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A novel XPNPEP3 gene variant manifesting as rhabdomyolysis and exercise intolerance

Katia Staedler1, Juliette Nectoux2, Corinne Metay3,4

  • 1Neuromuscular reference center Nord/Est/Ile de France, Myology Institute, Sorbonne University, Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France.

Journal of Neuromuscular Diseases
|September 15, 2025
PubMed

Insights

Genetic mutations in the XPNPEP3 gene can cause a metabolic myopathy. This case study highlights previously undescribed muscle and nervous system symptoms linked to XPNPEP3 gene variants.

Area of Science:

  • Genetics
  • Neurology
  • Mitochondrial Biology

Background:

  • Biallelic mutations in the XPNPEP3 gene are primarily associated with nephronophthisis.
  • Muscle involvement in XPNPEP3-related disorders is not well-characterized.

Purpose of the Study:

  • To describe a case of XPNPEP3-related disorder with significant muscle and nervous system manifestations.
  • To expand the known clinical spectrum of XPNPEP3 gene variants.

Main Methods:

  • Clinical evaluation including electroneuromyography and brain MRI.
  • Muscle biopsy with histopathological and electron microscopy analysis.
  • Whole genome sequencing to identify the genetic variant.

Main Results:

  • A 44-year-old male presented with childhood-onset exercise intolerance and recurrent rhabdomyolysis.
  • Electroneuromyography showed sensory axonal neuropathy; brain MRI revealed white matter lesions.
  • Muscle biopsy demonstrated ragged-red fibers, COX deficiency, and mitochondrial abnormalities.
  • Whole genome sequencing identified a homozygous frameshift variant in the XPNPEP3 gene.

Conclusions:

  • This case expands the phenotypic spectrum of XPNPEP3 variants to include metabolic myopathy.
  • Subclinical central and peripheral nervous system involvement should be considered in XPNPEP3-related disorders.
Keywords:
XPNPEP3mitochondrial myopathiesmuscular diseasesmyalgiarhabdomyolysis

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