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Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination

Chelban, V; Alsagob, M; Kloth, K; Chirita-Emandi, A; Vandrovcova, J; Maroofian, R; Davagnanam, I; ... Kaya, N; + view all (2019) Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination. European Journal of Neurology 10.1111/ene.14082. (In press). Green open access

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Abstract

BACKGROUND AND PURPOSE: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. METHODS: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided. RESULTS: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. CONCLUSIONS: NKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels.

Type: Article
Title: Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/ene.14082
Publisher version: https://doi.org/10.1111/ene.14082
Language: English
Additional information: © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).
Keywords: hypomyelination, leukodystrophy, NKX6‐2, spastic ataxia 8, SPAX8
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10085115
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