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Neurol Genet. 2019 Feb 1;5(1):e308. doi: 10.1212/NXG.0000000000000308. eCollection 2019 Feb.

GNE genotype explains 20% of phenotypic variability in GNE myopathy.

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Institute of Genetic Medicine (O.P., I.J.W.), Newcastle University, Newcastle upon Tyne, United Kingdom; Ultragenyx Pharmaceutical (H.M.), CA; Department of Neurology (Z.A.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neuromuscular Research (I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neuropediatrics and Muscle Disorders (H.L.), Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany; Centro Nacional de Análisis Genómico (CNAG-CRG) (H.L.), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Catalonia, Spain; and Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa, Ottawa, Canada and Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.



To test the hypothesis that common GNE mutations influence disease severity; using statistical analysis of patient cohorts from different countries.


Systematic literature review identified 11 articles reporting 759 patients. GNE registry data were used as a second data set. The relative contributions of the GNE mutations, homozygosity, and country to the age at onset were explored using linear modeling, and relative importance measures were calculated. The rate of ambulation loss for GNE mutations, homozygosity, country, and age at onset was analyzed using Cox proportional hazards models.


A spectrum of symptoms and large variability of age at onset and nonambulatory status was observed within families and cohorts. We estimated that 20% of variability is explained by GNE mutations. Individuals harboring p.Asp207Val have an expected age at onset 8.0 (s.e1.0) years later than those without and probability of continued ambulation at age 40 of 0.98 (95% confidence interval [CI] 0.96-1). In contrast, p.Leu539Ser results in onset on average 7.2 (s.e.2.7) years earlier than those without this mutation, and p.Val603Leu has a probability of continued ambulance of 0.61 (95% CI 0.50-0.74) at age 40, but has a nonsignificant effect on age at onset.


GNE myopathy severity significantly varies in all cohorts, with 20% of variability explained by the GNE mutation. Atypical symptoms and clinical presentation suggest that physical and instrumental examination should include additional clinical tests. Proven and measurable effect of GNE mutations on the disease severity should be factored in patient management and clinical research study for a better data interpretation.

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