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Sample records for adrenoleukodystrophy

  1. Adrenoleukodystrophy manifesting as spinocerebellar degeneration

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    Mishra Sanjay

    2006-01-01

    Full Text Available X-linked adrenoleukodystrophy (XALD is an inherited disorder of peroxisomal metabolism. Atypical presentations have been occasionally reported in literature. However, extrapyramidal and cerebellar manifestations are distinctly rare. We report a patient of X-linked adrenoleukodystrophy with cranial and cervical dystonia and neurological presentation resembling spinocerebellar degeneration followed by a brief review of relevant literature.

  2. Adrenoleukodystrophy

    Science.gov (United States)

    ... stiffness Problems with thinking speed and visual memory Adrenal gland failure (Addison type) symptoms include: Coma Decreased appetite Increased skin color Loss of weight and muscle mass (wasting) Muscle weakness Vomiting

  3. Adrenoleukodystrophy

    Science.gov (United States)

    ... beneficial effect in symptomatic boys with X-ALD. Bone marrow transplantations can provide long-term benefit to boys who have early evidence of the childhood cerebral form of X-ALD, but the procedure carries risk of mortality and morbidity and is ...

  4. A Case of Adrenoleukodystrophy Presenting as Progressive Cerebellar Dysfunction

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    Seunguk Jung

    2009-10-01

    Full Text Available X-linked adrenoleukodystrophy (X-ALD is a hereditary neurological disorder affecting the nervous system and adrenal cortex. The phenotype of X-ALD ranges from the rapidly progressive cerebral form to milder adrenomyeloneuropathy. However, cerebellar manifestations are rare. We report a case of adrenoleukodystrophy presenting as progressive cerebellar dysfunction resembling olivopontocerebellar degeneration, with a review of the literature

  5. Bezafibrate for X-linked adrenoleukodystrophy.

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    Marc Engelen

    Full Text Available X-linked adrenoleukodystrophy (X-ALD is caused by mutations in the ABCD1 gene and is characterized by impaired beta-oxidation of very-long-chain fatty acids (VLCFA and subsequent VLCFA accumulation in tissues. In adulthood X-ALD most commonly manifests as a gradually progressive myelopathy, (adrenomyeloneuropathy; AMN without any curative or disease modifying treatments. We recently showed that bezafibrate (BF, a drug used for the treatment of hyperlipidaemia, reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1, an enzyme involved in the VLCFA synthesis. We therefore designed a proof-of-principal clinical trial to determine whether BF reduces VLCFA levels in plasma and lymphocytes of X-ALD patients. Ten males with AMN were treated with BF for 12 weeks at a dose of 400 mg daily, followed by 12 weeks of 800 mg daily. Every 4 weeks patients were evaluated for side effects and blood samples were taken for analysis. Adherence was good as indicated by a clear reduction in triglycerides. There was no reduction in VLCFA in either plasma or lymphocytes. Plasma levels of BF did not exceed 25 µmol/L. We concluded that BF, at least in the dose given, is unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients. It is unclear whether this is due to the low levels of BF reached in plasma. Our future work is aimed at the identification of highly-specific inhibitors of ELOVL1 that act at much lower concentrations than BF and are well tolerated. BF appears to have no therapeutic utility in X-ALD.ClinicalTrials.gov NCT01165060.

  6. Chromosomal rearrangement segregating with adrenoleukodystrophy: Associated changes in color vision

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    Alpern, M.; Zhang, H. (Univ. of Michigan, Ann Arbor, MI (United States)); Sack, G.H. Jr.; Moser, H.W. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)); Krantz, D.H. (Columbia Univ., New York, NY (United States))

    1993-10-15

    A patient from a large kindred with adrenoleukodystrophy showed profound disturbance of color ordering, color matching, increment thresholds, and luminosity. Except for color matching, his performance was similar to blue-cone [open quotes]monochromacy,[close quotes] an X chromosome-linked recessive retinal dystrophy in which color vision is dichromatic, mediated by the visual pigments of rods and short-wave-sensitive cones. Color matching, however, indicated that an abnormal rudimentary visual pigment was also present. This may reflect the presence of a recombinant visual pigment protein or altered regulation of residual pigment genes, due to DNA changes - deletion of the long-wave pigment gene and reorganized sequence 5[prime] to the pigment gene cluster - that segregate with the metabolic defect in this kindred. 25 refs., 4 figs., 1 tab.

  7. [Anesthetic Management of an Adrenoleukodystrophy Patient for Intrathecal Baclofen Therapy].

    Science.gov (United States)

    Hashimoto, Yuichi; Takahashi, Kei; Yamamoto, Yuko; Ogata, Tokiko; Arai, Takero; Okuda, Yasuhisa

    2016-04-01

    A 34-year-old man with adrenoleukodystrophy (ALD) was scheduled for pump system insertion of intrathecal baclofen therapy under general anesthesia. ALD, a rare genetic disorder, is associated with a total body increase in long chain fatty acids caused by defective degradation, and includes various nervous system abnormalities, muscular weakness, in addition to adrenal insufficiency. He had contracture of the both legs, and muscular weakness of the left hand, and Mallampati class III, but no respiratory disability. In the operating room, we administered hydrocortisone 100 mg for steroid coverage, and low-dose midazolam, and fentanyl. As spontaneous breathing remained, we could easily see epiglottis and arytenoid cartilage by McGRATH. Therefore we selected rapid-induction of anesthesia with thiamylal, and rocuronium 40 mg, under cricoid pressure. We avoided propofol. Anesthsia was maintained with sevoflurane and remifentanil, monitoring BIS and train of four. No more rocuronium was administered, and anesthesia was uneventful. Intrathecal baclofen therapy is given to patients who have severe contracture. When we selected general anesthesia, we should be aware of the possibility of muscular weakness, and cannot intubate cannot ventilate scenario. PMID:27188115

  8. The value of new MRI techniques in adrenoleukodystrophy

    International Nuclear Information System (INIS)

    To evaluate the significance of new techniques in MRI examinations of the brain in children with X-linked adrenoleukodystrophy (ALD). Five patients aged between 2 and 15 years with childhood ALD were examined with MRI. Following conventional spin-echo (CSE) sequences, a fast spin-echo (FSE) sequence with T2 contrast was performed in four patients, an FSE turbo-inversion-recovery (TIR) sequence in two, magnetization transfer contrast (MTC) imaging in tow, and localized proton spectroscopy (MRS) in four patients. FSE compared favorably with CSE with a time saving of 70%. On TIR images the contrast between normal and demyelinated white matter was greater than on CSE and FSE images. Calculated MTC values revealed a severe MTC loss within the demyelinated regions and a moderate reduction in the border zones. In this way, calculation of MTC might be useful to differentiate between edematous changes and areas of irreversible demyelination. MRS revealed a reduction in N-acetylaspartate and an elevation in choline (Cho). The degree of MRS changes paralleled the severity of demyelination. A Cho elevation may precede visible demyelination on T2-weighted images. T2-weighted FSE sequences can replace CSE without any disadvantages and with effective time saving. The indication for MTC imaging and MRS in children with ALD is not yet finally defined. These new techniques may reveal the earliest signs of cerebral involvement or of disease progression, a matter of great importance in selecting the optimal therapeutic approach. (orig.)

  9. MRI findings in an asymptomatic boy with X-linked adrenoleukodystrophy and his symptomatic mother

    International Nuclear Information System (INIS)

    We report an asymptomatic 15-year-old boy with X-linked adrenoleukodystrophy and his symptomatic 38-year-old mother. MRI revealed similar, subtle high-signal lesions in the periventricular white matter of the parieto-occipital regions, without involvement of the corpus callosum, more pronounced in the mother. (orig.)

  10. Delayed-onset adrenoleukodystrophy after cerebral contusion : progressive pattern of demyelination on serial MR imaging

    International Nuclear Information System (INIS)

    We described serial MR findings in a 20-year-old male with adrenoleuko-dystrophy who presented progressive neurologic deterioration after cerebral contusion. On MR imaging, progressive demyelination was predominant in the white matter of the right temporal lobe as well as tn the parietalobe at the site of prior trauma and exteded into the contralateral hemisphere through the anterior commissure

  11. A three-year-old boy with X-linked adrenoleukodystrophy and congenital pulmonary adenomatoid malformation: a case report

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    Cakan Nedim

    2009-12-01

    Full Text Available Abstract Introduction X-linked adrenoleukodystrophy leads to demyelination of the nervous system, adrenal insufficiency, and accumulation of long-chain fatty acids. Most young patients with X-linked adrenoleukodystrophy develop seizures and progressive neurologic deficits, and die within the first two decades of life. Congenital or acquired disorders of the respiratory system have not been previously described in patients with X-linked adrenoleukodystrophy. Case presentation A 3-year-old Arabic boy from Yemen presented with discoloration of the mucous membranes and nail beds, which were considered cyanoses due to methemoglobinemia. He also had shortness of breath, fatigue, emesis and dehydration episodes for which he was admitted to our hospital. Chest radiograph and chest computed tomography scans showed congenital pulmonary adenomatoid malformation. A few weeks before the removal of the malformation, he had a significant episode of hypotension and hypoglycemia. This development required further in-hospital evaluation that led to the diagnosis of adrenal insufficiency and the initiation of treatment with corticosteroids. One year later, he developed seizures and loss of consciousness. Magnetic resonance imaging of his head showed diffuse demyelination secondary to X-linked adrenoleukodystrophy. He was treated with anti-seizure and anti-oxidants, and was referred for bone marrow transplant evaluation. Conclusion The presence of adrenal insufficiency, neurologic deficits and seizures are common manifestations of X-linked adrenoleukodystrophy. The association of congenital lung disease with X-linked adrenoleukodystrophy or Addison's disease has not been described previously.

