CTSD – Neuronal Ceroid Lipofuscinosis

CTSD encodes the lysosomal protease cathepsin D, and biallelic CTSD variants cause congenital neuronal ceroid lipofuscinosis (CLN10), a severe early-onset neurodegenerative lysosomal storage disorder. Affected infants present with microcephaly, hypertonia, rapid cerebral and cerebellar atrophy, and die within days after birth.

Inheritance is autosomal recessive. Two unrelated singleton cases were reported: a homozygous missense variant c.299C>T (p.Ser100Phe) with marginal enzyme activity in patient fibroblasts and successful prenatal exclusion in a sibling (PMID:18762956); and a congenital‐onset inframe deletion c.683TCT (p.Phe229del) with functional confirmation in overexpression studies (PMID:29284168). A cohort screen identified eight additional patients with homozygous or compound heterozygous loss‐of‐function CTSD alleles, including frameshift and splice site mutations, all lacking enzyme activity and showing absent cathepsin D in brain tissue (PMID:16670177).

Genetic evidence reaches a strong level with at least 10 probands showing autosomal recessive transmission of CTSD variants—missense and predicted loss‐of‐function—across unrelated families; familial segregation in consanguineous pedigrees; and concordant biochemical deficits (10 probands) (PMID:18762956; PMID:16670177).

Functional assays in patient cells demonstrate markedly reduced proteolytic activity and impaired processing of cathepsin D. Animal models, including CTSD-deficient mice, sheep, and Drosophila, recapitulate neuronal storage, synucleinopathy-like changes, and neurodegeneration; rescue of enzymatic activity ameliorates pathology (PMID:19761846).

No studies have convincingly refuted the CTSD–NCL10 association, though the c.863A>G (p.Glu288Gly) variant has been shown to be benign in functional assays (PMID:34331747).

Overall, CTSD deficiency meets ClinGen criteria for a Strong gene-disease association and strong genetic and functional evidence. Key take-home: CTSD variant screening and enzyme assays are clinically actionable for early diagnosis of congenital neuronal ceroid lipofuscinosis and enable informed prenatal testing.

References

• Acta neuropathologica • 2009 • Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). PMID:18762956
• Neuropediatrics • 2018 • Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder. PMID:29284168
• Brain : a journal of neurology • 2006 • Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. PMID:16670177
• Neurobiology of disease • 2009 • Genetic modifiers of degeneration in the cathepsin D deficient Drosophila model for neuronal ceroid lipofuscinosis. PMID:19761846

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