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Updated: May 11, 2025

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UDP-glucose dehydrogenase variants cause dystroglycanopathy

Anna M Reelfs1, Carrie M Stephan2, Theresa M Czech2,3

  • 1University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.

Annals of Clinical and Translational Neurology
|April 17, 2025
PubMed

Insights

Genetic variants in UDP-glucose dehydrogenase (UGDH) cause a rare neuromuscular disorder. This study identifies UGDH as a new gene linked to dystroglycanopathy, a condition affecting muscle and brain development.

Area of Science:

  • Genetics
  • Neuromuscular Disorders
  • Biochemistry

Background:

  • UDP-glucose dehydrogenase (UGDH) gene variants are implicated in developmental disorders like hypotonia, developmental delay, and epilepsy.
  • Dystroglycanopathies are a group of inherited neuromuscular disorders characterized by impaired muscle development and often brain abnormalities.

Observation:

  • This study presents the first pathologic evidence of dystroglycanopathy in siblings with identified UGDH variants.
  • Both siblings exhibited developmental delay and elevated creatinine kinase levels starting around six months of age.
  • Sibling A later developed epilepsy and underwent a muscle biopsy revealing necrotizing myopathy and reduced matriglycan, with Western blot showing low molecular weight alpha-dystroglycan.

Findings:

  • The siblings carried pathogenic UDP-glucose dehydrogenase (UGDH) variants in trans: c.305G>A p.(R102Q), predicted to disrupt protein structure, and c.265-6C>G, which affects splicing.
  • Pathologic findings in muscle tissue, including reduced matriglycan and altered alpha-dystroglycan, confirm a dystroglycanopathy phenotype.
  • The identified UGDH variants are strongly associated with the observed clinical symptoms and pathological muscle changes.

Implications:

  • UDP-glucose dehydrogenase (UGDH) is proposed as an additional gene associated with dystroglycanopathies.
  • This finding expands the genetic landscape of neuromuscular disorders and provides new insights into the molecular mechanisms of dystroglycanopathies.
  • Understanding the role of UGDH in dystroglycanopathy may lead to improved diagnostic approaches and potential therapeutic strategies for affected individuals.

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