First comprehensive characterisation of Niemann-Pick C disease in India

For families affected by an ultra-rare genetic disorder, one of he greatest challenges is often not treatment, but reaching the correct diagnosis in the first place.

Niemann-Pick disease type C (NPC) is a exemplar for this. It is a rare inherited lysosomal storage disorder that affect the liver, spleen, lungs, and brain. Yet, its symptoms vary enormously between patients and can resemble several other childhood metabolic, neurological, and lysosomal storage disorders.

At FRIGE Institute of Human Genetics, together with clinicians from centres across the length and breadth of India, we have now completed the largest clinical and molecular study of the Indian patients with NPC reported to date.

Our study, “Clinical and molecular spectrum of Niemann-Pick disease type C patients in India,” published in Frontiers in Pediatrics, describes 28 patients diagnosed over a 16-year period between 2010 and 2026.

The findings reveal not just the diversity of clinical presentations in NPC, but its genetic heterogeneity in India. Most importantly, the study demonstrates how combining clinical awareness with affordable targeted genomic testing can improve the recognition of rare disorders that might otherwise remain undiagnosed for years.

What is Niemann–Pick disease type C?

NPC is a rare autosomal recessive lysosomal storage disorder, usually caused by disease causing variants in either the NPC1 or NPC2 genes.

These genes are essential for transporting cholesterol and other lipids within cells. When either protein does not function correctly, cholesterol and other lipids accumulate within lysosomes, progressively affecting multiple organs including the liver, spleen and nervous system.

This creates an unusually wide spectrum of disease.

In infants, NPC may initially appear as:

• prolonged jaundice
• enlarged liver and spleen
• poor growth or failure to thrive
• unexplained splenomegaly
• occasionally respiratory disease

As children become older, neurological manifestations can emerge, including developmental delay, loss of previously acquired milestones, ataxia, seizures, movement disorders and a characteristic abnormality of eye movement known as vertical supranuclear gaze palsy.

The difficulty is that these features do not necessarily appear together.

In some patients, liver or spleen disease may precede neurological symptoms by months or even years. That creates both a diagnostic challenge and an important opportunity for earlier recognition.

Why is NPC difficult to diagnose in India?

One of the striking findings from our study was that most patients were not initially referred with a specific suspicion of NPC.

Among the 28 patients, only two had originally been referred specifically for investigation of Niemann-Pick disease type C. Many others entered the diagnostic pathway because clinicians suspected disorders such as Gaucher disease or Niemann-Pick disease types A/B.

There is a biological reason for this overlap.

Some NPC patients in our cohort showed abnormal biochemical results involving enzymes more commonly associated with other lysosomal disorders. Five had reduced β-glucosidase activity and ten had reduced sphingomyelinase activity despite ultimately having molecularly confirmed NPC.

This means that enzyme testing alone may not always distinguish between lysosomal disorders with overlapping phenotypes.

Historically, specialised filipin staining of cultured skin fibroblasts has been used to confirm NPC. However, it requires a skin biopsy, specialised expertise and considerable laboratory infrastructure.

Genomic testing offers a more scalable alternative.

smMIP sequencing detected genetic changes that could easily be missed

Our targeted smMIP assay identified not only single nucleotide changes and small insertions/deletions, but also two homozygous exon-level deletions:

• an exon 4 deletion in NPC1
• an exon 2–3 deletion in NPC2

Both were independently confirmed using amplification-based testing.

This is important because CNVs can sometimes escape conventional variant calling pipelines.

The ability to detect SNVs, small indels and exon-level CNVs within the same targeted assay is therefore an important advantage of the smMIP approach.

The DISHA effect: access to testing changes diagnosis

One of the most encouraging findings from the study was not simply genetic—it was about access.

Of the 28 patients accumulated over 16 years, 17 patients, or 60.7%, were diagnosed between 2022 and 2026.

Only 11 had been diagnosed during the preceding 12 years.

The sharp increase coincided with implementation of the FRIGE–Sanofi DISHA Program in 2022, through which biochemical and molecular diagnostic testing is provided free of cost for patients clinically suspected of selected lysosomal storage disorders.

Because NPC can clinically and biochemically resemble Gaucher disease and Niemann-Pick disease A/B, broader molecular assessment of these referred patients helped uncover NPC diagnoses that might otherwise have remained hidden.

This illustrates a larger lesson for rare disease care in India:

A rare disease may appear extremely rare simply because patients do not have access to the tests required to diagnose it.

Affordable testing, clinician awareness and efficient referral networks can fundamentally change that picture.

From rare-disease research to accessible diagnosis

At FRIGE-IHG, our broader objective is to translate genomic technologies into diagnostic tools that are practical for healthcare systems such as India.

The findings from this study demonstrate that an indigenously developed, targeted sequencing approach can identify an unusually broad range of mutations including novel variants and exon-level deletions while remaining suitable for high-throughput testing.

Combined with programs that reduce the financial barrier to diagnosis, such technologies offer an opportunity to shorten the diagnostic odyssey for families affected by rare genetic disorders.

For a condition as heterogeneous and difficult to recognise as Niemann–Pick disease type C, the most transformative innovation may ultimately be making an accurate molecular diagnosis accessible when it matters.