Hypomyelination

Hypomyelination is a condition in which myelin, the fatty sheath that insulates nerve fibers, is underdeveloped or inadequately maintained in the central nervous system (CNS), and less commonly in the peripheral nervous system (PNS). It is distinct from demyelination, where previously formed myelin is lost, and from dysmyelination, where myelin is abnormally formed. Hypomyelination typically presents in infancy or early childhood and can be static or, in some genetic disorders, progressively worsening.

Most cases are genetic and fall under the umbrella of hypomyelinating leukodystrophies. These disorders result from defects in genes involved in oligodendrocyte development, myelin lipid metabolism, or myelin structure. Examples include mutations in PLP1, POLR3A, POLR3B, and TUBB4A, among others. Non-genetic contributors may include perinatal brain injury, certain metabolic disorders, or infections that disrupt myelin formation during development. The exact course and severity depend on the underlying cause and can range from mild motor or cognitive impairment to severe disability.

Clinical features are variable but commonly include developmental delay, hypotonia in infancy followed by spasticity or ataxia, abnormal eye movements such as nystagmus, speech and language difficulties, and seizures in some cases. The progression may be slow and relatively stable in some conditions, while others show gradual decline.

Diagnosis relies on clinical assessment supported by neuroimaging and genetic testing. MRI typically shows diffuse, symmetric white matter abnormalities with signals indicative of reduced or delayed myelination for age. Serial imaging may reveal limited progression of myelination. Genetic testing, often whole-exome sequencing, helps identify the specific hypomyelinating disorder.

Treatment is supportive and multidisciplinary, focusing on rehabilitation, management of seizures if present, and addressing developmental and educational needs. Genetic counseling is recommended for affected families. Prognosis varies widely by subtype and can range from mild impairment to severe lifelong disability.