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Adeline Vanderver - One of the best experts on this subject based on the ideXlab platform.
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imaging patterns characterizing mitochondrial Leukodystrophies
American Journal of Neuroradiology, 2021Co-Authors: S D Roosendaal, Adeline Vanderver, Nicole I Wolf, Susan Blaser, T Van De Brug, C A P F Alves, M S Van Der KnaapAbstract:BACKGROUND AND PURPOSE: Achieving a specific diagnosis in Leukodystrophies is often difficult due to clinical and genetic heterogeneity. Mitochondrial defects cause 5%–10% of Leukodystrophies. Our objective was to define MR imaging features commonly shared by mitochondrial Leukodystrophies and to distinguish MR imaging patterns related to specific genetic defects. MATERIALS AND METHODS: One hundred thirty-two patients with a mitochondrial leukodystrophy with known genetic defects were identified in the data base of the Amsterdam Leukodystrophy Center. Numerous anatomic structures were systematically assessed on brain MR imaging. Additionally, lesion characteristics were scored. Statistical group analysis was performed for 57 MR imaging features by hierarchic testing on clustered genetic subgroups. RESULTS: MR imaging features indicative of mitochondrial disease that were frequently found included white matter rarefaction (n = 50 patients), well-delineated cysts (n = 20 patients), T2 hyperintensity of the middle blade of the corpus callosum (n = 85 patients), and symmetric abnormalities in deep gray matter structures (n = 42 patients). Several disorders or clusters of disorders had characteristic features. The combination of T2 hyperintensity in the brain stem, middle cerebellar peduncles, and thalami was associated with complex 2 deficiency. Predominantly periventricular localization of T2 hyperintensities and cystic lesions with a distinct border was associated with defects in complexes 3 and 4. T2-hyperintense signal of the cerebellar cortex was specifically associated with variants in the gene NUBPL. T2 hyperintensities predominantly affecting the directly subcortical cerebral white matter, globus pallidus, and substantia nigra were associated with Kearns-Sayre syndrome. CONCLUSIONS: In a large group of patients with a mitochondrial leukodystrophy, general MR imaging features suggestive of mitochondrial disease were found. Additionally, we identified several MR imaging patterns correlating with specific genotypes. Recognition of these patterns facilitates the diagnosis in future patients.
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update on Leukodystrophies a historical perspective and adapted definition
Neuropediatrics, 2016Co-Authors: Sietske H Kevelam, Adeline Vanderver, Raphael Schiffmann, Nicole I Wolf, Marjan E Steenweg, Siddharth Srivastava, Guy Helman, Sakkubai Naidu, Susan Blaser, Marjo S Van Der KnaapAbstract:Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel Leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare Leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the Leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.
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emerging treatments for pediatric Leukodystrophies
Pediatric Clinics of North America, 2015Co-Authors: Guy Helman, Maria L Escolar, Keith Van Haren, Adeline VanderverAbstract:The Leukodystrophies are a heterogeneous group of inherited disorders with broad clinical manifestations and variable pathologic mechanisms. Improved diagnostic methods have allowed identification of the underlying cause of these diseases, facilitating identification of their pathologic mechanisms. Clinicians are now able to prioritize treatment strategies and advance research in therapies for specific disorders. Although only a few of these disorders have well-established treatments or therapies, a number are on the verge of clinical trials. As investigators are able to shift care from symptomatic management of disorders to targeted therapeutics, the unmet therapeutic needs could be reduced for these patients.
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Case definition and classification of Leukodystrophies and leukoencephalopathies
Molecular Genetics and Metabolism, 2015Co-Authors: Adeline Vanderver, Fanny Mochel, Florian Eichler, Davide Tonduti, Guy Helman, Morgan Prust, Heather Hussey, James Garbern, Pierre Labauge, Patrick AubourgAbstract:OBJECTIVE: An approved definition of the term leukodystrophy does not currently exist. The lack of a precise case definition hampers efforts to study the epidemiology and the relevance of genetic white matter disorders to public health. METHOD: Thirteen experts at multiple institutions participated in iterative consensus building surveys to achieve definition and classification of disorders as Leukodystrophies using a modified Delphi approach. RESULTS: A case definition for the Leukodystrophies was achieved, and a total of 30 disorders were classified under this definition. In addition, a separate set of disorders with heritable white matter abnormalities but not meeting criteria for leukodystrophy, due to presumed primary neuronal involvement and prominent systemic manifestations, was classified as genetic leukoencephalopathies (gLE). INTERPRETATION: A case definition of Leukodystrophies and classification of heritable white matter disorders will permit more detailed epidemiologic studies of these disorders.
