Symptoms of NPC

VSSP affects the ability to make fast, up-and-down eye movements (called 'saccades'). It typically appears earlier in NPC as one of the first disease symptoms, with VSGP emerging as the disease advances.

Tests for VSSP involve observing how well an individual can move their gaze between two fixed points.

Gelastic cataplexy is a sudden loss of muscle control (without loss of consciousness), usually triggered by an emotional reaction, such as laughter. Loss of muscle control may affect the legs, neck, or jaw, meaning cataplexy may cause sudden head drops, jaw drops, or even full-body collapses.

Tests for gelastic cataplexy involve reviewing an individual’s history of 'drop attacks' or loss of posture after an emotional reaction, such as laughing.

Ataxia is characterised by clumsiness, unsteadiness, or frequent falls, which can begin after late childhood and progressively worsen over time, affecting walking, hand movements or speech. Mild NPC may make children appear slow, opting to walk instead of run, or handle objects more cautiously.

Ataxia is assessed using tools such as:

• 10-meter walk test (measures walking speed and pattern over 10 meters)
• Tandem gait test (walking heel-to-toe in a straight line)
• Ataxia Rating Scales (standardised clinical rating tools)

Recommended ataxia rating scales include the International Cooperative Ataxia Rating Scale (ICARS),¹⁰ the Brief Ataxia Rating Scale,¹¹ and the Scale for the Assessment and Rating of Ataxia (SARA).¹²

Dysarthria, characterised by slurred, slow or irregular speech or pronunciation, arises when muscles used for speaking, like those in the mouth, jaw, and tongue, become harder to control. People with dysarthria may struggle to control their volume or pitch when speaking, which is linked to other NPC symptoms such as ataxia (poor muscle control) and dystonia (abnormal muscle control and spasms).

Tools to evaluate dysarthria include:

• Frenchay Dysarthria Assessment (assesses speech function)
• Neurological imaging (brain scans to identify possible causes of speech difficulties)

Early signs of dysphagia include difficulty swallowing liquids or coughing and choking while eating. In severe cases, food or liquid may enter the lungs (aspiration), which can lead to pneumonia, or malnutrition due to an inability to eat. This symptom typically manifests in adulthood among individuals with NPC.

Healthcare professionals assess dysphagia using:

• Videofluoroscopy (X-ray of an individual swallowing)
• Fiberoptic endoscopic evaluation of swallowing (FEES) (passing a thin, flexible tube with a camera and light through the nose to observe the throat and ability to swallow)
• Clinical observation (clinical feeding and swallowing evaluations with different types of food, conducted by speech-language therapists or dysphagia experts)

Dystonia results in abnormal, uncontrollable, or repetitive muscle movements or twisting in various parts of the body, such as the hands, feet, or face, and is more commonly observed in adolescents and adults with NPC. Typically, evaluation involves a physical examination. Although originally developed for Parkinson’s disease, the Unified Dystonia Rating Scale (UDRS) is a well-established clinical scale to assess the severity of dystonia in different areas of the body.¹⁵

Spasticity is characterised by the gradual development of muscle tightness or stiffness. It progresses slowly and worsens over time, making walking and movement increasingly difficult.

Hypotonia is characterised by low muscle tone, leading to limp or 'loose' muscles. This condition makes it more difficult for a person to sit, stand, or maintain good posture. Babies and young children with hypotonia may appear 'floppy' or exhibit weak muscle strength.

Children with NPC may take longer to reach important milestones, such as learning to walk or talk. These delays can manifest later as intellectual or cognitive challenges, where the individual struggles to learn or think at the same pace as others.

Individuals with NPC, particularly those with late-infantile or juvenile-onset NPC, may experience seizures resulting from abnormal electrical activity in the brain. These seizures can be partial (affecting one area of the brain) or generalised (involving the entire brain), leading to symptoms such as shaking, confusion, or loss of awareness, and they may not respond to treatment.

Myoclonus refers to sudden, jerky movements of a muscle or a group of muscles. These irregular movements occur without warning and can resemble twitches or quick, shock-like jerks.

