Submission Details

Neuronal ceroid lipofuscinoses (NCLs) are progressive neurodegenerative diseases characterized by mental and motor deterioration, epilepsy, visual loss, ataxia, and a reduced life span. The unifying finding in NCL patients is the accumulation, in neurons and many other cell types, of autofluorescent storage material. There are 13 subtypes of NCLs that are categorized based on the particular gene that is mutated. TPP1 is associated with autosomal recessive NCL2, with typical onset at age 2-4, and is described as late infantile NCL (LINCL). Besides NCL, TPP1 has been associated with autosomal recessive spinocerebellar ataxia, characterized by progressive motor deficits and cerebellar atrophy. This gene-disease association was not curated, because it was only reported once in two Dutch families with the same compound heterozygous variants (c.509-1G>C/ p.Val466Gly; PMID: 23428007). Two other cases that were described as TPP1-associated spinocerebellar ataxia had questionable gene-disease association, because they had intellectual impairment (PMID: 26224725, 27217339). NCL2 was first reported to be associated with TPP1 in 1997 in a study that identified its product as a lysosomal protein absent in a patient with LINCL (Sleat et al. 1997 PMID: 9295267). Since then, 131 independent variants have been reported according to Gardner et al. 2019 (PMID: 31283065). Of the 131 variants, there were 63 missense, 21 frameshift, 17 nonsense, 22 splicing, and 8 other types of variants (https://www.ucl.ac.uk/ncl//mutation.shtml). While many of the variants were unique to each family, two variants, c.509-1G>C and c.622C>T (p.Arg208*) in NM_000391.3, collectively occurred in 60% of individuals reported and accounted for 50% of disease‐associated alleles (31283065). Fifteen symptomatic probands from 15 families with homozygous or compound heterozygous TPP1 variants reported by six studies were scored for genetic evidence (PMID: 10330339, 12376936, 17959406, 19793312, 27343025, 30541466). Six probands had two variants in trans that were not predicted/proven to be null, and were given scores ranging from 0 to 1. The remaining nine probands had at least one of the two variants in trans that were proven/predicted to be null, and were given scores ranging from 0 to 2. For ten probands, reduced TPP1 activity in patient cells was used to upgrade the points, whereas functional studies were used to upgrade the points for two probands in one study (12376936), because the results of TPP1 enzyme activity in patient cells were not available. No LOD scores could be calculated from these families, because only single affected individual was reported for each case. Supporting experimental evidence includes protein interaction with CLN5 (12134079), non-human model organisms (mouse: 15483130; dog: 16621647), and rescue in non-human model organisms by adeno associated virus-mediated gene transfer (mouse: 17637720; dog: 26560358). Additional non-human model organism studies in dog (18344450, 21745338) and gene transfer studies mouse (16452657, 17180118, 18639872) were also reviewed as supporting evidence. Furthermore, enzyme replacement therapies on mouse (18362923, 21730969, 24394185, 24394185, 28345005), dog (21784683, 24938720, 24954537, 25257657), and human (29688815) were reviewed, although not scored. In summary, a score of 12 was given to genetic evidence, and 3.5 to experimental evidence, reaching 15.5 in total. TPP1’s association with NCL is upgraded from strong to definitive, because it has been replicated for more than two decades.