The Leukodystrophies

Abstract

Leukodystrophies are a group of genetically determined disorders that affect development or maintenance of central nervous system myelin. Leukodystrophies have a reported incidence of 1 in 7500 live births, but fewer than half of patients receive a specific diagnosis. In this review, the authors discuss types of leukodystrophies: their prevalence, clinical presentation, symptoms, and diagnosis, as well as current and future treatments. Diagnosis is based on a combination of history, exam, radiological, and laboratory findings, including genetic testing. Leukodystrophies can present at any age from infancy to adulthood, with variability in disease progression and clinical presentation, ranging from developmental delay to seizures to spasticity. Although there are few cures, there are significant opportunities for care and improvements in patient well-being. Their high prevalence, combined with rapid advances in imaging, genetics, and potential treatments, makes an understanding of the leukodystrophies necessary for care providers in genetics and neurology.

Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity

“…We also found that lysosphingolipids accumulating in other LSDs [22, 31, 47–55, 123–127] had similar effects as Psy on lysosomal function. Exposure to sublethal concentrations of GluSph, lyso-SF, or LacSph caused increases in neutral lipid and phospholipid accumulation, endocytic transport time, cathepsin activity, and lysosomal pH.…”

“…Some of these lipids appear to have been only rarely studied for their effects on cell function in vitro (lyso-SF, GluSph, LacSph, LacCer) [119]. In the case of Gaucher disease, the majority of previous in vitro studies appears to have focused on GlcCer, and studies on both GlcCer and GlcSph often have required lipid concentrations severalfold greater than those at which Psy’s effects were observed (e.g., [22, 50, 51, 53, 55, 120–122]).…”

“…Such diseases include Krabbe disease (KD), metachromatic leukodystrophy (MLD), and Gaucher disease [22, 31, 47–55]. Although each of these diseases is associated with accumulation of a different lipid (or lipids) and with different disease pathologies, the effects of these lipids on cellular function are severe enough to suggest that such toxicities may contribute to disease pathogenesis.…”

Diversity Matters: A Revised Guide to Myelination

“…trauma), but leukodystrophy refers only to myelin disorders that arise from known genetic defects. This lack of consensus recently prompted a panel of experts in the field to achieve common definitions and classifications [104,105]. One of the major obstacles to a clear definition is the fact that, for a large proportion of pathologies, the triggering cause is unknown, and many of these disorders still lack clinical categorization; often, magnetic resonance image analysis is the only tool that clinicians can use to provide a diagnosis [106,107].…”

The use of targeted genomic capture and massively parallel sequencing in diagnosis of Chinese Leukoencephalopathies

“…It contains acquired leukoencephalopathy123 (leukoencephalopathy induced by ischemia, hypoxia, intoxication, infection, traumatic brain injuries, etc. ), genetic leukoencephalopathy456 (such as metachromatic leukodystrophy, globoid cell leukodystrophy, X-linked adrenoleukodystrophy, etc.) In addition, it also contains some mitochondrial diseases, cerebral cortical degenerative disorders, and so on.…”