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Molecular Genetics and Metabolism Apr 2015An 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... (Review)
Review
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.
Topics: Brain Diseases; Demyelinating Diseases; Humans; Leukoencephalopathies; Lysosomal Storage Diseases; Myelin Sheath; Neuroglia
PubMed: 25649058
DOI: 10.1016/j.ymgme.2015.01.006 -
Neuroscience Letters May 2021Krabbe disease (globoid cell leukodystrophy) is a lysosomal storage disease (LSD) characterized by progressive and profound demyelination. Infantile, juvenile and... (Review)
Review
Krabbe disease (globoid cell leukodystrophy) is a lysosomal storage disease (LSD) characterized by progressive and profound demyelination. Infantile, juvenile and adult-onset forms of Krabbe disease have been described, with infantile being the most common. Children with an infantile-onset generally appear normal at birth but begin to miss developmental milestones by six months of age and die by two to four years of age. Krabbe disease is caused by a deficiency of the acid hydrolase galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and sphingolipids, which are abundant in myelin membranes. The absence of GALC leads to the toxic accumulation of galactosylsphingosine (psychosine), a lysoderivative of galactosylceramides, in oligodendrocytes and Schwann cells resulting in demyelination of the central and peripheral nervous systems, respectively. Treatment strategies such as enzyme replacement, substrate reduction, enzyme chaperones, and gene therapy have shown promise in LSDs. Unfortunately, Krabbe disease has been relatively refractory to most single-therapy interventions. Although hematopoietic stem cell transplantation can alter the course of Krabbe disease and is the current standard-of-care, it simply slows the progression, even when initiated in pre-symptomatic children. However, the recent success of combinatorial therapeutic approaches in small animal models of Krabbe disease and the identification of new pathogenic mechanisms provide hope for the development of effective treatments for this devastating disease. This review provides a brief history of Krabbe disease and the evolution of single and combination therapeutic approaches and discusses new pathogenic mechanisms and how they might impact the development of more effective treatment strategies.
Topics: Animals; Combined Modality Therapy; Disease Models, Animal; Enzyme Replacement Therapy; Galactosylceramidase; Galactosylceramides; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Leukodystrophy, Globoid Cell; Myelin Sheath; Sphingolipids
PubMed: 33766733
DOI: 10.1016/j.neulet.2021.135841 -
Neurology Nov 2022Pathogenic variants in the gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive...
Pathogenic variants in the gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.
Topics: Infant, Newborn; Humans; Male; Adrenoleukodystrophy; Consensus; Hematopoietic Stem Cell Transplantation; Adrenal Insufficiency; Neonatal Screening
PubMed: 36175155
DOI: 10.1212/WNL.0000000000201374 -
Acta Neuropathologica Sep 2017Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age,... (Review)
Review
Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies.
Topics: Axons; Demyelinating Diseases; Humans; Myelin Sheath; Neuroglia; White Matter
PubMed: 28638987
DOI: 10.1007/s00401-017-1739-1 -
International Journal of Molecular... Jun 2022Primary microglial leukodystrophy or leukoencephalopathy are disorders in which a genetic defect linked to microglia causes cerebral white matter damage. Pigmented... (Review)
Review
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 (colony stimulating factor receptor 1) cause CSF-1R-related leukoencephalopathy (CRP). Yet, recessive ALSP with ovarian failure linked to (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 or , identified as PLOSL1 and PLOSL2, respectively. TYROBP associates with receptors expressed in NK cells, B and T lymphocytes, dendritic cells, monocytes, macrophages, and microglia. 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.
Topics: Adult; Demyelinating Diseases; Humans; Leukoencephalopathies; Lipodystrophy; Microglia; Osteochondrodysplasias; Subacute Sclerosing Panencephalitis
PubMed: 35683020
DOI: 10.3390/ijms23116341 -
NeuroImage. Clinical 2023Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders... (Review)
Review
Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies.
Topics: Humans; Demyelinating Diseases; Magnetic Resonance Imaging; Myelin Sheath; White Matter; Axons
PubMed: 37150021
DOI: 10.1016/j.nicl.2023.103427 -
Frontiers in Cell and Developmental... 2022Leukodystrophies are a broad spectrum of neurological disorders that are characterized primarily by deficiencies in myelin formation. Clinical manifestations of... (Review)
Review
Leukodystrophies are a broad spectrum of neurological disorders that are characterized primarily by deficiencies in myelin formation. Clinical manifestations of leukodystrophies usually appear during childhood and common symptoms include lack of motor coordination, difficulty with or loss of ambulation, issues with vision and/or hearing, cognitive decline, regression in speech skills, and even seizures. Many cases of leukodystrophy can be attributed to genetic mutations, but they have diverse inheritance patterns (e.g., autosomal recessive, autosomal dominant, or X-linked) and some arise from mutations. In this review, we provide an updated overview of 35 types of leukodystrophies and focus on cellular mechanisms that may underlie these disorders. We find common themes in specialized functions in oligodendrocytes, which are specialized producers of membranes and myelin lipids. These mechanisms include myelin protein defects, lipid processing and peroxisome dysfunction, transcriptional and translational dysregulation, disruptions in cytoskeletal organization, and cell junction defects. In addition, non-cell-autonomous factors in astrocytes and microglia, such as autoimmune reactivity, and intercellular communication, may also play a role in leukodystrophy onset. We hope that highlighting these themes in cellular dysfunction in leukodystrophies may yield conceptual insights on future therapeutic approaches.
PubMed: 36003149
DOI: 10.3389/fcell.2022.902261 -
Molecular Genetics and Metabolism... Sep 2021Mitochondrial alanyl-tRNA synthetase 2 gene () related disease is a rare genetic disorder affecting mitochondrial metabolism, leading to severe cardiac disease in...
BACKGROUND
Mitochondrial alanyl-tRNA synthetase 2 gene () related disease is a rare genetic disorder affecting mitochondrial metabolism, leading to severe cardiac disease in infants or progressive leukodystrophy in young adults. The disease is considered ultra-rare with only 39 cases of AARS2-leukodystrophy previously reported.
CASE PRESENTATION
We present the case of a young man of consanguineous heritage suffering from cognitive decline and progressive spasticity as well as weakness of the proximal musculature. Utilizing MRI and whole genome sequencing, the patient was diagnosed with a homozygous missense variant (NM_020745.3:c.650C > T; p.(Pro217Leu)) and a homozygous variant (NM_000070.2: c.1469G > A; p.(Arg490Gln)), both variants have previously been identified in patients suffering from related leukodystrophy and limb-girdle muscular dystrophy, respectively.
CONCLUSIONS
This case report presents a case of homozygous AARS2 leukodystrophy and serves to highlight the importance of whole genome sequencing in diagnosing rare neurological diseases as well as to add to the awareness of adult onset leukodystrophies.
PubMed: 34285876
DOI: 10.1016/j.ymgmr.2021.100782