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hypomyelinating Leukodystrophies translational research progress and prospects
Annals of Neurology, 2014Co-Authors: Petra J W Pouwels, Adeline Vanderver, A Kohlschutter, Nicole I Wolf, Genevieve Bernard, Enrico Bertini, Steffi F Drehakulczewksi, Sean C L Deoni, William D Richardson, Charles FfrenchconstantAbstract:Hypomyelinating Leukodystrophies represent a genetically heterogeneous but clinically overlapping group of heritable disorders. Current management approaches in the care of the patient with a hypomyelinating leukodystrophy include use of serial magnetic resonance imaging (MRI) to establish and monitor hypomyelination, molecular diagnostics to determine a specific etiology, and equally importantly, careful attention to neurologic complications over time. Emerging research in oligodendrocyte biology and neuroradiology with bedside applications may result in the possibility of clinical trials in the near term, yet there are significant gaps in knowledge in disease classification, characterization, and outcome measures in this group of disorders. Here we review the biological background of myelination, the clinical and genetic variability in hypomyelinating Leukodystrophies, and the insights that can be obtained from current MRI techniques. In addition, we discuss ongoing research approaches to define potential outcome markers for future clinical trials.
Marjo S Van Der Knaap - One of the best experts on this subject based on the ideXlab platform.
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hypomyelinating Leukodystrophies unravelling myelin biology
Nature Reviews Neurology, 2021Co-Authors: Nicole I Wolf, Marjo S Van Der Knaap, Charles FfrenchconstantAbstract:Hypomyelinating Leukodystrophies constitute a subset of genetic white matter disorders characterized by a primary lack of myelin deposition. Most patients with severe hypomyelination present in infancy or early childhood and develop severe neurological deficits, but the clinical presentation can also be mild with onset of symptoms in adolescence or adulthood. MRI can be used to visualize the process of myelination in detail, and MRI pattern recognition can provide a clinical diagnosis in many patients. Next-generation sequencing provides a definitive diagnosis in 80-90% of patients. Genes associated with hypomyelination include those that encode structural myelin proteins but also many that encode proteins involved in RNA translation and some lysosomal proteins. The precise pathomechanisms remain to be elucidated. Improved understanding of the process of myelination, the metabolic axonal support functions of myelin and the proposed contribution of myelin to CNS plasticity provide possible explanations as to why almost all patients with hypomyelination experience slow clinical decline after a long phase of stability. In this Review, we provide an overview of the hypomyelinating Leukodystrophies, the advances in our understanding of myelin biology and of the genes involved in these disorders, and the insights these advances have provided into their clinical presentations and evolution.
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diagnosis prognosis and treatment of Leukodystrophies
Lancet Neurology, 2019Co-Authors: Marjo S Van Der Knaap, Raphael Schiffmann, Fanny Mochel, Nicole I WolfAbstract:Leukodystrophies comprise a large group of rare genetic disorders primarily affecting CNS white matter. Historically, the diagnostic process was slow and patient prognosis regarded as poor because curative treatment was only available for very few Leukodystrophies in early stages of the disease. Whole-exome sequencing has both greatly increased the number of known Leukodystrophies and improved diagnosis. Whether MRI keeps its central place in diagnosis and what the role is of whole-exome sequencing are relevant questions for neurologists. Improved diagnosis has revealed the phenotypic variability of Leukodystrophies, requiring adaptation of prognostication. Technological advance in molecular techniques and improved insight into the pathophysiology of individual Leukodystrophies have led to therapeutic developments, including drug design and gene therapy. Despite this progress, therapies are only beneficial early in the disease course, emphasising the need for a speedy diagnosis and for research on regenerative approaches to repair the damage already present.
