Submission Details

PPT1 (originally called CLN1) was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis (NCL) (PMID: 7637805). NCL is a clinically and genetically heterogenous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. NCL presents with visual deficits due to retinal degeneration that gradually progresses to severe visual impairment. Many variants (variant types including missense, nonsense, splicing) have been described in literature (PMID:9664077). Of all variants described, one nonsense mutation, p.Arg151*, was described to account for 40% of the alleles and was associated with severe infantile-onset form of disease in the homozygous state (PMID: 9664077). The maximum score for genetic evidence (12 points) have been reached based on the abundance of patients with homozygous p.Arg151*. But more evidence is available in literature. This gene-disease association is supported by in-vitro and in-vivo studies. In patient-derived lymphoblast cell lines, those with the homozygous p.Arg151* mutation had a 6.76-fold decrease in PPT1 mRNA abundance and a corresponding decrease in PPT1 enzyme activity (PMID:23539563). A mouse model with the same homozygous nonsense mutation (PMID: 25205113) also recapitulates the molecular, histological and behavioral phenotypes of the human disease. The mouse model has a significant decrease in PPT1 mRNA and enzyme activity as well as an accumulation of autofluorescent storage material, astrocytosis and microglial activation in the brain(PMID: 25205113). The mechanism of pathogenicity appears to be loss-of-function. In summary, PPT1 is definitely associated with autosomal recessive NCL. This classification was approved by the ClinGen Retina GCEP on September 2, 2021.