Daniel’s case highlights how NPC can initially mimic more common adolescent neurological and psychiatric disorders, including ADHD and epilepsy. His early symptoms—declining concentration, behavioral change, staring spells, and academic deterioration—made the initial ADHD diagnosis understandable, particularly in the absence of obvious systemic findings such as hepatosplenomegaly or cerebellar ataxia (both of which were absent in this case). Similarly, the intermittent staring episodes and nonspecific EEG slowing created a reasonable concern for seizure-related pathology.

However, the key clinical lesson is that progressive neurological symptoms and the emergence of objective neurological findings should prompt reconsideration of the original diagnosis. Although not all patients with ADHD respond adequately to stimulant therapy, Daniel continued to demonstrate progressive cognitive and behavioral decline despite treatment. The subsequent development of dysarthria, dystonic posturing, and especially VSGP represented important neurological “red flag” findings that are not explained by uncomplicated ADHD and warranted further investigation for an underlying neurodegenerative disorder.

Careful reassessment of the diagnosis, combined with targeted neurological examination and metabolic investigation, ultimately revealed elevated pathogenic NPC1 variants, confirming juvenile-onset NPC. This case emphasizes the importance of revisiting initial assumptions when the clinical course becomes atypical, progressive, or treatment-resistant, particularly in adolescents with evolving neuropsychiatric symptoms.

Neurological Features of NPC¹⁴

Strong Indicators of NPC

VSGP (impaired voluntary vertical eye movements)

VSGP is one of the most characteristic neurological manifestations of NPC and is observed in the majority of affected individuals. It is characterized by impaired voluntary vertical eye movements, particularly affecting rapid and coordinated upward and downward gaze. Although VSGP is often among the earliest detectable neurological signs of NPC, it may be subtle initially and is frequently underrecognized in clinical practice or by relatives.

Early manifestations typically involve slowing or limitation of vertical saccadic eye movements during late childhood or adolescence. As the disease progresses, horizontal saccades may also be affected. Patients commonly compensate for impaired vertical gaze by moving their head rather than their eyes when tracking objects.

Assessment for VSGP should include examination of:

• smooth pursuit eye movements—the ability to continuously track a moving target smoothly;
• saccades—rapid voluntary eye movements between fixation points; and
• vergence movements—coordinated inward and outward eye movements required to maintain focus on objects at different distances.

Vertical supranuclear saccade palsy (VSSP) (impaired rapid vertical eye movements)

VSSP is an early ocular motor abnormality frequently associated with NPC. It affects the ability to perform rapid voluntary vertical eye movements (saccades), particularly in the upward and downward directions. VSSP often precedes the development of more generalized VSGP and may represent one of the earliest neurological manifestations of NPC.

Clinical assessment for VSSP involves evaluating the patient’s ability to rapidly shift gaze between fixed visual targets. Early findings may include slowed, delayed, or hypometric vertical saccades, while smooth pursuit movements can initially remain relatively preserved.

Gelastic cataplexy (emotion-triggered transient loss of muscle tone)

Gelastic cataplexy is a characteristic but underrecognized neurological manifestation of NPC. It is defined by brief episodes of sudden muscle tone loss triggered by emotional stimuli, most commonly laughter, without associated loss of consciousness.

Episodes may involve the neck, jaw, facial muscles, or lower limbs, resulting in transient head drops, jaw slackening, knee buckling, or sudden falls. Symptoms are typically short-lived, with rapid spontaneous recovery.

Evaluation for gelastic cataplexy relies primarily on detailed clinical history, particularly identification of recurrent emotionally triggered “drop attacks” or transient postural collapse occurring in the absence of impaired awareness or postictal symptoms.

Moderate Indicators of NPC

Ataxia (impaired coordination and balance)

Ataxia is a common neurological manifestation of NPC and is characterized by impaired coordination, gait instability, clumsiness, and frequent falls. Symptoms may emerge during late childhood or adolescence and typically progress over time, affecting gait, fine motor function, speech, and balance.

In milder or early-stage disease, affected individuals may appear unusually cautious during movement, avoid running, walk more slowly than peers, or demonstrate subtle difficulty with coordinated hand movements.

