic symptoms in phenylketonuria, and wish to draw attention to the possibility of cases missed in the screening program because of less than 100% coverage or insufficient food intake before blood sampling. Clinicians should keep in mind the possibility of treatable disorders in children with autism even when such disorders appear unlikely.

Assessing Executive Dysfunction in Neurodegenerative Disorders: A Critical Review of Brief Neuropsychological Tools

Directory of Open Access Journals (Sweden)

Helena S. Moreira

2017-11-01

Full Text Available Executive function (EF has been defined as a multifaceted construct that involves a variety of high-level cognitive abilities such as planning, working memory, mental flexibility, and inhibition. Being able to identify deficits in EF is important for the diagnosis and monitoring of several neurodegenerative disorders, and thus their assessment is a topic of much debate. In particular, there has been a growing interest in the development of neuropsychological screening tools that can potentially provide a reliable quick measure of EF. In this review, we critically discuss the four screening tools of EF currently available in the literature: Executive Interview-25 (EXIT 25, Frontal Assessment Battery (FAB, INECO Frontal Screening (IFS, and FRONTIER Executive Screen (FES. We first describe their features, and then evaluate their psychometric properties, the existing evidence on their neural correlates, and the empirical work that has been conducted in clinical populations. We conclude that the four screening tools generally present appropriate psychometric properties, and are sensitive to impairments in EF in several neurodegenerative conditions. However, more research will be needed mostly with respect to normative data and neural correlates, and to determine the extent to which these tools add specific information to the one provided by global cognition screening tests. More research directly comparing the available tools with each other will also be important to establish in which conditions each of them can be most useful.

Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG)

OpenAIRE

Worby, Carolyn A.; Gentry, Matthew S.; Dixon, Jack E.

2007-01-01

Lafora disease (LD) is an autosomal recessive neurodegenerative disease that results in progressive myoclonus epilepsy and death. LD is caused by mutations in either the E3 ubiquitin ligase malin or the dual-specificity phosphatase laforin. A hallmark of LD is the accumulation of insoluble glycogen in the cytoplasm of cells from most tissues. Glycogen metabolism is regulated by phosphorylation of key metabolic enzymes. One regulator of this phosphorylation is protein targeting to glycogen (PT...

Aptamer and its applications in neurodegenerative diseases.

Science.gov (United States)

Qu, Jing; Yu, Shuqing; Zheng, Yuan; Zheng, Yan; Yang, Hui; Zhang, Jianliang

2017-02-01

Aptamers are small single-stranded DNA or RNA oligonucleotide fragments or small peptides, which can bind to targets by high affinity and specificity. Because aptamers are specific, non-immunogenic and non-toxic, they are ideal materials for clinical applications. Neurodegenerative disorders are ravaging the lives of patients. Even though the mechanism of these diseases is still elusive, they are mainly characterized by the accumulation of misfolded proteins in the central nervous system. So it is essential to develop potential measures to slow down or prevent the onset of these diseases. With the advancements of the technologies, aptamers have opened up new areas in this research field. Aptamers could bind with these related target proteins to interrupt their accumulation, subsequently blocking or preventing the process of neurodegenerative diseases. This review presents recent advances in the aptamer generation and its merits and limitations, with emphasis on its applications in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, transmissible spongiform encephalopathy, Huntington's disease and multiple sclerosis.

Prions, prion-like prionoids, and neurodegenerative disordersVacancy

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Ashok Verma

2016-01-01

Full Text Available Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals. However, these prion-like “prionoids” are causal to a variety of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The remarkable recent discovery of at least two new α-syn prion strains and their transmissibility in transgenic mice and in vitro cell models raises a distinct question as to whether some specific strain of other prionoids could have the capability of disease transmission in a manner similar to prions. In this overview, we briefly describe human and other mammalian prion diseases and comment on certain similarities between prion and prionoid and the possibility of prion-like transmissibility of some prionoid strains.

LSTM for diagnosis of neurodegenerative diseases using gait data

Science.gov (United States)

Zhao, Aite; Qi, Lin; Li, Jie; Dong, Junyu; Yu, Hui

2018-04-01

Neurodegenerative diseases (NDs) usually cause gait disorders and postural disorders, which provides an important basis for NDs diagnosis. By observing and analyzing these clinical manifestations, medical specialists finally give diagnostic results to the patient, which is inefficient and can be easily affected by doctors' subjectivity. In this paper, we propose a two-layer Long Short-Term Memory (LSTM) model to learn the gait patterns exhibited in the three NDs. The model was trained and tested using temporal data that was recorded by force-sensitive resistors including time series, such as stride interval and swing interval. Our proposed method outperforms other methods in literature in accordance with accuracy of the predicted diagnostic result. Our approach aims at providing the quantitative assessment so that to indicate the diagnosis and treatment of these neurodegenerative diseases in clinic

Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases.

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González, Hugo; Elgueta, Daniela; Montoya, Andro; Pacheco, Rodrigo

2014-09-15

Neuroinflammation constitutes a fundamental process involved in the progression of several neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. Microglial cells play a central role in neuroinflammation, promoting neuroprotective or neurotoxic microenvironments, thus controlling neuronal fate. Acquisition of different microglial functions is regulated by intercellular interactions with neurons, astrocytes, the blood-brain barrier, and T-cells infiltrating the central nervous system. In this study, an overview of the regulation of microglial function mediated by different intercellular communications is summarised and discussed. Afterward, we focus in T-cell-mediated regulation of neuroinflammation involved in neurodegenerative disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

Assessing the putative roles of X-autosome and X-Y interactions in hybrid male sterility of the Drosophila bipectinata species complex.

Science.gov (United States)

Mishra, Paras Kumar; Singh, Bashisth Narayan

2007-07-01

Interspecific F1 hybrid males of the Drosophila bipectinata species complex are sterile, while females are fertile, following Haldane's rule. A backcross scheme involving a single recessive visible marker on the X chromosome has been used to assess the putative roles of X-autosome and X-Y interactions in hybrid male sterility in the D. bipectinata species complex. The results suggest that X-Y interactions are playing the major role in hybrid male sterility in the crosses D. bipectinata x D. parabipectinata and D. bipectinata x D. pseudoananassae, while X-autosome interactions are largely involved in hybrid male sterility in the crosses D. malerkotliana x D. bipectinata and D. malerkotliana x D. parabipectinata. However, by using this single marker it is not possible to rule out the involvement of autosome-autosome interactions in hybrid male sterility. These findings also lend further support to the phylogenetic relationships among 4 species of the D. bipectinata complex.

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 ... Epilepsy Society Citizens United for Research in Epilepsy (CURE) GeneReviews (1 link) Autosomal Dominant Nocturnal Frontal Lobe ...

Case report: Autosomal dominant non-epidermolytic palmoplantar ...

African Journals Online (AJOL)

Palmoplantar keratoderma (PPK) is a hereditary cutaneous disorder characterized by a marked hyperkeratosis of the palms and soles. A variant that was inherited in an autosomal dominant form was highlighted in a 20-month-old girl-child. The proband was brought to the Paediatric Outpatient Department by her mother ...

Cleft lip with or without cleft palate in Shanghai, China: Evidence for an autosomal major locus

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Marazita, M.L. (Virginia Commonwealth Univ., Richmond, VA (United States)); Hu, Dan-Ning; Liu, You-E. (Zhabei Eye Institute, Shanghai (China)); Spence, A. (Univ. of California, Los Angeles, CA (United States)); Melnick, M. (Univ. of Southern California, Los Angeles, CA (United States))

1992-09-01

Orientals are at higher risk for cleft lip with our without cleft palate (CL[+-] P) than Caucasians or blacks. The authors collected demographic and family data to study factors contributing to the etiology of CL[+-]P in Shanghai. The birth incidence of nonsyndromic CL[+-]P (SHanghai 1980-87) was 1.11/1,000, with a male/female ratio of 1.42. Almost 2,000 nonsyndromic CL[+-]P probands were ascertained from individuals operated on during the years 1956-83 at surgical hospitals in Shanghai. Detailed family histories and medical examinations were obtained for the probands and all available family members. Genetic analysis of the probands' families were performed under the mixed model with major locus (ML) and multifactorial (MFT) components. The hypothesis of no familial transmission and of MFT alone could be rejected. Of the ML models, the autosomal recessive was significantly most likely and was assumed for testing three complex hypothesis: (1) ML and sporadics; (2) ML and MFT; (3) ML, MFT, and sporadics. None of the complex models were more likely than the ML alone model. In conclusion, the best-fitting, most parsimonious model for CL[+-]P in Shanghai was that of an autosomal recessive major locus. 37 refs., 1 tab.

Excitatory amino acid neurotoxicity and neurodegenerative disease.

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Meldrum, B; Garthwaite, J

1990-09-01

The progress over the last 30 years in defining the role of excitatory amino acids in normal physiological function and in the abnormal neuronal activity of epilepsy has been reviewed in earlier articles in this series. In the last five years it has become clear that excitatory amino acids also play a role in a wide range of neurodegenerative processes. The evidence is clearest where the degenerative process is acute, but is more controversial for slow degenerative processes. In this article Brian Meldrum and John Garthwaite review in vivo and in vitro studies of the cytotoxicity of amino acids and summarize the contribution of such toxicity to acute and chronic neurodegenerative disorders.

Wolfram syndrome (diabetes insipidus, diabetes, optic atrophy, and deafness): clinical and genetic study.

Science.gov (United States)

d'Annunzio, Giuseppe; Minuto, Nicola; D'Amato, Elena; de Toni, Teresa; Lombardo, Fortunato; Pasquali, Lorenzo; Lorini, Renata

2008-09-01

Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, diabetes (nonautoimmune), optic atrophy, and deafness (a set of conditions referred to as DIDMOAD). The WFS1 gene is located on the short arm of chromosome 4. Wolfram syndrome prevalence is 1 in 770,000 live births, with a 1 in 354 carrier frequency. We evaluated six Italian children from five unrelated families. Genetic analysis for Wolfram syndrome was performed by PCR amplification and direct sequencing. Mutation screening revealed five distinct variants, one novel mutation (c.1346C>T; p.T449I) and four previously described, all located in exon 8. Phenotype-genotype correlation is difficult, and the same mutation gives very different phenotypes. Severely inactivating mutations result in a more severe phenotype than mildly inactivating ones. Clinical follow-up showed the progressive syndrome's seriousness.

Alstrom syndrome: A rare genetic disorder and its anaesthetic significance

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Akhilesh Tiwari

2010-01-01

Full Text Available Alstrom syndrome is a rare autosomal recessive disorder that was first described in 1959, by Carl Henry Alstrom, characterised by multiorgan system involvement ranging from ocular, aural, endocrinal, hepatorenal, gastrointestinal, respiratory and cardiac to the musculoskeletal system, among many others. It exposes the patient to various risks ranging from pulmonary aspiration and increased cardiac morbidity to separational anxiety, and may necessitate postoperative elective ventilation. We hereby present the successful management of one such diagnosed case in a 12-year-old boy, who presented to us for incision and drainage of an abscess present over the nape of his neck, along with foreign body removal from his right ear.

Terminal phalangeal accessory ossification center of the thumb: an additional radiographic finding in Larsen syndrome

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Alanay, Yasemin [Hacettepe University, Clinical Genetics Unit, Department of Pediatrics, Faculty of Medicine, Ankara (Turkey); Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, CA (United States); Utine, Gulen E.; Tuncbilek, Ergul [Hacettepe University, Clinical Genetics Unit, Department of Pediatrics, Faculty of Medicine, Ankara (Turkey); Lachman, Ralph S. [Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, CA (United States); David Geffen School of Medicine at UCLA, Department of Radiological Sciences, Los Angeles, CA (United States); David Geffen School of Medicine at UCLA, Department of Pediatrics, Los Angeles, CA (United States); Krakow, Deborah [Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, CA (United States); David Geffen School of Medicine at UCLA, Department of Obstetrics and Gynecology, Los Angeles, CA (United States)

2006-09-15

Larsen syndrome is an autosomal-dominant disorder characterized by multiple joint dislocations, vertebral anomalies and dysmorphic facies. Both autosomal-dominant and autosomal-recessive forms of the disorder have been proposed. Individuals with autosomal-dominant Larsen syndrome have characteristic ''cylindrical-shape'' thumbs caused by broad, shortened phalanges. Autosomal-dominant Larsen syndrome results from heterozygosity for mutations in filamin B, a cytoskeletal protein involved in multicellular processes. We report here a patient with a duplicated or accessory distal thumb phalanx and multiple large joint dislocations who was shown to be heterozygous for a filamin B mutation predicting the amino acid substitution G1691S. This adds a new radiographic finding, duplicated or accessory distal phalanx, to the radiographic abnormalities seen in this rare dominant disorder. (orig.)

A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease.

