CTSA – Galactosialidosis

Galactosialidosis is an autosomal recessive lysosomal storage disorder caused by biallelic loss-of-function variants in the protective protein/cathepsin A gene (CTSA), leading to combined secondary deficiencies of β-galactosidase and neuraminidase (galactosialidosis). Defective CTSA impairs multienzyme complex formation in lysosomes, resulting in accumulation of sialylated glycoconjugates and widespread tissue damage.

Genetic evidence demonstrates autosomal recessive inheritance with numerous pathogenic alleles identified in diverse populations. The recurrent missense variant c.1184A>G (p.Tyr395Cys) was homozygous in Japanese early-infantile cases with absent CTSA protein and markedly reduced enzyme activities (PMID:9636645). Frameshift alleles such as c.517_518del (p.Phe173fs) and splicing defects (e.g., IVS8+9C>G) cause truncated proteins and variable residual activity, correlating with late-infantile presentations (PMID:9603439).

Clinical phenotypes span early-infantile hydrops fetalis, late-infantile hepatosplenomegaly and coarse facies, to juvenile/adult forms with macular cherry-red spots, neuropathic pain, myoclonus, ataxia, and angiokeratoma. Disease onset ranges from neonatal to adult ages, with median presentation at 4.3 years and diagnosis often delayed by 8 years (PMID:30693535). Key features include coarse facial features, visceromegaly, hepatomegaly, cherry-red macula, and cerebellar ataxia.

Functional studies confirm that CTSA mutations disrupt protein folding, processing, and lysosomal localization. Immunoblot and immunocytochemistry reveal absence of precursor and mature CTSA in patient cells (PMID:9636645). Structural modeling of the K453E variant shows impaired dimer interface stability (PMID:10944848). A mouse model with inactive CTSA exhibits hypertension and defective elastic fibers due to reduced endothelin-1 catabolism, highlighting non-lysosomal roles of CTSA (PMID:18391110).

The pathogenic mechanism is loss of CTSA chaperone and carboxypeptidase activity, leading to destabilization of the β-galactosidase–neuraminidase complex and multi-system glycoprotein storage. Chaperone-mediated approaches using modified U1 snRNA have demonstrated rescue of aberrant splicing in vitro, suggesting potential therapeutic strategies (PMID:30010039).

Collectively, biallelic CTSA variants cause definitive galactosialidosis, diagnosable by combined biochemical enzyme assays and CTSA sequencing. Early genetic diagnosis enables prognostic counseling and guides emerging personalized therapies. Key Take-home: CTSA sequencing and enzymatic assessment are critical for definitive diagnosis and management of galactosialidosis.

References

• Biochemical and biophysical research communications • 1998 • Protective protein/cathepsin A loss in cultured cells derived from an early-infantile form of galactosialidosis patients homozygous for the A1184-G transition (Y395C mutation). PMID:9636645
• Human mutation • 1998 • Molecular pathology of galactosialidosis in a patient affected with two new frameshift mutations in the cathepsin A/protective protein gene. PMID:9603439
• Journal of human genetics • 2000 • Structural and functional study of K453E mutant protective protein/cathepsin A causing the late infantile form of galactosialidosis. PMID:10944848
• Circulation • 2008 • Enzymatic activity of lysosomal carboxypeptidase (cathepsin) A is required for proper elastic fiber formation and inactivation of endothelin-1. PMID:18391110
• Journal of inherited metabolic disease • 2019 • Quantitative natural history characterization in a cohort of 142 published cases of patients with galactosialidosis-A cross-sectional study. PMID:30693535

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