Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease

Hum Mutat. 2019 Nov;40(11):1924-1938. doi: 10.1002/humu.23860. Epub 2019 Jul 26.

PMID: 31283065

Emily Gardner, Mitch Bailey, Angela Schulz, Mikel Aristorena, Nicole Miller, Sara E Mole

Highlights: Effective CLN2 disease management requires early diagnosis. This article updates on the spectrum of TPP1 variants associated with CLN2 disease.

Abstract

Objective: Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive disorder caused by variants in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). This article updates on the spectrum of TPP1 variants associated with CLN2 disease, comprising 131 unique variants from 389 individuals (717 alleles) collected from the literature review, public databases, and laboratory communications.

Results: Previously unrecorded individuals were added to the UCL TPP1‐specific database. Two known pathogenic variants, c.509–1 G>C and c.622 C>T (p.(Arg208*)), collectively occur in 60% of affected individuals in the sample, and account for 50% of disease‐associated alleles. At least 86 variants (66%) are private to single families. Homozygosity occurs in 45% of individuals where both alleles are known (87% of reported individuals). Atypical CLN2 disease, TPP1 enzyme deficiency with disease onset and/or progression distinct from classic late‐infantile CLN2, represents 13% of individuals recorded with associated phenotype. National Center for Biotechnology Information (NCBI) ClinVar database currently holds records for 37% of variants collected here.

Conclusion: Effective CLN2 disease management requires early diagnosis; however, irreversible neurodegeneration occurs before a diagnosis is typically reached at age 5. Timely classification and public reporting of TPP1 variants is essential as molecular testing increases in use as a first‐line diagnostic test for pediatric‐onset neurological disease.

Keywords: genotype-phenotype correlation, late-infantile neuronal ceroid lipofuscinosis, lysosomal storage disorders, neurodegeneration, tripeptidyl peptidase I