Science.gov (United States)

Xiong, Huaqi; Chen, Yongxiong; Yi, Yajun; Tsuchiya, Karen; Moeckel, Gilbert; Cheung, Joseph; Liang, Dan; Tham, Kyi; Xu, Xiaohu; Chen, Xing-Zhen; Pei, York; Zhao, Zhizhuang Jeo; Wu, Guanqing

2002-07-01

Autosomal recessive polycystic kidney disease (ARPKD) is a common hereditary renal cystic disease in infants and children. By genetic linkage analyses, the gene responsible for this disease, termed polycystic kidney and hepatic disease 1 (PKHD1), was mapped on human chromosome 6p21.1-p12, and has been further localized to a 1-cM genetic interval flanked by the D6S1714/D6S243 (telomeric) and D6S1024 (centromeric) markers. We recently identified a novel gene in this genetic interval from kidney cDNA, using cloning strategies. The gene PKHD1 (PKHD1-tentative) encodes a novel 3396-amino-acid protein with no apparent homology with any known proteins. We named its gene product "tigmin" because it contains multiple TIG domains, which usually are seen in proteins containing immunoglobulin-like folds. PKHD1 encodes an 11.6-kb transcript and is composed of 61 exons spanning an approximately 365-kb genomic region on chromosome 6p12-p11.2 adjacent to the marker D6S1714. Northern blot analyses demonstrated that the gene has discrete bands with one peak signal at approximately 11 kb, indicating that PKHD1 is likely to have multiple alternative transcripts. PKHD1 is highly expressed in adult and infant kidneys and weakly expressed in liver in northern blot analysis. This expression pattern parallels the tissue involvement observed in ARPKD. In situ hybridization analysis further revealed that the expression of PKHD1 in the kidney is mainly localized to the epithelial cells of the collecting duct, the specific tubular segment involved in cyst formation in ARPKD. These features of PKHD1 make it a strong positional candidate gene for ARPKD.

Genetics Home Reference: autosomal recessive hyper-IgE syndrome

Science.gov (United States)

... is a disorder of the immune system. A hallmark feature of the condition is recurrent infections that ... have a greater-than-average risk of developing cancer, particularly cancers of the blood or skin. Related ...

Redox Imbalance and Viral Infections in Neurodegenerative Diseases

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Dolores Limongi

2016-01-01

Full Text Available Reactive oxygen species (ROS are essential molecules for many physiological functions and act as second messengers in a large variety of tissues. An imbalance in the production and elimination of ROS is associated with human diseases including neurodegenerative disorders. In the last years the notion that neurodegenerative diseases are accompanied by chronic viral infections, which may result in an increase of neurodegenerative diseases progression, emerged. It is known in literature that enhanced viral infection risk, observed during neurodegeneration, is partly due to the increase of ROS accumulation in brain cells. However, the molecular mechanisms of viral infection, occurring during the progression of neurodegeneration, remain unclear. In this review, we discuss the recent knowledge regarding the role of influenza, herpes simplex virus type-1, and retroviruses infection in ROS/RNS-mediated Parkinson’s disease (PD, Alzheimer’s disease (AD, and amyotrophic lateral sclerosis (ALS.

Cutis laxa and fatal pulmonary hypertension: a newly recognized syndrome?

Science.gov (United States)

Brunetti-Pierri, Nicola; Piccolo, Pasquale; Morava, Eva; Wevers, Ron A.; McGuirk, Megan; Johnson, Yvette R.; Urban, Zsolt; Dishop, Megan K.; Potocki, Lorraine

2015-01-01

Cutis laxa is a connective tissue disorder with distinctive lax, redundant, and inelastic skin. It is a genetically heterogenous disorder with autosomal dominant and recessive patterns of inheritance. We report a patient with cutis laxa supported by clinical, microscopic, and ultrastructural findings. Molecular analysis of fibulin-4 and -5, of the α2 subunit of the V-type H+ ATPase, and of the component of the oligomeric Golgi complex 7 (COG7) genes excluded the type I and type II autosomal recessive forms of cutis laxa, and congenital disorders of glycosylation associated with cutis laxa. Remarkably, our patient also presented severe and lethal pulmonary hypertension as a newborn. This case with cutis laxa, severe pulmonary hypertension, and no detectable mutations in fibulin-4 and -5 genes may represent a previously unrecognized syndrome. PMID:21285876

Gender and Race/Ethnicity Differences in Mental Health Care Use before and during the Great Recession.

Science.gov (United States)

Chen, Jie; Dagher, Rada

2016-04-01

This study examines the changes in health care utilization for mental health disorders among patients who were diagnosed with depressive and/or anxiety disorders during the Great Recession 2007-2009 in the USA. Negative binomial regressions are used to estimate the association of the economic recession and mental health care use for females and males separately. Results show that prescription drug utilization (e.g., antidepressants, psychotropic medications) increased significantly during the economic recession 2007-2009 for both females and males. Physician visits for mental health disorders decreased during the same period. Results show that racial disparities in mental health care might have increased, while ethnic disparities persisted during the Great Recession. Future research should separately examine mental health care utilization by gender and race/ethnicity.

Quantitative analysis on electrooculography (EOG) for neurodegenerative disease

Science.gov (United States)

Liu, Chang-Chia; Chaovalitwongse, W. Art; Pardalos, Panos M.; Seref, Onur; Xanthopoulos, Petros; Sackellares, J. C.; Skidmore, Frank M.

2007-11-01

Many studies have documented abnormal horizontal and vertical eye movements in human neurodegenerative disease as well as during altered states of consciousness (including drowsiness and intoxication) in healthy adults. Eye movement measurement may play an important role measuring the progress of neurodegenerative diseases and state of alertness in healthy individuals. There are several techniques for measuring eye movement, Infrared detection technique (IR). Video-oculography (VOG), Scleral eye coil and EOG. Among those available recording techniques, EOG is a major source for monitoring the abnormal eye movement. In this real-time quantitative analysis study, the methods which can capture the characteristic of the eye movement were proposed to accurately categorize the state of neurodegenerative subjects. The EOG recordings were taken while 5 tested subjects were watching a short (>120 s) animation clip. In response to the animated clip the participants executed a number of eye movements, including vertical smooth pursued (SVP), horizontal smooth pursued (HVP) and random saccades (RS). Detection of abnormalities in ocular movement may improve our diagnosis and understanding a neurodegenerative disease and altered states of consciousness. A standard real-time quantitative analysis will improve detection and provide a better understanding of pathology in these disorders.

Genetics Home Reference: autosomal dominant congenital stationary night blindness

Science.gov (United States)

... collapse boxes. Description Autosomal dominant congenital stationary night blindness is a disorder of the retina , which is the specialized tissue at the back of the eye that detects light and color. People with this condition typically have difficulty seeing ...

New evidence for the role of calpain 10 in autosomal recessive intellectual disability: identification of two novel nonsense variants by exome sequencing in Iranian families.

Science.gov (United States)

Oladnabi, Morteza; Musante, Luciana; Larti, Farzaneh; Hu, Hao; Abedini, Seyedeh Sedigheh; Wienker, Thomas; Ropers, Hans Hilger; Kahrizi, Kimia; Najmabadi, Hossein

2015-03-01

Knowledge of the genes responsible for intellectual disability, particularly autosomal recessive forms, is rapidly expanding. Increasing numbers of the gene show great heterogeneity and supports the hypothesis that human genome may contain over 2000 causative genes with a critical role in brain development. Since 2004, we have applied genome-wide SNP genotyping and next-generation sequencing in large consanguineous Iranian families with intellectual disability, to identify the genes harboring disease-causing mutations. The current study paved the way for identification of responsible genes in two unrelated Iranian families. We found two novel nonsense mutations, p.C77* and p.Q115*, in the calpain catalytic domain of CAPN10, which is a cysteine protease known to be involved in pathogenesis of noninsulin-dependent diabetes mellitus. Another different mutation in this gene (p.S138_R139ins5) has previously been reported in an Iranian family. All of these patients have common clinical features in spite of specific brain structural abnormalities on MRI. Different mutations in CAPN10 have already been found in three independent Iranian families. These results have strongly supported the possible role of CAPN10 in human brain development. Altogether, we proposed CAPN10 as a promising candidate gene for intellectual disability, which should be considered in diagnostic gene panels.

NSAIDs and cardiovascular drugs in neurodegenerative and cerebrovascular diseases

NARCIS (Netherlands)

M.D.M. Haag (Mendel)

2009-01-01

textabstractNeurodegenerative and cerebrovascular diseases are frequent in elderly populations and comprise primarily of dementia (mainly Alzheimer disease (AD)), Parkinson disease (PD) and stroke. The prevalence of these neurological disorders rises with older age. From 55 years to 90 years and

Cytogenetic diagnosis of Roberts SC phocomelia syndrome: First ...

African Journals Online (AJOL)

Tahir M. Malla

2015-07-14

/licenses/by-nc-nd/4.0/). 1. Introduction. Roberts SC phocomelia syndrome is an autosomal recessive developmental disorder characterized by pre and postnatal growth retardation, microcephaly, craniofacial anomalies,.

Convergent molecular defects underpin diverse neurodegenerative diseases.

Science.gov (United States)

Tofaris, George K; Buckley, Noel J

2018-02-19

In our ageing population, neurodegenerative disorders carry an enormous personal, societal and economic burden. Although neurodegenerative diseases are often thought of as clinicopathological entities, increasing evidence suggests a considerable overlap in the molecular underpinnings of their pathogenesis. Such overlapping biological processes include the handling of misfolded proteins, defective organelle trafficking, RNA processing, synaptic health and neuroinflammation. Collectively but in different proportions, these biological processes in neurons or non-neuronal cells lead to regionally distinct patterns of neuronal vulnerability and progression of pathology that could explain the disease symptomology. With the advent of patient-derived cellular models and novel genetic manipulation tools, we are now able to interrogate this commonality despite the cellular complexity of the brain in order to develop novel therapeutic strategies to prevent or arrest neurodegeneration. Here, we describe broadly these concepts and their relevance across neurodegenerative diseases. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Novel PMS2 Pseudogenes Can Conceal Recessive Mutations Causing a Distinctive Childhood Cancer Syndrome

OpenAIRE

De Vos, Michel; Hayward, Bruce E.; Picton, Susan; Sheridan, Eamonn; Bonthron, David T.

2004-01-01

We investigated a family with an autosomal recessive syndrome of café-au-lait patches and childhood malignancy, notably supratentorial primitive neuroectodermal tumor. There was no cancer predisposition in heterozygotes; nor was there bowel cancer in any individual. However, autozygosity mapping indicated linkage to a region of 7p22 surrounding the PMS2 mismatch-repair gene. Sequencing of genomic PCR products initially failed to identify a PMS2 mutation. Genome searches then revealed a previo...

[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. Sociedad Argentina de Pediatría.

Highly prevalent LIPH founder mutations causing autosomal recessive woolly hair/hypotrichosis in Japan and the genotype/phenotype correlations.

Directory of Open Access Journals (Sweden)

Kana Tanahashi

Full Text Available Mutations in LIPH cause of autosomal recessive woolly hair/hypotrichosis (ARWH, and the 2 missense mutations c.736T>A (p.Cys246Ser and c.742C>A (p.His248Asn are considered prevalent founder mutations for ARWH in the Japanese population. To reveal genotype/phenotype correlations in ARWH cases in Japan and the haplotypes in 14 Japanese patients from 14 unrelated Japanese families. 13 patients had woolly hair, and 1 patient had complete baldness since birth. An LIPH mutation search revealed homozygous c.736T>A mutations in 10 of the patients. Compound heterozygous c.736T>A and c.742C>A mutations were found in 3 of the patients, and homozygous c.742C>A mutation in 1 patient. The phenotype of mild hypotrichosis with woolly hair was restricted to the patients with the homozygous c.736T>A mutation. The severe phenotype of complete baldness was seen in only 1 patient with homozygous c.742C>A. Haplotype analysis revealed that the alleles containing the LIPH c.736T>A mutation had a haplotype identical to that reported previously, although 4 alleles out of 5 chromosomes containing the LIPH c.742C>A mutation had a different haplotype from the previously reported founder allele. These alleles with c.742C>A are thought to be the third founder LIPH mutation causing ARWH. To accurately determine the prevalence of the founder mutations, we investigated allele frequencies of those mutations in 819 Japanese controls. Heterozygous c.736T>A mutations were found in 13 controls (allele frequency: 0.0079; carrier rate: 0.016, and heterozygous c.742C>A mutations were found in 2 controls (allele frequency: 0.0012; carrier rate: 0.0024. In conclusion, this study confirms the more accurate allele frequencies of the pathogenic founder mutations of LIPH and shows that there is a third founder mutation in Japan. In addition, the present findings suggest that the mutation patterns of LIPH might be associated with hypotrichosis severity in ARWH.

Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype.

Science.gov (United States)

Tallapaka, Karthik; Venugopal, Vineeth; Dalal, Ashwin; Aggarwal, Shagun

2018-04-01

Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal (MIM # 610644) is a clinically distinctive form of SRY-negative 46,XX disorder of sex development. It is a rare autosomal recessive disorder caused due to biallelic loss of function mutations in RSPO1 gene. RSPO1 acts by activating the canonical β-catenin pathway and is one of the most important genes controlling female gonadal differentiation. RSPO1-associated disorders of sex development have been described only in three instances in the past. We report fourth such case with additional findings and perform a comparative review of previous phenotypic descriptions, thereby expanding the clinical phenotype of this syndrome. © 2018 Wiley Periodicals, Inc.

Gemfibrozil, a lipid-lowering drug, induces suppressor of cytokine signaling 3 in glial cells: implications for neurodegenerative disorders.

Science.gov (United States)

Ghosh, Arunava; Pahan, Kalipada

2012-08-03

Glial inflammation is an important feature of several neurodegenerative disorders. Suppressor of cytokine signaling (SOCS) proteins play a crucial role in inhibiting cytokine signaling and inflammatory gene expression in various cell types, including glial cells. However, mechanisms by which SOCS genes could be up-regulated are poorly understood. This study underlines the importance of gemfibrozil, a Food and Drug Administration-approved lipid-lowering drug, in up-regulating the expression of SOCS3 in glial cells. Gemfibrozil increased the expression of Socs3 mRNA and protein in mouse astroglia and microglia in both a time- and dose-dependent manner. Interestingly, gemfibrozil induced the activation of type IA phosphatidylinositol (PI) 3-kinase and AKT. Accordingly, inhibition of PI 3-kinase and AKT by chemical inhibitors abrogated gemfibrozil-mediated up-regulation of SOCS3. Furthermore, we demonstrated that gemfibrozil induced the activation of Krüppel-like factor 4 (KLF4) via the PI 3-kinase-AKT pathway and that siRNA knockdown of KLF4 abrogated gemfibrozil-mediated up-regulation of SOCS3. Gemfibrozil also induced the recruitment of KLF4 to the distal, but not proximal, KLF4-binding site of the Socs3 promoter. This study delineates a novel property of gemfibrozil in up-regulating SOCS3 in glial cells via PI 3-kinase-AKT-mediated activation of KLF4 and suggests that gemfibrozil may find therapeutic application in neuroinflammatory and neurodegenerative disorders.

Cannabinoids and value-based decision making: Implications for neurodegenerative disorders

NARCIS (Netherlands)

Lee, AM; Oleson, E.B.; Diergaarde, L.; Cheer, J.F.; Pattij, T.

2012-01-01

In recent years, disturbances in cognitive function have been increasingly recognized as important symptomatic phenomena in neurodegenerative diseases, including Parkinson's disease (PD). Value-based decision making in particular is an important executive cognitive function that is not only impaired

Shedding light on canine pituitary dwarfism

OpenAIRE

Voorbij, A.M.W.Y.

2015-01-01

Pituitary dwarfism, associated with growth hormone deficiency, is an autosomal, recessively inherited disorder in shepherd dogs. Due to the serious nature of pituitary dwarfism and lack of efficient treatment, it is preferable to prevent dwarfs from being born by applying a correct breeding policy. However, because pituitary dwarfism is a recessively inherited disorder and carriers do not differ phenotypically from non-carriers, genetic testing is required to prevent mating of 2 carriers. But...

Dihydropyrimidine Dehydrogenase Deficiency in Two Malaysian Siblings with Abnormal MRI Findings

NARCIS (Netherlands)

Chen, Bee Chin; Mohd Rawi, Rowani; Meinsma, Rutger; Meijer, Judith; Hennekam, Raoul C. M.; van Kuilenburg, André B. P.

2014-01-01

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine metabolism. Deficiency of this enzyme leads to an accumulation of thymine and uracil and a deficiency of metabolites distal to the catabolic enzyme. The disorder presents with a wide clinical

Mitochondrial recessive ataxia syndrome mimicking dominant spinocerebellar ataxia.

Science.gov (United States)

Palin, Eino J H; Hakonen, Anna H; Korpela, Mari; Paetau, Anders; Suomalainen, Anu

2012-04-15

We studied the genetic background of a family with SCA, showing dominant inheritance and anticipation. Muscle histology, POLG1 gene sequence, neuropathology and mitochondrial DNA analyses in a mother and a son showed typical findings for a mitochondrial disorder, and both were shown to be homozygous for a recessive POLG1 mutation, underlying mitochondrial recessive ataxia syndrome, MIRAS. The healthy father was a heterozygous carrier for the same mutation. Recessively inherited MIRAS mutations should be tested in dominantly inherited SCAs cases of unknown cause, as the high carrier frequency of MIRAS may result in two independent introductions of the mutant allele in the family and thereby mimic dominant inheritance. Copyright © 2011 Elsevier B.V. All rights reserved.

[From gene to disease: from the ABCA4 gene to Stargardt disease, cone-rod dystrophy and retinitis pigmentosa

NARCIS (Netherlands)

Cremers, F.P.M.; Maugeri, A.; Klevering, B.J.; Hoefsloot, L.H.; Hoyng, C.B.

2002-01-01

Autosomal recessive Stargardt disease is caused by mutations in the ABCA4 gene. Mutations in ABCA4 are also found in two-thirds of cases with autosomal recessive cone-rod dystrophy, and a small fraction of patients with autosomal recessive retinitis pigmentosa. Patients with autosomal recessive

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding.

Science.gov (United States)

Nakamura, T; Lipton, S A

2007-07-01

Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca(2+) influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones - such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins - can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

Sequence analysis of tyrosinase gene in ocular and oculocutaneous albinism patients: introducing three novel mutations.

Science.gov (United States)

Khordadpoor-Deilamani, Faravareh; Akbari, Mohammad Taghi; Karimipoor, Morteza; Javadi, Gholamreza

2015-01-01

Albinism is a heterogeneous genetic disorder of melanin synthesis that results in hypopigmented eyes (in patients with ocular albinism) or hair, skin, and eyes (in individuals with oculocutaneous albinism). It is associated with decreased visual acuity, nystagmus, strabismus, and photophobia. The tyrosinase gene is known to be involved in both oculocutaneous albinism and autosomal recessive ocular albinism. In this study, we aimed to screen the mutations in the TYR gene in the nonsyndromic OCA and autosomal recessive ocular albinism patients from Iran. The tyrosinase gene was examined in 23 unrelated patients with autosomal recessive ocular albinism or nonsyndromic OCA using DNA sequencing and bioinformatics analysis. TYR gene mutations were identified in 14 (app. 60%) albinism patients. We found 10 mutations, 3 of which were novel. No mutation was found in our ocular albinism patients, but one of them was heterozygous for the p.R402Q polymorphism.

Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy.

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Cécile Méjécase

Full Text Available GNAT1, encoding the transducin subunit Gα, is an important element of the phototransduction cascade. Mutations in this gene have been associated with autosomal dominant and autosomal recessive congenital stationary night blindness. Recently, a homozygous truncating GNAT1 mutation was identified in a patient with late-onset rod-cone dystrophy. After exclusion of mutations in genes underlying progressive inherited retinal disorders, by targeted next generation sequencing, a 32 year-old male sporadic case with severe rod-cone dystrophy and his unaffected parents were investigated by whole exome sequencing. This led to the identification of a homozygous nonsense variant, c.963C>A p.(Cys321* in GNAT1, which was confirmed by Sanger sequencing. The mother was heterozygous for this variant whereas the variant was absent in the father. c.963C>A p.(Cys321* is predicted to produce a shorter protein that lacks critical sites for the phototransduction cascade. Our work confirms that the phenotype and the mode of inheritance associated with GNAT1 variants can vary from autosomal dominant, autosomal recessive congenital stationary night blindness to autosomal recessive rod-cone dystrophy.

Genetic forms of neurohypophyseal diabetes insipidus.

Science.gov (United States)

Rutishauser, Jonas; Spiess, Martin; Kopp, Peter

2016-03-01

Neurohypophyseal diabetes insipidus is characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although in most patients non-hereditary causes underlie the disorder, genetic forms have long been recognized and studied both in vivo and in vitro. In most affected families, the disease is transmitted in an autosomal dominant manner, whereas autosomal recessive forms are much less frequent. Both phenotypes can be caused by mutations in the vasopressin-neurophysin II (AVP) gene. In transfected cells expressing dominant mutations, the mutated hormone precursor is retained in the endoplasmic reticulum, where it forms fibrillar aggregates. Autopsy studies in humans and a murine knock-in model suggest that the dominant phenotype results from toxicity to vasopressinergic neurons, but the mechanisms leading to cell death remain unclear. Recessive transmission results from AVP with reduced biologic activity or the deletion of the locus. Genetic neurohypophyseal diabetes insipidus occurring in the context of diabetes mellitus, optic atrophy, and deafness is termed DIDMOAD or Wolfram syndrome, a genetically and phenotypically heterogeneous autosomal recessive disorder caused by mutations in the wolframin (WFS 1) gene. Copyright © 2016 Elsevier Ltd. All rights reserved.

Autosomal Recessive Inheritance

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Alkaptonuria

Directory of Open Access Journals (Sweden)

G K Tharini

2011-01-01

Full Text Available A case of alkaptonuria, a rare disorder with autosomal recessive inheritance, is reported here. The patient had palmar pigmentation in addition to the usual features of alkaptonuria.

HFE gene variants affect iron in the brain.

Science.gov (United States)

Nandar, Wint; Connor, James R

2011-04-01

Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.

Primer in Genetics and Genomics, Article 4-Inheritance Patterns.

Science.gov (United States)

Aiello, Lisa B; Chiatti, Beth Desaretz

2017-07-01

Since the completion of the Human Genome Project, much has been uncovered about inheritance of various illnesses and disorders. There are two main types of inheritance: Mendelian and non-Mendelian. Mendelian inheritance includes autosomal dominant, autosomal recessive, X-linked, and Y-linked inheritance. Non-Mendelian inheritance includes mitochondrial and multifactorial inheritance. Nurses must understand the types of inheritance in order to identify red flags that may indicate the possibility of a hereditary disorder in a patient or family.

Olfactory Memory Impairment in Neurodegenerative Diseases

OpenAIRE

Bahuleyan, Biju; Singh, Satendra

2012-01-01

Olfactory disorders are noted in a majority of neurodegenerative diseases, but they are often misjudged and are rarely rated in the clinical setting. Severe changes in the olfactory tests are observed in Parkinson's disease. Olfactory deficits are an early feature in Alzheimer's disease and they worsen with the disease progression. Alterations in the olfactory function are also noted after severe head injuries, temporal lobe epilepsy, multiple sclerosis, and migraine. The purpose of the prese...

Old Things New View: Ascorbic Acid Protects the Brain in Neurodegenerative Disorders

Directory of Open Access Journals (Sweden)

Adriana Covarrubias-Pinto

2015-11-01

Full Text Available Ascorbic acid is a key antioxidant of the Central Nervous System (CNS. Under brain activity, ascorbic acid is released from glial reservoirs to the synaptic cleft, where it is taken up by neurons. In neurons, ascorbic acid scavenges reactive oxygen species (ROS generated during synaptic activity and neuronal metabolism where it is then oxidized to dehydroascorbic acid and released into the extracellular space, where it can be recycled by astrocytes. Other intrinsic properties of ascorbic acid, beyond acting as an antioxidant, are important in its role as a key molecule of the CNS. Ascorbic acid can switch neuronal metabolism from glucose consumption to uptake and use of lactate as a metabolic substrate to sustain synaptic activity. Multiple evidence links oxidative stress with neurodegeneration, positioning redox imbalance and ROS as a cause of neurodegeneration. In this review, we focus on ascorbic acid homeostasis, its functions, how it is used by neurons and recycled to ensure antioxidant supply during synaptic activity and how this antioxidant is dysregulated in neurodegenerative disorders.

Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders

Science.gov (United States)

Yang, Yaping; Muzny, Donna M.; Reid, Jeffrey G.; Bainbridge, Matthew N.; Willis, Alecia; Ward, Patricia A.; Braxton, Alicia; Beuten, Joke; Xia, Fan; Niu, Zhiyv; Hardison, Matthew; Person, Richard; Bekheirnia, Mir Reza; Leduc, Magalie S.; Kirby, Amelia; Pham, Peter; Scull, Jennifer; Wang, Min; Ding, Yan; Plon, Sharon E.; Lupski, James R.; Beaudet, Arthur L.; Gibbs, Richard A.; Eng, Christine M.

