Due to its complex and variable presentation, NPC can be challenging to recognize. However, ataxia and progressive motor or developmental regression—alongside a combination of vertical gaze abnormalities—particularly affecting downward movement should raise suspicion for NPC (Schiffmann R, et al. 2025).

Key Clinical Clues

Neurological Findings (Often Progressive)

• VSGP (especially impaired downward saccades)
• Progressive cerebellar ataxia or frequent falls
• Seizures (may be a late feature)
• Gelastic cataplexy (brief loss of muscle tone triggered by laughter)

Psychiatric/Cognitive Symptoms (Typically Adolescent or Adult Onset)

• Psychosis or schizophrenia-like symptoms
• Cognitive decline or dementia (early onset)
• Behavioral disturbances, impulsivity, social withdrawal

Visceral Signs

• Hepatosplenomegaly (especially if unexplained or persistent, organomegaly [especially splenomegaly] is common in adult onset)
• History of prolonged neonatal jaundice or cholestatic hepatitis
• Failure to thrive or feeding difficulties

Biochemical/Other Red Flags

• Elevated plasma oxysterols (eg cholestane-3β,5α,6β-triol)
• Abnormal filipin staining in fibroblasts (if tested)
• Positive family history of NPC or similar neurovisceral disorder

Once the diagnosis is confirmed, the cornerstone of management is multidisciplinary supportive care and disease-modifying therapies. Patients should be referred to a center with expertise in LSDs for coordinated follow-up.

In Lucy’s case, early recognition permits timely intervention to preserve function and quality of life. Monitoring should include serial assessments of growth, neurodevelopment, cognition, and behavior, as well as annual audiologic evaluations.

Given her ataxia, development regression, and VSGP, proactive engagement with physical therapy and dietary support is critical. Caregivers should be educated about the likelihood of feeding decline and the potential need for gastrostomy placement. Although disease-modifying therapies such as levacetylleucine and arimoclomol (often with miglustat) offer promising benefits in selected cases, symptomatic and rehabilitative strategies remain the foundation of comprehensive NPC care (Schiffmann R, et al. 2025).

NPC Laboratory Diagnosis Algorithm

Click the diagram to view it full-screen.

Note: in case clinical suspicion was first confirmed by positive biochemical markers, it is still important to identify mutations.

Abbreviations: GD = Gaucher disease; ASM = Acid sphingomyelinase deficiency; EM = Electron microscopy; MLPA = Multiplex ligation-dependent probe amplification; NGS = Next-generation sequencing.

Legend

• ᵃ Elevated cholestane-triol or bile acid derivative and/or lyso-SM-509, with normal or slightly elevated lyso-SM. Cholestane-triol also elevated in acid sphingomyelinase deficiency (ASMD), acid lipase deficiency, CTX, certain neonatal cholestasis conditions.
• ᵇ All lyso-SM analogues and bile acid derivatives are elevated in ASMD.
• ᶜ I-cell disease (ML-II and -III) can give a false positive result (very different clinical features).
• ᵈ ASMD can give a similar filipin pattern.
• ᵉ Check allele segregation by parental study or other test.

Introduction

NPC arises from mutations in the NPC1 or NPC2 genes, which disrupt the intracellular handling and trafficking of low-density lipoprotein (LDL) cholesterol and various macromolecules, such as glycosphingolipids. NPC occurs across all ethnic groups, is estimated to have a minimum incidence of 1 in 120 000 live births in Europe, and follows an autosomal recessive inheritance pattern (Patterson M, et al. 2025). The condition is linked to 2 distinct genetic loci: NPC1, found on chromosome 18q11–q12, and NPC2 (also known as HE1), located on chromosome 14q24.3 (Naureckiene S, et al. 2000; Vanier MT. 1997).

Variants in NPC1 are responsible for approximately 95% of diagnosed cases, whereas mutations in NPC2 account for about 4%. A variant historically referred to as Niemann-Pick type D is an allelic form of NPC caused by a specific point mutation in NPC1 (Winsor EJ, Welch JP. 1978).

