hypomyelinating

Hypomyelinating describes a pattern of abnormal brain development in which the formation of the myelin sheath around axons is reduced or absent, resulting in insufficient myelination of the central nervous system white matter. It is contrasted with demyelinating diseases, where myelin is lost after normal development, and with dysmyelination, where myelin is abnormally formed from the start. Hypomyelination can be congenital or acquired in early life and often underlies a class of genetic disorders collectively known as hypomyelinating leukodystrophies (HLs).

Myelin is produced by oligodendrocytes in the central nervous system; in hypomyelination, myelin production is delayed or reduced, leading to persistent anomalies on MRI. Common imaging features include diffuse or focal T2 hyperintensity in white matter with relatively reduced progression of T1 signal maturation for age; the pattern may vary by gene and developmental stage.

Genetic forms of hypomyelinating disorders include Pelizaeus–Merzbacher disease (PLP1) and POLR3-related leukodystrophies, such as 4H syndrome (hypomyelination, hypodontia, and hypogonadotropic hypogonadism) caused by POLR3A or POLR1C mutations. The spectrum is broad and encompasses several related conditions with varying severity and onset.

Clinically, affected individuals commonly present with developmental delay, motor dysfunction (early hypotonia with later spasticity), ataxia, nystagmus, and language or cognitive impairment; seizures may occur in some cases. Diagnosis relies on MRI features and targeted genetic testing; brain biopsy is rarely needed. Management is supportive and multidisciplinary, including physical, occupational, and speech therapies, management of seizures and other comorbidities, and genetic counseling.