  12. Deep Brain Stimulation and Dantrolene for Secondary Dystonia in X-Linked Adrenoleukodystrophy

    OpenAIRE

    Van Karnebeek, Clara; Horvath, Gabriella; Murphy, Tyler; Purtzki, Jacqueline; Bowden, Kristin; Sirrs, Sandra; Honey, Christopher R.; Stockler, Sylvia

    2014-01-01

    Deep brain stimulation (DBS) has been used to treat secondary dystonias caused by inborn errors of metabolism with varying degrees of effectiveness. Here we report for the first time the application of DBS as treatment for secondary dystonia in a 22-year-old male with X-linked adrenoleukodystrophy (X-ALD). The disease manifested at age 6 with ADHD, tics, and dystonic gait, and deteriorated to loss of ambulation by age 11, and speech difficulties, seizures, and characteristic adrenal insuffici...

  13. Role of ALDP (ABCD1) and Mitochondria in X-Linked Adrenoleukodystrophy

    OpenAIRE

    McGuinness, M. C.; Lu, J.-F.; Zhang, H.-P.; Dong, G.-X.; Heinzer, A. K.; Watkins, P.A.; Powers, J.; Smith, K D

    2003-01-01

    Peroxisomal disorders have been associated with malfunction of peroxisomal metabolic pathways, but the pathogenesis of these disorders is largely unknown. X-linked adrenoleukodystrophy (X-ALD) is associated with elevated levels of very-long-chain fatty acids (VLCFA; C>22:0) that have been attributed to reduced peroxisomal VLCFA β-oxidation activity. Previously, our laboratory and others have reported elevated VLCFA levels and reduced peroxisomal VLCFA β-oxidation in human and mouse X-ALD fibr...

  14. Lipoid pneumonia as a complication of Lorenzo's oil therapy in a patient with adrenoleukodystrophy.

    Science.gov (United States)

    Majori, Maria; Scarascia, Alessandro; Anghinolfi, Miriam; Pisi, Roberta; Gnetti, Letizia; Casalini, Angelo Gianni

    2014-07-01

    Lipoid pneumonia (LP) is a rare exogenous condition caused by inhalation or aspiration of lipid material into the lungs. It is often associated with the therapeutic use of different types of oil, and the diagnosis is based on the demonstration of lipid-laden macrophages in bronchoalveolar lavage fluid. We reported the case of a 39-year-old male with X-linked adrenoleukodystrophy who developed LP secondary to the use of Lorenzo's oil. To our knowledge, the association between the use of Lorenzo's oil and LP has never been reported in literature. PMID:24992138

  15. Anaesthesia for a child with adrenoleukodystrophy: A case report and review of the literature

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    Sien Hui Tan

    2014-01-01

    Full Text Available We present a 9-year-old boy with X-linked cerebral adrenoleukodystrophy (X-linked ALD and previous umbilical cord transplant who required general anaesthesia. An anaesthetic plan for each individual should be tailored to ensure the best possible anaesthetic care for these patients. The anaesthetic considerations include mental retardation, seizure disorder, hypotonia, liver function abnormalities, gastro-oesophageal reflux, impaired adrenocortical function and immunosuppression. Pre-operative sedation should be avoided because of hypotonia of the pharyngeal muscles. Anti-convulsants are continued, and potentially epileptogenic anaesthetic agents are avoided. The patient was intubated using a modified rapid sequence induction with a head up position of 30 degrees. Four other cases have been reported in literature. Nevertheless, there is still no established anaesthetic management for these patients, and total intravenous anaesthesia can be considered as a safe and alternative method of anaesthesia. To the best of our knowledge, this is the first reported use of total intravenous anaesthesia with propofol and remifentanil in a case of cerebral adrenoleukodystrophy, and with a favourable outcome.

  16. MR imaging with fluid attenuated inversion recovery sequence of childhood adrenoleukodystrophy : comparison with T2 weighted spin echo imaging

    International Nuclear Information System (INIS)

    The purpose of this study was to evaluate the usefulness of FLAIR(Fluid Attenuated Inversion Recovery) MR imaging in childhood adrenoleukodystrophy by comparing with those of T2-weighted FSE imaging, and to correlate MRI findings with clinical manifestations. Axial FLAIR images(TR/TE/TI=10004/123/2200) and T2-weighted FSE images(TR/TE=4000/104) of brain in six male patients(age range : 6-17 years, mean age : 10.2 years) with biochemically confirmed adrenoleukodystrophy were compared visually by two radiologists for detection, conspicuity, and the extent of lesion. Quantitatively, we compared lesion/CSF contrast, lesion/CSF contrast to noise ratio(CNR), lesion/white matter(WM) contrast, and lesion/WM CNR between FLAIR and T2 weighted image. We correlated MR findings with clinical manifestations of neurologic symptoms and evaluated whether MRI could detect white matter lesions in neurologically asymptomatic patients. Visual detection of lesions was better with FLAIR images in 2 of the 6 cases and it was equal in the remainders. Visual conspicuity and detection of the extent of lesion were superior on FLAIR images than T2-weighted images in all 6 cases. In the quantitative assessment of lesions, FLAIR was superior to T2-weighted image for lesion/CSF contrast and lesion/CSF CNR, but was inferior to T2 weighted image for lesion/WM contrast and lesion/WM CNR. In one case, FLAIR images distinguished the portion of encephalomalacic change from lesions. MR findings of adrenoleukodystrophy were correlated with clinical manifestations in symptomatic 4 cases, and also detected white matter lesions in asymptomatic 2 cases. MR imaging with FLAIR sequence provided images that were equal or superior to T2-weighted images in the evaluation of childhood adrenoleukodystrophy. MRI findings were well correlated with clinical manifestations and could detect white matter lesions in neurologically asymptomatic adrenoleukodystrophy patients

  17. A novel cell model to study the function of the adrenoleukodystrophy-related protein

    International Nuclear Information System (INIS)

    X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder due to mutations in the ABCD1 (ALD) gene. ALDRP, the closest homolog of ALDP, has been shown to have partial functional redundancy with ALDP and, when overexpressed, can compensate for the loss-of-function of ALDP. In order to characterize the function of ALDRP and to understand the phenomenon of gene redundancy, we have developed a novel system that allows the controlled expression of the ALDRP-EGFP fusion protein (normal or non-functional mutated ALDRP) using the Tet-On system in H4IIEC3 rat hepatoma cells. The generated stable cell lines express negligible levels of endogenous ALDRP and doxycycline dosage-dependent levels of normal or mutated ALDRP. Importantly, the ALDRP-EGFP protein is targeted correctly to peroxisome and is functional. The obtained cell lines will be an indispensable tool in our further studies aimed at the resolution of the function of ALDRP to characterize its potential substrates in a natural context

  18. Identification of new mutations in Israeli patients with X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Neumann, S; Topper, A; Mandel, H; Shapira, I; Golan, O; Gazit, E; Loewenthal, R

    2001-01-01

    X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder characterized by impaired peroxisomal betaoxidation of very-long-chain fatty acids (VLCFAs). This is probably due to reduced activation of the VLCFAs and results in demyelination of the nervous system and adrenocortical insufficiency. The ALD gene is localized on Xq28, has 10 exons and encodes a protein of 745 amino acids with significant homology to the membrane peroxisomal protein PMP70. Characterizing the disease causing mutations is of importance in prenatal diagnosis because 12-20% of women who are obligatory carriers show false-negative results when tested for VLCFA in plasma. We have analyzed DNA from blood samples of 7 Jewish (5 Sephardi and 2 Ashkenazi) and 3 Arab Israeli families suffering from ALD. Five missense-type mutations were identified: R104H, Y174C, L229P, R401Q, and G512C. A single mutation, R464X, was nonsense, and two, Y171 frameshift and E471 frameshift, were frameshift. Interestingly, a single mutation was identified in three families of Moroccan Jewish descent, probably due to a founder effect. PMID:11336405

