NPC2 – Niemann-Pick disease type C2

Niemann-Pick disease type C2 is a rare autosomal recessive lysosomal lipid storage disorder caused by biallelic variants in NPC2, encoding a small soluble cholesterol-binding protein in late endosomes and lysosomes. Clinically, NPC2 deficiency presents in early infancy with conjugated hyperbilirubinemia, progressive respiratory insufficiency due to pulmonary alveolar proteinosis, foam cell accumulation, hepatosplenomegaly, and neurovisceral storage manifesting as meganeurites and axonal spheroids. Diagnosis relies on molecular genetic testing and biochemical assays including plasma oxysterols and filipin staining, with gene sequencing confirming pathogenic NPC2 variants. Treatments remain limited to supportive measures and, in one report, allogeneic bone marrow transplantation showing a graft-versus-substrate effect.

Inheritance is autosomal recessive. To date, eight unrelated probands have been reported with homozygous or compound heterozygous NPC2 variants (8 probands (PMID:18668002, PMID:20002450, PMID:20393800, PMID:36553254, PMID:25772320)), with segregation demonstrated in one sibpair (1 family, PMID:18668002).

The variant spectrum includes frameshift, nonsense and missense alleles. The recurrent exon 4 frameshift c.408_409del (p.Phe139LeufsTer) reduces NPC2 protein levels in serum, lung lavage and alveolar macrophages, and was identified in multiple patients (PMID:20002450). Additional variants include c.141C>A (p.Cys47Ter) and c.436C>T (p.Gln146Ter) among others.

Functional evidence demonstrates markedly reduced or aberrant NPC2 protein in patient fibroblasts and alveolar macrophages, defective cholesterol trafficking, and resolution of lipid accumulation by wild-type NPC2 in complementation assays. An NPC2-hypomorph mouse model recapitulated pulmonary alveolar proteinosis and macrophage accumulation before death (PMID:20002450). Biochemical studies of recombinant NPC2 glycoforms establish sterol binding across diverse sterols and support its direct role in lysosomal cholesterol egress (PMID:17018531).

Integration of genetic and experimental data supports a loss-of-function mechanism owing to haploinsufficiency or unstable protein variants. Despite the rarity of NPC2 cases (<5% of NPC disease), the consistent phenotype across probands and concordant animal and cellular models underpin its diagnostic validity and utility in genetic counseling. Early recognition via oxysterol biomarkers and prompt sequencing of NPC2 can expedite diagnosis and management.

Key take-home: NPC2 fulfills ClinGen criteria for a Strong gene–disease association in Niemann-Pick disease type C2; genetic testing of NPC2 is essential for definitive diagnosis and informs family counseling.

References

• Medical science monitor • 2008 • Niemann-Pick disease type C2 presenting as fatal pulmonary alveolar lipoproteinosis: morphological findings in lung and nervous tissue. PMID:18668002
• Clinical genetics • 2010 • Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis. PMID:20002450
• Journal of inherited metabolic disease • 2010 • Successful allogeneic bone marrow transplant for Niemann-Pick disease type C2 is likely to be associated with a severe 'graft versus substrate' effect. PMID:20393800
• Children (Basel, Switzerland) • 2022 • A Niemann-Pick Disease Type C2 with Severe Pulmonary Involvement and Limited Therapeutic Options: A Case Report. PMID:36553254
• JIMD reports • 2015 • Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype PMID:25772320
• The Journal of biological chemistry • 2006 • NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols. PMID:17018531

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