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

Highlights

• Biallelic null variants are part of the genotypic spectrum associated with SPG75.

• SPG75 can manifest with prominent ataxic presentations.

• This is the first report to show a link between MAG mutations and dystonia.

• Loss of myelin-associated glycoprotein causes severe neurologic disease.

Abstract

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.

Introduction

The large-scale application of genomic analysis techniques is transforming Mendelian disease-gene discovery, especially in the field of neurology. Nonetheless, many of the newly defined genetic entities are extraordinarily rare, limiting our understanding of the associated variant spectra and phenotypic presentations [1]. Following the description of MAG as a candidate gene in a single family with a complex spastic disorder [2], Lossos and colleagues [3] reported the identification of a homozygous MAG missense variant in the offspring of a consanguineous union. The latter demonstrated a combination of neurodevelopmental delay, ataxic features, neuropathy, and prominent spastic para-/tetraparesis [3], resulting in the assignment of MAG as a locus for autosomal-recessive hereditary spastic paraplegia (SPG75, OMIM*616680). More recently, three distinct missense mutations in MAG were uncovered in two SPG75-affected pedigrees [4,5], implying allelic heterogeneity in MAG-associated disease. Although cellular and molecular-modeling studies have suggested that the disease-related MAG missense variants lead to loss of protein function [3,4], the mutational mechanisms contributing to SPG75 have not yet been sufficiently elucidated. Herein, we describe the first recessive null-allele variants in MAG, detected by whole-exome sequencing (WES) in four independent families. We review the clinical manifestations of the previously published and newly diagnosed cases with SPG75. Our data reinforce the importance of MAG in nervous system development and function and add to the phenotypic delineation of a pediatric syndrome caused by biallelic perturbation of this gene.