  19. Signs of testicular insufficiency in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy: a retrospective study.

    Science.gov (United States)

    Assies, J; Gooren, L J; Van Geel, B; Barth, P G

    1997-10-01

    X-linked adrenoleukodystrophy (X-ALD) is characterized by central nervous system demyelination, and impaired steroidogenesis in the adrenal cortex and testis. Most patients develop adrenocortical insufficiency. We studied retrospectively the frequency and severity of testicular dysfunction in 26 men with X-ALD. Twenty-one had adrenomyeloneuropathy and five patients were neurologically asymptomatic. In addition to obtaining a routine history and physical examination, we studied plasma levels of testosterone, sex hormone binding globulin, the free androgen index, and the plasma concentrations of dehydroepiandrosterone-sulphate, LH and FSH. In a subset of patients, the testosterone response to hCG and the LH and FSH responses to GnRH were also determined. Clinical signs of gonadal dysfunction were manifested by diminished libido (46%), largely overlapping with erectile dysfunction (58%), and failure of the testes to descend (15%). Physical examination revealed diminished body sexual hair (50%), gynaecomastia (35%), and small testes (12%). Laboratory studies showed low plasma total testosterone levels in 12%, and an insufficient increase after stimulation with hCG in 88% (15 of 17 patients tested). Plasma LH concentration was increased in 16%, and the plasma FSH level was elevated in 32%. The response of LH concentrations to GnRH stimulation was abnormally high in 47% (nine of 19 patients studied), and the response of FSH levels was too low in 16% (three of 19 patients tested). In conclusion, in a retrospective study of 26 men' with X-ALD, in 20 some signs of clinical hypogonadism were found. Plasma testosterone values were generally in the normal range, but upon testing of the hypothalamo-pituitary-testis axis some abnormalities became apparent. PMID:16130276

  20. USING SCIENTIFIC PAPERS TO STIMULATE THE STUDY OF BIOCHEMISTRY AND THE UNDERSTANDING OF SCIENTIFIC KNOWLEDGE CONSTRUCTION: THE RESEARCH ON ADRENOLEUKODYSTROPHY

    Directory of Open Access Journals (Sweden)

    R. B. Gagianone

    2015-08-01

    Full Text Available Introduction The X-linked adrenoleukodystrophy (X-ALD is characterized by mutations in very long chain fatty acids (VLCFA peroxisome transporter, leading to VLCFA accumulation in myelin sheath. In the 70’s and 80’s it was hypothesized that X-ALD is caused by enzymatic deficits in FA-coenzyme A connection, VLCFA degradation or FA elongation. The latter enabled Lorenzo’s oil (LO treatment, which became famous by the homonym movie. The apparent initial therapy effectiveness lead to LO administration in many patients, although with biochemical knowledge progress its relevance has been questioned.Objectives Our aim was to discuss X-ALD researches in “Lipids Metabolism” classes during 2014 Biochemistry courses to Biology and Biomedicine undergraduate students at Fluminense Federal University to illustrate how scientific knowledge is constructed.Materials and MethodsIn order to contrast the recent scientific advances with the information spread to society through “Lorenzo’s Oil”, the movie in edited version was presented to students followed by a questionnaire with Likert scale to evaluate the perception of scientific knowledge exposed by the movie. Afterwards, a Guided Study containing a brief history and discursive questions based upon a paper (Wiesingner et.al, J. Biol. Chem. 288:19269, 2013 was applied in class.Results and DiscussionFrom 58 students who filled in the questionnaire,72,4% considered the movie shows that X-ALD biochemical knowledge has been achieved. This notion was confirmed since 84,5% agreed LO is an effective alternative treatment if X-ALD is early detected. The same percentage agreed that based on the movie the biochemical deficiency relies on an enzyme involved in VLCFA degradation. Although the movie transmits the idea that the cure has been found, 67,2% believed X-ALD biochemical mechanisms are not fully comprehended. ConclusionsThe Guided Study/movie application was very effective because allowed the

  1. C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man

    Science.gov (United States)

    van de Beek, Malu-Clair; Dijkstra, Inge M. E.; van Lenthe, Henk; Ofman, Rob; Goldhaber-Pasillas, Dalia; Schauer, Nicolas; Schackmann, Martin; Engelen-Lee, Joo-Yeon; Vaz, Frédéric M.; Kulik, Wim; Wanders, Ronald J. A.; Engelen, Marc; Kemp, Stephan

    2016-01-01

    X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. Virtually all males develop progressive myelopathy (AMN). A subset of patients, however, develops a fatal cerebral demyelinating disease (cerebral ALD). Hematopoietic stem cell transplantation is curative for cerebral ALD provided the procedure is performed in an early stage of the disease. Unfortunately, this narrow therapeutic window is often missed. Therefore, an increasing number of newborn screening programs are including ALD. To identify new biomarkers for ALD, we developed an Abcd1 knockout mouse with enhanced VLCFA synthesis either ubiquitous or restricted to oligodendrocytes. Biochemical analysis revealed VLCFA accumulation in different lipid classes and acylcarnitines. Both C26:0-lysoPC and C26:0-carnitine were highly elevated in brain, spinal cord, but also in bloodspots. We extended the analysis to patients and confirmed that C26:0-carnitine is also elevated in bloodspots from ALD patients. We anticipate that validation of C26:0-carnitine for the diagnosis of ALD in newborn bloodspots may lead to a faster inclusion of ALD in newborn screening programs in countries that already screen for other inborn errors of metabolism. PMID:27124591

  2. Neurodegeneration in a Drosophila model of adrenoleukodystrophy: the roles of the Bubblegum and Double bubble acyl-CoA synthetases

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    Anna Sivachenko

    2016-04-01

    Full Text Available Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders there are neither cures nor disease-modifying therapies, and novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. To date, metabolic neurodegenerative disease has been modeled in animals with only limited success, in part because existing models constitute analyses of single mutants and have thus overlooked potential redundancy within metabolic gene pathways associated with disease. Here, we present the first analysis of a very-long-chain acyl-CoA synthetase (ACS double mutant. We show that the Drosophila bubblegum (bgm and double bubble (dbb genes have overlapping functions, and that the consequences of double knockout of both bubblegum and double bubble in the fly brain are profound, affecting behavior and brain morphology, and providing the best paradigm to date for an animal model of adrenoleukodystrophy (ALD, a fatal childhood neurodegenerative disease associated with the accumulation of very-long-chain fatty acids. Using this more fully penetrant model of disease to interrogate brain morphology at the level of electron microscopy, we show that dysregulation of fatty acid metabolism via disruption of ACS function in vivo is causal of neurodegenerative pathologies that are evident in both neuronal cells and their supporting cell populations, and leads ultimately to lytic cell death in affected areas of the brain. Finally, in an extension of our model system to the study of human disease, we describe our identification of an individual with leukodystrophy who harbors a rare mutation in SLC27a6 (encoding a very-long-chain ACS, a human homolog of bgm and dbb.

  3. The genotype and phenotype studies of 40 Chinese patients with X-linked adrenoleukodystrophy(X-ALD)%40例X连锁肾上腺脑白质营养不良患者的基因型与表型

    Institute of Scientific and Technical Information of China (English)

    平莉莉; 包新华; 王爱花; 潘虹; 吴晔; 熊晖; 张月华; 秦炯; 吴希如

    2006-01-01

    Obiective:To elucidate the phenotype and the genotype-phenotype correlations in Chinese patients with X-linked adrenoleukodystrophy(X-ALD).Methods:Clinical features of 40 Chinese patients with X-ALD were studied and mutation spectrums were investigated by polymerase chain reaction (PCR) and sequencing. Results:Among these patients, four were siblings from two unrelated families, the others were unrelated. There were 31 cases with childhood cerebral (CCALD), 8 cases with adolescent cerebral (ACALD) and 1 case with adrenomyeloneuropathy (AMN). Visual impairment, which presented in 12 cases (30%), was the most common initial symptom. Nine (69%) of 13 cases who had hydrocortisone and ACTH measured showed adrenal insufficiency. By follow-up date, 19 cases (47.5%) were dead. The interval from onset to death varied from 1 to 6 years and the average were 3.3 years. The mean age at death was 10.5 years. Eleven cases (27.5%) were in vegetable state. The mean interval from onset to apparently vegetable state was 2.8 years (range from 1 to 6 years). Four cases had progressive neurological disability. Four cases were lost follow-up. One case with CCALD and one case with ACALD progressed slowly. The courses of the disease of these two patients were 5 years and 15 years respectively. Thirty five mutations were identified in 40 cases. Most were located within exon 1-3 (40%, 16/40) and exon 6-8 (42%, 17/40). There is a distinct clustering of missense mutations in exon 6 (17%, 7/40). Five types of mutations were associated with CCALD, three with ACALD and a missense mutation was identified in the patients with AMN. The two patients with long disease courses had a missence mutation c.1559 T>A and a nonsense mutation c.1785 G>A respectively. The siblings with similar manifestations and onset age were observed in two families, whose mutations were c.887 A>G and c.1028 G>T. Conclusion:The phenotypes, disease severity and rate of neurodegeneration could not be predicted by the nature of