2014-01-01

BACKGROUND Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. METHODS We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. RESULTS We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic pheno-types. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had auto-somal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders. CONCLUSIONS Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.) PMID:24088041

Disease: H00768 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available us disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. ... JOURNAL ... Hum M... H00768 Nonsyndromic autosomal recessive mental retardation (NS-ARMR) Mental retardation (MR) is a neurodeve...lopmental disorder characterized by low intelligence quotient (IQ) and deficits in

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. Copyright © 2013 Elsevier Inc. All rights reserved.

Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene.

Science.gov (United States)

Bisserbe, A; Tertian, G; Buffet, C; Turhan, A; Lambotte, O; Nasser, G; Alvin, P; Tardieu, M; Riant, F; Bergametti, F; Tournier-Lasserve, E; Denier, C

2015-05-01

Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Clinical spectrum of early onset cerebellar ataxia with retained tendon reflexes: an autosomal recessive ataxia not to be missed Espectro clínico da ataxia cerebelar de início precoce com reflexos mantidos: uma ataxia autossômica recessiva para não ser esquecida

Directory of Open Access Journals (Sweden)

José Luiz Pedroso

2013-06-01

Full Text Available Autosomal recessive cerebellar ataxias are a heterogeneous group of neurological disorders. In 1981, a neurological entity comprised by early onset progressive cerebellar ataxia, dysarthria, pyramidal weakness of the limbs and retained or increased upper limb reflexes and knee jerks was described. This disorder is known as early onset cerebellar ataxia with retained tendon reflexes. In this article, we aimed to call attention for the diagnosis of early onset cerebellar ataxia with retained tendon reflexes as the second most common cause of autosomal recessive cerebellar ataxias, after Friedreich ataxia, and also to perform a clinical spectrum study of this syndrome. In this data, 12 patients from different families met all clinical features for early onset cerebellar ataxia with retained tendon reflexes. Dysarthria and cerebellar atrophy were the most common features in our sample. It is uncertain, however, whether early onset cerebellar ataxia with retained tendon reflexes is a homogeneous disease or a group of phenotypically similar syndromes represented by different genetic entities. Further molecular studies are required to provide definitive answers to the questions that remain regarding early onset cerebellar ataxia with retained tendon reflexes.As ataxias cerebelares autossômicas recessivas são um grupo heterogêneo de doenças neurológicas. Em 1981, foi descrita uma entidade neurológica incluindo ataxia cerebelar progressiva de início precoce, disartria, liberação piramidal e manutenção ou aumento dos reflexos tendíneos nos membros superiores e inferiores. Essa síndrome é conhecida como ataxia cerebelar de início precoce com reflexos mantidos. Neste artigo, o objetivo foi chamar a atenção para o diagnóstico de ataxia cerebelar de início precoce com reflexos mantidos como a segunda causa mais comum de ataxia cerebelar autossômica recessiva, após a ataxia de Friedreich, e também realizar um estudo do espectro cl

Xeroderma pigmentosum: A rare case report with review of literature

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B Anand

2012-01-01

Full Text Available Xeroderma pigmentosum, or XP, is an autosomal recessive genetic disorder in which the ability to repair DNA damage caused by ultraviolet (UV light is deficient. In extreme cases, all exposure to sunlight must be forbidden, no matter how small. As such, individuals with the disease are often colloquially referred to as ′Children of the Night′. Mutations in XP genes that regulate nucleotide excision repair, not only predispose persons with xeroderma pigmentosum to multiple malignancies, but also promote premature cutaneous and ocular ageing, and in some cases promote progressive neurodegenerative changes. There is a great involvement of many parts of the body, especially head and neck. The oral manifestations are mainly related to the occurrence of malignant tumors in the lips, tongue and buccal mucosa. This paper reports a rare case of XP in a 40-year-old female presenting with dermatological, oral and ophthalmological involvement.

A syndrome of epilepsy, dementia, and amelogenesis imperfecta: genetic and clinical features.

OpenAIRE

Christodoulou, J; Hall, R K; Menahem, S; Hopkins, I J; Rogers, J G

1988-01-01

A family is described with six members affected by a syndrome of epilepsy, dementia, and amelogenesis imperfecta (Kohlschütter's syndrome). An autosomal recessive pattern of inheritance is established for this disorder.

Pyle metaphyseal dysplasia in an African child: Case report and review of the literature.

Science.gov (United States)

Wonkam, A; Makubalo, N; Roberts, T; Chetty, M

2016-05-25

Pyle disease (OMIM 265900), also known as metaphyseal dysplasia, is a rare autosomal recessive disorder with no known gene mutation. We report a case of Pyle disease in a 7-year-old African boy of mixed ancestry who presented with finger and wrist fractures following minor trauma. The radiological findings revealed abnormally broad metaphyses of the tubular bones, known as Erlenmeyer-flask bone deformity, and mild cranial sclerosis, both hallmarks of the condition. We report the first case in a patient with African ancestry, which could help in the gene discovery of this rare autosomal recessive skeletal dysplasia with unknown mutations.

A case report of primary ciliary dyskinesia, laterality defects and developmental delay caused by the co-existence of a single gene and chromosome disorder.

LENUS (Irish Health Repository)

Casey, Jillian P

2015-01-01

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterised by abnormal ciliary motion and impaired mucociliary clearance, leading to recurrent respiratory infections, sinusitis, otitis media and male infertility. Some patients also have laterality defects. We recently reported the identification of three disease-causing PCD genes in the Irish Traveller population; RSPH4A, DYX1C1 and CCNO. We have since assessed an additional Irish Traveller family with a complex phenotype involving PCD who did not have any of the previously identified PCD mutations.

Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48)

Science.gov (United States)

Hirst, Jennifer; Madeo, Marianna; Smets, Katrien; Edgar, James R.; Schols, Ludger; Li, Jun; Yarrow, Anna; Deconinck, Tine; Baets, Jonathan; Van Aken, Elisabeth; De Bleecker, Jan; Datiles, Manuel B.; Roda, Ricardo H.; Liepert, Joachim; Züchner, Stephan; Mariotti, Caterina; De Jonghe, Peter; Blackstone, Craig

2016-01-01

Objective: Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotype–phenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious. Methods: We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1. Results: In 4 of the 6 patients, there was complete loss of AP-5 ζ protein. Clinical features encompassed not only prominent spastic paraparesis but also sensory and motor neuropathy, ataxia, dystonia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated lamellar storage material consistent with abnormal storage of lysosomal material. Conclusions: Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and lysosomal storage disorders. PMID:27606357

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases.

Science.gov (United States)

Ita, Kevin

2017-06-01

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer's disease, Parkinson's disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.

Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays.

Science.gov (United States)

H'mida-Ben Brahim, D; M'zahem, A; Assoum, M; Bouhlal, Y; Fattori, F; Anheim, M; Ali-Pacha, L; Ferrat, F; Chaouch, M; Lagier-Tourenne, C; Drouot, N; Thibaut, C; Benhassine, T; Sifi, Y; Stoppa-Lyonnet, D; N'Guyen, K; Poujet, J; Hamri, A; Hentati, F; Amouri, R; Santorelli, F M; Tazir, M; Koenig, M

2011-01-01

The diagnosis of rare inherited diseases is becoming more and more complex as an increasing number of clinical conditions appear to be genetically heterogeneous. Multigenic inheritance also applies to the autosomal recessive progressive cerebellar ataxias (ARCAs), for which 14 genes have been identified and more are expected to be discovered. We used homozygosity mapping as a guide for identification of the defective locus in patients with ARCA born from consanguineous parents. Patients from 97 families were analyzed with GeneChip Mapping 10K or 50K SNP Affymetrix microarrays. We identified six families homozygous for regions containing the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) gene, two families homozygous for the ataxia-telangiectasia gene (ATM), two families homozygous for the ataxia with oculomotor apraxia type 1 (AOA1) gene, and one family homozygous for the AOA type 2 (AOA2) gene. Upon direct gene testing, we were able to identify a disease-related mutation in all families but one of the two kindred homozygous at the ATM locus. Although linkage analyses pointed to a single locus on chromosome 11q22.1-q23.1 for this family, clinical features, normal levels of serum alpha-foetoprotein as well as absence of mutations in the ATM gene rather suggest the existence of an additional ARCA-related gene in that interval. While the use of homozygosity mapping was very effective at pointing to the correct gene, it also suggests that the majority of patients harbor mutations either in the genes of the rare forms of ARCA or in genes yet to be identified.

Rhizomelic chondrodysplasia punctata and cardiac pathology

NARCIS (Netherlands)

Huffnagel, Irene C.; Clur, Sally-Ann B.; Bams-Mengerink, Annemieke M.; Blom, Nico A.; Wanders, Ronald J. A.; Waterham, Hans R.; Poll-The, Bwee Tien

2013-01-01

Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive peroxisomal disorder characterised by rhizomelia, contractures, congenital cataracts, facial dysmorphia, severe psychomotor defects and growth retardation. Biochemically, the levels of plasmalogens (major constituents of cellular

Osteogenesis imperfecta

Directory of Open Access Journals (Sweden)

Justin Easow Sam

2017-01-01

Full Text Available Osteogenesis imperfecta is a common heritable connective tissue disorder. Nearly ninety percent are due to Type I collagen mutations. Type I-IV are autosomal dominant, and Type VI–XIII are autosomal recessive. They are Graded 1-5 based on severity. Genomic testing is done by collagen analysis from fibroblasts. The mainstay of treatment is bisphosphonate therapy. The prognosis is variable.

Cutis laxa and fatal pulmonary hypertension: a newly recognized syndrome?

OpenAIRE

Brunetti-Pierri, N; Piccolo, P; Morava, Eva; Wevers, RA; McGuirk, M; Johnson, YR; Urban, Z; Dishop, MK; Potocki, L

2011-01-01

Cutis laxa is a connective tissue disorder with distinctive lax, redundant, and inelastic skin. It is a genetically heterogenous disorder with autosomal dominant and recessive patterns of inheritance. We report a patient with cutis laxa supported by clinical, microscopic, and ultrastructural findings. Molecular analysis of fibulin-4 and -5, of the α2 subunit of the V-type H+ ATPase, and of the component of the oligomeric Golgi complex 7 (COG7) genes excluded the type I and type II autosomal r...

The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?

Science.gov (United States)

Doty, Kevin R; Guillot-Sestier, Marie-Victoire; Town, Terrence

2015-08-18

Neurodegenerative diseases share common features, including catastrophic neuronal loss that leads to cognitive or motor dysfunction. Neuronal injury occurs in an inflammatory milieu that is populated by resident and sometimes, infiltrating, immune cells - all of which participate in a complex interplay between secreted inflammatory modulators and activated immune cell surface receptors. The importance of these immunomodulators is highlighted by the number of immune factors that have been associated with increased risk of neurodegeneration in recent genome-wide association studies. One of the more difficult tasks for designing therapeutic strategies for immune modulation against neurodegenerative diseases is teasing apart beneficial from harmful signals. In this regard, learning more about the immune components of these diseases has yielded common themes. These unifying concepts should eventually enable immune-based therapeutics for treatment of Alzheimer׳s and Parkinson׳s diseases and amyotrophic lateral sclerosis. Targeted immune modulation should be possible to temper maladaptive factors, enabling beneficial immune responses in the context of neurodegenerative diseases. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. Copyright © 2014 Elsevier B.V. All rights reserved.

NCBI nr-aa BLAST: CBRC-FCAT-01-1153 [SEVENS

Lifescience Database Archive (English)

Full Text Available 1| polycystic kidney and hepatic disease 1 [Homo sapiens] emb|CAH73867.1| polycystic kidney and hepatic disease 1 (autos...omal recessive) [Homo sapiens] emb|CAH72781.1| polycystic kidney and hepatic disease 1 (autos...omal recessive) [Homo sapiens] emb|CAI16676.1| polycystic kidney and hepatic disease 1 (autos...omal recessive) [Homo sapiens] emb|CAI20324.1| polycystic kidney and hepatic disease 1 (autosomal r...ecessive) [Homo sapiens] emb|CAI20233.1| polycystic kidney and hepatic disease 1 (autosomal recessive) [Homo sapiens] NP_619639.3 0.0 76% ...

NCBI nr-aa BLAST: CBRC-CJAC-01-1207 [SEVENS

Lifescience Database Archive (English)

Full Text Available 1| polycystic kidney and hepatic disease 1 [Homo sapiens] emb|CAH73867.1| polycystic kidney and hepatic disease 1 (autos...omal recessive) [Homo sapiens] emb|CAH72781.1| polycystic kidney and hepatic disease 1 (autos...omal recessive) [Homo sapiens] emb|CAI16676.1| polycystic kidney and hepatic disease 1 (autos...omal recessive) [Homo sapiens] emb|CAI20324.1| polycystic kidney and hepatic disease 1 (autosomal r...ecessive) [Homo sapiens] emb|CAI20233.1| polycystic kidney and hepatic disease 1 (autosomal recessive) [Homo sapiens] NP_619639.3 0.0 87% ...

