Two recurrent mutations are associated with GNE myopathy in the North of Britain

Abstract

Objective: GNE myopathy is a rare recessive myopathy associated with inclusion bodies on muscle biopsy. The clinical phenotype is associated with distal muscle weakness with quadriceps sparing. Most of the current information on GNE myopathy has been obtained through studies of Jewish and Japanese patient cohorts carrying founder mutations in the GNE gene. However, little is known about GNE myopathy in Europe where the prevalence is thought to be very low.

Methods: Patients were referred through the National Specialist Commissioning Team service for limb-girdle muscular dystrophies at Newcastle (UK). All patients harbouring mutations in the GNE gene were recruited for our study. Detailed clinical and genetic data as well as muscle MRIs and muscle biopsies were reviewed.

Results: We identified 26 patients harbouring mutations in the GNE gene. Two previously reported mutations (c.1985C>T, p.Ala662Val and c.1225G>T, p.Asp409Tyr) were prevalent in the Scottish, Northern Irish and Northern English populations; with 90% of these patients carrying at least one of the two mutations. Clinically, we confirmed the homogenous pattern of selective quadriceps sparing but noted additional features like asymmetry of weakness at disease onset.

Conclusions: GNE myopathy is an important diagnosis to consider in patients presenting with distal leg muscle weakness. We report, for the first time, two common mutations in the north of Britain and highlight the broader spectrum of clinical phenotypes. We also propose that the prevalence of GNE myopathy may be underestimated due to the frequent absence of rimmed vacuoles in the muscle biopsy.

Keywords: GENETICS; INCL BODY MYOSITIS; MUSCLE DISEASE; MYOPATHY; NEUROMUSCULAR.

Figure 1. Geographical distribution of GNE myopathy patients referred to Newcastle between 1987 and 2012

A total of 87 full GNE gene screens have been performed in Newcastle since September 2010. 64% of the 87 referrals were from England, 14% were from Northern Ireland and 13% were from Scotland. The remaining referrals were from abroad. The majority of genetically confirmed GNE myopathy patients were referred from the North of Britain (Scotland, Northern Ireland and Northern England) with the highest numbers seen in Northern Ireland and Scotland.

Figure 2. T1-weighted MR images of 6 GNE myopathy patients.

Evidence of quadriceps sparing in all patients with distal involvement of muscles in the anterior and posterior compartments. (A) Patient 15. Severe atrophy of both glutei maximi muscles (*). Left peroneus longus seems relatively spared in the left lower leg more than right (arrow). (B) Patient 10. Asymmetrical atrophy of rectii femoris muscles (arrows). (C) Patient 16. Early involvement of glutei minimi (arrows) with sparing of glutei maximi muscles. (D) Patient 19. Bilateral atrophy of iliopsoas, pectineus, adductor brevis and longus muscles (arrows). (E) Patient 9. Early atrophy of rectus femorii and vastus intermedius muscles (arrows). (F) Patient 5. Atrophy of tensor fascia lata muscles bilaterally (arrows).

Figure 3. Evidence of myopathic features in tibialis anterior but not in quadriceps femoris.

H&E stained sections from patient 2. A. Quadriceps femoris muscle ×100: normal appearance. B. Tibialis anterior muscle ×200: occasional necrotic fibres, fibre splitting, atrophic fibre, internal nuclei