At a glance: the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years

Abstract

Niemann-Pick type C1 disease (NPC1 [OMIM 257220]) is a rare and severe autosomal recessive disorder, characterized by a multitude of neurovisceral clinical manifestations and a fatal outcome with no effective treatment to date. Aiming to gain insights into the genetic aspects of the disease, clinical, genetic, and biomarker PPCS data from 602 patients referred from 47 countries and diagnosed with NPC1 in our laboratory were analyzed. Patients’ clinical data were dissected using Human Phenotype Ontology (HPO) terms, and genotype–phenotype analysis was performed. The median age at diagnosis was 10.6 years (range 0–64.5 years), with 287 unique pathogenic/likely pathogenic (P/LP) variants identified, expanding NPC1 allelic heterogeneity. Importantly, 73 P/LP variants were previously unpublished. The most frequent variants detected were: c.3019C > G, p.(P1007A), c.3104C > T, p.(A1035V), and c.2861C > T, p.(S954L). Loss of function (LoF) variants were significantly associated with earlier age at diagnosis, highly increased biomarker levels, and a visceral phenotype (abnormal abdomen and liver morphology). On the other hand, the variants p.(P1007A) and p.(S954L) were significantly associated with later age at diagnosis (p < 0.001) and mildly elevated biomarker levels (p ≤ 0.002), consistent with the juvenile/adult form of NPC1. In addition, p.(I1061T), p.(S954L), and p.(A1035V) were associated with abnormality of eye movements (vertical supranuclear gaze palsy, p ≤ 0.05). We describe the largest and most heterogenous cohort of NPC1 patients published to date. Our results suggest that besides its utility in variant classification, the biomarker PPCS might serve to indicate disease severity/progression. In addition, we establish new genotype–phenotype relationships for “frequent” NPC1 variants.

Optimization of systemic AAV9 gene therapy in Niemann-Pick disease type C1 mice

“…More than 600 pathogenic or likely pathogenic NPC1variants have been described, most of which are missense mutations [ 42 – 44 ]. One of the most prevalent variants results in a missense mutation in the NPC1 p.I1061T protein, causing NPC1 to misfold and undergo endoplasmic reticulum associated degradation (ERAD) [ 45 , 46 ]. A knock-in, hypomorphic Npc1 I1061T allele was generated to recapitulate the human disorder [ 47 , 48 ]: Npc1 I1061T mice have a slightly protracted disease course compared to the Npc1 m1N mouse model that has a premature stop codon in the Npc1 gene resulting in production of truncated, non-functional NPC1 protein [ 47 ].…”