GNE Myopathy: Genotype - Phenotype Correlation and Disease Progression in an Indian Cohort

Abstract

Introduction: GNE myopathy is a rare slowly progressive adult-onset distal myopathy with autosomal recessive inheritance. It has distinctive features of quadriceps sparing with preferential anterior tibial involvement. Most patients eventually become wheelchair bound by 10-20 years after onset. This study analyzes the phenotype-genotype characteristics and disease progression in a large cohort of GNEM patients from India.

Materials and methods: Retrospective observational study on GNEM from a quaternary neurology referral hospital in southern India. Data was collected from clinical phenotyping, serum creatine kinase levels, muscle biopsy histopathology, genetic analysis and functional assessment scales - IBMFRS and MDFRS.

Results: 157 patients were included with mean age at onset and diagnosis: 26.5±6.2 years and 32.8±7.8 years, respectively. M:F ratio was 25 : 13. Most common presenting symptom: foot drop (46.5%) and limb girdle weakness (19.1%). Wasting and weakness of small muscles of hand and finger flexors seen in 66.2% and as an initial symptoms in 5.2%. Though tibialis anterior involvement was most common (89.2%), early quadriceps weakness was noted in 3.2% and Beevor's sign in 59.2%. Rimmed vacuoles were present in 75% of patients with muscle biopsy. Most common variant was the Indian Founder variant identified in 129 patients (c.2179 G>A, p.Val727Met - 82.2%) and most common zygosity being compound heterozygous state (n = 115, 87.5%). Biallelic kinase domain variations predisposed to a more severe phenotype. Wheelchair bound state noted in 8.9% with a mean age and duration of 32.0±7.1 and 6.3±4.9 years respectively, earlier than previous studies on other ethnic groups.

Conclusion: This is the largest GNEM cohort reported from South Asia. The p.Val727Met variant in compound heterozygous state is noted in majority (82.2%) of the cases. Observed relationships between genotype and clinical parameters shows that severity of the disease might be attributable to specific GNE genotype and thus could aid in predicting the disease progression.

Keywords: GNE myopathy; India; disease progression; genotype-phenotype; hIBM.

Fig. 1

Types of zygosity – Pie-chart showing the various zygosities and most common pathogenic variants in each category. Parentheses next to the variant shows allele frequency. “n” represents number of patients in each zygosity.

Fig. 2

Exon distribution of various pathogenic variants and mutation spectrum – A – Exons are represented as rectangular boxes with respective exonic numbers (Transcript ID: NM_001128227.3). White boxes at the ends represent untranslated regions (UTRs). The novel variants are highlighted in bold. ‘X’n represents number of individuals carrying the variant. SE – skipped exon, Het-Heterozygous, Hom-Homozygous, C.Het – Compound heterozygous. Size of exons /introns is not represented at scale. B – hGNE2 protein structure.: Gray UF - unknown function, vertical lined box denote putative nuclear export signal (NES) and dotted box denote experimental allosteric region (AR) for CMP-sialic acid binding. Light grey boxes denote UDP-GlcNAc 2-epimerase and dark grey denote ManNAc kinase domains. Amino acid numbering is indicated below the structure.