Homozygous missense TPP1 mutation associated with mild late infantile neuronal ceroid lipofuscinosis and the genotype-phenotype correlation

Purpose: TPP1 mutations have been identified in patients with variable phenotypes such as late infantile neuronal ceroid lipofuscinosis (LINCL), juvenile neuronal ceroid lipofuscinosis (JNCL), and spinocerebellar ataxia 7. However, the mechanism underlying phenotype variation is unknown. We screened TPP1 mutations in patients with epilepsies and analyzed the genotype-phenotype correlation to explain the phenotypic variations. Methods: We performed targeted next-generation sequencing in a cohort of 330 patients with epilepsies. All previously reported TPP1 mutations were systematically retrieved from the PubMed and NCL Mutation Database. Results: The homozygous missense TPP1 mutation c.646 G > A/ p.Val216Met was identified in a family with two affected siblings. The proband presented with seizures from three years of age, while no ataxia, cognitive regression, or visual abnormalities were observed. Further analysis of all reported TPP1 mutations revealed that the LINCL group had a significantly higher frequency of truncating and invariant splice-site mutations than the JNCL group. In contrast, the JNCL group had a higher frequency of variant splice-site mutations than LINCL. There was a significant correlation between phenotype severity and the frequency of destructive mutation. Conclusion: This study suggested that the phenotype of mainly epilepsy can be included in the phenotypic spectrum of TPPI mutations, which are candidate targets for genetic screening in patients with epilepsy. With the development of therapy techniques, early genetic diagnosis may enable the improvement of etiology-targeted treatments. The relationship between phenotype severity and the genotype of TPP1 mutations may help explain the phenotypic variations.