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Leukodystrophies five new things
Neurology: Clinical Practice, 2016Co-Authors: Marjo S Van Der Knaap, Nicole I Wolf, Vivi M HeineAbstract:Abstract Purpose of review: Leukodystrophies are genetic disorders primarily and predominantly affecting CNS white matter. They are associated with connotations such as “much unknown,” “progressive myelin loss,” and “nothing can be done.” Recent technological progress is reversing this picture. Recent findings: Next-generation sequencing has created the revolution of whole-exome/genome sequencing, allowing disease definition and gene identification for numerous ultra-rare disorders by focusing on very small groups and individual patients. Knowledge of many new “white matter proteins” is transforming our understanding of white matter physiology and pathophysiology. Regarding therapy, especially stem cell and gene therapy are evolving rapidly, aiming at personalized therapy for a specific patient with a specific disease. Multimodal approaches targeting multiple aspects of the disease hold the highest promise. Summary: Technological developments are revolutionizing the leukodystrophy field. Unknown becomes known and untreatable becomes treatable. New insight is that not all Leukodystrophies are irreversible and that some improve spontaneously.
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update on Leukodystrophies a historical perspective and adapted definition
Neuropediatrics, 2016Co-Authors: Sietske H Kevelam, Adeline Vanderver, Raphael Schiffmann, Nicole I Wolf, Marjan E Steenweg, Siddharth Srivastava, Guy Helman, Sakkubai Naidu, Susan Blaser, Marjo S Van Der KnaapAbstract:Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel Leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare Leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the Leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.
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Leukodystrophies and genetic leukoencephalopathies in childhood a national epidemiological study
Developmental Medicine & Child Neurology, 2016Co-Authors: L Stellitano, Marjo S Van Der Knaap, Anne Marie Winstone, Christopher M VerityAbstract:Aim To report on the epidemiology of the brain white matter disorders of children identified via a national prospective study. Method Since 1997 a study of UK children with progressive intellectual and neurological deterioration (PIND) has used the British Paediatric Surveillance Unit system to identify children with progressive neurodegenerative disease. This paper reports on children in the study with brain white matter disorders. Results Between May 1997 and November 2014 the PIND study identified 349 children with diagnosed Leukodystrophies, giving an estimated UK lifetime risk of 31/million live births. There were 18 specific diseases in the group and relatively large numbers of affected children came from consanguineous Pakistani families. In addition there were 454 children with genetic leukoencephalopathies – in this group there were 38 diseases. 5.8% of children with scan evidence of brain white matter disorders did not receive a specific diagnosis. Interpretation These unique prospectively-obtained national data avoid the selection bias inherent in reports from single centres. White matter disorders of the central nervous system comprise more than half of UK paediatric neurodegenerative diseases meeting the PIND criteria. This paper reports the lifetime risk/million live births for the commonest Leukodystrophies, providing a basis for comparison with future studies.
Genevieve Bernard - One of the best experts on this subject based on the ideXlab platform.
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pediatric Leukodystrophies the role of the otolaryngologist
International Journal of Pediatric Otorhinolaryngology, 2017Co-Authors: Emily Kayrivest, Genevieve Bernard, Leticia Khendek, Sam J DanielAbstract:Abstract Background Leukodystrophies consist of degenerative neurogenetic diseases often associated with comorbidities that extend beyond the neurological system. Despite their impacts on patients' quality of life and risks of complications, head and neck symptomology is poorly reported in the literature. The objective of this study was to identify and quantify the main head and neck complaints among a cohort of patients diagnosed with Leukodystrophies and define the role of the otolaryngologist as part of a multidisciplinary team for treating these patients. Methods During the First Canadian National Conference on Leukodystrophies held at the Montreal's Children Hospital, a cohort of 12 patients diagnosed with Leukodystrophies were recruited and evaluated by a multidisciplinary team. An otolaryngology-focused assessment was done through history and physical examination, and included a screening questionnaire for 23 common otolaryngology issues. If families reported a history of sialorrhea, a validated questionnaire (Drool Quality of Life Assessment Questionnaire (DroolQoL)) was subsequently distributed. Results from the questionnaires were then compiled and analyzed. Results Of the 12 recruited patients, 83% (10/12) were known to an otolaryngologist. Drooling affected 67% (8/12) of patients although only 37.5% (3/8) of patients had undergone medical or surgical therapies for this issue. Four patients experienced at least one aspiration pneumonia. 58% (7/12) of the patients had dysphagia, of whom 43% (3/12) were fed exclusively via gastrostomy tube and 28% (2/7) required thickening of feeds. Two patients, despite suspicion of dysphagia and aspiration, had never undergone evaluation. As for otologic issues, it was noted that 25% (3/12) of patients had a history of pressure equalizing tubes (PETs) and one patient had a history of hearing loss. Conclusion Head and neck comorbidities affect children with Leukodystrophies. Therefore, the otolaryngologist should be part of the multidisciplinary team, specifically for the management of dysphagia and sialorrhea.
