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Case Reports
. 2025 Jun;12(6):1302-1308.
doi: 10.1002/acn3.70002. Epub 2025 Apr 17.

UDP-glucose dehydrogenase variants cause dystroglycanopathy

Anna M Reelfs  1 , Carrie M Stephan  2 , Theresa M Czech  2   3 , Mary O Cox  4 , Soumya Joseph  5 , Benjamin W Darbro  2 , Steven A Moore  4 , Kevin P Campbell  3   5 , Katherine D Mathews  2   3
Affiliations
Case Reports

UDP-glucose dehydrogenase variants cause dystroglycanopathy

Anna M Reelfs et al. Ann Clin Transl Neurol. 2025 Jun.

Abstract

UDP-glucose dehydrogenase (UGDH) variants have been associated with hypotonia, developmental delay, and epilepsy. We report the first pathologic evidence of dystroglycanopathy in siblings with UGDH variants. Both presented around 6 months with developmental delay and elevated creatinine kinase. Sibling A developed epilepsy at age 9 years. Muscle biopsy from sibling A showed necrotizing myopathy with reduced matriglycan immunostaining. Western blot revealed α-dystroglycan with abnormally low molecular weight. The siblings shared pathogenic UGDH variants in trans: c.305G>A p.(R102Q) is predicted to disrupt protein structure and function; c.265-6C>G is deleterious to splicing. We propose that UGDH is an additional dystroglycanopathy gene.

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Conflict of interest statement

KDM receives research funding from the Paul D. Wellstone Muscular Dystrophy Cooperative Research Center grant (NIH U54 NS053672), Friedreich Ataxia Research Alliance (FARA), Muscular Dystrophy Association (MDA), and the Centers for Disease Control (U01 DD001248). She serves as an advisory board member for MDA and the FSH Society and is a board member for the FARA. She has served on advisory boards for Sarepta Therapeutics, Edgewise Therapeutics, ML Bio, and Asklepios. She receives or has recently received clinical trial funding from PTC Therapeutics, Sarepta Therapeutics, Pfizer, Reata, Fibrogen, Italfarmaco, Biohaven, Novartis, AMO, Capricor, Asklepios, ML Bio, and Scholar Rock.

Figures

Figure 1
Figure 1
UGDH produces substrates for the glycosylation of α‐dystroglycan. (A) The dystroglycan complex (DGC) is illustrated connecting the cytoskeleton actin to components of the extracellular matrix. Glycosylation of α‐dystroglycan (α‐DG) is necessary for binding to the extracellular matrix. (B) UDP‐glucose dehydrogenase (UGDH) oxidizes UDP‐glucose to UDP‐glucuronate (UDP‐GlcA) and reduces NAD+. UDP‐GlucA is converted to UDP‐xylose (UDP‐Xyl) via UDP‐xylose synthase. In the final steps of α‐DG glycosylation, xylose (from UDP‐Xyl), and glucuronate (from UDP‐GlcA), are transferred to α‐DG by RXYLT1, B4GAT1, and LARGE to form a linear polysaccharide of alternating xylose and glucuronate called matriglycan.
Figure 2
Figure 2
Muscle biopsy from sibling A reveals dystroglycanopathy. (A, B) H&E stains of frozen sections demonstrate necrotizing myopathy in Sibling A (A, control; B, Sibling A). Inside the dashed line oval of panel B are several regenerating muscle fibers with basophilic cytoplasm. The size bar in panel A applies also to panel B. (C–L) Immunofluorescence stains reveal reduced α‐DG staining in Sibling A compared to control. The antibodies used for the immunostaining include anti‐dystrophin carboxy terminus (ab15277; Abcam), anti‐matriglycan (IIH6 and VIA4‐1; Developmental Studies Hybridoma Bank [DSHB]), anti‐β‐dystroglycan (7D11; DSHB) and anti‐merosin (5H2; Millipore). The size bar in panel C applies also to panels E, G, I, and K. The size bar in panel D applies also to panels F, H, J, and L. The location of a small artery and vein are marked by “V” in serial sections of the UGDH biopsy. (M) Western blot from Sibling A demonstrates reduced molecular weight of core α‐DG protein using the AF6868 antibody (upper blot) and reduced matriglycan staining (IIH6, lower blot).
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References

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