Hermansky-Pudlak syndrome: A case report

Directory of Open Access Journals (Sweden)

R Vani

2014-01-01

Full Text Available Hermansky-Pudlak syndrome (HPS is a rare autosomal recessive disorder, which results in oculocutaneous albinism, bleeding disorders, and storage of abnormal fat protein compound (liposomal accumulation of ceroid lipofuscin. The major complications of this disorder are pulmonary fibrosis (PF and colitis. This is a case report of an HPS patient with PF.

Missense Mutations in CRYAB Are Liable for Recessive Congenital Cataracts.

Directory of Open Access Journals (Sweden)

Xiaodong Jiao

Full Text Available This study was initiated to identify causal mutations responsible for autosomal recessive congenital cataracts in consanguineous familial cases.Affected individuals underwent a detailed ophthalmological and clinical examination, and slit-lamp photographs were ascertained for affected individuals who have not yet been operated for the removal of the cataractous lens. Blood samples were obtained, and genomic DNA was extracted from white blood cells. A genome-wide scan was completed with short tandem repeat (STR markers, and the logarithm of odds (LOD scores were calculated. Protein coding exons of CRYAB were sequenced, bi-directionally. Evolutionary conservation was investigated by aligning CRYAB orthologues, and the expression of Cryab in embryonic and postnatal mice lens was investigated with TaqMan probe.The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis suggested a potential region on chromosome 11q23 harboring CRYAB. DNA sequencing identified a missense variation: c.34C>T (p.R12C in CRYAB that segregated with the disease phenotype in the family. Subsequent interrogation of our entire cohort of familial cases identified a second familial case localized to chromosome 11q23 harboring a c.31C>T (p.R11C mutation. In silico analyses suggested that the mutations identified in familial cases, p.R11C and p.R12C will not be tolerated by the three-dimensional structure of CRYAB. Real-time PCR analysis identified the expression of Cryab in mouse lens as early as embryonic day 15 (E15 that increased significantly until postnatal day 6 (P6 with steady level of expression thereafter.Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.

Disease: H00766 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available oepiphyseal dysplasia. Diabetes appears during the first months of life in most patients and major skeletal ...rome is a rare autosomal recessive disorder characterized by neonatal insulin-requiring diabetes and spondyl

Neurodegenerative Dementia

International Nuclear Information System (INIS)

Allard, Michelle

2006-01-01

Full text: With increasing life expectancy across the world, the number of elderly people at risk of developing dementia is growing rapidly. Thus, progressive neurodegenerative disorders such as dementia represent a growing public health concern. These diseases are characterized by a progressive loss in most of the cognitive functions. The promise, possibly in a near future, of disease-modifying therapies has made the characterization of the early stages of dementia a topic of major interest. The assessment of these early stages is a challenge for neuroimaging studies. In order to conceive prevention trials; it is of major outcome to fully understand the mechanisms of the cognitive system impairment and its evolution, with a particular reference to the symptomatic pre-dementia stage, when subjects just begin to depart from normality. In this article we review recent progress in neuroimaging, and their potentiality for increasing a diagnostic accuracy. (author)

Role of Different Alpha-Synuclein Strains in Synucleinopathies, Similarities with other Neurodegenerative Diseases

OpenAIRE

Melki, Ronald

2015-01-01

Abstract Misfolded protein aggregates are the hallmark of several neurodegenerative diseases in humans. The main protein constituent of these aggregates and the regions within the brain that are affected differ from one neurodegenerative disorder to another. A plethora of reports suggest that distinct diseases have in common the ability of protein aggregates to spread and amplify within the central nervous system. This review summarizes briefly what is known about the nature of the protein ag...

Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities.

Science.gov (United States)

Ali, Zafar; Klar, Joakim; Jameel, Mohammad; Khan, Kamal; Fatima, Ambrin; Raininko, Raili; Baig, Shahid; Dahl, Niklas

2016-12-15

We describe eight subjects from two consanguineous families segregating with autosomal recessive childhood onset spastic ataxia, peripheral neuropathy and intellectual disability. The degree of intellectual disability varied from mild to severe and all four affected individuals in one family developed aggressive behavior and epilepsy. Using exome sequencing, we identified two novel truncating mutations (c.2656C>T (p.Gln886*)) and (c.4756_4760delAATCA (p.Asn1586Tyrfs*3)) in the SACS gene responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). MRI revealed typical cerebellar and pontine changes associated with ARSACS as well as multiple supratentorial changes in both families as likely contributing factors to the cognitive symptoms. Intellectual disability and behavioral abnormalities have been reported in some cases of ARSACS but are not a part of the characteristic triad of symptoms that includes cerebellar ataxia, spasticity and peripheral neuropathy. Our combined findings bring further knowledge to the phenotypic spectrum, neurodegenerative changes and genetic variability associated with the SACS gene of clinical and diagnostic importance. Copyright © 2016. Published by Elsevier B.V.

Meier-Gorlin syndrome Clinical genetics and genomics

NARCIS (Netherlands)

S. de Munnik (Sonja); E.H. Hoefsloot (Lies); J. Roukema (Jolt); J. Schoots (Jeroen); N.V.A.M. Knoers (Nine); H.G. Brunner; A.P. Jackson (Andrew); E. Bongers (Ernie)

2015-01-01

textabstractMeier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia

Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy

DEFF Research Database (Denmark)

Bisgaard, A-M; Kirchhoff, M; Nielsen, J E

2008-01-01

A deletion on one chromosome and a mutant allele on the other may cause an autosomal recessive disease. We report on two patients with mental retardation, dysmorphic features and low catalytic activity of arylsulfatase A. One patient had a pathogenic mutation in the arylsulfatase A gene (ARSA......) and succumbed to metachromatic leukodystrophy (MLD). The other patient had a pseudoallele, which does not lead to MLD. The presenting clinical features and low arylsulfatase A activity were explained, in each patients, by a deletion of 22q13 and, thereby, of one allele of ARSA....

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. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Bio-effectiveness of the main flavonoids of Achillea millefolium in the pathophysiology of neurodegenerative disorders- a review

Directory of Open Access Journals (Sweden)

Fatemeh Ayoobi

2017-06-01

Full Text Available The Achillea millefolium L. (Yarrow is a common herb which is widely being used, worldwide. Achillea is being used for treatment of many disorders since centuries. It is considered safe for supplemental use and flavonoids such as kaempferol, luteolin and apigenin are of main constituents present in Achillea. Most of both antioxidant and anti-inflammatory properties of this herb have been attributed to its flavonoid content. Oxidative and inflammatory processes play important roles in pathogenesis of neurodegenerative diseases. Present review was aimed to review the latest literature evidences regarding application of Achillea and/or its three main flavonoid constituents on epilepsy, Alzheimer's disease, multiple sclerosis, Parkinson's disease and stroke.

Recessive Mutations in ACPT, Encoding Testicular Acid Phosphatase, Cause Hypoplastic Amelogenesis Imperfecta.

Science.gov (United States)

Seymen, Figen; Kim, Youn Jung; Lee, Ye Ji; Kang, Jenny; Kim, Tak-Heun; Choi, Hwajung; Koruyucu, Mine; Kasimoglu, Yelda; Tuna, Elif Bahar; Gencay, Koray; Shin, Teo Jeon; Hyun, Hong-Keun; Kim, Young-Jae; Lee, Sang-Hoon; Lee, Zang Hee; Zhang, Hong; Hu, Jan C-C; Simmer, James P; Cho, Eui-Sic; Kim, Jung-Wook

2016-11-03

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders affecting tooth enamel. The affected enamel can be hypoplastic and/or hypomineralized. In this study, we identified ACPT (testicular acid phosphatase) biallelic mutations causing non-syndromic, generalized hypoplastic autosomal-recessive amelogenesis imperfecta (AI) in individuals from six apparently unrelated Turkish families. Families 1, 4, and 5 were affected by the homozygous ACPT mutation c.713C>T (p.Ser238Leu), family 2 by the homozygous ACPT mutation c.331C>T (p.Arg111Cys), family 3 by the homozygous ACPT mutation c.226C>T (p.Arg76Cys), and family 6 by the compound heterozygous ACPT mutations c.382G>C (p.Ala128Pro) and 397G>A (p.Glu133Lys). Analysis of the ACPT crystal structure suggests that these mutations damaged the activity of ACPT by altering the sizes and charges of key amino acid side chains, limiting accessibility of the catalytic core, and interfering with homodimerization. Immunohistochemical analysis confirmed localization of ACPT in secretory-stage ameloblasts. The study results provide evidence for the crucial function of ACPT during amelogenesis. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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)

International Nuclear Information System (INIS)

Cordes, M.; Wszolek, Z.K.; Pfeiffer, R.F.; Calne, D.B.

1993-01-01

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 [ 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 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.) [de

Autosomal dominant craniometaphyseal dysplasia with atypical features.

Science.gov (United States)

McKay, D R; Fialkov, J A

2002-03-01

Craniometaphyseal dysplasia (CMD) is a rare genetic disorder of bone modelling characterised by hyperostosis and sclerosis of the craniofacial bones, and abnormal modelling of the metaphyses. Clinically, autosomal dominant (AD) CMD is characterised by facial distortion and cranial-nerve compression. The goals of surgical treatment for AD CMD are cosmetic recontouring of the sclerotic craniofacial bones, correction of nasal obstruction and correction or prevention of neurological manifestations. We describe the successful correction of AD CMD craniofacial manifestations in an individual with atypical findings, and outline an approach for correcting the craniofacial deformities associated with this rare disorder. Copyright 2002 The British Association of Plastic Surgeons.

Current novel-gene-finding strategy for autosomal-dominant hypercholesterolaemia needs refinement

NARCIS (Netherlands)

Fouchier, Sigrid W.; Hutten, Barbara A.; Defesche, Joep C.

2015-01-01

Autosomal-dominant hypercholesterolaemia (ADH) is a heterogeneous common disorder, and uncovering the molecular determinants that underlie ADH is a major focus of cardiovascular research. However, despite rapid technical advances, efforts to identify novel ADH genes have yet not been very successful

Normal expression of the Fanconi anemia proteins FAA and FAC and sensitivity to mitomycin C in two patients with Seckel syndrome

NARCIS (Netherlands)

Abou-Zahr, F; Bejjani, B; Kruyt, FAE; Kurg, R; Bacino, C; Shapira, SK; Youssoufian, H

1999-01-01

Seckel syndrome is a rare autosomal recessive disorder. The classical presentation includes pre- and postnatal growth deficiency, mental retardation, and characteristic facial appearance. There have been several reports of associated hematological abnormalities and chromosomal breakage, findings

Meier-Gorlin syndrome Clinical genetics and genomics

NARCIS (Netherlands)

De Munnik, Sonja A.; Hoefsloot, Elisabeth H.; Roukema, Jolt; Schoots, Jeroen; Knoers, Nine Vam; Brunner, Han G.; Jackson, Andrew P.; Bongers, Ernie Mhf

2015-01-01

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia in females

Meier-Gorlin syndrome

NARCIS (Netherlands)

Munnik, S.A. de; Hoefsloot, E.H.; Roukema, J.; Schoots, J.; Knoers, N.V.A.M.; Brunner, H.G.; Jackson, A.P.; Bongers, E.M.H.F.

2015-01-01

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia in females

VARIED MALIGNANT PRESENTATIONS IN A SINGLE CASE OF XERODERMA PIGMENTOS

Directory of Open Access Journals (Sweden)

Rahul Shetty

2013-10-01

Full Text Available Xeroderma pigmentosum is a autosomal recessive genetic disorder in which cutaneous malignancies are very common. We report a rare case where four different varieties of cutaneous malignancies were seen in the same patient..

Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria

NARCIS (Netherlands)

Marcadier, Julien L.; Smith, Amanda M.; Pohl, Daniela; Schwartzentruber, Jeremy; Al-Dirbashi, Osama Y.; Majewski, Jacek; Ferdinandusse, Sacha; Wanders, Ronald J. A.; Bulman, Dennis E.; Boycott, Kym M.; Chakraborty, Pranesh; Geraghty, Michael T.; Boycott, Kym; Friedman, Jan; Michaud, Jacques; Bernier, Francois; Brudno, Michael; Fernandez, Bridget; Knoppers, Bartha; Samuels, Mark; Scherer, Steve

2013-01-01

Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well as β-alanine. Existing reports describe a

A case of Kartagener syndrome with rhinolalia clausa | Raoufi | Pan ...

African Journals Online (AJOL)

Kartagener syndrome is an autosomal recessive genetic ciliary disorder comprising of a classic triad of sinusitis, situs inversus and bronchiectasis. It's the one of primary ciliary dyskinesia disorders with manifestations present from childhood. Most patients of PCD have situs inversus. We present a case of 18 year-old women ...

