A child with developmental delay, hypotonia, splenomegaly, and a history of neonatal jaundice may initially appear to have a nonspecific developmental or genetic disorder. However, the coexistence of developmental abnormalities and visceral involvement should raise suspicion for NPC.

In this case, markedly elevated plasma bile acid metabolites (TCG) and pathogenic NPC1 variants identified by WES confirmed the diagnosis, highlighting the importance of recognizing the early systemic manifestations of NPC. Timely biomarker testing and genetic evaluation can help reduce diagnostic delay and support earlier specialist referral in this progressive lysosomal storage disorder.

Fast Facts

• NPC is frequently overlooked or diagnosed late because early symptoms may appear nonspecific and are often attributed to isolated developmental delay, hypotonia, motor difficulties, or other common childhood developmental concerns. Hepatosplenomegaly may be subtle, overlooked on examination, or not recognized as part of a broader neurovisceral disorder.
• In infants and young children, NPC may initially present with developmental delay, hypotonia, splenomegaly, hepatomegaly, or a history of prolonged neonatal jaundice before the emergence of more characteristic neurological manifestations.
• The coexistence of visceral disease and developmental abnormalities or neurological symptoms should strongly prompt consideration of NPC.
• Biomarker testing (eg bile acid metabolites, oxysterols, and related NPC biomarkers) and genetic testing are complementary diagnostic tools in NPC. Depending on clinical suspicion, local practice patterns, test availability, and insurance considerations, clinicians may pursue biomarker testing, genetic testing, or both as part of the diagnostic evaluation.
• Earlier recognition of developmental delay, hypotonia, hepatosplenomegaly, and other early manifestations of NPC may help reduce diagnostic delay and facilitate specialist referral and disease-specific management.

The clinical presentation and survival of patients with NPC are highly variable and exist along a broad disease spectrum. In infants and children, NPC may first appear as a systemic disorder, with neurological features emerging gradually or remaining subtle in the early stages. Classification is primarily based on the age at onset of neurological symptoms, as this is strongly associated with disease progression and overall prognosis:¹⁹

• Pre/perinatal (<2 months)
• Early infantile (2 months–2 years)
• Late infantile (2–6 years)
• Juvenile (6–16 years)
• Adult (>16 years)

In the pre/perinatal period, NPC most commonly presents as a hepatic disorder, often characterized by prolonged cholestatic jaundice and hepatosplenomegaly. Some patients may also develop fetal ascites, hydrops fetalis, acute liver failure, and occasionally associated pulmonary involvement, although this is rare.

Neurological involvement in early infantile NPC is typically marked by hypotonia and delayed motor development. Most patients also have a history of hepatosplenomegaly and/or prolonged neonatal jaundice, although some infants may initially present predominantly with severe hypotonia without clear visceral manifestations. Pulmonary involvement can also occur in this age group.

Late-infantile NPC commonly presents with clumsiness, gait abnormalities, and impaired fine motor coordination. Additional features may include speech delay, seizures, pulmonary involvement, variable hepatosplenomegaly, and delayed or regressing developmental milestones. Many patients have a prior history of neonatal cholestasis. Vertical supranuclear saccadic palsy (VSSP), which may later progress to vertical supranuclear gaze palsy (VSGP), is frequently present but often overlooked during early assessment. In some cases, gelastic cataplexy, narcolepsy-like symptoms, or sensorineural hearing loss may represent the earliest neurological manifestations.

Juvenile-onset NPC typically presents with progressive cognitive difficulties, including declining academic performance, language impairment, and learning challenges. Neurological manifestations commonly include clumsiness, frequent falls, worsening ataxia, dystonia, seizures, and VSGP.

Adult-onset NPC may account for up to one-third of all cases. Patients commonly develop progressive cognitive impairment accompanied by a range of neurological manifestations. Psychiatric symptoms can occur across the disease spectrum; however, among NPC patients who do develop psychiatric manifestations, adult-onset disease is disproportionately represented. Diagnosis is often delayed, although recognition of characteristic eye movement abnormalities, particularly VSGP, can improve identification of the disease.

