Clinical Spectrum and Phenotypic Variability of GNE Myopathy: Insights from Two Sibling Cases

Dr. B Sandeep, Dr. Veena Narisetty

Abstract: Background: GNE myopathy (GNEM), also known as hereditary inclusion body myopathy (HIBM), distal myopathy with rimmed vacuoles (DMRV), or Nonaka myopathy, is a rare autosomal recessive myopathy caused by biallelic pathogenic variants in the GNE gene, which encodes the bifunctional enzyme responsible for the rate-limiting steps of sialic acid biosynthesis. The estimated worldwide prevalence of GNE myopathy is approximately 1?9 cases per million population. Clinically, the disorder is characterized by slowly progressive distal muscle weakness beginning in early adulthood, classically presenting with bilateral foot drop and selective sparing of the quadriceps muscles until the advanced stages of the disease. Owing to its rarity, phenotypic heterogeneity, and overlap with other inherited neuromuscular disorders, diagnosis is frequently delayed. Case Presentation: We report two siblings with a classical clinical phenotype suggestive of GNE myopathy who exhibited marked phenotypic variability despite sharing the same familial background. The elder sibling, a 39-year-old man, presented with a nine-year history of slowly progressive bilateral foot drop, characterized by selective weakness of the ankle dorsiflexors and hip adductor muscles. Despite the chronic course of the disease, he remained independently ambulant and was able to continue his occupational activities without significant functional limitation. In contrast, his younger sibling, a 32-year-old woman, experienced symptom onset at an earlier age and demonstrated a more severe clinical phenotype with involvement of both distal and proximal lower-limb muscles. She reported progressive difficulty in climbing stairs, rising from a chair, and standing from a squatting position, reflecting greater functional impairment. Electrophysiological evaluation in both patients revealed preserved sensory nerve conduction studies with chronic myopathic changes on needle electromyography, consistent with a primary myopathic process. Muscle magnetic resonance imaging demonstrated selective fatty infiltration and involvement of the tibialis anterior and hip adductor muscles in both siblings. Additionally, the younger sibling exhibited gluteal muscle involvement, which correlated with her more pronounced proximal muscle weakness and greater disease severity. These findings highlight the marked phenotypic heterogeneity that can occur within the same family in GNE myopathy, emphasizing the importance of comprehensive clinical, electrophysiological, and radiological evaluation for accurate phenotypic characterization. Discussion: The clinical, electrophysiological, and radiological findings in both patients were consistent with the characteristic phenotype of GNE myopathy. The younger sister demonstrated earlier onset and more extensive proximal lower-limb involvement than her brother, despite the shared familial background. These findings highlight the substantial intrafamilial phenotypic variability that may occur in GNE myopathy. Conclusion: These cases emphasize the importance of recognizing the characteristic clinical and radiological pattern of GNE myopathy while acknowledging its variable expression within the same family. Early-adult-onset bilateral foot drop, preserved sensation, normal sensory nerve conduction, relative quadriceps sparing, and selective muscle involvement on MRI should prompt molecular evaluation of the GNE gene.

Keywords: GNE myopathy, hereditary inclusion body myopathy, distal myopathy with rimmed vacuoles, Nonaka myopathy, bilateral foot drop, quadriceps sparing, muscle magnetic resonance imaging, electromyography, intrafamilial phenotypic variability

How to Cite?: Dr. B Sandeep, Dr. Veena Narisetty, "Clinical Spectrum and Phenotypic Variability of GNE Myopathy: Insights from Two Sibling Cases", Volume 15 Issue 8, August 2026, International Journal of Science and Research (IJSR), Pages: 1254-1261, https://www.ijsr.net/getabstract.php?paperid=SR26818151500, DOI: https://dx.doi.org/10.21275/SR26818151500

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