The First Korean Siblings With Adult-Onset 4H Leukodystrophy Related to Nonsynonymous POLR3B Mutations

Hui-Jun Yang; Gyeongmin Park; Il Seong Nam-Goong; Jun-Woo Ahn; Young Cheol Weon

doi:10.1212/NXG.0000000000000667

The First Korean Siblings With Adult-Onset 4H Leukodystrophy Related to Nonsynonymous POLR3B Mutations

Neurol Genet. 2022 Apr 13;8(3):e667. doi: 10.1212/NXG.0000000000000667. eCollection 2022 Jun.

Authors

Hui-Jun Yang¹, Gyeongmin Park¹, Il Seong Nam-Goong¹, Jun-Woo Ahn¹, Young Cheol Weon¹

Affiliation

¹ Department of Neurology (H.-J.Y.), Department of Radiology (G.P., Y.C.W.), Department of Internal Medicine (I.S.N.-G.), and Department of Obstetrics and Gynecology (J.-W.A.), Ulsan University Hospital, University of Ulsan College of Medicine, South Korea.

Abstract

Objectives: 4H leukodystrophy is a rare autosomal recessive hypomyelinating disorder characterized by several combinations of motor dysfunction, abnormal dentition, and ophthalmic and endocrine abnormalities. To date, only a single Korean case report of pediatric leukodystrophy caused by the POLR1C sequence variation has been published, while there are no reports on the POLR3B, POLR3A, or POLR3K variants.

Methods: Genetic tests of Korean sibling pairs with primary amenorrhea due to normosmic isolated hypogonadotropic hypogonadism and cognitive or behavioral symptoms were performed by whole-exome sequencing (WES). The WES results were validated by direct Sanger sequencing.

Results: We identified biallelic variations in the POLR3B gene of p.Tyr685* and p.Tyr746Cys, which have not been associated with 4H leukodystrophy. Both sequence variants lie in the hybrid-binding domain of the protein RPC2. The protein structure analysis predicted that cysteine substitution of the phylogenetically conserved amino acid tyrosine can cause destabilization.

Discussion: The siblings reported are the first POLR3B-related hypomyelinating leukodystrophy cases in Korea. Our report expands the mutational spectrum of 4H leukodystrophy and suggests that it is mandatory to consider its diagnostic possibility in adult patients presenting with primary amenorrhea and mild cognitive or behavioral symptoms.