Bleeding Episodes Among Patients with Congenital Fibrinogen Disorders, a Study On 12 New Iranian Patients

Directory of Open Access Journals (Sweden)

Majid Naderi

2018-01-01

Full Text Available Background: Congenital fibrinogen disorders (CFDs comprise about 10% of rare bleeding disorders (RBDs. CFDs are divided into two groups of quantitative (afibrinogenemia and hypofibrinogenemia with autosomal recessive inheritance pattern, and qualitative (dysfibrinogenemia, hypodysfibrogenemia disorders, mainly with autosomal dominant inheritance pattern. Sistan and Baluchestan Province in Iran, with its high rate of consanguineous marriages, has a high incidence of RBDs including CFD. In the current study, we report clinical manifestations of patients with CFDs.Methods: Twelve new Iranian patients from Sistan and Baluchestan Province with different types of CFDs were selected for this study. Diagnosis of CFDs was based on clinical features and familial history followed by laboratory assessment by routine and specific coagulation tests including prothrombin time (PT and activated partial time tests (APTT, as well as FI activity assay by Clauss method.Results: Out of 12 patients, 3(25% had afibrinogenemia, 7(58.3% had hypofibrinogenemia while 2(16/7% were suspected of having dysfibrinogenemia. Although umbilical cord bleeding (UCB 9(75% was the most common clinical presentation among the study population, this feature was not observed among patients with dysfibrinogenemia. Hematoma (100% was the most common presentation of patients with dysfibrinogenemia.  Conclusion: Results of this study revealed that some clinical presentations are the diagnostic features of CFDs and can be used for precise and in-time diagnosis CFDs in conjunction with family history and laboratory findings.Keywords: Fibrinogen Deficiency; Congenital Afibrinogenemia; Blood Coagulation Disorder; Afibrinogenemia

Cerebral correlates of psychotic syndromes in neurodegenerative diseases

OpenAIRE

Jellinger, Kurt A

2012-01-01

Abstract Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer?s disease, synucleinopathies (Parkinson?s disease, dementia with Lewy bodies), Huntington?s disease, frontotemporal degenerations, motoneuron and prion...

Huntington's disease does not appear to increase the risk of diabetes mellitus

DEFF Research Database (Denmark)

Boesgaard, T W; Nielsen, Troels Tolstrup; Josefsen, Knud Elnegaard

2009-01-01

Huntington's disease (HD) is an autosomal, dominantly inherited, neurodegenerative disorder characterised by neurological, cognitive and psychiatric symptoms. HD has been associated with diabetes mellitus, which is, to some extent, supported by studies in transgenic HD mice. In transgenic mice...

SCA28

DEFF Research Database (Denmark)

Svenstrup, Kirsten; Nielsen, Troels Tolstrup; Aidt, Frederik

2017-01-01

The spinocerebellar ataxias (SCA) are a group of rare inherited neurodegenerative diseases characterized by slowly progressive cerebellar ataxia, resulting in unsteady gait, clumsiness, and dysarthria. The disorders are predominantly inherited in an autosomal dominant manner. Mutations in the gen...

Movement and Other Neurodegenerative Syndromes in Patients with Systemic Rheumatic Diseases: A Case Series of 8 Patients and Review of the Literature.

Science.gov (United States)

Menezes, Rikitha; Pantelyat, Alexander; Izbudak, Izlem; Birnbaum, Julius

2015-08-01

Patients with rheumatic diseases can present with movement and other neurodegenerative disorders. It may be underappreciated that movement and other neurodegenerative disorders can encompass a wide variety of disease entities. Such disorders are strikingly heterogeneous and lead to a wider spectrum of clinical injury than seen in Parkinson's disease. Therefore, we sought to stringently phenotype movement and other neurodegenerative disorders presenting in a case series of rheumatic disease patients. We integrated our findings with a review of the literature to understand mechanisms which may account for such a ubiquitous pattern of clinical injury.Seven rheumatic disease patients (5 Sjögren's syndrome patients, 2 undifferentiated connective tissue disease patients) were referred and could be misdiagnosed as having Parkinson's disease. However, all of these patients were ultimately diagnosed as having other movement or neurodegenerative disorders. Findings inconsistent with and more expansive than Parkinson's disease included cerebellar degeneration, dystonia with an alien-limb phenomenon, and nonfluent aphasias.A notable finding was that individual patients could be affected by cooccurring movement and other neurodegenerative disorders, each of which could be exceptionally rare (ie, prevalence of ∼1:1000), and therefore with the collective probability that such disorders were merely coincidental and causally unrelated being as low as ∼1-per-billion. Whereas our review of the literature revealed that ubiquitous patterns of clinical injury were frequently associated with magnetic resonance imaging (MRI) findings suggestive of a widespread vasculopathy, our patients did not have such neuroimaging findings. Instead, our patients could have syndromes which phenotypically resembled paraneoplastic and other inflammatory disorders which are known to be associated with antineuronal antibodies. We similarly identified immune-mediated and inflammatory markers of injury

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA

NARCIS (Netherlands)

van Berge, Laura; Dooves, Stephanie; van Berkel, Carola G. M.; Polder, Emiel; van der Knaap, Marjo S.; Scheper, Gert C.

2012-01-01

LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is an autosomal recessive white matter disorder with slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction. Magnetic resonance imaging shows characteristic abnormalities in the

Molecular genetic analysis of consanguineous families with primary ...

Indian Academy of Sciences (India)

RESEARCH NOTE Volume 96 Issue 2 June 2017 pp 383-387 ... Autosomal recessive primary microcephaly is a rare genetic disorder that is ... Department of Cell and Developmental Biology, School of Life Sciences, University of Science and ...

Fraser syndrome

DEFF Research Database (Denmark)

Barisic, Ingeborg; Odak, Ljubica; Loane, Maria

2013-01-01

Fraser syndrome is a rare autosomal recessive disorder characterized by cryptophthalmos, cutaneous syndactyly, laryngeal, and urogenital malformations. We present a population-based epidemiological study using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network of...

Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

Science.gov (United States)

Liu, Ying; Deng, Wenbin

2016-05-01

With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control

Gastrocnemius Recession Leads to Increased Ankle Motion and Improved Patient Satisfaction After 2 Years of Follow-Up

DEFF Research Database (Denmark)

Holtmann, Julia Alessandra; Südkamp, Norbert P; Schmal, Hagen

2017-01-01

The isolated gastrocnemius contracture present in neurologic healthy patients results in a significant limitation of ankle dorsiflexion causing pathologic gait patterns and a greater risk of further foot disorders. Gastrocnemius recession is an established procedure to increase ankle dorsiflexion....... However, little evidence is available of the use of gastrocnemius recession in these patients. Complication rates, recurrence of gastrocnemius contracture, and the prevalence of additional foot disorders needs further evaluation. A study group of 64 operated limbs undergoing gastrocnemius recession...... was evaluated to determine the prevalence of foot disorders, pre- and postoperative ankle dorsiflexion, and incidence of complications. A subgroup of 15 (23.4%) patients without additional operative procedures was examined regarding ankle dorsiflexion, strength (Janda method), sensitivity in the operated limb...

Application of a high-throughput genotyping method for loci exclusion in non-consanguineous Australian pedigrees with autosomal recessive retinitis pigmentosa.

Science.gov (United States)

Paterson, Rachel L; De Roach, John N; McLaren, Terri L; Hewitt, Alex W; Hoffmann, Ling; Lamey, Tina M

2012-01-01

Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, cost-effective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP. DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses. Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (pA) and USH2A in two families (c.2276 G>T). This study has shown that SNP genotyping cosegregation analysis can be successfully used to refine and expedite the genetic characterization of arRP in a non-consanguineous population; however, this method is effective only when DNA samples are

FDTD-based Transcranial Magnetic Stimulation model applied to specific neurodegenerative disorders.

Science.gov (United States)

Fanjul-Vélez, Félix; Salas-García, Irene; Ortega-Quijano, Noé; Arce-Diego, José Luis

2015-01-01

Non-invasive treatment of neurodegenerative diseases is particularly challenging in Western countries, where the population age is increasing. In this work, magnetic propagation in human head is modelled by Finite-Difference Time-Domain (FDTD) method, taking into account specific characteristics of Transcranial Magnetic Stimulation (TMS) in neurodegenerative diseases. It uses a realistic high-resolution three-dimensional human head mesh. The numerical method is applied to the analysis of magnetic radiation distribution in the brain using two realistic magnetic source models: a circular coil and a figure-8 coil commonly employed in TMS. The complete model was applied to the study of magnetic stimulation in Alzheimer and Parkinson Diseases (AD, PD). The results show the electrical field distribution when magnetic stimulation is supplied to those brain areas of specific interest for each particular disease. Thereby the current approach entails a high potential for the establishment of the current underdeveloped TMS dosimetry in its emerging application to AD and PD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: A cross-sectional analysis

NARCIS (Netherlands)

J.D. Rohrer (Jonathan D); J.M. Nicholas (Jennifer M); D.M. Cash (David M); J.C. van Swieten (John); E.G.P. Dopper (Elise); L.C. Jiskoot (Lize); R. van Minkelen (Rick); S.A.R.B. Rombouts (Serge); M.J. Cardoso (Manuel Jorge); S. Clegg (Shona); M. Espak (Miklos); S. Mead (Simon); D.L. Thomas (David L); E. De Vita (Enrico); M. Masellis (Mario); S.E. Black (Sandra); M. Freedman (Morris); R. Keren (Ron); B.J. MacIntosh (Bradley J); E. Rogaeva (Ekaterina); D. Tang-Wai (David); M.C. Tartaglia (Maria Carmela); R. Laforce (Robert); F. Tagliavini (Fabrizio); P. Tiraboschi (Pietro); V. Redaelli (Veronica); S. Prioni (Sara); M. Grisoli (Marina); B. Borroni (Barbara); A. Padovani (Alessandro); D. Galimberti (Daniela); E. Scarpini (Elio); A. Arighi (Andrea); G. Fumagalli (Giorgio); J.B. Rowe (James); I. Coyle-Gilchrist (Ian); C. Graff (Caroline); M. Fallström (Marie); S. Jelic (Svetislav Svetislav); A.K. Ståhlbom (Anne Kinhult); C. Andersson (Christin); H. Thonberg (Håkan); L. Lilius (Lena); G.B. Frisoni (Giovanni B.); M. Pievani (Michela); M. Bocchetta (Martina); L. Benussi (Luisa); R. Ghidoni (Roberta); E. Finger (Elizabeth); S. Sorbi (Sandro); B. Nacmias (Benedetta); G. Lombardi (Gemma); C. Polito (Cristina); J.D. Warren (Jason); S. Ourselin (Sebastien); N.C. Fox (Nick); M. Rossor (Martin)

2015-01-01

textabstractBackground: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (. GRN), microtubule-associated protein tau (. MAPT), or chromosome

Recurrent Skin and Lung Infections in Autosomal Dominant Hyper IgE Syndrome with Transactivation Domain STAT3 Mutation

Directory of Open Access Journals (Sweden)

Chad J. Cooper

2014-01-01

Full Text Available Background. Hyper IgE is a rare systemic disease characterized by the clinical triad of high serum levels of IgE (>2000 IU/mL, eczema, and recurrent staphylococcal skin and lung infections. The presentation of hyper IgE syndrome is highly variable, which makes it easy to confuse the diagnosis with that of severe atopy or other rare immunodeficiency disorders. Case Report. A 23-year-old Hispanic presented with history of frequent respiratory and gastrointestinal infections as a child and multiple episodes of skin and lung infections (abscess with Staphylococcus aureus throughout his adult life. He had multiple eczematous lesions and folliculitis over his entire body, oral/esophageal candidiasis, and retention of his primary teeth. The IgE was elevated (>5000 IU/mL. Genetic mutation analysis revealed a mutation affecting the transactivation domain of the STAT3 gene. Conclusion. The hallmark of hyper IgE syndrome is serum IgE of >2000 IU/mL. Hyper IgE syndrome is a genetic disorder that is either autosomal dominant or recessive. A definite diagnosis can be made with genetic mutation analysis, and in this case, it revealed a very rare finding of the transactivation domain STAT3 mutation. Hyper IgE syndrome is a challenge for clinicians in establishing a diagnosis in suspected cases.

Translational neuroscience of basolateral amygdala lesions : Studies of Urbach-Wiethe disease

NARCIS (Netherlands)

Koen, N.; Fourie, J.; Terburg, D.; Stoop, R.; Morgan, B.; Stein, D. J.; van Honk, J.

