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CTSD – Neuronal Ceroid Lipofuscinosis Type 10

CTSD biallelic variants underlie juvenile-onset neuronal ceroid lipofuscinosis type 10 (Neuronal Ceroid Lipofuscinosis Type 10), an autosomal recessive neurodegenerative disorder. To date, six juvenile-onset cases have been reported, and a novel homozygous missense variant c.1097G>A (p.Cys366Tyr) was identified in a nine-year-six-month-old girl presenting with abnormal speech pattern, cognitive and motor decline, ataxia, and visual impairment (PMID:39656415). No additional segregation data are available, and a multi-patient study excluded c.863A>G (p.Glu288Gly) as a pathogenic allele in CLN10 (PMID:34331747).

Loss-of-function of CTSD leads to profound lysosomal dysfunction and NCL-like pathology in multiple models. Congenital NCL patients harbor truncating CTSD alleles demonstrating absent enzyme activity and rapid degradation in vivo (PMID:16670177), and two missense mutations (p.Phe229Ile, p.Trp383Cys) cause impaired proteolysis and misprocessing in patient fibroblasts and animal models (PMID:16685649). These functional studies concordantly support a loss-of-function mechanism in CTSD-related NCL. Additional model and rescue experiments exceed current scoring but reinforce clinical utility.

Key Take-home: Biallelic loss-of-function CTSD variants cause juvenile-onset NCL10, and targeted genomic testing can confirm diagnosis and inform genetic counseling.

References

  • Cerebellum (London, England) | 2024 | A Novel Variant of the CTSD Gene Associated with Juvenile-onset Neuronal Ceroid Lipofuscinosis Type 10: A Case Report and Literature Review. PMID:39656415
  • Molecular genetics & genomic medicine | 2021 | The c.863A>G (p.Glu288Gly) variant of the CTSD gene is not associated with CLN10 disease. PMID:34331747
  • Brain : a journal of neurology | 2006 | Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. PMID:16670177
  • American journal of human genetics | 2006 | Cathepsin D deficiency is associated with a human neurodegenerative disorder. PMID:16685649

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

7 probands (6 previously reported + 1 novel homozygous case) with CTSD variants but no segregation or recurrent alleles demonstrated ([PMID:39656415])

Genetic Evidence

Limited

Single homozygous missense c.1097G>A (p.Cys366Tyr) in JNCL10; absence of segregation data and no recurrent pathogenic alleles; benign c.863A>G (p.Glu288Gly) excluded ([PMID:34331747])

Functional Evidence

Moderate

Multiple in vitro and in vivo loss-of-function studies demonstrate CTSD deficiency causes NCL-like pathology ([PMID:16670177]; [PMID:16685649])