  4. Clinical manifest x-linked recessive adrenoleukodystrophy in a female

    DEFF Research Database (Denmark)

    Jack, Gyda Hlin Skuladottir; Malm-Willadsen, Karolina; Frederiksen, Anja;

    2013-01-01

    primarily affects males; however, females may develop milder symptoms that may be difficult to recognize. The present report describes a 35-year-old female who experienced a feeling of heaviness in the upper and lower limbs, pain in both knees, and difficulty climbing stairs, running, and jumping. Clinical...... examination revealed decreased sensitivity in the feet, particularly to touch. Deep tendon reflexes in the lower limbs were brisk, and Babinski's sign was present bilaterally. Multiple sclerosis (MS) was excluded, and all clinical and biochemical tests were normal. After two years of progressing symptoms, the...... could be attributed to ALD. The present case underlines the importance of reevaluating family history in women presenting with vague neurological symptoms....

  5. Recurrent Anion Gap Acidosis: An Unusual Presentation of X-Linked Adrenoleukodystrophy in a Five-year-old Male

    OpenAIRE

    Schwab, Joel; Pena, Loren; Sigman, Laura; Waggoner, Darrel

    2010-01-01

    We are presenting a five-year-old male with recurrent anion gap acidosis. During his last admission, it was detected that he had elevated VLCFA and the evaluation discovered that he had X-linked Adrenooleukodystrophy. He had the Addisonian only phenotype without any clinical or radiographic CNS findings. We were unable to find any other reports of this presentation of ALD. If the work-up of recurrent anion gap acidosis does not uncover an etiology, X-linked ALD should be considered in the dif...

  6. Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders

    Science.gov (United States)

    2016-01-21

    Mucopolysaccharidosis; Hurler Syndrome; Hunter Syndrome; Maroteaux-Lamy Syndrome; Sly Syndrome; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Adrenoleukodystrophy (ALD); Krabbe Disease; Metachromatic Leukodystrophy (MLD); Sphingolipidoses; Peroxisomal Disorders

  7. Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    2005-06-23

    I Cell Disease; Fucosidosis; Globoid Cell Leukodystrophy; Adrenoleukodystrophy; Mannosidosis; Niemann-Pick Disease; Pulmonary Complications; Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Metachromatic Leukodystrophy; Gaucher's Disease; Wolman Disease

  8. Stem Cell Transplant for Inborn Errors of Metabolism

    Science.gov (United States)

    2012-11-06

    Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Gaucher's Disease; Fucosidosis; Wolman Disease; Niemann-Pick Disease; Batten Disease; GM1 Gangliosidosis; Tay Sachs Disease; Sandhoff Disease

  9. UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

    Science.gov (United States)

    2016-07-27

    Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn

  10. Human Placental-Derived Stem Cell Transplantation

    Science.gov (United States)

    2015-04-29

    Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Adrenoleukodystrophy; Niemann-Pick Disease; Metachromatic Leukodystrophy; Wolman Disease; Krabbe's Disease; Gaucher's Disease; Fucosidosis; Batten Disease; Severe Aplastic Anemia; Diamond-Blackfan Anemia; Amegakaryocytic Thrombocytopenia; Myelodysplastic Syndrome; Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia

  11. Neurodegeneration in D-bifunctional protein deficiency: diagnostic clues and natural history using serial magnetic resonance imaging

    International Nuclear Information System (INIS)

    We report serial neurodegenerative changes on neuroimaging in a rare peroxisomal disease called D-bifunctional protein deficiency. The pattern of posterior to anterior demyelination with white matter disease resembles X-linked adrenoleukodystrophy. We feel this case is important to (1) highlight that D-bifunctional protein deficiency should be considered in cases where the neuroimaging resembles X-linked adrenoleukodystrophy, (2) to show different stages of progression to help identify this disease using neuroimaging in children, and (3) to show that neuroimaging suggesting a leukodystrophy can warrant peroxisomal beta-oxidation studies in skin fibroblasts even when plasma very long chain fatty acids are normal. (orig.)

  12. Neurodegeneration in D-bifunctional protein deficiency: diagnostic clues and natural history using serial magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Aneal [University of Calgary, Department of Medical Genetics and Pediatrics, Alberta Children' s Hospital, Calgary, AB (Canada); Wei, Xing-Chang [University of Calgary, Department of Radiology, Alberta Children' s Hospital, Calgary, AB (Canada); Snyder, Floyd F. [Alberta Children' s Hospital, Biochemical Genetics Laboratory, Calgary, AB (Canada); Mah, Jean K. [University of Calgary, Division of Neurology, Department of Pediatrics, Calgary, AB (Canada); Waterham, Hans; Wanders, Ronald J.A. [University of Amsterdam, Academic Medical Center, Lab Genetic Metabolic Diseases, Amsterdam (Netherlands)

    2010-12-15

    We report serial neurodegenerative changes on neuroimaging in a rare peroxisomal disease called D-bifunctional protein deficiency. The pattern of posterior to anterior demyelination with white matter disease resembles X-linked adrenoleukodystrophy. We feel this case is important to (1) highlight that D-bifunctional protein deficiency should be considered in cases where the neuroimaging resembles X-linked adrenoleukodystrophy, (2) to show different stages of progression to help identify this disease using neuroimaging in children, and (3) to show that neuroimaging suggesting a leukodystrophy can warrant peroxisomal beta-oxidation studies in skin fibroblasts even when plasma very long chain fatty acids are normal. (orig.)

  13. Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders

    Science.gov (United States)

    2016-04-05

    Hurler Syndrome (MPS I); Hurler-Scheie Syndrome With Early Neurologic Involvement and/or Sensitization to Enzyme Replacement Therapy (ERT); Hunter Syndrome (MPS II); Sanfilippo Syndrome (MPS III); Krabbe Disease (Globoid Leukodystrophy); Metachromatic Leukodystrophy (MLD); Adrenoleukodystrophy (ALD and AMN); Sandhoff Disease; Tay Sachs Disease; Pelizaeus Merzbacher (PMD); Niemann-Pick Disease; Alpha-mannosidosis

  14. MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis

    Science.gov (United States)

    2016-08-15

    Mucopolysaccharidosis I; Mucopolysaccharidosis II; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Hurler Syndrome; Hunter Syndrome; Maroteaux Lamy Syndrome; Sly Syndrome; Glycoprotein Metabolic Disorders; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Adrenoleukodystrophy; Peroxisomal Disorders; Osteopetrosis; Sphingolipidosis; Gangliosidosis; Globoid Cell Leukodystrophy; Metachromatic Leukodystrophy; Niemann Pick B; Niemann Pick C Subtype 2; I-cell Disease

  15. Retraction of an intrathecal baclofen infusion catheter following suprapubic cystotomy: a case report.

    NARCIS (Netherlands)

    Martens, F.M.J.; Somford, D.M.; Kuppevelt, D.H. van; Burg, M.J. van den; Heesakkers, J.P.F.A.

    2009-01-01

    INTRODUCTION: Intrathecal baclofen, administered via a Baclofen pump, is used for patients with spasticity. We report here a case of intrathecal catheter retraction following surgery. CASE REPORT: A male patient with adrenoleukodystrophy and a baclofen pump implant was admitted to the urology depart

  16. Intravenous immunoglobulin treatment in a patient with adrenomyeloneuropathy

    DEFF Research Database (Denmark)

    Jønch, Aia E; Danielsen, Else R; Thomsen, Carsten; Meden, Per; Svenstrup, Kirsten; Nielsen, Jørgen Erik

    2012-01-01

    ABSTRACT: BACKGROUND: Adrenomyeloneuropathy (AMN) is one of several phenotypes of the adrenoleukodystrophy spectrum caused by mutations in the ABCD1 gene on the X chromosome. An inflammatory component is part of the disease complex ranging from severe childhood CNS demyelination to spinal cord and...

