Phenotypic variability of GNE myopathy

Abstract

GNE myopathy is a rare autosomal recessive disease with an estimated prevalence of 1 in 1.000.000 worldwide. It is caused by mutation in GNE gene that encode, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), a rate limiting enzyme in the biosynthesis of Salic Acid. GNE myopathy classically manifests during adulthood as distal muscle weakness predominantly affecting anterior tibial muscles that later on involves other muscle groups. Another encountered phenotype is limb-girdle spectrum. Quadriceps muscles sparing is a characteristic findings promoting the diagnosis of GNE myopathy. We present two Middle Eastern siblings with atypical clinical presentation of GNE myopathy. Both patients presented with proximal muscle weakness involving quadriceps and significant myalgia that interfere with Activity of Daily Living. Serum CPK was elevated in both. Histopathological findings of muscle biopsy showed necrotic fibers with fiber size variation. Genetic testing showed homozygous mutation on GNE gene c.2228T>C (p.Met743Thr) on chromosome 9. The disease progression was more rapid in the younger brother who also had clinically stable Fanconi aplastic anemia status post allogenic bone marrow transplantation from his brother who has GNE myopathy. Intravenous immunoglobulin (IVIG) was started and showed modest effect mainly in the symptoms of weakness, pain and fatigue. In conclusion, we demonstrate that same genetic variants can present with variable phenotypes. Recognize a wide spectrum of GNE myopathy help early recognition of the disease hence allows providing the patients with trial of IVIG which might alleviate some of the patient symptoms and improved their quality of life.