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disease specific therapies in Leukodystrophies and leukoencephalopathies
Molecular Genetics and Metabolism, 2015Co-Authors: Guy Helman, Joshua L Bonkowsky, Genevieve Bernard, Keith Van Haren, Amy Pizzino, Nancy Braverman, Dean Suhr, Marc C Patterson, Ali S Fatemi, Jeff LeonardAbstract:Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with Leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.
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hypomyelinating Leukodystrophies translational research progress and prospects
Annals of Neurology, 2014Co-Authors: Petra J W Pouwels, Adeline Vanderver, A Kohlschutter, Nicole I Wolf, Genevieve Bernard, Enrico Bertini, Steffi F Drehakulczewksi, Sean C L Deoni, William D Richardson, Charles FfrenchconstantAbstract:Hypomyelinating Leukodystrophies represent a genetically heterogeneous but clinically overlapping group of heritable disorders. Current management approaches in the care of the patient with a hypomyelinating leukodystrophy include use of serial magnetic resonance imaging (MRI) to establish and monitor hypomyelination, molecular diagnostics to determine a specific etiology, and equally importantly, careful attention to neurologic complications over time. Emerging research in oligodendrocyte biology and neuroradiology with bedside applications may result in the possibility of clinical trials in the near term, yet there are significant gaps in knowledge in disease classification, characterization, and outcome measures in this group of disorders. Here we review the biological background of myelination, the clinical and genetic variability in hypomyelinating Leukodystrophies, and the insights that can be obtained from current MRI techniques. In addition, we discuss ongoing research approaches to define potential outcome markers for future clinical trials.
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brain magnetic resonance imaging mri pattern recognition in pol iii related Leukodystrophies
Journal of Child Neurology, 2014Co-Authors: Roberta La Piana, Davide Tonduti, Heather Gordish Dressman, Johanna L Schmidt, Jonathan Murnick, Bernard Brais, Genevieve Bernard, Adeline VanderverAbstract:Pol III-related Leukodystrophies are caused by mutations in POLR3A and POLR3B genes and all share peculiar imaging and clinical features. The objectives of this study are (1) to define the neuroradiologic pattern in a cohort of POLR3A and POLR3B subjects and (2) to compare the neuroradiologic pattern of Pol III-related Leukodystrophies with other hypomyelinating disorders. The magnetic resonance imaging (MRI) examinations of 13 patients with POLR3A and POLR3B mutations and of 14 patients with other hypomyelinating disorders were analyzed. All the subjects with Pol III-related Leukodystrophies presented hypomyelination associated with T2 hypointensity of the thalami and/or the pallida. Twelve subjects (92%) presented T2 hypointensity of the optic radiations. Cerebellar atrophy was observed in most patients (92%). The combination of the analyzed criteria identified patients with Pol III-related Leukodystrophies with a sensitivity of 84.6% and a specificity of 92.9%.
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advances in the diagnosis of Leukodystrophies
Future Neurology, 2012Co-Authors: Bradley Osterman, Roberta La Piana, Genevieve BernardAbstract:Leukodystrophies are a heterogeneous group of inherited disorders that preferentially affect the CNS white matter. They are classified as demyelinating (or classic) or hypomyelinating according to brain MRI characteristics. As these disorders often have a similar clinical presentation according to their age of onset, the initial diagnostic approach is often challenging. This review aims to help clinicians approach these disorders using information from the history (e.g., age of onset), the examination (e.g., presence of macrocrania) and MRI scans in order to reduce the number of possible diagnoses for a given patient and to hopefully lead to a precise (molecular) diagnosis.
A Kohlschutter - One of the best experts on this subject based on the ideXlab platform.
