LARGE1 – Walker-Warburg Syndrome (Muscular Dystrophy-Dystroglycanopathy Type A)

Walker-Warburg syndrome (WWS) is a severe autosomal recessive congenital muscular dystrophy characterized by cobblestone lissencephaly, ocular malformations, encephalocele, hydrocephalus and other brain anomalies (PMID:27493321; PMID:28116189). Six glycosyltransferases—including LARGE1—are implicated in α-dystroglycan modification. Although LARGE1 variants are infrequently identified, the clinical phenotype overlaps those of POMT1/2, POMGNT1, FCMD and FKRP defects.

Genetic evidence for LARGE1 in WWS is limited: no pathogenic LARGE1 variants were reported in a cohort of 43 ethnically diverse WWS patients (PMID:18752264), and case studies have yet to confirm bona fide coding changes. No segregation analyses are available.

Functional studies demonstrate that LARGE-deficient mouse (Large(myd)) cells and patient fibroblasts lack glucuronyltransferase activity essential for α-dystroglycan glycosylation, supporting a loss-of-function mechanism (PMID:25138275). Structural modeling of the missense mutation p.Ser331Phe reveals disruption of the GT-A fold and catalytic stability, concordant with severe muscle-eye-brain disease phenotypes (PMID:32356985).

No studies have refuted the role of LARGE1 in dystroglycanopathies, but the absence of recurrent variants and negative screens in large cohorts weaken genetic support.

In summary, although LARGE1 is biochemically and structurally critical for α-dystroglycan function, its direct contribution to WWS via pathogenic variants remains poorly substantiated. Functional assays of enzyme activity provide the most reliable evidence for clinical interpretation.

Key Take-home: Functional assessment of LARGE1 glycosyltransferase activity can aid diagnosis in WWS when genetic findings are inconclusive.

References

• Sudanese journal of paediatrics • 2011 • Walker-Warburg Syndrome: A Case with multiple uncommon features. PMID:27493321
• Case Reports in Neurological Medicine • 2016 • A Successful Treatment of Endoscopic Third Ventriculostomy with Choroid Plexus Cauterization for Hydrocephalus in Walker-Warburg Syndrome. PMID:28116189
• Human Mutation • 2008 • Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East. PMID:18752264
• The Journal of Biological Chemistry • 2014 • Endogenous glucuronyltransferase activity of LARGE or LARGE2 required for functional modification of α-dystroglycan in cells and tissues PMID:25138275
• Journal of Chemical Information and Modeling • 2020 • Identification and Modeling of a GT-A Fold in the α-Dystroglycan Glycosylating Enzyme LARGE1 PMID:32356985

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