Diverse clinical spectrum of Niemann-Pick C: insights from a single center.

Abstract

Objectives: Niemann-Pick disease type C (NPC) is a lysosomal lipid trafficking disorder characterized by impaired intracellular cholesterol transport, resulting in progressive neurovisceral involvement. While neurological progression has been extensively described, metabolic biomarkers and lipid abnormalities may provide earlier diagnostic clues, particularly in high-consanguinity populations.

Methods: We retrospectively evaluated 14 genetically confirmed NPC patients followed at a tertiary pediatric metabolic center between 2018 and 2025. Clinical presentation, biochemical parameters including HDL cholesterol and lysosphingolipids (LysoSM, LysoSM-509), neuroimaging findings, and molecular genetic results were systematically reviewed.

Results: The cohort (eight males, six females; age range: 9 days-24 years) demonstrated marked phenotypic heterogeneity, including neonatal cholestasis (29 %), pulmonary-dominant disease (29 %), juvenile neurodegeneration (64 %), psychiatric-onset presentation (14 %), and inflammatory bowel disease-like colitis. Low HDL cholesterol was observed in 86 % of patients. LysoSM-509 was elevated in all cases, irrespective of phenotype, supporting its diagnostic robustness. Eleven patients carried NPC1 variants and three carried NPC2 variants, including several novel truncating pathogenic variants. Marked intrafamilial variability was observed among siblings with identical genotypes. Miglustat treatment appeared to be associated with clinical stabilization in some patients, particularly when initiated at earlier stages of neurological involvement; however, given the limited sample size, no definitive conclusions can be drawn.

Conclusions: NPC should be considered across a broad clinical spectrum, ranging from prenatal presentations such as non-immune hydrops fetalis to adult-onset psychiatric manifestations, as well as neurological involvement at all ages. It should also be suspected in patients presenting with cholestasis, hepatosplenomegaly, developmental delay, interstitial lung disease, or treatment-refractory IBD-like colitis. LysoSM-509 is a highly sensitive biomarker across phenotypes. High consanguinity facilitates early cascade screening but also reveals substantial genotype-phenotype variability. Early biomarker-driven testing remains critical for timely diagnosis and management.