Abstracts

Rationale: CLN2 disease is caused by autosomal recessive inheritance of 2 pathogenic variants in trans in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). A subtype of neuronal ceroid lipofuscinosis, CLN2 disease is diagnosed through clinical findings, TPP1 enzyme deficiency, and/or molecular findings in TPP1. CLN2 disease classically presents with seizures at 2-4 years of age and a history of early language delay, followed by rapid psychomotor decline and death in the second decade. A form of juvenile onset disease was initially described as autosomal recessive spinocerebellar ataxia 7 (SCAR7) before being attributed to TPP1 enzyme deficiency. Methods: We collected individuals reported to have TPP1 enzyme deficiency from literature review, public databases and laboratory communication. Previously unrecorded individuals collected were added to the University College London TPP1-specific database. Variant level data without individual-level information was not added to UCL. Results: We present an update on the spectrum of TPP1 gene variants associated with CLN2 disease including 178 unique variants and 405 individuals reported to have TPP1 enzyme deficiency (739 alleles). Two known pathogenic variants, c.509-1G>C and c.622C>T (p.Arg208Ter), collectively occur in 54% of affected individuals collected; at least 91 variants are private to single families. Homozygosity occurs in 43% of individuals where both alleles are known (84% of reported individuals). Atypical CLN2 disease represents 17% of individuals recorded with associated phenotype. Increased use and early adoption of diagnostic testing for a genetic basis of epilepsy is aided by description of TPP1 variants in association with clinical and laboratory findings. NCBI ClinVar currently holds records for only 23% of variants collected from literature. Conclusions: Effective CLN2 disease management requires timely diagnosis; however, irreversible neurodegeneration occurs before 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. Funding: This study was funded by BioMarin Pharmaceutical Inc.