Submission Details

The neuronal ceroid lipofuscinoses (NCL) are a heterogeneous group of progressive neurodegenerative disorders characterized by the intracellular accumulation of auto-fluorescent storage material. Biallelic pathogenic variants in CTSD are causative of neuronal ceroid lipofuscinosis, type 10 (NCL10). NCL10 is characterized by acquired microcephaly, developmental regression, seizures, ataxia, cardiomyopathy and retinitis pigmentosa. Onset of symptoms can range from the prenatal period to the second decade and affected individuals demonstrate cerebral and cerebellar atrophy on MRI, significantly reduced cathepsin D enzyme activity in leukocytes or fibroblasts and the characteristic autofluorescent storage bodies in a variety of cell types. The disease mechanism is loss of function and CTSD mutations result in a significantly reduced cathepsin D, a lysosomal aspartyl proteinase essential to neuronal cell homeostasis. Over 10 different disease-causing mutations reported in families in the literature, the majority of which are homozygous variants identified in consanguineous families. The mutation spectrum includes nonsense, frameshift, and missense variants (Doccini et al, PMID 27072142; Steinfeld et al, PMID 16685649; Thottath et al, PMID 31086824; Hersheson et al, PMID 25298308; Fokstuen et al, PMID 27353043; Varvagiannis et al, PMID 29284168; Meyer et al, PMID 26059544; Komlosi et al, PMID 29373990; Sintola et al, PMID 16670177; Seidahmed et al, PMID 23101555; Alazami et al, PMID 25558065; Shaheen et al, PMID 30214071; Fritchie et al, PMID 18762956; Santorelli et al, PMID 23374165). Missense variant point assignment was upgraded due to functional data and/or the presence of the variant in individuals with proven reduced cathepsin D enzyme activity. Additionally, a number of reported families demonstrate complete co-segregation in affected and unaffected individuals. Supporting experimental evidence includes functional alteration in non-patient cells (Paranen et al, PMID 12350228), expression (Reid et al, 3543065), non-human model organism (Tyynela et al, 10856224 ; Koike et al, 10995834 ; Awano et al, 16386934), and rescue in non-human model organism (Marques et al, 31282275). A genetic evidence score of 12 and experimental evidence score of 5 results in a total score of 17. Evidence supporting an association between CTSD and NCL has been replicated over time; therefore, the gene-disease validity has been classified as DEFINITIVE.