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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)

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Open Access Green as soon as Postprint is submitted to ZB.

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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

Corresponding Author

Keywords Mag ; Loss-of-function Variants ; Ataxia ; Spastic Paraplegia ; Dystonia; Diagnosis; Mutation; Disease

ISSN (print) / ISBN 1353-8020

e-ISSN 1873-5126

Journal Parkinsonism & Related Disorders

Quellenangaben Volume: 77, Pages: 70-75

Publisher Elsevier

Publishing Place The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

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