The NPC1 gene encodes a large membrane-associated glycoprotein that resides mainly in late endosomes and is essential for regulating intracellular LDL-cholesterol transport and distribution (Carstea ED, et al. 1997). When this pathway is disrupted, cholesterol and other lipids accumulate within cells, particularly neurons, leading to progressive neurodegeneration (Patel SC, et al. 999).

The NPC2 gene produces a small, soluble protein located in lysosomes, historically referred to as a cholesterol-binding protein (Naureckiene et al, 2000). Mutations in either NPC1 or NPC2 lead to the accumulation of unesterified cholesterol and glycolipids within late endosomes and lysosomes, resulting in a shared biochemical profile. Both proteins are critically involved in the intracellular movement of cholesterol, sphingosine, and, potentially, other lipids (Platt FM, et al. 2023; Vanier MT, et al. 2022).

General Features by Age of Onset

NPC can manifest at any age, from the perinatal period through late adulthood. In over 85% of cases, systemic involvement—affecting the liver, spleen, or lungs—appears before the onset of neurological symptoms (Vanier MT, et al. 2010).

Perinatal Onset

Perinatal presentation of NPC often begins with prolonged cholestatic jaundice and liver dysfunction due to hepatic infiltration. Prenatal ultrasound may reveal findings such as hepatosplenomegaly, ascites, or non-immune hydrops fetalis (Spiegel R, et al. 2009; Kelly DA, et al. 1993). In some cases, respiratory complications arise from pulmonary involvement, including alveolar proteinosis or a similar syndrome, which can present alongside or independently of liver disease (Bjurulf B, et al. 2008). While jaundice typically resolves within 3 to 4 months after birth, it may persist in some infants, and approximately 10% progress to life-threatening hepatic failure during the neonatal period (Kelly DA, et al. 1993).

Early Infantile Onset (Age 2 Months to 2 Years)

Early infantile onset of NPC typically occurs between 2 months and 2 years of age. Affected children often have a history of prolonged neonatal jaundice or hepatosplenomegaly before neurological signs emerge. Early neurologic features may include delayed motor development, central hypotonia, tremors, and poor trunk control. As the disease progresses, these children may experience loss of previously acquired motor abilities, cognitive decline, spasticity, and dystonia. VSGP can occur at this stage, although it is often subtle and easily missed (Berry-Kravis E. et al. 2021).

In some circumstances, an infantile form of NPC can be primarily presented by hypotonia and developmental delay, with minimal or absent liver and lung involvement (Vanier MT, et al. 1988).

Late Infantile Onset (Age 2 to 6 Years)

Late infantile onset of NPC emerges between the ages of 2 and 6 years. Hepatosplenomegaly is commonly present before neurological symptoms appear, and some children may have experienced cholestatic jaundice during the neonatal period (Geberhiwot T, et al. 2018). Early neurological signs often include clumsiness, impaired fine motor coordination, gait disturbances, falls, delayed speech or language development, and VSGP. Additional features may include cerebellar tremor, gelastic cataplexy—with or without narcolepsy—and sensorineural hearing loss. As the disease progresses, affected children may develop increasing ataxia, dystonia, spasticity, cognitive decline, seizures (either focal or generalized), and difficulty swallowing (Berry-Kravis E, et al. 2021).

Juvenile Onset (Age 6 to 15 Years)

Juvenile onset of NPC typically begins between ages 6 and 15, following normal early development (Geberhiwot T, et al. 2018). While hepatosplenomegaly may be observed, it is not consistently present in this age group. Neurologically, children often first exhibit signs of cerebellar dysfunction, such as clumsiness and balance issues that progress to overt ataxia, along with gradual cognitive decline. Difficulties with learning and language loss may emerge over time. VSGP is commonly seen early in the disease course. Gelastic cataplexy—sudden loss of muscle tone triggered by laughter—is reported in up to half of affected individuals and is often accompanied by abnormal sleep studies. As the condition advances, patients may develop progressive dystonia, slurred speech, and swallowing difficulties, and about one-third experience seizures. Most individuals in this group succumb to complications such as aspiration pneumonia between their second and fourth decades of life (Berry-Kravis E. et al. 2021; Patterson M, et al. 2025).