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genetic testing of Leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants
Scientific Reports, 2021Co-Authors: A Kohlschutter, Nejat Mahdieh, Mahdieh Soveizi, Ali Reza Tavasoli, Ali Rabbani, Mahmoud Reza Ashrafi, Bahareh RabbaniAbstract:This study evaluates the genetic spectrum of Leukodystrophies and leukoencephalopathies in Iran. 152 children, aged from 1 day to 15 years, were genetically tested for Leukodystrophies and leukoencephalopathies based on clinical and neuroradiological findings from 2016 to 2019. Patients with a suggestive specific leukodystrophy, e. g. metachromatic leukodystrophy, Canavan disease, Tay-Sachs disease were tested for mutations in single genes (108; 71%) while patients with less suggestive findings were evaluated by NGS. 108 of 152(71%) had MRI patterns and clinical findings suggestive of a known leukodystrophy. In total, 114(75%) affected individuals had (likely) pathogenic variants which included 38 novel variants. 35 different types of Leukodystrophies and genetic leukoencephalopathies were identified. The more common identified disorders included metachromatic leukodystrophy (19 of 152; 13%), Canavan disease (12; 8%), Tay-Sachs disease (11; 7%), megalencephalic leukodystrophy with subcortical cysts (7; 5%), X-linked adrenoleukodystrophy (8; 5%), Pelizaeus-Merzbacher-like disease type 1 (8; 5%), Sandhoff disease (6; 4%), Krabbe disease (5; 3%), and vanishing white matter disease (4; 3%). Whole exome sequencing (WES) revealed 90% Leukodystrophies and genetic leukoencephalopathies. The total diagnosis rate was 75%. This unique study presents a national genetic data of Leukodystrophies; it may provide clues to the genetic pool of neighboring countries. Patients with clinical and neuroradiological evidence of a genetic leukoencephalopathy should undergo a genetic analysis to reach a definitive diagnosis. This will allow a diagnosis at earlier stages of the disease, reduce the burden of uncertainty and costs, and will provide the basis for genetic counseling and family planning.
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hypomyelinating Leukodystrophies translational research progress and prospects
Annals of Neurology, 2014Co-Authors: Petra J W Pouwels, Adeline Vanderver, A Kohlschutter, Nicole I Wolf, Genevieve Bernard, Enrico Bertini, Steffi F Drehakulczewksi, Sean C L Deoni, William D Richardson, Charles FfrenchconstantAbstract:Hypomyelinating Leukodystrophies represent a genetically heterogeneous but clinically overlapping group of heritable disorders. Current management approaches in the care of the patient with a hypomyelinating leukodystrophy include use of serial magnetic resonance imaging (MRI) to establish and monitor hypomyelination, molecular diagnostics to determine a specific etiology, and equally importantly, careful attention to neurologic complications over time. Emerging research in oligodendrocyte biology and neuroradiology with bedside applications may result in the possibility of clinical trials in the near term, yet there are significant gaps in knowledge in disease classification, characterization, and outcome measures in this group of disorders. Here we review the biological background of myelination, the clinical and genetic variability in hypomyelinating Leukodystrophies, and the insights that can be obtained from current MRI techniques. In addition, we discuss ongoing research approaches to define potential outcome markers for future clinical trials.
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lysosomal Leukodystrophies krabbe disease and metachromatic leukodystrophy
Handbook of Clinical Neurology, 2013Co-Authors: A KohlschutterAbstract:Abstract Genetic deficiencies of lysosomal catabolic pathways lead to storage disorders with multiple organ abnormalities or to degeneration of purely nervous structures. Krabbe disease and metachromatic leukodystrophy are caused by metabolic errors concerning lipids of neural membranes. They are characterized by demyelination of the central nervous system and, variably, the peripheral nerves. Their clinical presentation is a relentlessly progressive motor and mental deterioration starting at any age between infancy and adolescence. MRI demonstrates characteristic lesions of brain white matter. In Krabbe disease, deficient galactocerebroside β-galactosidase activity causes accumulation of lipids in “globoid” macrophages and of psychosine, which is toxic to oligodendrocytes. Diagnosis depends on demonstration of the enzyme deficiency. Experimental treatment is limited to hematopoietic stem cell transplantation, which can favorably alter the course of disease in certain situations. In metachromatic leukodystrophy, deficient activity of arylsulfatase A, or lack of a cofactor, causes accumulation of sulfatide in various tissues and diffuse demyelination. Symptoms are neurological, but gallbladder dysfunction may be present. Diagnosis depends on demonstrating the enzyme deficiency and elevated urinary sulfatide. In a rare variant, multiple sulfatases are deficient. Stem cell transplantation may prevent disease progression in selected cases. Enzyme replacement is being evaluated, and gene therapies are being developed.
