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Zech, M. ; Brunet, T.* ; Škorvánek, M.* ; Blaschek, A.* ; Vill, K.* ; Hanker, B.* ; Hüning, I.* ; Haň, V.* ; Došekova, P.* ; Gdovinová, Z.* ; Alhaddad, B.* ; Berutti, R. ; Strom, T.M.* ; Růžička, E.* ; Kamsteeg, E.J.* ; van der Smagt, J.J.* ; Wagner, M. ; Jech, R.* ; Winkelmann, J.

Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia.

Parkinsonism Relat. Disord. 77, 70-75 (2020)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
Introduction:The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation.Methods: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed.Results: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date.Conclusions: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mag ; Loss-of-function Variants ; Ataxia ; Spastic Paraplegia ; Dystonia; Diagnosis; Mutation; Disease
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 1353-8020
e-ISSN 1873-5126
Journal Parkinsonism & Related Disorders
Quellenangaben Volume: 77, Issue: , Pages: 70-75 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
G-503292-001
Grants internal research program at Helmholtz Zentrum Munchen, Munich, Germany ("Physician Scientists for Groundbreaking Projects")
Slovak Research and Grant Agency
Slovak Grant and Development Agency
European Joint Programme on Rare Diseases (EJP RD COFUND-EJP)
Czech Ministry of Education
Charles University, Prague, Czech Republic
Helmholtz Zentrum Munchen, Munich, Germany
Technische Universitat Munchen, Munich, Germany
DOI 10.1016/j.parkreldis.2020.06.027
WOS ID WOS:000578015000016
Scopus ID 85087294875
Erfassungsdatum 2020-07-23
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