TPP1 – Neuronal Ceroid Lipofuscinosis

TPP1 encodes the lysosomal protease tripeptidyl-peptidase 1, and biallelic loss-of-function variants cause classical late infantile neuronal ceroid lipofuscinosis (LINCL), a progressive autosomal recessive neurodegenerative disorder. Affected children typically present between ages 2–4 years with myoclonic and generalized seizures, motor and cognitive regression, hypotonia, microcephaly, visual loss and extrapyramidal signs, progressing to fatality by the second decade of life (PMID:9097964).

Genetic mapping in consanguineous families established linkage to chromosome 11p15 in classical LINCL, leading to identification of TPP1 (CLN2) as the causal gene (PMID:9097964). Subsequent mutational surveys in 74 families identified biallelic pathogenic variants in 57/60 LINCL kindreds, comprising >32 nonsense/splice alleles, missense changes, small insertions/deletions and recurrent splice junction variants (PMID:10330339). The commonest allele, c.622C>T (p.Arg208Ter), accounts for ~28% of CLN2 alleles worldwide.

Segregation analysis across multiple studies demonstrated co-segregation of recessive TPP1 variants in at least 19 affected siblings and extended relatives within 15 pedigrees, providing robust genetic confirmation of pathogenicity (PMID:11071145; PMID:19748052).

Functional assays of patient-derived cells revealed absent or severely reduced TPP1 enzymatic activity, retention of misfolded precursor protein in the endoplasmic reticulum, and lack of mature lysosomal enzyme for nonsense and splice variants such as p.Arg208Ter and p.Asn286Ser (PMID:15317752). Mouse knockout models of CLN2 recapitulate key neuropathological and behavioural features, including autofluorescent storage material, cerebellar atrophy and motor deficits (PMID:11588979). Intraventricular enzyme replacement therapy in the Tpp1–/– mouse restores CNS enzyme activity and ameliorates tremor and storage pathology, supporting therapeutic benefit (PMID:18362923).

No credible reports dispute TPP1’s role in LINCL, and extensive concordant genetic and experimental evidence firmly establishes this gene–disease relationship.

Key take-home: Genetic testing for TPP1 variants enables early molecular diagnosis of LINCL, informs reproductive counseling, and supports timely initiation of enzyme replacement therapy to modify disease progression.

References

• Human molecular genetics • 1997 • Loci for classical and a variant late infantile neuronal ceroid lipofuscinosis map to chromosomes 11p15 and 15q21-23 PMID:9097964
• American journal of human genetics • 1999 • Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder PMID:10330339
• Neuropediatrics • 2000 • A CLN2 gene nonsense mutation is associated with severe caudate atrophy and dystonia in LINCL PMID:11071145
• Pediatric neurology • 2009 • Late infantile neuronal ceroid lipofuscinosis: a new mutation in Arabs PMID:19748052
• Human molecular genetics • 2004 • Mutations in classical late infantile neuronal ceroid lipofuscinosis disrupt transport of tripeptidyl-peptidase I to lysosomes PMID:15317752
• European journal of paediatric neurology • 2001 • Mouse gene knockout models for the CLN2 and CLN3 forms of ceroid lipofuscinosis PMID:11588979
• Molecular therapy : the journal of the American Society of Gene Therapy • 2008 • Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis PMID:18362923

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