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childhood Leukodystrophies a clinical perspective
Expert Review of Neurotherapeutics, 2011Co-Authors: A Kohlschutter, Florian EichlerAbstract:Leukodystrophies are white matter disorders that are genetic in nature. In the young, they represent an important cause of progressive neurological disability. They are frequently recognized on MRI, but their identification remains a challenge. Their diagnosis is important for prognostication, palliative and experimental treatment, as well as family screening. The diagnostic strategy rests upon clinical clues and MRI patterns, complemented by appropriately selected electrophysiological and laboratory testing. Considerable overlap exists between white and gray matter disease, as neuronal degeneration will result in myelin loss. An understanding of the pathophysiology and natural disease evolution is necessary to understand the risks and benefits of experimental and palliative treatments.
Ali Reza Tavasoli - One of the best experts on this subject based on the ideXlab platform.
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genetic testing of Leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants
Scientific Reports, 2021Co-Authors: A Kohlschutter, Nejat Mahdieh, Mahdieh Soveizi, Ali Reza Tavasoli, Ali Rabbani, Mahmoud Reza Ashrafi, Bahareh RabbaniAbstract:This study evaluates the genetic spectrum of Leukodystrophies and leukoencephalopathies in Iran. 152 children, aged from 1 day to 15 years, were genetically tested for Leukodystrophies and leukoencephalopathies based on clinical and neuroradiological findings from 2016 to 2019. Patients with a suggestive specific leukodystrophy, e. g. metachromatic leukodystrophy, Canavan disease, Tay-Sachs disease were tested for mutations in single genes (108; 71%) while patients with less suggestive findings were evaluated by NGS. 108 of 152(71%) had MRI patterns and clinical findings suggestive of a known leukodystrophy. In total, 114(75%) affected individuals had (likely) pathogenic variants which included 38 novel variants. 35 different types of Leukodystrophies and genetic leukoencephalopathies were identified. The more common identified disorders included metachromatic leukodystrophy (19 of 152; 13%), Canavan disease (12; 8%), Tay-Sachs disease (11; 7%), megalencephalic leukodystrophy with subcortical cysts (7; 5%), X-linked adrenoleukodystrophy (8; 5%), Pelizaeus-Merzbacher-like disease type 1 (8; 5%), Sandhoff disease (6; 4%), Krabbe disease (5; 3%), and vanishing white matter disease (4; 3%). Whole exome sequencing (WES) revealed 90% Leukodystrophies and genetic leukoencephalopathies. The total diagnosis rate was 75%. This unique study presents a national genetic data of Leukodystrophies; it may provide clues to the genetic pool of neighboring countries. Patients with clinical and neuroradiological evidence of a genetic leukoencephalopathy should undergo a genetic analysis to reach a definitive diagnosis. This will allow a diagnosis at earlier stages of the disease, reduce the burden of uncertainty and costs, and will provide the basis for genetic counseling and family planning.
