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

E Jurkiewicz,D Dunin-Wąsowicz,G Bernard,D Gieruszczak-Białek,M Gutierrez,L Tran,K Guerrero,K Malczyk

doi:10.1007/s00062-015-0472-1

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.

Highlights

Hypomyelination, hypogonadotropic hypogonadism, and hypodontia is an autosomal recessive hypomyelinating disorder first reported in children and adults by Wolf et al and Timmons et al [1, 2]
Whole exome sequencing analysis is still ongoing in order to identify the etiology of the PMG and cataracts as these clinical features are hypothesized to be caused by a mutation(s) in a second gene
The two patients we investigated with mutations in POLR3B genes showed diffuse hypomyelination of the cerebral and cerebellar white matter, hypodontia, and cataracts

Summary

Introduction

Hypomyelination, hypogonadotropic hypogonadism, and hypodontia is an autosomal recessive hypomyelinating disorder first reported in children and adults by Wolf et al and Timmons et al [1, 2]. Mutations of the genes encoding POLR3 (RNA polymerase III) subunits POLR3A (POLR3A), subunit POLR3B (POLR3B) and POLR1C (POLR1C) have been identified as the genetic causes of this disorder [3, 8, 12,13,14,15,16,17,18]. It is suggested that mutations in POLR3A, POLR3B, and POLR1C lead to abnormal POLR3 function and abnormal production of proteins important for development of the central nervous system white matter [18, 20]

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