  17. Determination of long-chain fatty acids in serum by gas chromatography coupled to mass spectrometry

    International Nuclear Information System (INIS)

    The quantification of long-chain fatty acids is fundamental for the diagnosis of several peroxisome disorders, particularly those in which the β-oxidation peroxisome of fatty acids is affected. In this work the implementation of an analytical method for the determination of these markers in serum by gas chromatography coupled to mass spectrometry is described. Besides, samples from patients with a diagnostic impression of adrenoleukodystrophy linked to the X chromosome were analyzed. The necessary experimental conditions were achieved for the separation and quantification of C22:0, C24:0 and C26:0 fatty acids in serum, which are biochemical markers of various peroxisome diseases. The application of this method allowed confirming the diagnosis of three patients with a diagnostic impression of adrenoleukodystrophy linked to the X chromosome. The application of the method in daily practice will allow the Cuban medical system to count on a new laboratory parameter for the diagnosis of peroxisome disorders

  18. Mutations in the Arabidopsis Peroxisomal ABC Transporter COMATOSE Allow Differentiation between Multiple Functions In Planta: Insights from an Allelic Series

    OpenAIRE

    Dietrich, Daniela; Schmuths, Heike; Lousa, Carine De Marcos; Baldwin, Jocelyn M.; Baldwin, Stephen A.; Baker, Alison; Theodoulou, Frederica L; Holdsworth, Michael J

    2009-01-01

    COMATOSE (CTS), the Arabidopsis homologue of human Adrenoleukodystrophy protein (ALDP), is required for import of substrates for peroxisomal β-oxidation. A new allelic series and a homology model based on the bacterial ABC transporter, Sav1866, provide novel insights into structure-function relations of ABC subfamily D proteins. In contrast to ALDP, where the majority of mutations result in protein absence from the peroxisomal membrane, all CTS mutants produced stable protein. Mutation of con...

  19. Child Neurology: Zellweger syndrome

    OpenAIRE

    Lee, Paul R.; Raymond, Gerald V.

    2013-01-01

    Zellweger syndrome (ZS) is a severe manifestation of disease within the spectrum of peroxisome biogenesis disorders that includes neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondroplasia punctata. Patients with ZS present in the neonatal period with a characteristic phenotype of distinctive facial stigmata, pronounced hypotonia, poor feeding, hepatic dysfunction, and often seizures and boney abnormalities. In patients with ZS, a mutation in one of the PEX genes co...

  20. Le leucodistrofie: aspetti clinici e quadri con Tomografia Computerizzata e con Risonanza Magnetica

    International Nuclear Information System (INIS)

    Leukodystrophies are inherited white matter diseases due to abnormalities occurring in myelin synthesis and/or maintenance. The most common types of these rare childhood conditions are represented by adrenoleukodystrophy, metachromatic leukodystrophy, Canavan's, Alexander's, Krabbe's, and Pelizaeus-Merzbacher's diseases. Most of them are lethal during childhood, with the exception of the adrenoleukodystrophy-adrenomyeloneuropathy complex, which sometimes, during its early phases, may be cured with a dietary therapy. The aims of this paper are: 1) the description of inheritance factors, pathogenesis, pathological and clinical findings of each of the most frequent childhood leukodystrophies; 2) the description of the most common patterns of these conditions on CT and MR imaging; 3) the evaluation of the diagnostic capabilities of these two imaging techniques and the comparison of their results. Finally, some of the therapies suggested for the mild forms of these conditions are discussed. The evaluation of leukodystrophic patients with CT and MR imaging shows both imaging modalities to have high sensitivity, thanks to the detection of abnormally myelinated areas, which appear hypodense on CT and Hypertense on T2-weighted MR images. Frequently, both imaging modalities exhibit high specificity as well: they allow a differential diagnosis between the different types through the demonstration of their location in the early stages and of their mode of spread. The most typical example is represented by adrenoleukodystrophy, which is the most common type of leukodystrophy: the frequent occipito-parietal onset and the anterior and caudal progression allow a correct diagnosis to be made on CT and MR images in most cases. The comparison between CT and MR findings demonstrates a slight superiority of the latter: multiplanarity and high contrast resolution make MR imaging more sensitive than CT in the detection of the both caudal spread and involvement of optic and acoustic

  1. Recent Trends of Polymer Mediated Liposomal Gene Delivery System

    Directory of Open Access Journals (Sweden)

    Shyamal Kumar Kundu

    2014-01-01

    Full Text Available Advancement in the gene delivery system have resulted in clinical successes in gene therapy for patients with several genetic diseases, such as immunodeficiency diseases, X-linked adrenoleukodystrophy (X-ALD blindness, thalassemia, and many more. Among various delivery systems, liposomal mediated gene delivery route is offering great promises for gene therapy. This review is an attempt to depict a portrait about the polymer based liposomal gene delivery systems and their future applications. Herein, we have discussed in detail the characteristics of liposome, importance of polymer for liposome formulation, gene delivery, and future direction of liposome based gene delivery as a whole.

  2. Computed tomography of neurodegenerative disease in childhood

    International Nuclear Information System (INIS)

    Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author)

  3. Metabolic disorders with typical alterations in MRI; Stoffwechselstoerungen mit typischen Veraenderungen im MRT

    Energy Technology Data Exchange (ETDEWEB)

    Warmuth-Metz, M. [Klinikum der Universitaet Wuerzburg, Abteilung fuer Neuroradiologie, Wuerzburg (Germany)

    2010-09-15

    The classification of metabolic disorders according to the etiology is not practical for neuroradiological purposes because the underlying defect does not uniformly transform into morphological characteristics. Therefore typical MR and clinical features of some easily identifiable metabolic disorders are presented. Canavan disease, Pelizaeus-Merzbacher disease, Alexander disease, X-chromosomal adrenoleukodystrophy and adrenomyeloneuropathy, mitochondrial disorders, such as MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and Leigh syndrome as well as L-2-hydroxyglutaric aciduria are presented. (orig.) [German] Die Einteilung von Stoffwechselstoerungen nach ihrer Aetiologie ist fuer den diagnostischen Neuroradiologen nicht sinnvoll, da sich aus der zugrunde liegenden Stoerung keine Rueckschluesse auf die zu erwartende MR-Morphologie ziehen lassen. Deshalb sollen anhand typischer bildmorphologischer Veraenderungen in Zusammenschau mit den jeweiligen klinischen Charakteristika einige leicht einzuordnende Stoffwechselstoerungen dargestellt werden. Es handelt sich um den Morbus Canavan, Morbus Pelizaeus-Merzbacher, Morbus Alexander, die X-chromosomal vererbte Adrenoleukodystrophie und Adrenomyeloneuropathie, die mitochondrialen Stoerungen MELAS (mitochondriale Enzephalomyopathie, Laktazidose und Stroke-like-Episoden) und Leigh-Syndrom sowie die L-2-Hydroxyglutarazidurie. (orig.)

  4. Computed tomography of neurodegenerative disease in childhood. Serial CT findings and their diagnostic values

    Energy Technology Data Exchange (ETDEWEB)

    Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

    1984-12-01

    Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author).

  5. Adrenomyeloneuropathy with bulbar palsy: A rare association

    Directory of Open Access Journals (Sweden)

    Vishal Annaji Chafale

    2014-01-01

    Full Text Available Adrenomyeloneuropathy (AMN is a variant of adrenoleukodystrophy (ALD, an X-linked recessive peroxisomal disorder associated with accumulation of very long chain fatty acids (VLCFA. Mutations of this gene lead to abnormal peroxisomal β-oxidation, which results in the harmful accumulation of VLCFAs in affected cells. Neurological symptoms occur due to progressive demyelination and destruction of cerebral white matter and primary adrenal insufficiency. Bulbar palsy in a case of AMN is very unusual. We report a case of a 22-year-old male with AMN who developed adrenal insufficiency at the age of 4 years successfully treated by gluco- and mineralocorticoids followed by features of myeloneuropathy with bulbar palsy. AMN with prominent bulbar symptoms emphasizes the diverse clinical manifestation of this disease.

  6. A pragmatic discussion on establishing a multicenter digital imaging network.

    Science.gov (United States)

    Ingeholm, Mary Lou; Levine, Betty A; Fatemi, Seyed Ali; Moser, And Hugo W

    2002-01-01

    Multicenter clinical trials for therapy evaluation of rare diseases are necessary. A digital imaging network improves the ability to share information between collaborating institutions for adrenoleukodystrophy. The DICOM 3.0 standard is used to move images over the Internet from contributing sites to the central clinical database and on to the reviewing physicians' workstations. Patient confidentiality and data integrity are ensured during transmission using virtual private network technology. Fifteen sites are participating in the network. Of these sites, 6 use the proposed protocol. The other 9 sites have either security policy issues or technical considerations that dictate alternative protocols. Network infrastructure, Internet access, image management practices, and security policies vary significantly between sites. Successful implementation of a multicenter digital imaging network requires flexibility in the implementation of network connectivity. Flexibility increases participation as well as complexity of the network. PMID:12105723

  7. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications

    Directory of Open Access Journals (Sweden)

    David Escors

    2013-07-01

    Full Text Available The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(g-retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and b-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells.

