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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 möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Mag ; Loss-of-function Variants ; Ataxia ; Spastic Paraplegia ; Dystonia; Diagnosis; Mutation; Disease
ISSN (print) / ISBN 1353-8020
e-ISSN 1873-5126
Zeitschrift Parkinsonism & Related Disorders
Quellenangaben Band: 77, Heft: , Seiten: 70-75 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen 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