2016-01-01

Urbach-Wiethe disease (UWD) is an extremely rare autosomal recessive disorder characterized by mutations in the extracellular matrix protein 1 gene on chromosome 1. Typical clinical manifestations include voice hoarseness in early infancy and neuropsychiatric, laryngeal, and dermatological

Congenital insensitivity to pain with anhidrosis (CIPA): Novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency

NARCIS (Netherlands)

Y. Indo (Yasuhiro); S. Mardy (Sek); Y. Miura (Yuichi); A. Moosa (Allie); E.A.R. Ismail (Essam A.); E. Toscano (Ennio); G. Andria (Generoso); V. Pavone (Vito); D.L. Brown (Deborah); A.S. Brooks (Alice); F. Endo (Fumio); I. Matsuda (Ichiro)

2001-01-01

textabstractCongenital insensitivity to pain with anhidrosis is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The human TRKA gene

Ny klassifikation og molekylærgenetisk viden om arvelig iktyose

DEFF Research Database (Denmark)

Andersen, Rikke Elkjær; Hertz, Jens Michael; Bygum, Anette

2014-01-01

A new classification of inherited ichthyoses is presented based on clinical features, genetic background and pathophysiology. Ichthyoses are disorders of cornification and may be part of syndromes. Ichthyosis vulgaris, X-linked ichthyosis, autosomal recessive congenital ichthyosis and syndrome...

Debut af arvelig metabolisk encefalopati kan ses efter neonatalperioden

DEFF Research Database (Denmark)

Sørensen, Line Carøe; Rehman, Shazia; Lund, Allan Meldgaard

2016-01-01

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder causing accumulation of the branched amino acids valin, isoleucin, leucin and their toxic metabolites resulting in ketoacidosis, progressive neurological deterioration and cerebral oedema. The classical form presents...

Diagnosing mucopolysaccharidosis IVA

NARCIS (Netherlands)

T.C. Wood (Timothy); K. Harvey (Kirsten); M. Beck (Markus); M.G. Burin (Maira Graeff); Y.H. Chien; H.J. Church (Heather); V. D'Almeida (Vânia); O.P. van Diggelen (Otto); M. Fietz (Michael); R. Giugliani (Roberto); P. Harmatz (Paul); S.M. Hawley (Sara); W.L. Hwu; D. Ketteridge (David); Z. Lukacs; N. Miller (Nicola); M. Pasquali (Marzia); A. Schenone (Andrea); J.N. Thompson; K. Tylee (Karen); C. Yu (Cong); C. Hendriksz (Chris)

2013-01-01

textabstractMucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and

Cerebro-costo-mandibular syndrome

International Nuclear Information System (INIS)

Flodmark, P.; Wattsgaard, C.

2001-01-01

Cerebro-costo-mandibular syndrome is a rare disorder characterized by rib malformations, various degrees of cerebral maldevelopment, mental deficiency, palatal defects, and micrognatia. This syndrome was first described in 1966. The majority of cases are sporadic, but a few instances of familial occurrence have been reported, some with an autosomal recessive pattern of inheritance. Mortality in early age has been high, probably mostly due to respiratory insufficiency secondary to rib abnormalities and flail chest. We report a mother and son with this disorder, suggesting autosomal dominant transmission. (orig.)

Two siblings with immunodeficiency, facial abnormalities and chromosomal instability without mutation in DNMT3B gene but liability towards malignancy; a new chromatin disorder delineation?

Science.gov (United States)

Polityko, Anna; Khurs, Olga; Rumyantseva, Natalia; Naumchik, Irina; Kosyakova, Nadezda; Tönnies, Holger; Sperling, Karl; Neitzel, Heidemarie; Weise, Anja; Liehr, Thomas

2010-03-08

ICF syndrome (standing for Immunodeficiency, Centromere instability and Facial anomalies syndrome) is a very rare autosomal recessive immune disorder caused by mutations of the gene de novo DNA-methyltransferase 3B (DNMT3B). However, in the literature similar clinical cases without such mutations are reported, as well. We report on a family in which the unrelated spouses had two female siblings sharing similar phenotypic features resembling ICF-syndrome, i.e. congenital abnormalities, immunodeficiency, developmental delay and high level of chromosomal instability, including high frequency of centromeric/pericentromeric rearrangements and breaks, chromosomal fragments despiralization or pulverization. However, mutations in DNMT3B could not be detected. The discovery of a new so-called 'chromatin disorder' is suggested. Clinical, molecular genetic and cytogenetic characteristics are reported and compared to other 'chromatin disorders'.

Disease: H00696 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available H00696 Haim-Munk syndrome; Prepubertal periodontitis (PPP) Haim-Munk syndrome is a... rare autosomal recessive disorder of keratinization characterized by palmoplantar hyperkeratosis and marked periodontitis... acroosteolysis. Prepubertal periodontitis (PPP) is a rare and rapidly progressiv

An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study

DEFF Research Database (Denmark)

Steenweg, Marjan E; Jakobs, Cornelis; Errami, Abdellatif

2010-01-01

L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of ...

A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy.

NARCIS (Netherlands)

G. Weeda (Geert); E. Eveno; I. Donker (Ingrid); W. Vermeulen (Wim); O. Chevalier-Lagente (Odile); A. Taieb; A. Stary; J.H.J. Hoeijmakers (Jan); M. Mezzina; A. Sarasin

1997-01-01

textabstractTrichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is

RESEARCH ARTICLE The prevalence and spectrum of thalassemia ...

Indian Academy of Sciences (India)

Navya

Thalassemia is the most common autosomal recessive disorder worldwide (Joly et al. ... results from a gross gene deletion (Bank 2015; Colah et al. ... France) to assess the concentration of hemoglobin (Hb) A, A2, and F, and any abnormal.

Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene

DEFF Research Database (Denmark)

Mercimek-Mahmutoglu, Saadet; Ndika, Joseph; Kanhai, Warsha

2014-01-01

Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients 5...

Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency

NARCIS (Netherlands)

Vaz, F. M.; Scholte, H. R.; Ruiter, J.; Hussaarts-Odijk, L. M.; Pereira, R. R.; Schweitzer, S.; de Klerk, J. B.; Waterham, H. R.; Wanders, R. J.

1999-01-01

Systemic carnitine deficiency is a potentially lethal, autosomal recessive disorder characterized by cardiomyopathy, myopathy, recurrent episodes of hypoketotic hypoglycemia, hyperammonemia, and failure to thrive. This form of carnitine deficiency is caused by a defect in the active cellular uptake

Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

NARCIS (Netherlands)

Brunetti, Dario; Dusi, Sabrina; Giordano, Carla; Lamperti, Costanza; Morbin, Michela; Fugnanesi, Valeria; Marchet, Silvia; Fagiolari, Gigliola; Sibon, Ody; Moggio, Maurizio; d'Amati, Giulia; Tiranti, Valeria

Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2,

COLEC10 is mutated in 3MC patients and regulates early craniofacial development

DEFF Research Database (Denmark)

Munye, Mustafa M.; Diaz-Font, Anna; Ocaka, Louise

2017-01-01

3MC syndrome is an autosomal recessive heterogeneous disorder with features linked to developmental abnormalities. The main features include facial dysmorphism, craniosynostosis and cleft lip/palate; skeletal structures derived from cranial neural crest cells (cNCC). We previously reported...

Yunis-Varón syndrome caused by biallelic VAC14 mutations

NARCIS (Netherlands)

Lines, Matthew A.; Ito, Yoko; Kernohan, Kristin D.; Mears, Wendy; Hurteau-Miller, Julie; Venkateswaran, Sunita; Ward, Leanne; Khatchadourian, Karine; McClintock, Jeff; Bhola, Priya; Campeau, Philippe M.; Boycott, Kym M.; Michaud, Jean; van Kuilenburg, André Bp; Ferdinandusse, Sacha; Dyment, David A.

2017-01-01

Yunis-Varón syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in

Abetalipoproteinemia: A novel mutation of microsomal triglyceride ...

African Journals Online (AJOL)

Abetalipoproteinemia (ABL), or Bassen–Kornzweig syndrome, is a rare autosomal recessive disorder of lipoprotein metabolism, characterized by fat malabsorption, hypocholesterolemia, retinitis pigmentosa, progressive neuropathy and acanthocytosis. We report the case of a Tunisian male child born from consanguineous ...

Seeking environmental causes of neurodegenerative disease and envisioning primary prevention.

Science.gov (United States)

Spencer, Peter S; Palmer, Valerie S; Kisby, Glen E

2016-09-01

Pathological changes of the aging brain are expressed in a range of neurodegenerative disorders that will impact increasing numbers of people across the globe. Research on the causes of these disorders has focused heavily on genetics, and strategies for prevention envision drug-induced slowing or arresting disease advance before its clinical appearance. We discuss a strategic shift that seeks to identify the environmental causes or contributions to neurodegeneration, and the vision of primary disease prevention by removing or controlling exposure to culpable agents. The plausibility of this approach is illustrated by the prototypical neurodegenerative disease amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC). This often-familial long-latency disease, once thought to be an inherited genetic disorder but now known to have a predominant or exclusive environmental origin, is in the process of disappearing from the three heavily affected populations, namely Chamorros of Guam and Rota, Japanese residents of Kii Peninsula, Honshu, and Auyu and Jaqai linguistic groups on the island of New Guinea in West Papua, Indonesia. Exposure via traditional food and/or medicine (the only common exposure in all three geographic isolates) to one or more neurotoxins in seed of cycad plants is the most plausible if yet unproven etiology. Neurotoxin dosage and/or subject age at exposure might explain the stratified epidemic of neurodegenerative disease on Guam in which high-incidence ALS peaked and declined before that of PD, only to be replaced today by a dementing disorder comparable to Alzheimer's disease. Exposure to the Guam environment is also linked to the delayed development of ALS among a subset of Chamorro and non-Chamorro Gulf War/Era veterans, a summary of which is reported here for the first time. Lessons learned from this study and from 65 years of research on ALS-PDC include the exceptional value of initial, field-based informal investigation of

Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders.

Science.gov (United States)

Goemaere, Julie; Knoops, Bernard

2012-02-01

Redox changes are observed in neurodegenerative diseases, ranging from increased levels of reactive oxygen/nitrogen species and disturbance of antioxidant systems, to nitro-oxidative damage. By reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides, peroxiredoxins (Prdxs) represent a major potential protective barrier against nitro-oxidative insults in the brain. While recent works have investigated the putative role of Prdxs in neurodegenerative disorders, less is known about their expression in the healthy brain. Here we used immunohistochemistry to map basal expression of Prdxs throughout C57BL/6 mouse brain. We first confirmed the neuronal localization of Prdx2-5 and the glial expression of Prdx1, Prdx4, and Prdx6. Then we performed an in-depth analysis of neuronal Prdx distribution in the brain. Our results show that Prdx2-5 are widely detected in the different neuronal populations, and especially well expressed in the olfactory bulb, in the cerebral cortex, in pons nuclei, in the red nucleus, in all cranial nerve nuclei, in the cerebellum, and in motor neurons of the spinal cord. In contrast, Prdx expression is very low in the dopaminergic neurons of substantia nigra pars compacta and in the CA1/2 pyramidal cells of hippocampus. This low basal expression may contribute to the vulnerability of these neurons to nitro-oxidative attacks occurring in Parkinson's disease and Alzheimer's disease. In addition, we found that Prdx expression levels are unevenly distributed among neurons of a determined region and that distinct regional patterns of expression are observed between isoforms, reinforcing the hypothesis of the nonredundant function of Prdxs. Copyright © 2011 Wiley-Liss, Inc.

Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders.

Science.gov (United States)

Di Domenico, Fabio; Tramutola, Antonella; Butterfield, D Allan

2017-10-01

Oxidative stress is involved in various and numerous pathological states including several age-related neurodegenerative diseases. Peroxidation of the membrane lipid bilayer is one of the major sources of free radical-mediated injury that directly damages neurons causing increased membrane rigidity, decreased activity of membrane-bound enzymes, impairment of membrane receptors and altered membrane permeability and eventual cell death. Moreover, the peroxidation of polyunsaturated fatty acids leads to the formation of aldehydes, which can act as toxic by-products. One of the most abundant and cytotoxic lipid -derived aldehydes is 4-hydroxy 2-nonenal (HNE). HNE toxicity is mainly due to the alterations of cell functions by the formation of covalent adducts of HNE with proteins. A key marker of lipid peroxidation, HNE-protein adducts, were found to be elevated in brain tissues and body fluids of Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis subjects and/or models of the respective age-related neurodegenerative diseases. Although only a few proteins were identified as common targets of HNE modification across all these listed disorders, a high overlap of these proteins occurs concerning the alteration of common pathways, such as glucose metabolism or mitochondrial function that are known to contribute to cognitive decline. Within this context, despite the different etiological and pathological mechanisms that lead to the onset of different neurodegenerative diseases, the formation of HNE-protein adducts might represent the shared leit-motif, which aggravates brain damage contributing to disease specific clinical presentation and decline in cognitive performance observed in each case. Copyright © 2016 Elsevier Inc. All rights reserved.

