Diffuse central hypomyelination presenting as 4H syndrome caused by compound heterozygous mutations in POLR3A...

Area of Science:

• Neurogenetics
• Neuroimaging
• Rare Diseases

Background:

• 4H syndrome is a rare genetic disorder characterized by hypomyelination, hypogonadotropic hypogonadism, and hypodontia.
• Mutations in the POLR3A gene are a known cause of 4H syndrome, affecting myelin production.

Observation:

• A 33-year-old male with mental retardation and cerebellar ataxia presented with diffuse central hypomyelination on brain MRI.
• Clinical features included hypogonadotropic hypogonadism and hypodontia, consistent with 4H syndrome.
• Brain MRI revealed cerebellar and corpus callosum atrophy, diffuse hypomyelination extending to U-fibers, and T2 hyperintensity in the middle cerebellar peduncles.

Findings:

• Two compound heterozygous mutations in POLR3A (p.Met852Val and p.Asn1249His) were identified.
• Electrophysiological studies confirmed corticospinal tract involvement, while peripheral nerve conduction remained normal.
• The patient exhibited normal development until age 4-5, followed by gradual motor and cognitive deterioration after age 25.

Implications:

• This case illustrates that neurological dysfunction in 4H syndrome can manifest later in life, even with initially normal brain development.
• The findings suggest that subtle or not-yet-evident pathophysiological changes may underlie late-onset deterioration in hypomyelination disorders.
• Understanding the long-term clinical course is crucial for managing patients with 4H syndrome and similar genetic leukodystrophies.