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an update on clinical pathological diagnostic and therapeutic perspectives of childhood Leukodystrophies
Expert Review of Neurotherapeutics, 2020Co-Authors: Mahmoud Reza Ashrafi, Man Amanat, Masoud Garshasbi, Reyhaneh Kameli, Yalda Nilipour, Morteza Heidari, Zahra Rezaei, Ali Reza TavasoliAbstract:Introduction: Leukodystrophies constitute heterogenous group of rare heritable disorders primarily affecting the white matter of central nervous system. These conditions are often under-appreciated among physicians. The first clinical manifestations of Leukodystrophies are often nonspecific and can occur in different ages from neonatal to late adulthood periods. The diagnosis is, therefore, challenging in most cases.Area covered: Herein, the authors discuss different aspects of Leukodystrophies. The authors used MEDLINE, EMBASE, and GOOGLE SCHOLAR to provide an extensive update about epidemiology, classifications, pathology, clinical findings, diagnostic tools, and treatments of Leukodystrophies. Comprehensive evaluation of clinical findings, brain magnetic resonance imaging, and genetic studies play the key roles in the early diagnosis of individuals with Leukodystrophies. No cure is available for most heritable white matter disorders but symptomatic treatments can significantly decrease the burden of events. New genetic methods and stem cell transplantation are also under investigation to further increase the quality and duration of life in affected population.Expert opinion: The improvements in molecular diagnostic tools allow us to identify the meticulous underlying etiology of Leukodystrophies and result in higher diagnostic rates, new classifications of Leukodystrophies based on genetic information, and replacement of symptomatic managements with more specific targeted therapies.Abbreviations: 4H: Hypomyelination, hypogonadotropic hypogonadism and hypodontia; AAV: Adeno-associated virus; AD: autosomal dominant; AGS: Aicardi-Goutieres syndrome; ALSP: Axonal spheroids and pigmented glia; APGBD: Adult polyglucosan body disease; AR: autosomal recessive; ASO: Antisense oligonucleotide therapy; AxD: Alexander disease; BAEP: Brainstem auditory evoked potentials; CAA: Cerebral amyloid angiopathy; CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy; CARASIL: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; CGH: Comparative genomic hybridization; ClC2: Chloride Ion Channel 2; CMTX: Charcot-Marie-Tooth disease, X-linked; CMV: Cytomegalovirus; CNS: central nervous system; CRISP/Cas9: Clustered regularly interspaced short palindromic repeat/CRISPR-associated 9; gRNA: Guide RNA; CTX: Cerebrotendinous xanthomatosis; DNA: Deoxyribonucleic acid; DSB: Double strand breaks; DTI: Diffusion tensor imaging; FLAIR: Fluid attenuated inversion recovery; GAN: Giant axonal neuropathy; H-ABC: Hypomyelination with atrophy of basal ganglia and cerebellum; HBSL: Hypomyelination with brainstem and spinal cord involvement and leg spasticity; HCC: Hypomyelination with congenital cataracts; HEMS: Hypomyelination of early myelinated structures; HMG CoA: Hydroxy methylglutaryl CoA; HSCT: Hematopoietic stem cell transplant; iPSC: Induced pluripotent stem cells; KSS: Kearns-Sayre syndrome; L-2-HGA: L-2-hydroxy glutaric aciduria; LBSL: Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate; LCC: Leukoencephalopathy with calcifications and cysts; LTBL: Leukoencephalopathy with thalamus and brainstem involvement and high lactate; MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; MERRF: Myoclonic epilepsy with ragged red fibers; MLC: Megalencephalic leukoencephalopathy with subcortical cysts; MLD: metachromatic leukodystrophy; MRI: magnetic resonance imaging; NCL: Neuronal ceroid lipofuscinosis; NGS: Next generation sequencing; ODDD: Oculodentodigital dysplasia; PCWH: Peripheral demyelinating neuropathy-central-dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschprung disease; PMD: Pelizaeus-Merzbacher disease; PMDL: Pelizaeus-Merzbacher-like disease; RNA: Ribonucleic acid; TW: T-weighted; VWM: Vanishing white matter; WES: whole exome sequencing; WGS: whole genome sequencing; X-ALD: X-linked adrenoleukodystrophy; XLD: X-linked dominant; XLR: X-linked recessive.
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childhood Leukodystrophies a literature review of updates on new definitions classification diagnostic approach and management
Brain & Development, 2017Co-Authors: Mahmoud Reza Ashrafi, Ali Reza TavasoliAbstract:Childhood Leukodystrophies are a growing category of neurological disorders in pediatric neurology practice. With the help of new advanced genetic studies such as whole exome sequencing (WES) and whole genome sequencing (WGS), the list of childhood heritable white matter disorders has been increased to more than one hundred disorders. During the last three decades, the basic concepts and definitions, classification, diagnostic approach and medical management of these disorders much have changed. Pattern recognition based on brain magnetic resonance imaging (MRI), has played an important role in this process. We reviewed the last Global Leukodystrophy Initiative (GLIA) expert opinions in definition, new classification, diagnostic approach and medical management including emerging treatments for pediatric Leukodystrophies.