  8. Subcellular location and species specificity of pipecolate degradation

    International Nuclear Information System (INIS)

    Defects in pipecolic acid (PA) catabolism are characteristic of several inherited metabolic diseases including hyperpipecolic acidemia, Zellweger's Syndrome, neonatal-onset adrenoleukodystrophy, and infantile Refsum's disease. In the latter three diseases, peroxisomes are abnormal. The authors have studied the subcelluar distribution of the PA degradation to determine a mammalian model for the normal pathway. Crude light and heavy mitochondrial fractions (including lysosomes and peroxisomes) from kidney cortex or liver were separated on Percoll gradients. Individual fractions were then incubated at 370C with 3H-2,3,4,5,6 L-PA. Using ion exchange chromatography, the production of 3H α-aminoadipic acid (AAA) and 3H-H2O were quantitated. AAA production paralleled the activity of the mitochondrial marker enzyme, glutamate dehydrogenase, in the rabbit, guinea pig, dog, pig, and sheep. 3H-AAA production ranged from 382 to 13,900 pmol/mg prot/h. Guinea pig kidney cortex exhibited highest specific activity. The mitochondrial enzyme was absent from human liver (n=3) and liver and kidney cortex from rat, mouse, and monkey. In these tissues, the activity followed the pattern of the peroxisomal core enzyme, urate oxidase

  9. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications

    International Nuclear Information System (INIS)

    The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(γ-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and β-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells

  10. The MR spectrum of peroxisomal disorders

    International Nuclear Information System (INIS)

    In the last decade an increasing number of peroxisomal disorders has been recognized. Almost all peroxisomal disorders affect the central nervous system. Many of them lead to demyelination, some of them lead to migrational disturbances. The MR pattern of X-linked adrenoleukodystrophy is well known, but the pattern of the other peroxisomal disorders is less well known. We evaluated the gray and white matter abnormalities of 20 patients on 32 occasions. We compared the results with histological data and in this way came to the description of a number of characteristic MR patterns occurring in peroxisomal disorders: (1) Neuronal migrational disturbances in combination with hypomyelination, dysmyelination or demyelination. (2) Symmetrical demyelination of posterior limb of the internal capsule, cerebellar white matter and brain stem tracts with a variable affection of cerebral hemispheres. (3) Symmetrical demyelination, exhibiting two zones, starting in the occipital area and spreading outwards and forwards; affection of brain stem tracts. (4) Less characteristic patterns of demyelination. The patterns are illustrated and differentiation from other disorders is discussed. (orig.)

  11. Diffusion-weighted MR imaging in leukodystrophies

    International Nuclear Information System (INIS)

    Leukodystrophies are genetically determined metabolic diseases, in which the underlying biochemical abnormality interferes with the normal build-up and/or maintenance of myelin, which leads to hypo- (or arrested) myelination, or dysmyelination with resultant demyelination. Although conventional magnetic resonance imaging has significantly contributed to recent progress in the diagnostic work-up of these diseases, diffusion-weighted imaging has the potential to further improve our understanding of underlying pathological processes and their dynamics through the assessment of normal and abnormal diffusion properties of cerebral white matter. Evaluation of conventional diffusion-weighted and ADC map images allows the detection of major diffusion abnormalities and the identification of various edema types, of which the so-called myelin edema is particularly relevant to leukodystrophies. Depending on the nature of histopathological changes, stage and progression gradient of diseases, various diffusion-weighted imaging patterns may be seen in leukodystrophies. Absent or low-grade myelin edema is found in mucopolysaccharidoses, GM gangliosidoses, Zellweger disease, adrenomyeloneuropathy, L-2-hydroxyglutaric aciduria, non-ketotic hyperglycinemia, classical phenylketonuria, Van der Knaap disease and the vanishing white matter, medium grade myelin edema in metachromatic leukodystrophy, X-linked adrenoleukodystrophy and HMG coenzyme lyase deficiency and high grade edema in Krabbe disease, Canavan disease, hyperhomocystinemias, maple syrup urine disease and leukodystrophy with brainstem and spinal cord involvement and high lactate. (orig.)

  12. A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies

    Science.gov (United States)

    Leventer, Richard J.; van der Knaap, Marjo S.; van Hove, Johan; Pizzino, Amy; McNeill, Nathan H.; Helman, Guy; Simons, Cas; Schmidt, Johanna L.; Rizzo, William B.

    2015-01-01

    Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive – many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroim-aging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders. PMID:25655951

  13. The MR spectrum of peroxisomal disorders

    Energy Technology Data Exchange (ETDEWEB)

    Knaap, M.S. van der (Wilhelmina Kinderziekenhuis, Utrecht (Netherlands). Dept. of Child Neurology); Valk, J. (Vrije Univ., Amsterdam (Netherlands). Dept. of Diagnostic Radiology Vrije Univ., Amsterdam (Netherlands). Dept. of Neuroradiology)

    1991-02-01

    In the last decade an increasing number of peroxisomal disorders has been recognized. Almost all peroxisomal disorders affect the central nervous system. Many of them lead to demyelination, some of them lead to migrational disturbances. The MR pattern of X-linked adrenoleukodystrophy is well known, but the pattern of the other peroxisomal disorders is less well known. We evaluated the gray and white matter abnormalities of 20 patients on 32 occasions. We compared the results with histological data and in this way came to the description of a number of characteristic MR patterns occurring in peroxisomal disorders: (1) Neuronal migrational disturbances in combination with hypomyelination, dysmyelination or demyelination. (2) Symmetrical demyelination of posterior limb of the internal capsule, cerebellar white matter and brain stem tracts with a variable affection of cerebral hemispheres. (3) Symmetrical demyelination, exhibiting two zones, starting in the occipital area and spreading outwards and forwards; affection of brain stem tracts. (4) Less characteristic patterns of demyelination. The patterns are illustrated and differentiation from other disorders is discussed. (orig.).

  14. Pathogenicity of novel ABCD1 variants: The need for biochemical testing in the era of advanced genetics.

    Science.gov (United States)

    Schackmann, Martin J A; Ofman, Rob; van Geel, Björn M; Dijkstra, Inge M E; van Engelen, Klaartje; Wanders, Ronald J A; Engelen, Marc; Kemp, Stephan

    2016-06-01

    X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. In male patients, an increased plasma VLCFA levels in combination with a pathogenic mutation in ABCD1 confirms the diagnosis. Recent studies have shown that many women with ALD also develop myelopathy. Correct diagnosis is important for management including genetic counseling. Diagnosis in women can only be confirmed when VLCFA levels are elevated or when a known pathogenic ABCD1 mutation is identified. However, in 15-20% of women with ALD VLCFA plasma levels are not elevated. Demonstration that a novel sequence variant is pathogenic can be a challenge when VLCFA levels are in the normal range. Here we report two women with a clinical presentation compatible with ALD, an ABCD1 variation (p.Arg17His and p.Ser358Pro) of unknown significance, but with normal VLCFA levels. We developed a diagnostic test that is based on generating clonal cell lines that express only one of the two alleles. Subsequent biochemical studies enabled us to show that the two sequence variants were not pathogenic, thereby excluding the diagnosis ALD in these women. We conclude that the clonal approach is an important addition to the existing diagnostic array. PMID:27067449

  15. Endocrine manifestations related to inherited metabolic diseases in adults

    Directory of Open Access Journals (Sweden)

    Vantyghem Marie-Christine

    2012-01-01

    Full Text Available Abstract Most inborn errors of metabolism (IEM are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.. IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects, and metal (hemochromatosis and storage disorders (cystinosis. Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes, whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure, congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last. This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses.

  16. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications

    Energy Technology Data Exchange (ETDEWEB)

    Liechtenstein, Therese, E-mail: t.liechtenstein.12@ucl.ac.uk [University College London, 5 University Street, London, WC1E 6JF (United Kingdom); Perez-Janices, Noemi; Escors, David [University College London, 5 University Street, London, WC1E 6JF (United Kingdom); Navarrabiomed Fundacion Miguel Servet, 3 Irunlarrea St., Hospital Complex of Navarra, 31008 Pamplona, Navarra (Spain)

    2013-07-02

    The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(γ-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and β-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells.

