GNE myopathy in Roma patients homozygous for the p.I618T founder mutation

Highlights

• In the Bulgarian Roma/Gypsy population p.I618T is the founder mutation accounting for 99% of mutant alleles.

• Distal muscle weakness in upper limbs was the initial presentation of the disease in three of our patients.

• Genetic modifying factors possibly account for significant variation in disease severity among the affected.

Abstract

GNE myopathy is an autosomal-recessive disorder caused by mutations in the GNE gene, encoding the key enzyme in the sialic acid biosynthetic pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase. We studied 50 Bulgarian Roma patients homozygous for p.I618T, an ancient founder mutation in the kinase domain of the GNE gene, dating before the Gypsy exodus from North West India. The clinical features in the Bulgarian GNE group can be described with disease onset mostly in the third decade, but in individual cases, onset was as early as 10 years of age. The majority of patients had foot drop as the first symptom, but three patients developed hand weakness first. Muscle weakness was early and severe for the tibialis anterior, and minimal or late for quadriceps femoris, and respiratory muscles were only subclinically affected even in the advanced stages of the disease. During a 15-year follow-up period, 32 patients became non-ambulant. The average period between disease onset and loss of ambulation was 10.34 ± 4.31 years, ranging from 3 to 20 years. Our analysis of affected sib pairs suggested a possible role of genetic modifying factors, accounting for significant variation in disease severity.

Introduction

GNE myopathy, also known as distal myopathy with rimmed vacuoles (DMRV), Nonaka myopathy, hereditary inclusion body myopathy (HIBM) or inclusion body myopathy (IBM2), is an autosomal-recessive (AR) disorder with juvenile to adult onset and slow progression. It affects initially the tibialis anterior muscle and spares the quadriceps femoris [1], [2], [3].

The disorder is caused by mutations in the GNE gene, encoding the key enzyme in the sialic acid biosynthetic pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase [4], [5]. GNE myopathy has a pan-ethnic distribution and is particularly frequent in the Persian Jewish community and in Japan with strong contributions of founder mutations [6], [7], [8], [9], [10], [11], [12], [13]. Recently common mutations have also been described in the North of Britain [14].

Most reported cases are compound heterozygotes carrying mutations in the epimerase or the kinase domains of the gene. A limited number of founder mutations that facilitate genotype–phenotype correlations have been discovered so far. The amino acid substitution, p.M743T, was first described in Persian Jews with a prevalence of ~1:1500 [15], [16], [17] and subsequently found to be common across the Middle East (in Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin) [16]. In Japanese patients, p.V603L was identified as the most common founder mutation, accounting for about 60% of mutant alleles [6], [18], while p.D207V was discovered as the second most common defect in this population.

The Roma/Gypsies are a young isolate of Asian ancestry with strong founder effects and numerous population-specific AR mutations identified to-date [19]. In this study, we present 50 Roma patients homozygous for the p.I618T founder mutation in the kinase domain of the GNE gene. We describe the phenotypic spectrum of the GNE myopathy in this large genetically homogeneous group of patients.