General description

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC)), also known as hypomyelinating leukodystrophy 6 (HLD6), is a autosomal dominant inheritance disorder caused by a heterozygous mutation in the TUBB4A gene, which encodes tubulin β-4A, a protein specifically expressed in the brain. Tubulin plays a crucial role in the formation and maintenance of neurons, and mutations in TUBB4A lead to microtubule dysfunction in neurons and oligodendrocytes. This dysfunction secondarily results in gliocyte impairment and defective myelination.

The disease typically manifests before the age of three, with both intellectual and motor development being delayed. Motor impairments commonly include hypotonia, nystagmus, dystonia, and rigidity, while intellectual disability, though frequent, is generally milder than the motor deficits. Seizures may also occur.

The c.745G>A variant is the most common and is associated with a milder presentation compared to other variants. However, spastic paralysis, cerebellar ataxia, and dystonia are observed regardless of the specific mutation.