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Published on: August 3, 2021
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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
Summary
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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