Recessive Mutations in POLR3B Encoding RNA Polymerase III Subunit Causing Diffuse Hypomyelination in Patients with 4H Leukodystrophy with Polymicrogyria and Cataracts

Abstract

The diagnosis of 4H leukodystrophy (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) is based on clinical findings and magnetic resonance imaging (MRI). Recently, mutations of the genes encoding Pol III (RNA polymerase III) subunit A (POLR3A) and subunit B (POL3B) have been identified as the genetic causes of hypomyelination. We describe two Polish female siblings aged 5 and 10 years with compound heterozygous mutations in POLR3B. They both presented with similar clinical symptoms and MRI findings presenting as 4H leukodystrophy, and the association of polymicrogyria and cataract. According to our observation in young children with the absence of hypogonadotropic hypogonadism, brain MRI pattern is very essential in proper early diagnosis of 4H leukodystrophy. All clinical and radiological results are of course helpful, however genetic conformation is always necessary.

Keywords: 4H leukodystrophy; Cataract; Children; Hypomyelination; Magnetic resonance imaging; Polymicrogyria.

Fig. 1

Brain magnetic resonance imaging (MRI) of the patients. T2-weighted images. Case 1 is seen in A–L. The first column (A–F) shows the brain MRI at the age of 8 years while the second column (G–L)—the MRI at the age of 10 years. Case 2 is shown in M–Z. The third column (M–S) shows the brain MRI at the age of 3 years while the fourth column (T–Z) shows the MRI—at the age of 5 years. Coronal T2-weighted images demonstrated very thin and slightly myelinated optic radiation (arrow on G) and myelinated inferior colliculi (arrow on M). Typical hypointensity of the dentate nucleus is seen on axial T2-weighted images (arrow on B) more evident in the older girl (B, H). Note the hyperintense signal of the middle cerebellar peduncle (arrow on I) demonstrating hypomyelination of this structure. In the older girl axial images (C, I) mild atrophy of cerebellar hemispheres is seen with little progression over 2 years. Cerebellar hemispheres did not show atrophy in the younger girl (N, O, U, V). Diffuse hyperintensity of the cerebral white matter is seen on supratentorial axial images of the brain. Ventroanterolateral nucleus of the thalamus appeared hypointense (arrow, picture D). Posterior limbs of internal capsules are not myelinated. Mild enlargement of the lateral ventricles is visible. Corpus callosum is thin and unmyelinated on midline sagittal T2-weighted images of the older girl (F, L). Note atrophy of the vermis. Slight progression of the atrophy of the vermis is seen. Corpus callosum of the younger girl (S, Z) is also unmyelinated and thinned posteriorly (isthmus and splenium); slight progression of changes. Note prominent, but within normal limits, primary fissure of the vermis (arrow, picture Z), which remained unchanged over 2 years

Fig. 2

Sagittal (a), and coronal (b) T2-weighted images of case 1 showing irregularity of the frontal cortex with shallow sulci and numerous small gyri, consistent with polymicrogyria