Hypomyelinating leukodystrophies — unravelling myelin biology

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. In this Review, Wolf et al. provide an overview of the hypomyelinating leukodystrophies and discuss how identification of the genes involved in these disorders have provided insight into the clinical presentations of these disorders and into myelin biology. Key points Myelination is a finely regulated process that involves interactions between oligodendrocytes, axons, astrocytes and microglia. Hypomyelinating leukodystrophies are a group of disorders characterized by primary lack of myelin deposition. Characteristic patterns on brain MRI can guide the diagnosis of hypomyelinating disorders; quantitative MRI techniques can provide measures of white matter myelin content with potential as biomarkers. The spectrum of clinical severity of hypomyelinating disorders is broad, ranging from mild to severe neurological impairment. The genetic causes of hypomyelinating leukodystrophies are diverse; the most important groups of affected proteins are structural myelin proteins and proteins involved in cellular processes such as transcription and translation. Improved understanding of hypo