In-Frame Deletion in ISPD Gene Causes Limb Girdle Muscular Dystrophy: A Case Report

Background: Dystroglycanopathies are a subgroup of congenital myopathies and show high clinical variability. The clinical spectrum ranges from Walker-Warburg syndrome with severe brain and eye malformations to milder forms of limb girdle muscular dystrophy. Mutations in numerous genes have been identified to cause incorrect O-glycosylation of especially α-dystroglycan.

Methods/Case Report: We present a 10-year-old girl, second child of consanguineous parents. The family history presents two females affected by congenital muscle disease of unknown cause. First motor delays with proximal muscle weakness and reduced endurance were noticed in early infancy. Up until today she presents progressive muscle weakness, reduced walking distance and beginning wheelchair dependency. Serum creatine kinase determinations showed values ​​of > 2,000 IU/L. Muscle ultrasound indicated a significant myopathic pattern; muscle biopsy revealed dystrophic tissue and reduced laminin α-2 expression. Neuroradiological, ophthalmological, neurophysiological, cardiological, and pulmonological findings were unremarkable.

Results: Molecular analysis of candidate genes led to the detection of a homozygous mutation in ISPD-gene (c.1114–1116del, p. Val372del, exon 8, chromosome 7). The ISPD gene encodes for the isoprenoid synthase, an enzyme involved in the o-glycosylation of α-dystroglycan.

Conclusion: Similar to the inhomogeneity of the clinical manifestation of dystroglycanopathies in general, mutations in ISPD-gene show a broad clinical spectrum. Publications show—as we do with this case report—mainly mild manifestations of ISPD-mutations with “LGMD-like” symptoms, though we found reports of Walker Warburg syndrome associated with ISPD-mutations. Reason for that could be mutation-specific consequences on residual activity of isoprenoid synthase.