  17. The memory-enhancing effect of erucic acid on scopolamine-induced cognitive impairment in mice.

    Science.gov (United States)

    Kim, Eunji; Ko, Hae Ju; Jeon, Se Jin; Lee, Sunhee; Lee, Hyung Eun; Kim, Ha Neul; Woo, Eun-Rhan; Ryu, Jong Hoon

    2016-03-01

    Erucic acid is a monounsaturated omega-9 fatty acid isolated from the seed of Raphanus sativus L. that is known to normalize the accumulation of very long chain fatty acids in the brains of patients suffering from X-linked adrenoleukodystrophy. Here, we investigated whether erucic acid enhanced cognitive function or ameliorated scopolamine-induced memory impairment using the passive avoidance, Y-maze and Morris water maze tasks. Erucic acid (3mg/kg, p.o.) enhanced memory performance in normal naïve mice. In addition, erucic acid (3mg/kg, p.o.) ameliorated scopolamine-induced memory impairment, as assessed via the behavioral tasks. We then investigated the underlying mechanism of the memory-enhancing effect of erucic acid. The administration of erucic acid increased the phosphorylation levels of phosphatidylinositide 3-kinase (PI3K), protein kinase C zeta (PKCζ), extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB) and additional protein kinase B (Akt) in the hippocampus. These results suggest that erucic acid has an ameliorative effect in mice with scopolamine-induced memory deficits and that the effect of erucic acid is partially due to the activation of PI3K-PKCζ-ERK-CREB signaling as well as an increase in phosphorylated Akt in the hippocampus. Therefore, erucic acid may be a novel therapeutic agent for diseases associated with cognitive deficits, such as Alzheimer's disease. PMID:26780350

  18. Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients

    Institute of Scientific and Technical Information of China (English)

    Yasuharu Ohno; Taichirou Kosaka; Izumi Muraoka; Takashi Kanematsu; Akira Tsuru; Eiichi Kinoshita; Hiroyuki Moriuchi

    2006-01-01

    We report the remission of primary gastric lymphoma of the mucosa-associated lymphoid tissue (MALT) type in two immunocompromised pediatric patients. Patient 1,a 14-year-old boy in an immunocompromised state of unknown cause, complained of repeated abdominal pain.Examinations revealed gastric MALT with local invasionand lymph node involvement. Serum anti-Helicobacter pylori (H pylori) antibody was positive. H pylori eradication was abandoned due to its adverse effects. The MALT lesion spontaneously regressed over the next 24 months without any treatment for lymphoma. Patient 2, a 6-year-old boy, underwent cord blood transplantation for the treatment of adrenoleukodystrophy. He was administered immunosuppressants for graft-versus-host disease after transplantation. Nausea and hematochezia appeared and further examinations revealed gastric MALT with H pylori gastritis. Treatment consisting of medication for the H pylori infection alone eradicated the Hpylori and completely resolved the patient's MALT lesion,as well. Patients 1 and 2 were followed up over periods of 10 years and 3 years, respectively, without any signs of relapse. In conclusion, gastric lymphoma of the MALT type can be cured by conservative treatment even in immunocompromised pediatric patients.

  19. Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis.

    Science.gov (United States)

    Schackmann, Martin J A; Ofman, Rob; Dijkstra, Inge M E; Wanders, Ronald J A; Kemp, Stephan

    2015-02-01

    X-linked adrenoleukodystrophy (X-ALD) is a neurometabolic disease that is caused by mutations in the ABCD1 gene. ABCD1 protein deficiency impairs peroxisomal very long-chain fatty acid (VLCFA) degradation resulting in increased cytosolic VLCFA-CoA levels, which are further elongated by the VLCFA-specific elongase, ELOVL1. In adulthood, X-ALD most commonly manifests as a gradually progressive myelopathy (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1. Although, in a clinical trial, bezafibrate was unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients, inhibition of ELOVL1 remains an attractive therapeutic option. In this study, we investigated the kinetic characteristics of ELOVL1 using X-ALD fibroblasts and microsomal fractions from ELOVL1 over-expressing HEK293 cell lines and analyzed the inhibition kinetics of a series of fibrates. Our data show that the CoA esters of bezafibrate and gemfibrozil reduce chain elongation by specifically inhibiting ELOVL1. These fibrates can therefore serve as lead compounds for the development of more potent and more specific inhibitors for ELOVL1. PMID:25499606

  20. Human ATP-binding cassette (ABC transporter family

    Directory of Open Access Journals (Sweden)

    Vasiliou Vasilis

    2009-04-01

    Full Text Available Abstract There exist four fundamentally different classes of membrane-bound transport proteins: ion channels; transporters; aquaporins; and ATP-powered pumps. ATP-binding cassette (ABC transporters are an example of ATP-dependent pumps. ABC transporters are ubiquitous membrane-bound proteins, present in all prokaryotes, as well as plants, fungi, yeast and animals. These pumps can move substrates in (influx or out (efflux of cells. In mammals, ABC transporters are expressed predominantly in the liver, intestine, blood-brain barrier, blood-testis barrier, placenta and kidney. ABC proteins transport a number of endogenous substrates, including inorganic anions, metal ions, peptides, amino acids, sugars and a large number of hydrophobic compounds and metabolites across the plasma membrane, and also across intracellular membranes. The human genome contains 49 ABC genes, arranged in eight subfamilies and named via divergent evolution. That ABC genes are important is underscored by the fact that mutations in at least I I of these genes are already known to cause severe inherited diseases (eg cystic fibrosis and X-linked adrenoleukodystrophy [X-ALD]. ABC transporters also participate in the movement of most drugs and their metabolites across cell surface and cellular organelle membranes; thus, defects in these genes can be important in terms of cancer therapy, pharmacokinetics and innumerable pharmacogenetic disorders.

  1. Brain microsomal fatty acid elongation is increased in abcd1-deficient mouse during active myelination phase.

    Science.gov (United States)

    Morita, Masashi; Kawamichi, Misato; Shimura, Yusuke; Kawaguchi, Kosuke; Watanabe, Shiro; Imanaka, Tsuneo

    2015-12-01

    The dysfunction of ABCD1, a peroxisomal ABC protein, leads to the perturbation of very long chain fatty acid (VLCFA) metabolism and is the cause of X-linked adrenoleukodystrophy. Abcd1-deficient mice exhibit an accumulation of saturated VLCFAs, such as C26:0, in all tissues, especially the brain. The present study sought to measure microsomal fatty acid elongation activity in the brain of wild-type (WT) and abcd1-deficient mice during the course of development. The fatty acid elongation activity in the microsomal fraction was measured by the incorporation of [2-(14)C]malonyl-CoA into fatty acids in the presence of C16:0-CoA or C20:0-CoA. Cytosolic fatty acid synthesis activity was completely inhibited by the addition of N-ethylmaleimide (NEM). The microsomal fatty acid elongation activity in the brain was significantly high at 3 weeks after birth and decreased substantially at 3 months after birth. Furthermore, we detected two different types of microsomal fatty acid elongation activity by using C16:0-CoA or C20:0-CoA as the substrate and found the activity toward C20:0-CoA in abcd1-deficient mice was higher than the WT 3-week-old animals. These results suggest that during the active myelination phase the microsomal fatty acid elongation activity is stimulated in abcd1-deficient mice, which in turn perturbs the lipid composition in myelin. PMID:26108493

  2. Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells.

    Directory of Open Access Journals (Sweden)

    Jaspreet Singh

    Full Text Available In X-ALD, mutation/deletion of ALD gene (ABCD1 and the resultant very long chain fatty acid (VLCFA derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD. The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal β-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs (1 and 3 in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL and cell survival (phospho-Erk1/2 proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC inhibitor suberoylanilide hydroxamic acid (SAHA corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD.

  3. Methodology and software to detect viral integration site hot-spots

    Directory of Open Access Journals (Sweden)

    Kim Namshin

    2011-09-01

    Full Text Available Abstract Background Modern gene therapy methods have limited control over where a therapeutic viral vector inserts into the host genome. Vector integration can activate local gene expression, which can cause cancer if the vector inserts near an oncogene. Viral integration hot-spots or 'common insertion sites' (CIS are scrutinized to evaluate and predict patient safety. CIS are typically defined by a minimum density of insertions (such as 2-4 within a 30-100 kb region, which unfortunately depends on the total number of observed VIS. This is problematic for comparing hot-spot distributions across data sets and patients, where the VIS numbers may vary. Results We develop two new methods for defining hot-spots that are relatively independent of data set size. Both methods operate on distributions of VIS across consecutive 1 Mb 'bins' of the genome. The first method 'z-threshold' tallies the number of VIS per bin, converts these counts to z-scores, and applies a threshold to define high density bins. The second method 'BCP' applies a Bayesian change-point model to the z-scores to define hot-spots. The novel hot-spot methods are compared with a conventional CIS method using simulated data sets and data sets from five published human studies, including the X-linked ALD (adrenoleukodystrophy, CGD (chronic granulomatous disease and SCID-X1 (X-linked severe combined immunodeficiency trials. The BCP analysis of the human X-linked ALD data for two patients separately (774 and 1627 VIS and combined (2401 VIS resulted in 5-6 hot-spots covering 0.17-0.251% of the genome and containing 5.56-7.74% of the total VIS. In comparison, the CIS analysis resulted in 12-110 hot-spots covering 0.018-0.246% of the genome and containing 5.81-22.7% of the VIS, corresponding to a greater number of hot-spots as the data set size increased. Our hot-spot methods enable one to evaluate the extent of VIS clustering, and formally compare data sets in terms of hot-spot overlap