Adult Onset (Age 15 Years and Older)

Adult onset of NPC begins at age 15 or later, and may resemble the juvenile form in terms of symptoms, such as ataxia, VSGP, and cognitive decline, but generally follows a slower clinical course (Patterson M, et al. 2025). Some individuals may have a history of unrecognized childhood signs, including splenomegaly or learning difficulties. In many adult cases, the initial presentation includes psychiatric or cognitive symptoms (Geberhiwot T, et al. 2018). In fact, psychiatric manifestations are the first noticeable signs in at least one-third of adult-onset patients (Berry-Kravis E, et al. 2021). Conditions such as depression, bipolar disorder, schizophrenia, or early-onset dementia may be the only clinical clues for some time (Josephs KA, et al. 2003; Sullivan D, et al. 2005). In others, subtle early features—such as isolated splenomegaly, hepatomegaly, hearing impairment, learning challenges, or impaired vertical gaze—may precede neurological decline that becomes apparent only in adulthood (Sévin M, et al. 2007).

Evaluation and Diagnosis

NPC should be considered when clinical features are suggestive, particularly in combination with positive biomarker screening such as elevated oxysterols. The findings most strongly linked to NPC include:

VSGP

Gelastic cataplexy, which is highly specific though not sensitive for NPC

Unexplained isolated splenomegaly, with or without concurrent hepatomegaly

Prolonged neonatal jaundice or cholestasis

Early-onset cognitive decline or dementia, which is common but not unique to NPC.

Additional clinical features that are moderately associated with NPC include:

Ataxia, frequent stumbling, or clumsiness

Slurred speech (dysarthria) and/or difficulty swallowing (dysphagia)

Dystonia, or involuntary muscle contractions causing abnormal postures

Psychotic symptoms, such as delusions or hallucinations.

Confirming a Diagnosis of NPC

Once clinical suspicion is raised, the diagnostic workup should begin with NPC-specific biomarkers or, in cases with strong suspicion, direct genetic testing. Both approaches are appropriate, and gene testing is increasingly used as a first-line tool. If genetic results are inconclusive or do not identify biallelic pathogenic variants, filipin staining in cultured skin fibroblasts can provide diagnostic confirmation (Wijburg FA, et al. 2012).

Biomarker Testing

In individuals with suspected NPC, the first-line biomarker assessment typically involves measuring oxysterols, with cholestane-3β,5α,6β-triol being the preferred marker. This assay offers high sensitivity (97–100%) and reasonable specificity (89–100%). An alternative marker—a bile acid derivative of cholestane triol (C-triol; specifically, the glycine-conjugated trihydroxycholanic acid)—may provide even greater specificity (Schiffmann R. 2025). Biomarker testing has largely supplanted skin biopsy with fibroblast culture in the diagnosis of NPC, as it offers faster results and greater sensitivity (Pajares S, et al. 2015).

Genetic Testing

Diagnosis of NPC is confirmed when pathogenic variants are identified on both alleles of either the NPC1 or NPC2 genes through gene panel analysis or whole-exome sequencing. Mutations in NPC1, located on chromosome 18q11, account for roughly 95% of cases, while fewer than 5% involve NPC2, found on chromosome 14q24.3 (Patterson MC, et al. 2017; Patterson M, et al. 2025; Park WD, et al. 2003).

Skin Biopsy

When biomarker testing and initial genetic analysis are inconclusive, such as when variants of uncertain significance are identified, a skin biopsy may help confirm the diagnosis of NPC. This involves culturing fibroblasts from a skin sample, exposing them to LDL-derived cholesterol in a lipoprotein-deficient medium, and performing filipin staining. A positive result shows bright, punctate fluorescence near the nucleus, indicating the accumulation of unesterified cholesterol. Cholesterol esterification studies typically reveal impaired processing of LDL-derived cholesterol. While useful in select cases, this method is time-intensive and less sensitive than biomarker assays. Additionally, specialized centers may use electron microscopy to identify polymorphous cytoplasmic inclusion bodies in fibroblasts—findings that are diagnostic when present (Jiang X, et al. 2011; Imrie J, Wraith JE. et al. 2001).