Isoprostanes and Neuroprostanes as Biomarkers of Oxidative Stress in Neurodegenerative Diseases

Directory of Open Access Journals (Sweden)

Elżbieta Miller

2014-01-01

Full Text Available Accumulating data shows that oxidative stress plays a crucial role in neurodegenerative disorders. The literature data indicate that in vivo or postmortem cerebrospinal fluid and brain tissue levels of F2-isoprostanes (F2-IsoPs especially F4-neuroprotanes (F4-NPs are significantly increased in some neurodegenerative diseases: multiple sclerosis, Alzheimer's disease, Huntington's disease, and Creutzfeldt-Jakob disease. Central nervous system is the most metabolically active organ of the body characterized by high requirement for oxygen and relatively low antioxidative activity, what makes neurons and glia highly susceptible to destruction by reactive oxygen/nitrogen species and neurodegeneration. The discovery of F2-IsoPs and F4-NPs as markers of lipid peroxidation caused by the free radicals has opened up new areas of investigation regarding the role of oxidative stress in the pathogenesis of human neurodegenerative diseases. This review focuses on the relationship between F2-IsoPs and F4-NPs as biomarkers of oxidative stress and neurodegenerative diseases. We summarize the knowledge of these novel biomarkers of oxidative stress and the advantages of monitoring their formation to better define the involvement of oxidative stress in neurological diseases.

Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific

NARCIS (Netherlands)

Jansen, Anne H. P.; van Hal, Maurik; Op den Kelder, Ilse C.; Meier, Romy T.; de Ruiter, Anna-Aster; Schut, Menno H.; Smith, Donna L.; Grit, Corien; Brouwer, Nieske; Kamphuis, Willem; Boddeke, H. W. G. M.; den Dunnen, Wilfred F. A.; van Roon, Willeke M. C.; Bates, Gillian P.; Hol, Elly M.; Reits, Eric A.

2017-01-01

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is caused by a CAG expansion in the Huntingtin (HTT) gene, leading to HTT inclusion formation in the brain. The mutant huntingtin protein (mHTT) is ubiquitously expressed and therefore nuclear inclusions

Frequency of Nuclear Mutant Huntingtin Inclusion Formation in Neurons and Glia is Cell-Type-Specific

NARCIS (Netherlands)

Jansen, Anne H P; van Hal, Maurik; op den Kelder, Ilse C.; Meier, Romy T.; de Ruiter, Anna-Aster; Schut, Menno H.; Smith, Donna L.; Grit, Corien; Brouwer, Nieske; Kamphuis, Willem; Boddeke, H. W. G. M.; den Dunnen, Wilfred F. A.; van Roon, Willeke M. C.; Bates, Gillian P.; Hol, Elly M.; Reits, Eric A.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is caused by a CAG expansion in the Huntingtin (HTT) gene, leading to HTT inclusion formation in the brain. The mutant huntingtin protein (mHTT) is ubiquitously expressed and therefore nuclear inclusions

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders.

Science.gov (United States)

Jęśko, Henryk; Wencel, Przemysław; Strosznajder, Robert P; Strosznajder, Joanna B

2017-03-01

Sirtuins (SIRT1-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD + levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair. Through these functions sirtuins modulate the course of aging and affect neurodegenerative diseases. SIRTSs interact with multiple signaling proteins, transcription factors (TFs) and poly(ADP-ribose) polymerases (PARPs) another class of NAD + -dependent post-translational protein modifiers. The cross-talk between SIRTs TFs and PARPs is a highly promising research target in a number of brain pathologies. This review describes updated results on sirtuins in brain aging/neurodegeneration. It focuses on SIRT1 but also on the roles of mitochondrial SIRTs (SIRT3, 4, 5) and on SIRT6 and SIRT2 localized in the nucleus and in cytosol, respectively. The involvement of SIRTs in regulation of insulin-like growth factor signaling in the brain during aging and in Alzheimer's disease was also focused. Moreover, we analyze the mechanism(s) and potential significance of interactions between SIRTs and several TFs in the regulation of cell survival and death. A critical view is given on the application of SIRT activators/modulators in therapy of neurodegenerative diseases.

Prenatal-Onset Niemann–Pick Type C Disease with Nonimmune Hydrops Fetalis

Directory of Open Access Journals (Sweden)

Ozge Surmeli-Onay

2013-10-01

Full Text Available Niemann–Pick type C (NPC; OMIM 257219 disease is a neurodegenerative lysosomal storage disorder characterized by accumulation of unesterified cholesterol in the lysosomal/late endosomal system. This autosomal recessive disorder occurs in approximately 1/150,000 births. The broad clinical spectrum ranges from a prenatal severe presentation to an adult-onset chronic neurodegenerative disease. Data about prenatal presentation of NPC are limited. A female newborn was born at 342 weeks' gestation with a birth weight of 3070 g, and transferred to the Neonatal Intensive Care Unit because of nonimmune hydrops fetalis (NIHF and respiratory distress. On admission, a physical examination revealed skin edema, mild respiratory distress, and abdominal distention due to massive ascites. Hepatosplenomegaly and cholestasis increased progressively and bleeding diathesis occurred. Results of an abdominal ultrasonography showed hepatosplenomegaly and segmental multicystic dysplastic left kidney. Foamy cells with a lysosomal phospholipid storage pattern compatible with NPC were found in the bone marrow smear. Cultured fibroblasts showed a strongly elevated filipin staining (classical NPC cellular phenotype, establishing the diagnosis of NPC. The infant died on the 52nd day of life because of respiratory distress due to lung involvement of NPC, massive ascites, and progressive liver failure. Results of an autopsy showed multiorgan storage disease involving the liver, spleen, lymph nodes, thymus, lungs, and brain. Here, we present a preterm infant with NIHF as a sign of severe prenatal-onset NPC and review the literature.

Circulating matrix gamma-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome

NARCIS (Netherlands)

Cranenburg, E. C. M.; van Spaendonck-Zwarts, K. Y.; Bonafe, L.; Crettol, L. Mittaz; Rodiger, L. A.; Dikkers, F. G.; van Essen, A. J.; Superti-Furga, A.; Alexandrakis, E.; Vermeer, C.; Schurgers, L. J.; Laverman, G. D.

Background and objectives: Matrix gamma-carboxyglutamate protein (MGP), a vitamin K-dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an

Serial postural and motor assessment of Fetal Akinesia Deformation Sequence (FADS)

NARCIS (Netherlands)

Donker, M.E.; Eijckelhof, B.H.; Tan, G.M.; de Vries, J.I.

2009-01-01

Background: Fetal Akinesia Deformation Sequence (FADS) is a rare, in most cases autosomal recessive, disorder. Its heterogeneous origin results in variable onset and expression of motor and postural anomalies. DNA-diagnostic possibilities are limited, thus prenatal diagnosis is chiefly dependent on

Intra- und postoperative Analgesie mit Kaudalkatheter bei einem Kind mit Schwartz-Jampel-Syndrom

NARCIS (Netherlands)

Stevens, M. F.; Golla, E.; Lipfert, P.

2006-01-01

The Schwartz-Jampel syndrome, also known as myotonia chondrodystrophica, is a rare autosomal recessive disorder characterized by bone dysplasia, growth retardation and generalized myotonia. Laryngoscopy and intubation may be difficult because of micrognathia and limited mouth opening due to myotonia

The genetic basis of DOORS syndrome : an exome-sequencing study

NARCIS (Netherlands)

Campeau, Philippe M.; Kasperaviciute, Dalia; Lu, James T.; Burrage, Lindsay C.; Kim, Choel; Hori, Mutsuki; Powell, Berkley R.; Stewart, Fiona; Felix, Temis Maria; van den Ende, Jenneke; Wisniewska, Marzena; Kayserili, Huelya; Rump, Patrick; Nampoothiri, Sheela; Aftimos, Salim; Mey, Antje; Nair, Lal D. V.; Begleiter, Michael L.; De Bie, Isabelle; Meenakshi, Girish; Murray, Mitzi L.; Repetto, Gabriela M.; Golabi, Mahin; Blair, Edward; Male, Alison; Giuliano, Fabienne; Kariminejad, Ariana; Newman, William G.; Bhaskar, Sanjeev S.; Dickerson, Jonathan E.; Kerr, Bronwyn; Banka, Siddharth; Giltay, Jacques C.; Wieczorek, Dagmar; Tostevin, Anna; Wiszniewska, Joanna; Cheung, Sau Wai; Hennekam, Raoul C.; Gibbs, Richard A.; Lee, Brendan H.; Sisodiya, Sanjay M.

Background Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals. Methods Through a search

Cranioectodermal Dysplasia : A Probable Ciliopathy

NARCIS (Netherlands)

Konstantinidou, Anastasia E.; Fryssira, Helen; Sifakis, Stavros; Karadimas, Charalampos; Kaminopetros, Petros; Agrogiannis, Georgios; Velonis, Stylianos; Nikkels, Peter G. J.; Patsouris, Efstratios

2009-01-01

Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a rare autosomal recessive genetic disorder characterized by typical craniofacial, skeletal and ectodermal defects, and tubulointerstitial nephritis leading to early end-stage renal failure. We report on a new familial case

Twenty years of treatment for Gaucher disease: emerging challenges

NARCIS (Netherlands)

van Dussen, L.

2014-01-01

Gaucher disease is an autosomal recessively inherited lysosomal storage disorder (LSD). Type I Gaucher disease, the so-called non-neuronopathic variant, is mainly characterised by cytopenia, hepatosplenomegaly and bone complications. Gaucher disease was the first LSD for which enzyme replacement

ABCD syndrome is caused by a homozygous mutation in the EDNRB gene

NARCIS (Netherlands)

Verheij, JBGM; Kunze, J; Osinga, J; van Essen, AJ; Hofstra, RMW

2002-01-01

ABCD syndrome is an autosomal recessive syndrome characterized by albinism, black lock, cell migration disorder of the neurocytes of the gut (Hirschsprung disease [HSCR]), and deafness. This phenotype clearly overlaps with the features of the Shah-Waardenburg syndrome, comprising sensorineural

Symptomatic lipid storage in carriers for the PNPLA2 gene

NARCIS (Netherlands)

Janssen, M.C.H.; Engelen, B.G.M. van; Kapusta, L.; Lammens, M.M.; Dijk, M.; Fischer, J.; Graaf, M. van der; Wevers, R.A.; Fahrleitner, M.; Zimmermann, R.; Morava, E.

2013-01-01

Neutral lipid storage disease comprises a heterogeneous group of inherited disorders characterized by severe accumulation of cytoplasmic triglyceride droplets in several tissues and neutrophils. A novel type of autosomal recessive lipid myopathy due to PNPLA2 mutations was recently described with

Circulating matrix gamma-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome

NARCIS (Netherlands)

Cranenburg, E. C. M.; van Spaendonck-Zwarts, K. Y.; Bonafe, L.; Mittaz Crettol, L.; Rödiger, L. A.; Dikkers, F. G.; van Essen, A. J.; Superti-Furga, A.; Alexandrakis, E.; Vermeer, C.; Schurgers, L. J.; Laverman, G. D.

2011-01-01

Background and objectives: Matrix gamma-carboxyglutamate protein (MGP), a vitamin K-dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an

X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3.

NARCIS (Netherlands)

Olcese, C.; Patel, M.P.; Shoemark, A.; Kiviluoto, S.; Legendre, M.; Williams, H.J.; Vaughan, C.K.; Hayward, J.; Goldenberg, A.; Emes, R.D.; Munye, M.M.; Dyer, L.; Cahill, T.; Bevillard, J.; Gehrig, C.; Guipponi, M.; Chantot, S.; Duquesnoy, P.; Thomas, L.; Jeanson, L.; Copin, B.; Tamalet, A.; Thauvin-Robinet, C.; Papon, J.F.; Garin, A.; Pin, I.; Vera, G.; Aurora, P.; Fassad, M.R.; Jenkins, L.; Boustred, C.; Cullup, T.; Dixon, M.; Onoufriadis, A.; Bush, A.; Chung, E.M.; Antonarakis, S.E.; Loebinger, M.R.; Wilson, R.; Armengot, M.; Escudier, E.; Hogg, C.; Amselem, S.; Sun, Z.; Bartoloni, L.; Blouin, J.L.; Mitchison, H.M.; Schmidts, M.; et al.,

2017-01-01

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of

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African Journals Online (AJOL)

Nicky

First described by Rogers, thiamine-responsive megaloblastic anaemia (TRMA) is a rare autosomal- recessive disorder characterised by megaloblastic anaemia, insulin-dependent diabetes mellitus and sensorineural deafness.1. The diagnosis is supported by a megaloblastic bone marrow, particularly the presence of ...