SGCA – autosomal recessive limb-girdle muscular dystrophy type 2D

SGCA encodes alpha-sarcoglycan, a transmembrane glycoprotein integral to the dystrophin–glycoprotein complex in skeletal muscle. Biallelic loss-of-function variants in SGCA disrupt sarcoglycan assembly at the sarcolemma, causing autosomal recessive limb-girdle muscular dystrophy type 2D (LGMD2D), also known as alpha-sarcoglycanopathy.

Inheritance of LGMD2D is autosomal recessive, with at least nine unrelated probands described individually: an 11-year-old British girl with absent 50 kDa alpha-sarcoglycan and novel missense and splice mutations (PMID:9393893), a boy presenting with myoglobinuria at onset (PMID:23989969), two Turkish siblings with a homozygous missense change in exon 3 (PMID:24742800), a Saudi consanguineous family with p.Leu76Phe (PMID:27857043), a late-onset mild phenotype in three siblings with an intronic deletion (PMID:30007747), and a Turkish boy with a 7 bp exon 3 deletion (PMID:25050186). More extensive series include five patients from a Taiwanese founder population sharing c.101G>T (p.Arg34Leu) (PMID:26944168), eighteen Chinese patients in a cohort of 218 LGMDs (PMID:30764848), and 159 European patients in a multicenter consortium (PMID:32875335).

The SGCA variant spectrum encompasses missense (e.g., c.518T>C (p.Leu173Pro)), splicing, small deletions (7 bp), intronic rearrangements, and founder alleles. Missense substitutions predominate, particularly hotspot exon 3 changes (p.Leu76Phe, p.Arg81Cys) and the Taiwanese p.Arg34Leu founder variant. Recurrent alleles include c.662G>A (p.Arg221His) in Chinese patients, while private and family-specific truncating or deep intronic variants further diversify the mutational landscape.

Functional studies uniformly show absent or markedly reduced sarcolemmal alpha-sarcoglycan on immunohistochemistry and Western blot, confirming loss of protein expression as the principal pathogenic mechanism. In LGMD2D muscle biopsies, severity of alpha-sarcoglycan reduction correlates with clinical progression and residual protein levels (PMID:30764848).

Clinically, LGMD2D presents with childhood to adolescent-onset proximal muscle weakness, calf hypertrophy, gait disturbance, and occasional myoglobinuria. Phenotypic variability ranges from severe early-onset forms to milder late-onset axial involvement. Cardiac involvement is rare but should be monitored in extensive series.

Integration of robust genetic and experimental data across >190 probands, combined with consistent loss-of-function pathology, supports a Definitive gene–disease association. Genetic testing for SGCA variants is essential for diagnosis, family counseling, and eligibility for future therapeutic trials.

References

• Developmental medicine and child neurology • 1997 • Absence of alpha-sarcoglycan and novel missense mutations in the alpha-sarcoglycan gene in a young British girl with muscular dystrophy. PMID:9393893
• European journal of pediatrics • 2014 • Myoglobinuria as first clinical sign of a primary alpha-sarcoglycanopathy. PMID:23989969
• Pediatric neurology • 2014 • Sarcolemmal alpha and gamma sarcoglycan protein deficiencies in Turkish siblings with a novel missense mutation in the alpha sarcoglycan gene. PMID:24742800
• Neuro endocrinology letters • 2016 • LGMD2D syndrome: the importance of clinical and molecular genetics in patient and family management. Case Report. PMID:27857043
• Neuromuscular disorders : NMD • 2018 • A new mutation of the SCGA gene is the cause of a late onset mild phenotype limb girdle muscular dystrophy type 2D with axial involvement. PMID:30007747
• Case reports in genetics • 2014 • Concomitant alpha- and gamma-sarcoglycan deficiencies in a Turkish boy with a novel deletion in the alpha-sarcoglycan gene. PMID:25050186
• Journal of the neurological sciences • 2016 • Probable high prevalence of limb-girdle muscular dystrophy type 2D in Taiwan. PMID:26944168
• Orphanet journal of rare diseases • 2019 • Clinical and genetic spectrum of sarcoglycanopathies in a large cohort of Chinese patients. PMID:30764848
• Brain : a journal of neurology • 2020 • New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy. PMID:32875335

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