This case highlights the importance of maintaining a broad differential diagnosis when evaluating psychiatric symptoms with atypical features. George R. presented with treatment-resistant psychosis at age 31, followed by a progressive neurological decline marked by gait instability. His poor tolerance to multiple antipsychotics at low doses was overlooked as isolated or unrelated findings.

Over time, the failure of conventional psychiatric treatments and the emergence of subtle neurological signs should have prompted earlier consideration of an underlying neurodegenerative disorder. Ultimately, a targeted workup revealed the patient's NPC Suspicion Index score of 75, elevated oxysterols and lyso-SM-509, and biallelic pathogenic NPC1 mutations, confirming a diagnosis of NPC.

This case highlights the importance of clinicians recognizing the constellation of visceral, psychiatric, and neurologic signs that can evolve over time in NPC. Early suspicion and appropriate testing can reduce diagnostic delays and facilitate access to disease-modifying interventions and supportive care tailored to this rare condition.

Follow-up Planning

After diagnosis, long-term care should be guided by multidisciplinary follow-up, consistent with current guidelines. This includes pharmacological interventions, annual assessments of swallowing function, evaluation of nutritional status, physical therapy for mobility and spasticity, speech and communication support, and neurocognitive monitoring to track disease progression and adapt interventions accordingly (Schiffmann et al. 2025).

Overlooked Diagnostic Clues Suggestive of NPC

• This patient had a progressive psychiatric illness course despite appropriate psychiatric treatment, with multiple relapses and minimal sustained improvement.
• Adverse reactions to psychotropic medications, including extrapyramidal symptoms at low doses, were attributed to drug sensitivity rather than raising suspicion for an underlying disorder.

Clinical Pearls

• Cognitive impairment is a hallmark feature of adult-onset NPC and often coexists with neurological manifestations (Rego T, et al. 2019).
• Patients presenting with psychiatric symptoms combined with one or more of cognitive impairment, neurological symptoms, and visceral symptoms should be screened for NPC (Bonnot O, et al. 2017).
• In adults, psychotic and mood-related manifestations are predominant, whereas children exhibit a range of psychiatric features (Bonnot O, et al. 2017).
• Patients with undiagnosed NPC may show poor response or intolerance to psychotropic medications, especially antipsychotics (Bonnot O, et al. 2017).
• The International Niemann-Pick Disease Registry found that 34% of NPC patients presented with psychiatric symptoms, often alongside cognitive impairment, neurological signs, or visceral involvement (Bonnot O, et al. 2017).
• Atypical findings in NPC may include ataxia, splenomegaly, vertical supranuclear gaze palsy (VSGP), dysarthria, dysphagia, early-onset dementia, treatment-resistant psychiatric symptoms (especially in young adults), gelastic cataplexy, dystonia, and refractory epilepsy (Patterson MC, et al. 2017).

Overview

Niemann-Pick disease is an autosomal recessive disorder requiring mutations in both gene copies. Types A and B result from mutations in the SMPD1 gene, with over 180 variants identified. NPC is caused by mutations in the NPC1 (chromosome 18) or NPC2 (chromosome 14) genes, leading to defective lipid transport and intracellular accumulation (Xu Y, et al. 2019). NPC can present at any age and is frequently underdiagnosed or misdiagnosed (Geberhiwot T, et al. 2018).

The prevalence of NPC is estimated at approximately 1 in 150 000, increasing to 1 in 100 000 when including prenatal cases that did not result in live births. Early-life prevalence is likely underestimated due to nonspecific clinical presentations, and overall prevalence may exceed incidence estimates given the prolonged survival seen in later-onset forms of the disease (Vanier MT. 2010).

NPC largely depends on age at onset. Infantile-onset cases typically have poor survival beyond age 5, while individuals with later onset may live into their 20s. However, prognosis varies by patient based on disease severity and clinical presentation. Older adolescents and young adults may initially present with early-onset dementia or psychiatric symptoms. However, a thorough evaluation often reveals neurologic features of NPC. (Chen KJ. 2018).

NPC is classified into type C1 and type C2, depending on whether mutations occur in the NPC1 or NPC2 genes. NPC1 mutations account for approximately 95% of cases, with over 30 different pathogenic variants identified. The NPC1 and NPC2 proteins are located in late endosomes and lysosomes, where they play key roles in cholesterol and sterol transport. Loss of function in either protein impairs cholesterol egress from lysosomes, leading to pathological accumulation of unesterified cholesterol within cells. This lysosomal cholesterol build-up is toxic and ultimately results in progressive cellular dysfunction and multisystem organ damage (Bajwa H, Azhar W. 2023).