The clinical features of NPC are often nonspecific and may overlap with other neurological, developmental, cognitive, behavioral, or psychiatric conditions, frequently leading to delayed recognition of the underlying disease. Patients may initially be labeled as having learning difficulties, behavioral disorders, isolated ataxia, or primary psychiatric illness before the broader neurovisceral pattern becomes apparent. However, the presence of VSSP, VSGP, and/or cataplexy should raise a strong suspicion for NPC and may help distinguish it from alternative neurological disorders. While cataplexy is more commonly observed in late-infantile disease and juvenile disease, the combination of cataplexy and characteristic saccadic eye movement abnormalities is highly suggestive of NPC.

NPC-specific disease severity scales can support clinical assessment by helping evaluate disease burden, progression, and therapeutic response. In addition, objective oculomotor measures—including horizontal saccadic peak velocity and latency, vertical saccadic amplitude and duration, and smooth pursuit eye movements—can provide reliable indicators of disease status with low interobserver variability. However, detailed quantitative assessment of these parameters often requires specialized testing and evaluation by a neuro-ophthalmologist or other clinicians experienced in oculomotor disorders.

Investigations

Biochemical biomarker testing should be considered an important component of the diagnostic evaluation for NPC. Current biomarkers include oxysterols, lysosphingomyelin-509 (lyso-SM-509), and bile acid metabolites such as TCG. TCG is highly sensitive for NPC and is more specific than oxysterols, being elevated primarily in NPC and ASMD. Biomarkers may be used individually or in combination to improve diagnostic accuracy. Confirmation of the diagnosis is typically achieved through genetic testing of NPC-associated genes, although the diagnostic pathway may vary depending on clinical suspicion, local test availability, insurance coverage, and healthcare resources.

Any patient with clinical features or biomarker findings suggestive of NPC should undergo genetic testing of NPC-associated genes to confirm the diagnosis. Following confirmation, referral to a clinical geneticist or genetic counselor is recommended to support diagnostic interpretation, family counseling, and ongoing management. Family-based genetic evaluation should also be considered, as siblings may be affected despite having mild, atypical, or not-yet recognized manifestations of disease. Genetic testing can help identify affected family members, facilitate earlier diagnosis and monitoring, and determine carrier status among at-risk relatives.

The Niemann-Pick Disease Type C Clinical Severity Scale (NPCCSS)

The NPCCSS is an NPC-specific clinician-reported tool designed to assess and quantify disease progression over time. An abbreviated 5-domain version was developed to focus on the symptoms considered most clinically meaningful by patients, caregivers, and NPC specialists, specifically ambulation, fine motor skills, swallow, cognition, and speech. Each domain is scored from 0 to 5, generating a total score from 0 to 25, with higher scores reflecting greater neurological impairment. The 5-domain NPCCSS has demonstrated strong intrarater and interrater reliability and correlates closely with the original 17-domain scale, supporting its use in routine clinical practice to monitor disease burden, progression, and response to therapy.²⁰

Key Clinical Clues That Should Raise Suspicion for NPC

• Progressive clumsiness, gait instability, and frequent falls in a previously healthy child
• Cognitive decline or worsening school performance alongside neurological symptoms
• Dysarthria and progressive coordination impairment
• VSGP or slowed vertical saccades, particularly difficulty with upward gaze
• Combination of neurological findings with hepatosplenomegaly (“neurovisceral” presentation)
• History of prolonged neonatal cholestatic jaundice, hepatosplenomegaly, or unexplained splenomegaly in infancy or childhood, particularly when accompanied by progressive neurological symptoms
• Gradual progression over months to years rather than an acute presentation
• Brain MRI may demonstrate cerebellar atrophy or other neurodegenerative changes, particularly in more advanced disease, although normal neuroimaging does not exclude NPC
• Elevated plasma oxysterols suggesting impaired intracellular cholesterol trafficking
• Pathogenic variants in NPC1 or NPC2 identified on genetic testing, confirming the diagnosis of NPC