Disease specific therapies in leukodystrophies and leukoencephalopathies.
Ontology highlight
ABSTRACT:
SUBMITTER: Helman G
PROVIDER: S-EPMC4390468 | biostudies-literature | 2015 Apr
REPOSITORIES: biostudies-literature
Publications
Disease specific therapies in leukodystrophies and leukoencephalopathies.
Helman Guy G Van Haren Keith K Bonkowsky Joshua L JL Bernard Genevieve G Pizzino Amy A Braverman Nancy N Suhr Dean D Patterson Marc C MC Ali Fatemi S S Leonard Jeff J van der Knaap Marjo S MS Back Stephen A SA Damiani Stephen S Goldman Steven A SA Takanohashi Asako A Petryniak Magdalena M Rowitch David D Messing Albee A Wrabetz Lawrence L Schiffmann Raphael R Eichler Florian F Escolar Maria L ML Vanderver Adeline A
Molecular genetics and metabolism 20150207 4
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 pilo ...[more]
Similar Datasets
Project description: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.
| S-EPMC4390457 | biostudies-literature
Project description:BackgroundThe genes responsible for genetic white matter disorders (GWMD; leukodystrophies and leukoencephalopathies) are incompletely known. Our goal was to revise the list of genes considered to cause GWMD. We considered a GWMD to consist of any genetic disease causing T2 signal white matter changes in magnetic resonance images.Methods and resultsUsing a systematic review of PubMed, Google, published literature reviews, and commercial gene panels, we identified 399 unique genes meeting the GWMD definition. Of this, 87 (22%) genes were hypomyelinating. Only 3 genes had contrast enhancement on magnetic resonance imaging (MRI): ABCD1, GFAP, and UNC13D.ConclusionsA significantly greater number of genes than previously recognized, 399, are associated with white matter signal changes on T2 MRI. This expansion of GWMD genes can be useful in analysis and interpretation of next-generation sequencing results for GWMD diagnosis, and for understanding shared pathophysiological mechanisms of GWMDs.
| S-EPMC7359642 | biostudies-literature
Project description:The leukodystrophies are a group of inherited white matter disorders with a heterogeneous genetic background, considerable phenotypic variability and disease onset at all ages. This Review focuses on leukodystrophies with major prevalence or primary onset in adulthood. We summarize 20 leukodystrophies with adult presentations, providing information on the underlying genetic mutations and on biochemical assays that aid diagnosis, where available. Definitions, clinical characteristics, age of onset, MRI findings and treatment options are all described, providing a comprehensive overview of the current knowledge of the various adulthood leukodystrophies. We highlight the distinction between adult-onset leukodystrophies and other inherited disorders with white matter involvement, and we propose a diagnostic pathway for timely recognition of adulthood leukodystrophies in a routine clinical setting. In addition, we provide detailed clinical information on selected adult-onset leukodystrophies, including X-linked adrenoleukodystrophy, metachromatic leukodystrophy, cerebrotendinous xanthomatosis, hereditary diffuse leukoencephalopathy with axonal spheroids, autosomal dominant adult-onset demyelinating leukodystrophy, adult polyglucosan body disease, and leukoencephalopathy with vanishing white matter. Ultimately, this Review aims to provide helpful suggestions to identify treatable adulthood leukodystrophies at an early stage in the disease course.
| S-EPMC11348681 | biostudies-literature
Project description:Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults.
| S-EPMC5405235 | biostudies-literature
Project description: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.
| S-EPMC5712822 | biostudies-literature
Project description:Background and purposeAchieving 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 methodsOne 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.ResultsMR 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.ConclusionsIn 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.
| S-EPMC8324261 | biostudies-literature
Project description:Primary microglial leukodystrophy or leukoencephalopathy are disorders in which a genetic defect linked to microglia causes cerebral white matter damage. Pigmented orthochromatic leukodystrophy, adult-onset orthochromatic leukodystrophy associated with pigmented macrophages, hereditary diffuse leukoencephalopathy with (axonal) spheroids, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) are different terms apparently used to designate the same disease. However, ALSP linked to dominantly inherited mutations in CSF1R (colony stimulating factor receptor 1) cause CSF-1R-related leukoencephalopathy (CRP). Yet, recessive ALSP with ovarian failure linked to AARS2 (alanyl-transfer (t)RNA synthase 2) mutations (LKENP) is a mitochondrial disease and not a primary microglial leukoencephalopathy. Polycystic membranous lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; Nasu-Hakola disease: NHD) is a systemic disease affecting bones, cerebral white matter, selected grey nuclei, and adipose tissue The disease is caused by mutations of one of the two genes TYROBP or TREM2, identified as PLOSL1 and PLOSL2, respectively. TYROBP associates with receptors expressed in NK cells, B and T lymphocytes, dendritic cells, monocytes, macrophages, and microglia. TREM2 encodes the protein TREM2 (triggering receptor expressed on myeloid cells 2), which forms a receptor signalling complex with TYROBP in macrophages and dendritic cells. Rather than pure microglial leukoencephalopathy, NHD can be considered a multisystemic "immunological" disease.
