Nonaka Myopathy: First Report of a Rare Mutation from India (c.1571C>T)

Introduction

Glucosamine N-acetylmannosamine kinase (GNE) myopathy, also known as Nonaka myopathy or hereditary inclusion body myopathy (HIBM), is a rare and progressive autosomal recessive disorder caused by mutations in the GNE gene.¹ In 1981, Ikuya Nonaka and colleagues described a rare distal myopathy with rimmed vacuoles and lamellar body depositions called distal myopathy with rimmed vacuoles (DMRV) or Nonaka myopathy.² In 2001, the Mitrani-Rosenbaum group identified mutations in the GNE gene, which encodes N-acetylglucosamine epimerase/GNE.³

Case Report

A 22-year-old male presented with progressive quadriparesis for 7 years. He was born of a nonconsanguineous marriage and had an uneventful perinatal and neonatal period. He remained healthy until the age of 15, when he began to lag behind his cousins while walking. He subsequently developed difficulty in clearing the ground while walking, frequent tripping, and an inability to retain his footwear. Over the next 2 years, he developed difficulty in gripping objects with his hands. There was no history suggestive of proximal upper limb weakness, voice change, dysarthria, dysphagia, visual complaints, or facial weakness.

On examination, the patient was moderately built. Higher mental functions were intact. Neck weakness was present. Shoulder strength was normal, while weakness was observed across all the muscles at the elbow and small muscles of the upper limbs symmetrically. Wasting of the small muscles of the hand was noted. The lower limbs had significant weakness at the hip and ankle. The patient was noted to have bilateral foot drop.

A workup revealed normal haemogram, liver and kidney function tests. Creatine phosphokinase (CPK) levels were within normal limits. Electromyography (EMG) was suggestive of a myopathic pattern in both proximal and distal muscles of the upper and lower limbs. Protein electrophoresis and vasculitic profile were unremarkable. A muscle biopsy could not be performed. After obtaining a written consent, the genetic analysis was sent to MedGenome Laboratories. Whole-exome sequencing (WES) showed a heterozygous missence mutation on Exon 9 of the GNE gene on chromosome 9 (c.1571C>T), classified as pathogenic. This resulted in an amino acid substitution of valine for alanine at codon 524 (p.Ala524Val).

Discussion

The observed variation lies within the regulator of optimum kinases (ROK) family domain of the GNE protein. Early-onset cases of GNE myopathy are rare,¹ generally manifesting in the third decade of life. However, earlyonset cases before the age of 10 and late-onset cases in the fifth decade of life have also been reported.⁴ The primary presentation of the disease is foot drop. Progressively, the patient develops weakness in the hamstrings and hips. However, characteristic sparing of the quadriceps is noted. Investigations may reveal a normal or mildly increased creatine kinase (CK) level. The clinical and biochemical findings of the present case were comparable to those of previously reported cases. Magnetic resonance imaging (MRI) may show short tau inversion recovery (STIR) hyperintensity with fatty infiltration in the affected muscles. Muscle biopsy may show rimmed vacuoles, fibre size variation, amyloid deposition, endomysial fibrosis, and 14–18 nm filamentous inclusions, without inflammatory infiltrates. The patient declined muscle biopsy due to personal reasons.

More than 1,000 individuals with GNE myopathy and about 255 GNE variants have been reported worldwide. Most of the pathogenic variants are missense mutations. Other less common mutations include insertions, deletions, large deletions, intronic mutations, and splice-site mutations. Diagnosis of GNE myopathy is confirmed by homozygous or compound heterozygous GNE gene mutations.¹

Thirty-one patients with undiagnosed genetic myopathies in the Indian subcontinent were found to harbour a pathogenic GNE mutation. In a review of 207 genetic myopathies from the Indian subcontinent, GNE mutations contributed to 28% of cases.⁵ The c.2179G>A (p.Val727Met) variant is a common mutation in India, identified in approximately 75% of GNE-myopathy patients in a reported Indian cohort. It also accounts for 32.7% of all GNE mutations reported in Indian studies, supporting p.Val727Met as a likely founder mutation in the Indian subcontinent.

Khadilkar et al. have recently documented an interesting occurrence of homozygous mutation c.1853T>C (p.I618T) (24.5%) in the Rajasthani Jain and Maheshwari communities, a founder mutation encountered exclusively in European Roma Gypsies.^6,7 The present mutation was previously reported in a single patient from mainland China.⁸

Declarations

Informed consent: Written informed consent was taken from the patient.

Conflict of interest: Nil.