Niemann-Pick Disease Type C

Niemann-Pick Type C (NPC) is a rare inherited neurodegenerative disease that affects infants, children and adults. It is caused by an accumulation of lipids (fats) in the liver, brain and spleen. The age of onset and rate of disease progression can vary greatly from person to person; for example some children develop neurological symptoms early in childhood, whereas others may remain symptom free for a number of years.

It is inherited when two copies of a faulty gene (a mutation) are passed on to a child. In every pregnancy of a couple who each carry a copy of the faulty Niemann-Pick gene, there is a 1 in 4 chance (25%) that their child will have Niemann-Pick disease. This is known as autosomal recessive inheritance.

NPC is divided into two subtypes, NPC1 and NPC2, as each is caused by a different gene mutation. Approximately 95 per cent of NPC cases are caused by genetic mutations in the NPC1 gene, with the other five per cent caused by mutations in the NPC2 gene.

The incidence of NPC is widely reported at 1 in 100,000, although recent evidence suggests this may be an under-estimate.

Niemann-Pick disease Type C (NPC) is caused by an accumulation of cholesterol and other fatty substances in the liver, brain and spleen.

Niemann-Pick disease Type C (NPC) diagnosis is challenging due to its non-specific, variable symptoms. Modern diagnostic methods have largely replaced older approaches, focusing on:

1. Biomarker Testing: Blood tests measuring biomarkers, such as oxysterols (e.g., cholestane-3β,5α,6β-triol) or lysosphingolipids, are now standard for initial screening. These non-invasive tests are highly sensitive for NPC and guide further investigation.
2. Genetic Testing: DNA analysis, typically using blood or saliva, identifies mutations in the NPC1 or NPC2 genes. Advances in next-generation sequencing and gene panels have improved access, though testing is mainly conducted at specialist centres. Known family mutations can simplify the process.
3. Skin Biopsy (Less Common): Once used to detect fatty substance accumulation in cells, this invasive method is now rarely needed due to reliable biomarker and genetic tests, but may be used in unclear cases.

These combined approaches enable quicker, more accurate diagnosis, minimising invasive procedures. Availability may vary, with specialist centres required for confirmation.

Symptoms of Niemann-Pick disease Type C (NPC) vary with age of onset and from patient to patient.They may include:

• Jaundice at (or shortly after) birth
• An enlarged spleen and/or liver (hepatosplenomegaly)
• Difficulty with upward and downward eye movements (Vertical Supranuclear Gaze Palsy)
• Unsteadiness of gait, clumsiness, problems in walking (ataxia)
• Difficulty in posturing of limbs (dystonia)
• Slurred, irregular speech (dysarthria)
• Learning difficulties and progressive intellectual decline (cognitive dysfunction/dementia)
• Sudden loss of muscle tone which may lead to falls (cataplexy)
• Tremors accompanying movement and, in some cases, seizures
• Swallowing problems (dysphagia)

There is no cure for Niemann-Pick Disease Type C (NPC), but patients can benefit from palliative treatments to manage symptoms, such as medications tailored to individual needs. Occupational therapy may also help improve posture, speech, and movement.

Approved Treatments

Miglustat (Zavesca®)

In 2009, the European Medicines Agency (EMA) approved the use of Zavesca® (miglustat) for the treatment of progressive neurological manifestations in adult and pediatric patients with NPC. Miglustat, an inhibitor of glucosylceramide synthase, has been shown to delay the progression and stabilize certain neurological symptoms by reducing glycosphingolipid accumulation in the brain. However, miglustat is not suitable for all patients, and its use should be discussed with a healthcare provider to evaluate potential benefits and risks.

FDA-Approved Treatments (United States)

In 2024, the U.S. Food and Drug Administration (FDA) approved two new treatments for NPC, which are not yet approved in the UK:

• Miplyffa (arimoclomol): Approved on September 20, 2024, Miplyffa is an oral medication used in combination with miglustat to treat neurological symptoms associated with NPC in adults and children 2 years of age and older. It is the first drug specifically approved by the FDA for NPC. Clinical trials showed that Miplyffa, when used with miglustat, slowed disease progression as measured by the rescored 4-domain NPC Clinical Severity Scale (R4DNPCCSS), assessing ambulation, speech, swallowing, and fine motor skills. Potential side effects include hypersensitivity reactions, such as hives and angioedema.

• Aqneursa (levacetylleucine): Approved on September 24, 2024, Aqneursa is a stand-alone therapy for neurological symptoms associated with NPC in adults and pediatric patients weighing at least 15 kg. Its efficacy was demonstrated in a 24-week crossover study using a modified Scale for the Assessment and Rating of Ataxia (fSARA), showing improvements in gait, sitting, stance, and speech. Common side effects include abdominal pain, dysphagia, upper respiratory tract infections, and vomiting.