TCAP – Autosomal recessive limb-girdle muscular dystrophy type 2G

Biallelic TCAP variants have been reported in four unrelated Chinese patients presenting with distal myopathy consistent with autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G). All affected individuals carried recessive loss-of-function or splice-site variants, including the intronic c.110+5G>A variant, and exhibited distal lower limb weakness, rimmed vacuoles on muscle biopsy, and progressive ambulation decline (4 probands; PMID:32761539). No extended segregation beyond proband-level data was reported.

Functional studies support a loss-of-function mechanism. In one patient, autophagolysosomes were observed on electron microscopy, implicating altered autophagy in pathogenesis (PMID:32761539). A Tcap-null mouse model recapitulated key histopathological features—central nucleation and fiber-size variation—and demonstrated impaired motor performance and increased muscle stiffness in knockout animals, mirroring human LGMD2G phenotypes (PMID:20233748).

Integration of genetic and experimental data provides a compelling link between TCAP deficiency and LGMD2G, although current evidence remains limited by small case numbers and lack of extensive familial segregation. Further studies are warranted to expand variant spectra and elucidate modifier effects. Key take-home: Biallelic TCAP variants are a clinically actionable cause of autosomal recessive limb-girdle muscular dystrophy type 2G with diagnostic and potential therapeutic implications.

References

• Neurogenetics • 2021 • Distal myopathy due to TCAP variants in four unrelated Chinese patients. PMID:32761539
• Human molecular genetics • 2010 • Functional muscle analysis of the Tcap knockout mouse. PMID:20233748

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