Abstract
Background
Niemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal disorder caused by pathogenic variants in
NPC1
or
NPC2
, resulting in impaired intracellular cholesterol trafficking and progressive neurovisceral disease. Although the clinical and molecular spectrum of NPC has been well characterized in several populations, data from India remain limited. The present study aimed to describe the clinical and molecular characteristics of NPC in Indian patients and to expand the mutational spectrum of the disease.
Methods
We conducted a retrospective multicentre study of 28 patients with NPC diagnosed between 2010 and 2026 based on clinical, biochemical, and molecular investigations. Filipin staining was done in two patients. Plasma chitotriosidase activity (
n
= 21),
β
-glucosidase (
n
= 16) and sphingomyelinase activities (
n
= 21) were measured in plasma sample and leukocytes respectively using fluorometric enzyme assays. Molecular testing included clinical exome sequencing and Sanger sequencing in 2 patients and 1 patient, respectively while single-molecule molecular inversion probes (smMIP)-based targeted sequencing assay was performed in 25 patients.
In-silico
tools were used to predict the effect of novel variants on protein function and structure.
Results
Hepatosplenomegaly was the most common presenting feature, followed by developmental delay, neuroregression, ataxia, seizures, and vertical supranuclear gaze palsy. Importantly, nearly one-third of patients presented with isolated visceral manifestations in the absence of neurological involvement. Molecular analysis identified 32 variants (27 in
NPC1
and 5 in
NPC2
), including 11 novel variants and two exon-level deletions. More than 60% of diagnoses were established during the final four years of the study following implementation of the FRIGE–Sanofi DISHA Program, highlighting the impact of improved access to affordable biochemical and molecular testing for lysosomal storage disorders. The indigenous smMIP assay enabled simultaneous detection of single nucleotide variants, small insertions/deletions, and exon-level copy number variants within a single cost-effective workflow. Structural analysis predicted that novel missense variants affect functionally critical domains of NPC1, resulting in disruption of protein stability, cholesterol trafficking, and lysosomal function.
Conclusion
The present study provides a comprehensive characterization of the clinical spectrum and molecular heterogeneity of NPC in a large cohort of patients of Indian origin.