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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; Bakhtiari, S; AlSayed, MD; Rahbeeni, Z; et al. Chelban, V; Alsagob, M; Kloth, K; Chirita-Emandi, A; Vandrovcova, J; Maroofian, R; Davagnanam, I; Bakhtiari, S; AlSayed, MD; Rahbeeni, Z; AlZaidan, H; Malintan, NT; Johannsen, J; Efthymiou, S; Ghayoor Karimiani, E; Mankad, K; Al-Shahrani, SA; Beiraghi Toosi, M; AlShammari, M; Groppa, S; Haridy, NA; AlQuait, L; Qari, A; Huma, R; Salih, MA; Almass, R; Almutairi, FB; Hamad, MH; Alorainy, IA; Ramzan, K; Imtiaz, F; Puiu, M; Kruer, MC; Bierhals, T; Wood, NW; Colak, D; Houlden, H; Kaya, N (2020) Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination. Eur J Neurol, 27 (2). pp. 334-342. ISSN 1468-1331 https://doi.org/10.1111/ene.14082
SGUL Authors: Maroofian, Reza

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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.

Item Type: Article
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/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: NKX6-2, SPAX8, hypomyelination, leukodystrophy, spastic ataxia 8, hypomyelination, leukodystrophy, NKX6-2, spastic ataxia 8, SPAX8, 1103 Clinical Sciences, 1109 Neurosciences, Neurology & Neurosurgery
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Eur J Neurol
ISSN: 1468-1331
Language: eng
Dates:
DateEvent
7 January 2020Published
17 October 2019Published Online
21 August 2019Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
UNSPECIFIEDBritish Neurological Surveillance Unit (BNSU)UNSPECIFIED
UNSPECIFIEDNational Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
14-MED2007-20King Abdulaziz City for Science and Technologyhttp://dx.doi.org/10.13039/501100004919
RAC#2120022King Faisal Specialist Hospital and Research Centrehttp://dx.doi.org/10.13039/501100002382
NS083739National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
RGP-VPP-301Deanship of Scientific Research, King Saud University, RiyadhUNSPECIFIED
MR/J004758/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0802760Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G1001253Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
WT093205MAWellcome Trusthttp://dx.doi.org/10.13039/100004440
WT104033/Z/14/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
UNSPECIFIEDAtaxia UKhttp://dx.doi.org/10.13039/501100000346
PubMed ID: 31509304
Web of Science ID: WOS:000490756800001
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111215
Publisher's version: https://doi.org/10.1111/ene.14082

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