Hepatosplenomegaly refers to an enlarged liver and spleen. In babies and young children, it often causes a swollen or bloated belly. This symptom is present in about half of individuals with NPC, though its severity can vary. It can be more challenging to detect in adults, as it typically doesn't cause obvious symptoms. If hepatosplenomegaly is suspected, healthcare professionals conduct an abdominal ultrasound to assess the size of the liver and spleen.

Jaundice is a yellowish tint to the skin and eyes caused by high bilirubin levels – substances produced by the breakdown of red blood cells – in the blood. It is a common early sign of NPC. When jaundice persists for more than two weeks in newborns, it is called prolonged neonatal jaundice. Diagnosis involves a blood test to measure bilirubin levels in the baby’s blood.

Another sign of neonatal jaundice is acholic stools (pale-coloured faeces), which parents can identify using a stool chart to compare their newborn’s stool with examples of healthy and unhealthy colours.

Hydrops fetalis is a life-threatening condition caused by the build-up of fluid in a baby’s body, leading to swelling. This swelling can occur both before birth (in the womb) and after birth. In severe cases, it may result in breathing difficulties, bruising, or even heart failure. Doctors can identify hydrops fetalis before birth through an ultrasound scan of the baby during pregnancy. After birth, it can be confirmed with a physical examination and additional imaging tests.

Often associated with hydrops fetalis, foetal ascites is the abnormal fluid build-up in the foetal abdomen, typically detected by ultrasound.

Pulmonary infiltrates are substances that accumulate in the lungs, such as fluid or cells, making it more difficult to breathe normally. Pulmonary infiltrates can be assessed using a chest X-ray.

Direct bilirubinaemia occurs when a type of bilirubin builds up in the blood. Elevated levels of direct bilirubin can mean that the liver is not efficiently processing and filtering bilirubin, which can be observed in conditions like NPC and may result in yellowing of the skin and eyes (jaundice). Diagnosis is performed through a blood or urine test that measures direct bilirubin levels, which can assist in distinguishing direct bilirubinaemia from other causes of jaundice.

Cholestasis occurs when the flow of bile – a fluid produced by the liver to aid digestion – from the liver to the duodenum (the first part of the small intestine) is reduced or obstructed. This leads to a build-up of bile acids and substances like direct bilirubin in the liver and bloodstream. The accumulation of direct bilirubin in the blood causes direct hyperbilirubinemia, which can present as prolonged jaundice in newborns (neonatal jaundice).

Diagnosis involves assessing liver function through a liver function test (LFT) or a bile acid test, which measures the levels of liver enzymes and bile acids in the blood.

Early-onset cognitive decline or dementia involves a progressive or persistent loss of brain function, particularly impacting memory and abstract thinking. This condition typically appears in individuals during their 30s, 40s, or 50s. A combination of cognitive tests, such as the Mini-Mental State Examination, and biological assessments is used to diagnose presenile cognitive decline or dementia.

Psychotic symptoms may appear in individuals with NPC as:

• Paranoid delusions (feeling like other people want to harm them)
• Hallucinations (hearing, seeing, or sensing things that aren’t there)
• Delusional ideation (believing things that aren’t based on reality)
• Aggressive behaviour (outbursts of anger or violence)
• Self-mutilation (intentionally injuring oneself)
• Social withdrawal (avoiding friends, family, and social situations)

Initially, these symptoms may be mistaken for psychiatric (mental health) conditions. However, as other NPC symptoms develop (like poor coordination, difficulty moving the eyes, and swallowing problems), healthcare professionals may reconsider NPC as the underlying cause.

Individuals with NPC may present psychotic symptoms that do not improve with standard treatments, such as medications and therapy.

Psychiatric disorders, particularly schizophrenia (a condition that can cause hallucinations, delusions, and disorganised thinking) and depression (persistent low mood and loss of interest in daily activities), are common among individuals with NPC.

Individuals with NPC may display antisocial behaviours, including angry outbursts, physical aggression towards others, and difficulties adhering to rules in various social and educational environments. These behaviours can create challenges in both school and home settings, and teachers may be among the first to observe them.