NPC1 – Niemann-Pick Disease Type C

Niemann-Pick disease type C is a rare, autosomal recessive neurovisceral lipid storage disorder caused predominantly by biallelic variants in the NPC1 gene (HGNC:7897). Affected individuals present with visceral signs—prolonged neonatal jaundice, hepatosplenomegaly—followed by progressive neurological features including vertical supranuclear gaze palsy and cerebellar ataxia. The worldwide prevalence is estimated at 1:120 000–150 000 births, although founder effects have been described in specific populations. Early diagnosis is critical as substrate reduction therapy (miglustat) and supportive seizure management can stabilize neurologic decline.

1 Clinical Validity

The gene–disease relationship is classified as Definitive. Over 200 independent patients with confirmed biallelic NPC1 variants have been reported across multiple cohorts (>200 probands) (PMID:10480349; PMID:12408188; PMID:12955717). Segregation analyses in at least 20 families demonstrate autosomal recessive inheritance of pathogenic variants with complete cosegregation (PMID:10480349). Concordant functional data from cell, zebrafish, and mouse models underpin the clinical observations.

2 Genetic Evidence

NPC1-related NPC is inherited in an autosomal recessive manner. Segregation studies in 20 affected relatives across unrelated families confirm biallelic transmission, with compound heterozygotes and homozygotes observed (PMID:12408188). More than 250 unique NPC1 variants have been described, including missense, nonsense, frameshift, splice-site, and deep-intronic changes. Variant spectrum comprises >140 missense substitutions and >60 loss-of-function alleles; some recurrent/founder mutations include c.2974G>T (p.Gly992Trp) in Nova Scotian Acadians and NM_000271.5:c.3182T>C (p.Ile1061Thr) in European populations (PMID:16778374; PMID:18216017). Example pathogenic variant: c.3182T>C (p.Ile1061Thr).

3 Functional / Experimental Evidence

Loss-of-function is the predominant pathogenic mechanism, with mutant NPC1 proteins showing misfolding, ER-associated degradation, and impaired cholesterol export from lysosomes. Chemical chaperones rescue NPC1(I1061T) stability and restore cholesterol trafficking in patient fibroblasts (PMID:18216017). Zebrafish npc1 morphants exhibit defective early embryonic cell movements reversible by sterol supplementation (PMID:21576600). Mouse knock-in of an NPC1 N-terminal domain cholesterol-binding mutant reproduces full NPC phenotype, establishing the critical role of cholesterol binding (PMID:21896731). Autophagy is upregulated via Beclin-1 in NPC1 deficiency, linking lipid trafficking defects to neurodegeneration (PMID:17611388; PMID:17468177).

4 Conflicting Evidence

No robust evidence disputes the NPC1–NPC association. A small subset of “NPC variants” with near-normal filipin staining underscores the need for comprehensive genetic and biochemical testing to avoid false negatives (PMID:11349231).

5 Integration & Conclusion

Collectively, the abundant genetic and experimental data establish NPC1 as essential for endolysosomal cholesterol egress; pathogenic variants cause Niemann-Pick disease type C through loss-of-function. Genetic testing panels should include deep intronic regions and copy-number assays to capture rare pseudoexon and large deletion events. Early molecular diagnosis enables timely initiation of miglustat therapy and seizure control, improving neurological outcomes.

Key Take-home: NPC1 variant analysis is critical to confirm Niemann-Pick disease type C and guide early treatment decisions.

References

• Human genetics • 1999 • NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C PMID:10480349
• Journal of inherited metabolic disease • 2002 • Identification of novel mutations in the NPC1 gene in German patients with Niemann-Pick C disease PMID:12408188
• Human mutation • 2003 • Identification of 58 novel mutations in Niemann-Pick disease type C PMID:12955717
• The Tohoku journal of experimental medicine • 2006 • Niemann-Pick disease type C: cataplexy and hypocretin in cerebrospinal fluid PMID:16778374
• The Journal of biological chemistry • 2008 • Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding PMID:18216017
• Proceedings of the National Academy of Sciences of the USA • 2011 • Amino acid substitution in NPC1 that abolishes cholesterol binding reproduces phenotype of complete NPC1 deficiency in mice PMID:21896731
• Autophagy • 2007 • Lipid trafficking defects increase Beclin-1 and activate autophagy in Niemann-Pick type C disease PMID:17611388
• Human molecular genetics • 2007 • Autophagy in Niemann-Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects PMID:17468177

Evidence Based Scoring (AI generated)