SGCA – Autosomal Recessive Limb-Girdle Muscular Dystrophy

Biallelic pathogenic variants in SGCA (alpha-sarcoglycan) cause autosomal recessive limb-girdle muscular dystrophy (LGMD2D), classified under MONDO:0015152. Patients present with progressive proximal muscle weakness, often leading to loss of ambulation in the second to fourth decade, and up to 17% exhibit cardiac involvement (HP:0001627) (PMID:30919934).

In a large Chinese cohort, 18 unrelated LGMD2D probands were identified with bi-allelic SGCA variants, including the recurrent hotspot c.662G>A (p.Arg221His) (PMID:30764848). A separate consanguineous pedigree demonstrated homozygosity for c.226C>T (p.Leu76Phe) with complete co-segregation in the affected child and heterozygous parents and sibling (PMID:27857043).

The variant spectrum encompasses missense changes (e.g., c.662G>A (p.Arg221His)), nonsense and frameshift alleles (e.g., c.402C>A (p.Tyr134Ter)) and canonical splice-site defects. Exon 3 of SGCA is a mutation hotspot in certain populations (PMID:30764848).

Clinical heterogeneity is marked by age at onset ranging from infancy to late adulthood; loss of independent ambulation typically occurs between ages 5 and 74 (HP:0002505) (PMID:30919934). Routine cardiac screening is recommended given reported cardiomyopathy in a subset of patients.

Functional studies show that reduced α-sarcoglycan expression on muscle biopsy correlates with disease severity, supporting a loss-of-function mechanism. In silico and immunohistochemical analyses confirm deleterious structural effects of missense variants such as p.Leu76Phe (PMID:27857043; PMID:30764848).

Together, robust segregation, multiple unrelated probands, and concordant expression studies establish a strong gene–disease relationship. Genetic testing for SGCA variants enables definitive diagnosis, guides surveillance for cardiac and respiratory complications, and informs genetic counseling.

References

• Clinical genetics • 2019 • Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients PMID:30919934
• Orphanet journal of rare diseases • 2019 • Clinical and genetic spectrum of sarcoglycanopathies in a large cohort of Chinese patients PMID:30764848
• Neuro endocrinology letters • 2016 • LGMD2D syndrome: the importance of clinical and molecular genetics in patient and family management. Case Report PMID:27857043

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