Abstract
Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive condition caused by variants in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). We update 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. 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. NCBI ClinVar currently holds records for 37% of variants collected here. 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.
Highlights
The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative lysosomal storage disorders characterized by the accumulation of neuronal and extraneuronal ceroid lipopigments (Jalanko & Braulke, 2009)
One form of juvenile onset disease was initially described as spinocerebellar ataxia 7 (SCAR7; MIM# 609270) and was later attributed to a TPP1 enzyme deficiency (Sun et al, 2013)
Data from the University College London (UCL) TPP1 Locus‐specific Database was combined with the described literature searches to collect all TPP1 variants reported to be associated with TPP1 enzyme deficiency and/or related disorders
Summary
The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative lysosomal storage disorders characterized by the accumulation of neuronal and extraneuronal ceroid lipopigments (Jalanko & Braulke, 2009). CLN2 disease (MIM# 204500) classically presents with seizure onset at 2–4 years of age, preceded by delayed language. Whereas classic late‐infantile CLN2 disease has a very well defined natural history, there exists a phenotypic spectrum of TPP1 enzyme deficiency in small numbers of patients, some with later onset or protracted disease course (Kohan et al, 2013; Kousi, Lehesjoki, & Mole, 2012). The American College of Medical Genetics (ACMG) guidelines recommend that gene variants be reported in combination with their assessed pathogenicity (Richards et al, 2015) The purpose of this mutation update is to summarize the identified disease‐related genetic variation in the TPP1 gene, with emphasis on clinical classification and genotype–phenotype correlations. We collected and analyzed variant information from 389 individuals (131 different/independent variants) associated with CLN2 disease to uniformly summarize all TPP1 gene variants
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