Genetic testing of leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants

Nejat Mahdieh,Ali Reza Tavasoli,Alfried Kohlschütter,Mahmoud Reza Ashrafi,Ali Rabbani,Mahdieh Soveizi,Bahareh Rabbani

doi:10.1038/s41598-021-82778-0

Abstract

This study evaluates the genetic spectrum of leukodystrophies and leukoencephalopathies in Iran. 152 children, aged from 1 day to 15 years, were genetically tested for leukodystrophies and leukoencephalopathies based on clinical and neuroradiological findings from 2016 to 2019. Patients with a suggestive specific leukodystrophy, e. g. metachromatic leukodystrophy, Canavan disease, Tay-Sachs disease were tested for mutations in single genes (108; 71%) while patients with less suggestive findings were evaluated by NGS. 108 of 152(71%) had MRI patterns and clinical findings suggestive of a known leukodystrophy. In total, 114(75%) affected individuals had (likely) pathogenic variants which included 38 novel variants. 35 different types of leukodystrophies and genetic leukoencephalopathies were identified. The more common identified disorders included metachromatic leukodystrophy (19 of 152; 13%), Canavan disease (12; 8%), Tay-Sachs disease (11; 7%), megalencephalic leukodystrophy with subcortical cysts (7; 5%), X-linked adrenoleukodystrophy (8; 5%), Pelizaeus–Merzbacher-like disease type 1 (8; 5%), Sandhoff disease (6; 4%), Krabbe disease (5; 3%), and vanishing white matter disease (4; 3%). Whole exome sequencing (WES) revealed 90% leukodystrophies and genetic leukoencephalopathies. The total diagnosis rate was 75%. This unique study presents a national genetic data of leukodystrophies; it may provide clues to the genetic pool of neighboring countries. Patients with clinical and neuroradiological evidence of a genetic leukoencephalopathy should undergo a genetic analysis to reach a definitive diagnosis. This will allow a diagnosis at earlier stages of the disease, reduce the burden of uncertainty and costs, and will provide the basis for genetic counseling and family planning.

Highlights

Leukodystrophies and genetic leukoencephalopathies are a large heterogeneous group of genetic diseases affecting the white matter of the central nervous system
The single diseases are rare, but overall they affected 1 per 7663 live births, in a US American s tudy[1]; the estimated prevalence of leukodystrophies is about 1–2/100,000 live births in G ermany[2]. Most of these diseases are associated with severe progressive functional losses of motor and cognitive abilities, helplessness and early death. Their causes are either related to primary defects of myelin synthesis and myelin stability, but myelin damage may be secondary to disturbances outside this structure[3]
The distribution of the more common referred diseases among the patients was as follows: 25 patients clinically diagnosed with MLD9, 13 CD, 10 PMLD, 6 PMD, 2 PMD or PMLD, 12 TSD, 10 X-ALD, 8 SHS, 8 MLC1 gene (MLC), 3 Alexander disease (AxD), 3 Krabbe disease (KD), 4 hypomyelination and congenital cataract (HCC; Hypomyelinating Leukodystrophy 5; HLD5; MIM 253260), 1 Sialic disease, 1 RNAse T2 deficient leukoencephalopathy (MIM 612951), and 2 biotinidase deficiency (MIM 253260)

Summary

Introduction

Leukodystrophies and genetic leukoencephalopathies are a large heterogeneous group of genetic diseases affecting the white matter of the central nervous system. The single diseases are rare, but overall they affected 1 per 7663 live births, in a US American s tudy[1]; the estimated prevalence of leukodystrophies is about 1–2/100,000 live births in G ermany[2]. Most of these diseases are associated with severe progressive functional losses of motor and cognitive abilities, helplessness and early death. Pediatric Neurology Division, Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. Pediatric Neurology Division, Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. 4Department of Pediatrics, University Medical Center Hamburg Eppendorf, Hamburg, Germany. 5Iranian Comprehensive Hemophilia Care Center, Tehran, Iran. *email: baharehrabbani@

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