  4. Diffusion Magnetic Resonance Imaging Patterns in Metabolic and Toxic Brain Disorders

    International Nuclear Information System (INIS)

    Purpose: To evaluate metabolic and toxic brain disorders that manifest with restricted, elevated, or both restricted and elevated diffusion patterns on diffusion magnetic resonance imaging (MRI). Material and Methods: Echo-planar diffusion MRI examinations were obtained in 34 pediatric patients with metabolic and toxic brain disorders proved by appropriate laboratory studies. The MRI unit operated at 1.5T with a gradient strength of 30 mT/meter, and a rise time of 600 s. b=1000 s/mm2 images and apparent diffusion coefficient (ADC) maps with ADC values were studied. Results: Three patterns were observed: 1. A restricted diffusion pattern (high signal on b=1000 s/mm2 images and low ADC values); 2. an elevated diffusion pattern (normal signal on b=1000 s/mm2 images and high ADC values); and 3. a mixed pattern (coexistent restricted and increased diffusion patterns in the same patient). Disorders manifesting with a restricted diffusion pattern included metachromatic leukodystrophy (n=2), phenylketonuria (n=3), maple syrup urine disease (intermediate form) (n=1), infantile neuroaxonal dystrophy (n=1), Leigh (n=2), Wilson (n=3), and Canavan disease (n=1). Disorders with an elevated diffusion pattern included phenylketonuria (n=1), adrenoleukodystrophy (n=1), merosin-deficient congenital muscular dystrophy (n=2), mucopolysaccharidosis (n=2), Lowe syndrome (n=1), Leigh (n=2), Alexander (n=1), Pelizaeus-Merzbacher (n=1), and Wilson (n=3) disease. Disorders with a mixed pattern included L-2 hydroxyglutaric aciduria (n=2), non-ketotic hyperglycinemia (n=1), infantile neuroaxonal dystrophy (n=2), maple syrup urine disease (n=1), and Leigh (n=1) disease. Conclusion: The findings suggested that the three different diffusion patterns reflect the histopathological changes associated with the disorders and different stages of a particular disorder. It is likely that the restricted diffusion pattern corresponds to abnormalities related to myelin, and the elevated diffusion pattern

  5. Diffusion Magnetic Resonance Imaging Patterns in Metabolic and Toxic Brain Disorders

    Energy Technology Data Exchange (ETDEWEB)

    Sener, R.N. [Ege Univ. Hospital, Bornova, Izmir (Turkey). Dept. of Radiology

    2004-08-01

    Purpose: To evaluate metabolic and toxic brain disorders that manifest with restricted, elevated, or both restricted and elevated diffusion patterns on diffusion magnetic resonance imaging (MRI). Material and Methods: Echo-planar diffusion MRI examinations were obtained in 34 pediatric patients with metabolic and toxic brain disorders proved by appropriate laboratory studies. The MRI unit operated at 1.5T with a gradient strength of 30 mT/meter, and a rise time of 600 s. b=1000 s/mm{sup 2} images and apparent diffusion coefficient (ADC) maps with ADC values were studied. Results: Three patterns were observed: 1. A restricted diffusion pattern (high signal on b=1000 s/mm{sup 2} images and low ADC values); 2. an elevated diffusion pattern (normal signal on b=1000 s/mm2 images and high ADC values); and 3. a mixed pattern (coexistent restricted and increased diffusion patterns in the same patient). Disorders manifesting with a restricted diffusion pattern included metachromatic leukodystrophy (n=2), phenylketonuria (n=3), maple syrup urine disease (intermediate form) (n=1), infantile neuroaxonal dystrophy (n=1), Leigh (n=2), Wilson (n=3), and Canavan disease (n=1). Disorders with an elevated diffusion pattern included phenylketonuria (n=1), adrenoleukodystrophy (n=1), merosin-deficient congenital muscular dystrophy (n=2), mucopolysaccharidosis (n=2), Lowe syndrome (n=1), Leigh (n=2), Alexander (n=1), Pelizaeus-Merzbacher (n=1), and Wilson (n=3) disease. Disorders with a mixed pattern included L-2 hydroxyglutaric aciduria (n=2), non-ketotic hyperglycinemia (n=1), infantile neuroaxonal dystrophy (n=2), maple syrup urine disease (n=1), and Leigh (n=1) disease. Conclusion: The findings suggested that the three different diffusion patterns reflect the histopathological changes associated with the disorders and different stages of a particular disorder. It is likely that the restricted diffusion pattern corresponds to abnormalities related to myelin, and the elevated

  6. Methodology and software to detect viral integration site hot-spots

    Science.gov (United States)

    2011-01-01

    Background Modern gene therapy methods have limited control over where a therapeutic viral vector inserts into the host genome. Vector integration can activate local gene expression, which can cause cancer if the vector inserts near an oncogene. Viral integration hot-spots or 'common insertion sites' (CIS) are scrutinized to evaluate and predict patient safety. CIS are typically defined by a minimum density of insertions (such as 2-4 within a 30-100 kb region), which unfortunately depends on the total number of observed VIS. This is problematic for comparing hot-spot distributions across data sets and patients, where the VIS numbers may vary. Results We develop two new methods for defining hot-spots that are relatively independent of data set size. Both methods operate on distributions of VIS across consecutive 1 Mb 'bins' of the genome. The first method 'z-threshold' tallies the number of VIS per bin, converts these counts to z-scores, and applies a threshold to define high density bins. The second method 'BCP' applies a Bayesian change-point model to the z-scores to define hot-spots. The novel hot-spot methods are compared with a conventional CIS method using simulated data sets and data sets from five published human studies, including the X-linked ALD (adrenoleukodystrophy), CGD (chronic granulomatous disease) and SCID-X1 (X-linked severe combined immunodeficiency) trials. The BCP analysis of the human X-linked ALD data for two patients separately (774 and 1627 VIS) and combined (2401 VIS) resulted in 5-6 hot-spots covering 0.17-0.251% of the genome and containing 5.56-7.74% of the total VIS. In comparison, the CIS analysis resulted in 12-110 hot-spots covering 0.018-0.246% of the genome and containing 5.81-22.7% of the VIS, corresponding to a greater number of hot-spots as the data set size increased. Our hot-spot methods enable one to evaluate the extent of VIS clustering, and formally compare data sets in terms of hot-spot overlap. Finally, we show that the

  7. Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy: in vivo assessment of structural changes.

    Science.gov (United States)

    Castellano, Antonella; Papinutto, Nico; Cadioli, Marcello; Brugnara, Gianluca; Iadanza, Antonella; Scigliuolo, Graziana; Pareyson, Davide; Uziel, Graziella; Köhler, Wolfgang; Aubourg, Patrick; Falini, Andrea; Henry, Roland G; Politi, Letterio S; Salsano, Ettore

    2016-06-01

    Adrenomyeloneuropathy is the late-onset form of X-linked adrenoleukodystrophy, and is considered the most frequent metabolic hereditary spastic paraplegia. In adrenomyeloneuropathy the spinal cord is the main site of pathology. Differently from quantitative magnetic resonance imaging of the brain, little is known about the feasibility and utility of advanced neuroimaging in quantifying the spinal cord abnormalities in hereditary diseases. Moreover, little is known about the subtle pathological changes that can characterize the brain of adrenomyeloneuropathy subjects in the early stages of the disease. We performed a cross-sectional study on 13 patients with adrenomyeloneuropathy and 12 age-matched healthy control subjects who underwent quantitative magnetic resonance imaging to assess the structural changes of the upper spinal cord and brain. Total cord areas from C2-3 to T2-3 level were measured, and diffusion tensor imaging metrics, i.e. fractional anisotropy, mean, axial and radial diffusivity values were calculated in both grey and white matter of spinal cord. In the brain, grey matter regions were parcellated with Freesurfer and average volume and thickness, and mean diffusivity and fractional anisotropy from co-registered diffusion maps were calculated in each region. Brain white matter diffusion tensor imaging metrics were assessed using whole-brain tract-based spatial statistics, and tractography-based analysis on corticospinal tracts. Correlations among clinical, structural and diffusion tensor imaging measures were calculated. In patients total cord area was reduced by 26.3% to 40.2% at all tested levels (P statistics showed a marked reduction of fractional anisotropy, increase of radial diffusivity (P < 0.001) and no axial diffusivity changes in several white matter tracts, including corticospinal tracts and optic radiations, indicating predominant demyelination. Tractography-based analysis confirmed the results within corticospinal tracts. No