Clinical assessment of ataxia may include:

• 10-meter walk test—evaluates gait speed and walking pattern over a defined distance;
• tandem gait assessment—evaluates balance and coordination during heel-to-toe walking; and
• standardized ataxia rating scales, including:
• International Cooperative Ataxia Rating Scale
• Brief Ataxia Rating Scale, and
• Scale for the Assessment and Rating of Ataxia.

These tools assist in quantifying disease severity and monitoring neurological progression over time.

Dysarthria (speech impairment due to impaired motor control)

Dysarthria is a frequent neurological feature of NPC and is characterized by slurred, slowed, or poorly articulated speech resulting from impaired control of the muscles involved in speech production, including the tongue, lips, jaw, and palate.

Affected individuals may demonstrate reduced speech clarity, altered speech rhythm, abnormal vocal volume, or difficulty controlling pitch and tone. Dysarthria in NPC commonly occurs alongside other neurological manifestations such as ataxia and dystonia, reflecting progressive involvement of motor control pathways.

Assessment of dysarthria may include:

• Frenchay Dysarthria Assessment—evaluates speech motor function and articulation abnormalities; and
• Neurological imaging studies—performed to investigate associated neurodegenerative or structural abnormalities contributing to speech dysfunction.

Dysphagia (difficulty swallowing)

Dysphagia is an important neurological manifestation of NPC and may develop as the disease progresses. Early symptoms can include difficulty swallowing liquids, prolonged eating time, coughing during meals, or choking episodes.

Progressive dysphagia increases the risk of aspiration, recurrent lower respiratory tract infections, aspiration pneumonia, dehydration, and malnutrition. In more advanced disease, impaired swallowing and reduced airway protection can become major contributors to respiratory morbidity, reduced quality of life, and disease-related complications.

Assessment of dysphagia may include:

• Videofluoroscopic swallow study—dynamic radiographic evaluation of swallowing function during ingestion of liquids and solids;
• fiberoptic endoscopic evaluation of swallowing—endoscopic assessment of pharyngeal swallowing and aspiration risk; and
• Clinical swallowing assessment—bedside evaluation of feeding, swallowing safety, and oral motor function performed by speech-language therapists or dysphagia specialists.

Early recognition and monitoring of dysphagia are important to reduce aspiration-related complications and support nutritional management. As swallowing function declines, enteral feeding support may become necessary. Gastrostomy tubes are frequently considered in patients who cannot swallow safely or who are unable to maintain adequate nutrition, hydration, or weight through oral intake alone.

Dystonia (involuntary muscle contractions and abnormal posturing)

Dystonia is a recognized neurological manifestation of NPC, particularly in adolescent- and adult-onset disease. It is characterized by sustained or intermittent involuntary muscle contractions resulting in abnormal movements, repetitive twisting motions, or abnormal posturing affecting areas such as the hands, neck, face, or lower limbs.

Symptoms may fluctuate in severity and can interfere with fine motor tasks, gait, speech, and daily activities. In NPC, dystonia often occurs alongside other progressive neurological features, including dysarthria, cognitive decline, and ocular motor abnormalities.

Clinical evaluation of dystonia primarily involves a detailed neurological examination assessing muscle tone, posture, involuntary movements, and task-specific motor abnormalities.

Other Indicators of NPC

Additional Neurological Features That May Raise Suspicion for NPC

Spasticity (progressive muscle stiffness and increased tone)

Spasticity is characterized by gradually increasing muscle stiffness and resistance to movement resulting from upper motor neuron dysfunction. Symptoms may progress slowly over time and can contribute to gait impairment, reduced mobility, muscle tightness, and difficulty performing coordinated movements.

Clinical assessment includes neurological examination, evaluating muscle tone, reflexes, range of motion, and motor function.

Hypotonia (reduced muscle tone)

Hypotonia refers to decreased muscle tone resulting in reduced resistance to passive movement and a “floppy” appearance, particularly in infants and young children. Affected individuals may demonstrate poor posture, delayed motor development, reduced strength, or difficulty maintaining sitting and standing positions.

Assessment involves neurological and developmental examination, evaluating muscle tone, posture, strength, and motor milestones.

