CTSF – Adult Neuronal Ceroid Lipofuscinosis

Adult neuronal ceroid lipofuscinosis (Type B Kufs disease) is an autosomal recessive lysosomal storage disorder characterized by adult-onset dementia and motor dysfunction. Genetic heterogeneity has previously implicated CLN6 in Type A presentations, whereas the molecular basis of Type B remained unknown.

Genome-wide linkage mapping in two consanguineous families localized a shared region on chromosome 11. Exome sequencing of five affected individuals from these families identified homozygous and compound heterozygous variants in CTSF. Subsequent CTSF screening in 22 additional suspected cases revealed one further patient with compound heterozygous CTSF mutations, totaling six probands (PMID:23297359).

Variants include c.594T>A (p.Tyr198Ter) and c.329_347del (p.Val110fs), four additional frameshifts, two canonical splice-site changes, and three missense substitutions, supporting a loss-of-function spectrum (PMID:23297359).

Segregation analysis across both pedigrees demonstrated co-segregation of recessive CTSF alleles with disease in four affected relatives, consistent with autosomal recessive inheritance.

Functional studies corroborate haploinsufficiency: in silico modeling predicted structural disruption of cathepsin F, Ctsf-knockout mice recapitulate the light and electron-microscopic features of Kufs disease (PMID:23297359), and patient-derived mutant enzymes fail to process LIMP-2 in vitro and in lysosomal extracts (PMID:25576872).

Collectively, these data establish CTSF loss of function as a strong cause of adult neuronal ceroid lipofuscinosis. CTSF genetic testing should be considered in patients with adult-onset dementia and motor signs to enable precise diagnosis and avoid invasive biopsies. Key take-home: CTSF analysis provides a clinically actionable target for diagnosing Type B Kufs disease.

References

• Human Molecular Genetics • 2013 • Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis. PMID:23297359
• Biochemical and Biophysical Research Communications • 2015 • Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease. PMID:25576872

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