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

Michael Zech*, Theresa Brunet, Matej Škorvánek, Astrid Blaschek, Katharina Vill, Britta Hanker, Irina Hüning, Vladimír Haň, Petra Došekova, Zuzana Gdovinová, Bader Alhaddad, Riccardo Berutti, Tim M. Strom, Evžen Růžička, Erik Jan Kamsteeg, Jasper J. van der Smagt, Matias Wagner, Robert Jech, Juliane Winkelmann

*Corresponding author for this work


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.

Original languageEnglish
JournalParkinsonism and Related Disorders
Pages (from-to)70-75
Number of pages6
Publication statusPublished - 08.2020

Research Areas and Centers

  • Research Area: Medical Genetics


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