Delayed developmental milestones (developmental delay and cognitive impairment)

Children with NPC may demonstrate delayed acquisition of developmental milestones, including speech, language, and motor skills. Over time, developmental delay may evolve into progressive cognitive impairment, learning difficulties, or intellectual decline.

Evaluation typically includes developmental screening, neuropsychological assessment, and formal cognitive testing where appropriate. Educational and vocational support should also be considered, including individualized educational plans, school accommodations, and workplace or vocational program modifications to help maintain cognitive, social, and physical participation. As the disease progresses, increasing cognitive and physical impairment may significantly affect academic achievement, employment, independence, and activities of daily living, and some individuals may ultimately be unable to continue formal education or employment.

Seizures (partial or generalized epileptic events)

Seizures may occur in individuals with NPC, particularly in late-infantile and juvenile-onset disease. Seizure types may include focal (partial) or generalized events and can present with staring episodes, involuntary movements, altered awareness, or convulsive activity. In some patients, seizures may become difficult to control despite multiple antiseizure therapies.

Assessment generally includes neurological evaluation, EEG, and neuroimaging studies, where clinically indicated.

Myoclonus (sudden involuntary muscle jerks)

Myoclonus refers to brief, shock-like involuntary muscle jerks affecting an individual muscle or group of muscles. Movements are typically abrupt, irregular, and unpredictable in timing and distribution.

Clinical evaluation includes neurological examination assessing the frequency, distribution, triggers, and functional impact of involuntary movements, with electrophysiological testing considered in selected cases.

Psychiatric Symptoms of NPC

Psychiatric and Neurocognitive Features Associated With NPC

Presenile cognitive decline and dementia (progressive decline in cognitive function occurring before older adulthood)

Individuals with NPC may develop progressive cognitive impairment involving deterioration in memory, executive function, attention, abstract reasoning, and daily functioning. Early-onset cognitive decline may emerge during adolescence or adulthood and can progress to presenile dementia.

Assessment typically involves formal cognitive evaluation using standardized neuropsychological tools, such as the Mini-Mental State Examination or broader neurocognitive testing batteries, alongside neurological and functional assessment.

Psychotic symptoms (disturbances in perception, thought content, or reality testing)

Psychiatric manifestations of NPC may include psychotic symptoms such as hallucinations, paranoid delusions, delusional thinking, social withdrawal, agitation, aggressive behavior, or self-injurious behavior. In some individuals, psychiatric symptoms may precede overt neurological findings and initially lead to a primary psychiatric diagnosis.

As neurological abnormalities emerge—including impaired vertical eye movements, dysarthria, ataxia, dystonia, or dysphagia—reconsideration of an underlying neurodegenerative disorder such as NPC becomes important.

Clinical psychiatric assessment should evaluate symptom progression, behavioral changes, psychosis severity, cognitive decline, and associated neurological features.

Treatment-resistant psychiatric symptoms (psychiatric manifestations with poor response to standard therapy)

Individuals with NPC may present with psychiatric symptoms that respond poorly or incompletely to conventional psychiatric treatments, including antipsychotic medications, antidepressants, or behavioral interventions.

Progressive symptoms despite optimized psychiatric management should prompt reassessment for an underlying neurological or metabolic disorder, particularly when accompanied by cognitive decline or abnormal neurological examination findings.

Other psychiatric disorders (neuropsychiatric conditions associated with NPC)

A range of psychiatric disorders has been reported in individuals with NPC, including schizophrenia-spectrum disorders, depression, anxiety, mood instability, and behavioral dysregulation.

These symptoms may occur in isolation early in the disease course, contributing to delayed diagnosis before more characteristic neurological manifestations become apparent.

Disruptive and aggressive behavior in childhood or adolescence (behavioral dysregulation affecting social and educational functioning)¹⁵

Children and adolescents with NPC may exhibit irritability, impulsivity, emotional dysregulation, aggression, oppositional behaviors, or socially inappropriate behavior. Difficulties in school performance, interpersonal relationships, and adherence to rules may become increasingly apparent over time.

Behavioral changes are often initially attributed to primary psychiatric or developmental disorders before progressive neurological features emerge.