| S-EPMC9181167 | biostudies-literature
Project description:ObjectivesLeukodystrophies are diseases of the white matter for which data concerning clinical characteristics, incidence, disease burden, and description of outcomes are sparse. The purpose of our study was to determine the incidence and most common types of inherited leukodystrophies in a population, the mortality and time course of deaths, common neurologic features in patients, and health care costs associated with leukodystrophies.MethodsWe conducted a retrospective, hospital- and clinic-based surveillance of inherited leukodystrophies among children younger than 18 years presenting to a regional children's hospital. We enrolled children evaluated from January 1, 1999, through December 31, 2007; clinical information was obtained from medical records. We calculated incidence based on state birth rates.ResultsA total of 122 children with an inherited leukodystrophy were identified; 542 patients were excluded. A total of 49% had epilepsy, 43% required a gastrostomy tube, and 32% had a history of developmental regression. Mortality was 34%; average age at death was 8.2 years. No final diagnosis was reported in 51% of patients. The most common diagnoses were metachromatic leukodystrophy (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). Endocrine abnormalities and hypoplastic cerebellum were noted in significant portions of patients (15% and 14%). Average yearly per-patient medical costs were $22,579. Population incidence was 1 in 7,663 live births.ConclusionsInherited leukodystrophies are associated with substantial morbidity and mortality in children. Overall population incidence is higher than generally appreciated (1 in 7,663 live births). Most leukodystrophies remain undiagnosed, but a logical algorithm based on prevalence could aid testing.
| S-EPMC2931652 | biostudies-literature
Project description:Leukodystrophies are a heterogeneous class of genetic diseases affecting the white matter in the central nervous system with a broad range of clinical manifestations and a frequently progressive course. An interest in precision medicine has emerged over the last several decades, and biomedical research in leukodystrophies has made exciting advances along this front through therapeutic target discovery and novel disease model systems. In this review, we discuss current and emerging therapeutic approaches in leukodystrophies, including gene therapy, antisense oligonucleotide therapy, CRISPR/CAS-based gene editing, and cell and stem cell based therapies.
| S-EPMC6698898 | biostudies-literature
Project description:Leukodystrophies (LD) are rare inherited disorders that primarily affect the white matter (WM) of the central nervous system. The large heterogeneity of LD results from the diversity of the genetically determined defects that interfere with glial cells functions. Astrocytes have been identified as the primary target of LD with cystic myelin breakdown including those related to mutations in the ubiquitous translation initiation factor eIF2B. EIF2B is involved in global protein synthesis and its regulation under normal and stress conditions. Little is known about how eIF2B mutations have a major effect on WM. We performed a transcriptomic analysis using fibroblasts of 10 eIF2B-mutated patients with a severe phenotype and 10 age matched patients with other types of LD in comparison to control fibroblasts. ANOVA was used to identify genes that were statistically significantly differentially expressed at basal state and after ER-stress. The pattern of differentially expressed genes between basal state and ER-stress did not differ significantly among each of the three conditions. However, 70 genes were specifically differentially expressed in eIF2B-mutated fibroblasts whatever the stress conditions tested compared to controls, 96% being under-expressed. Most of these genes were involved in mRNA regulation and mitochondrial metabolism. The 13 most representative genes, including genes belonging to the Heterogeneous Nuclear Ribonucleoprotein (HNRNP) family, described as regulators of splicing events and stability of mRNA, were dysregulated during the development of eIF2B-mutated brains. HNRNPH1, F and C mRNA were over-expressed in foetus but under-expressed in children and adult brains. The abnormal regulation of HNRNP expression in the brain of eIF2B-mutated patients was concomitant with splicing dysregulation of the main genes involved in glial maturation such as PLP1 for oligodendrocytes and GFAP in astrocytes. These findings demonstrate a developmental deregulation of splicing events in glial cells that is related to abnormal production of HNRNP, in eIF2B-mutated brains.
| S-EPMC3380860 | biostudies-literature