Hypomyelinating leukodystrophies - unravelling myelin biology.

摘要

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.