Neonatal and Infantile Presentations

In early life, NPC often presents as nonspecific signs that even experienced clinicians may miss. Some infants are identified prenatally due to fetal ascites and go on to develop severe neonatal liver disease, sometimes accompanied by pulmonary involvement due to foam cell infiltration. Many affected infants do not survive this stage; those who do may either exhibit ongoing hypotonia and developmental delay or recover temporarily and present with neurologic symptoms years later. Hepatosplenomegaly is common in infants with hepatic disease but may resolve over time, making organomegaly an unreliable diagnostic marker—its absence does not exclude NPC. Some children present primarily with hypotonia and developmental delay without initial liver or lung disease and may later develop VSGP and signs of progressive neurologic decline (Patterson M. 2000).

Pediatric Presentations

The classic onset of NPC typically occurs in mid-to-late childhood, beginning with clumsiness and gait disturbances that evolve into ataxia. Affected children often show early impairment in vertical gaze, with VSGP emerging as slowed or delayed vertical saccades, eventually progressing to horizontal gaze abnormalities in later stages. These physical symptoms are accompanied by subtle cognitive decline, initially mistaken for learning or behavioral issues, but eventually revealing global cognitive deterioration. Many children develop progressive dystonia, starting in one limb and spreading, along with worsening speech (dysarthria and dysphonia) and swallowing difficulties. Seizures—partial or generalized—occur in about one-third of patients, sometimes refractory to treatment, though they may lessen over time. Around 20% experience gelastic cataplexy, triggered by laughter and potentially causing injury due to sudden muscle tone loss. Rare features may include peripheral neuropathy and disrupted sleep linked to hypocretin deficiency, suggesting hypothalamic involvement (Patterson M. 2000).

Adolescent and Adult Presentations

In adolescents and adults, NPC may present with neurologic features similar to those seen in childhood, but with a slower progression. Some individuals have survived for decades after symptom onset. In this age group, initial presentation may resemble primary psychiatric illness, such as major depression, schizophrenia, or even bipolar disorder, often delaying diagnosis. While psychiatric symptoms may dominate early clinical impressions, careful neurologic examination typically reveals subtle signs of underlying neurodegeneration (Imrie J, et al. 2002).

Suggestive Findings

NPC should be suspected in individuals with the following clinical findings (Patterson M. 2000).

Early infantile (<2 years): fetal ascites or neonatal liver disease; prolonged jaundice and/or pulmonary infiltrates.

Late infantile (2 to <6 years): hypotonia and developmental delay; progressive clumsiness evolving into ataxia; vertical supranuclear saccadic palsy (VSGP).

Juvenile (6 to <15 years): initial clumsiness progressing to ataxia; academic difficulties (often misdiagnosed as ADHD); progressive cognitive decline and regression; VSGP is typically present before other neurologic signs; possible seizures, gelastic cataplexy, dystonia, and/or spasticity.

Adolescent/adult (>15 years): cognitive impairment or early-onset dementia; psychiatric symptoms (eg, treatment-resistant depression, psychosis, bipolar-like illness); full range of neurologic signs may eventually emerge.

Other presentations: isolated splenomegaly in childhood, with delayed neurologic symptoms; rare cases: splenomegaly without neurologic involvement in adulthood.

Atypical features (any age): ataxia, splenomegaly, VSGP, dysarthria, dysphagia; early-onset dementia; treatment-resistant psychiatric illness in young adults; gelastic cataplexy, dystonia, epilepsy (especially if refractory).

Diagnosis of NPC

Definitive diagnosis is made by identifying biallelic pathogenic or likely pathogenic variants in either NPC1 or NPC2 through molecular genetic testing.

“Likely pathogenic” and “pathogenic” are both considered diagnostic and valid for clinical decision-making. Variants of uncertain significance (VUS) do not confirm or rule out the diagnosis (Richards S, et al. 2015).

Establishing the Diagnosis of NPC when NPC is Initially Suspected

Diagnosis is confirmed by identifying biallelic pathogenic or likely pathogenic variants in NPC1 or NPC2 using molecular genetic testing (Geberhiwot, et al. 2018).

The preferred approach is gene-targeted testing using a multigene panel that includes: NPC1 and NPC2, other relevant genes associated with: lysosomal storage disorders, treatable neurometabolic conditions, mendelian psychiatric syndromes, metabolic causes of nonimmune hydrops fetalis.

Testing methods may include: sequence analysis; deletion/duplication analysis; custom phenotype-driven panels or targeted exome analysis.

Notes: a diagnosis cannot be confirmed if only one pathogenic variant and one VUS are found. Some laboratories offer flexible, customizable panels based on clinical input. Chromosomal microarray may detect large-scale deletions/duplications not picked up by sequencing.

Establishing the Diagnosis of NPC when NPC is not Initially Suspected

If NPC is not considered at the outset, diagnosis is typically made via comprehensive genomic testing: exome sequencing (most commonly used); genome sequencing (alternative option).

This approach does not require prior selection of candidate genes and is ideal when: the clinical presentation is nonspecific or atypical; there is diagnostic uncertainty despite extensive evaluation.