Case of the Week

Background:

• POLR3-related leukodystrophies are a group of autosomal recessive hypomyelinating leukodystrophies caused by biallelic mutations in 1 of the 3 genes: POLR3A, POLR3B, and POLR1C. These genes basically encode for subunits of RNA polymerase III.

Clinical Presentation:

• Typically, patients present with 4 major clinical findings (which may be in varying degrees of presentation):
  • neurologic dysfunction
  • abnormal dentition
  • hypogonadotrophic hypogonadism
  • ocular abnormalities.
• The classic neurologic findings are slowly progressive intellectual disability and prominent cerebellar signs.

Key Diagnostic Features:

• Diffuse cerebral hypomyelination manifesting as diffuse T2/FLAIR hyperintensity
• Relative T2 hypointensity of basal ganglia, dentate nuclei, anterolateral thalami, and pyramidal tracts in the posterior limbs of internal capsules
• Cerebellar atrophy (notably vermian atrophy)
• Hypoplasia of corpus callosum

Differential Diagnoses:

• Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC): Early atrophy of basal ganglia is characteristic (especially putamen).
• Hypomyelination with congenital cataract (HCC): Clinical presence of cataracts; neuroimaging findings of marked periventricular T2 hyperintensity demonstrating corresponding T1-weighted hypointensity; cerebellar atrophy is rare.
• Pelizaeus Merzbacker disease: Homogeneous cerebral T2 hyperintense hypomyelination; early cerebellar atrophy is less common.

Treatment:

• Cell transplantation therapy, gene transfer therapy, and gene editing techniques are under research for the treatment of POLR3-related leukodystrophies.