Niemann-Pick Disease Type C

Niemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and lipids inside of cells. This leads to the abnormal accumulation of these fatty substances within various tissues of the body, including brain tissue.[1] The accumulation of these substances damages the affected areas.

The estimated incidence of NPC is 1/120,000 live births reported world-wide. In the United States, prevalence from the epidemiology calculations of 2.9 per million approximates the number of NPC cases if disease awareness, screening and diagnosis efforts were enhanced.[2] NPC is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes.[3] NPC occurs in many different populations, but it occurs more often in people of Acadian and Bedouin descent. The onset of symptoms may affect individuals at different ages, from perinatal to adult. The severity of symptoms and progression of disease is highly individualized.

NORD’s Rare Disease Report on Niemann-Pick Disease Type C provides the main symptoms according to age group[4]:

Perinatal NPC (shortly before or after birth)

  • Systemic symptoms

    • Fetal ascites (abnormal fluid in the abdomen, leading to swelling)

    • Hypotonia (weak muscle tone)

    • Hepatosplenomegaly (enlarged liver and spleen)

    • Jaundice (yellowing of the skin and eyes)

    • Thrombocytopenia (low platelet count)

    • Lung disease

    • Liver failure

    • Failure to thrive (poor growth and development)

  • Neurological symptoms

    • Hypotonia (weak muscle tone)

Early Infantile NPC (2 months to under 2 years)

  • Systemic symptoms

    • Hepatosplenomegaly or splenomegaly (enlarged liver or spleen, sometimes the only symptom)

    • Prolonged jaundice in newborns

  • Neurological symptoms

    • Central hypotonia (weak muscle tone affecting the core muscles)

    • Delayed developmental milestones (e.g., sitting, crawling)

    • Speech delay

    • Dysphagia (difficulty swallowing)

    • Spasticity (stiff or rigid muscles)

    • Vertical supranuclear gaze palsy (VSGP) – difficulty moving the eyes up and down

Late Infantile NPC (2 to under 6 years)

  • Systemic symptoms

    • Hepatosplenomegaly or splenomegaly (with or without neurological symptoms)

    • History of prolonged jaundice in newborns

  • Neurological symptoms

    • Developmental delays or regression (losing previously learned skills)

    • Speech delay

    • Clumsiness and frequent falls

    • Progressive ataxia (loss of coordination)

    • Dystonia (involuntary muscle contractions)

    • Dysarthria (speech difficulties)

    • Dysphagia (trouble swallowing)

    • Seizures (partial or generalized)

    • Cataplexy (sudden muscle weakness, often triggered by laughter)

    • Abnormal eye movements

    • Hearing loss

Juvenile NPC (6 to 15 years)

  • Systemic symptoms

    • Hepatosplenomegaly or Splenomegaly (may or may not be present)

  • Neurological and psychiatric symptoms

    • Poor school performance and learning disabilities

    • Loss of language skills

    • Frequent falls and clumsiness

    • Progressive ataxia

    • Dysarthria (slurred speech)

    • Dystonia (abnormal muscle movements)

    • Dysmetria (difficulty with coordination)

    • Dyskinesia (abnormal, involuntary movements)

    • Dysphagia (difficulty swallowing)

    • Abnormal eye movements (VSGP)

    • Gelastic cataplexy (sudden muscle weakness triggered by laughter)

    • Seizures

    • Behavioral problems

Adolescent and Adult NPC (15 years and older)

  • Systemic symptoms

    • Splenomegaly (may or may not be present; rarely, it is the only symptom)

  • Neurological and psychiatric symptoms

    • Cognitive decline (memory problems, difficulty thinking clearly)

    • Dementia

    • Learning disabilities

    • Psychiatric issues (e.g., schizophrenia, psychosis, depression)

    • Clumsiness

    • Progressive motor symptoms (tremors, difficulty walking, dystonia)

    • Dysarthria (difficulty speaking)

    • Dysphagia (difficulty swallowing)

    • Abnormal eye movements (VSGP)

Neurological and psychiatric symptoms (common across ages)

  • Seizures

  • Cataplexy (sudden muscle weakness, often triggered by emotions like laughter)

  • Dystonia (involuntary muscle contractions that cause abnormal movements or postures)

  • Tremors (shaking movements)

  • Sleep disturbances (e.g., narcolepsy or sleep apnea)

  • Psychiatric conditions (depression, obsessive-compulsive disorder, bipolar disorder, hallucinations)

End-stage disease

  • Progressive neurological decline, leading to death from complications such as

    • Aspiration pneumonia (caused by food or liquids entering the lungs)

    • Respiratory failure

    • Uncontrollable epilepsy.

Currently there is no cure for NPC. Treatment is supportive and includes both pharmaceutical and non-pharmaceutical management.[5] In September 2024, in a groundbreaking move, the FDA approved two drugs specifically for NPC. On September 20, 2024, the FDA approved Miplyffa (arimoclomol) in combination with the enzyme inhibitor miglustat to treat neurological symptoms associated with NPC in adults and children 2 years of age and older.[6]  Miplyffa is the first drug approved by the FDA to treat NPC. Four days later, on September 24, 2024, the FDA approved Aqneursa (Levacetylleucine) for the treatment of neurological symptoms associated with NPC in adults and pediatric patients weighing at least 15 kilograms.[7] Our experience with the three-drug regimen has had reimbursement costs from $1.2M-$2.8M/annually depending on dosage and contract. Orsini Specialty Pharmacy can source Miglustat and MIPLYFFA™ (arimoclomol). Curant Health is the exclusive specialty pharmacy for AQNEURSA™ (levacetylleucine) per IntraBio.[8]

Developing a gene therapy for NPC has some significant challenges including the large size of the NPC1 gene, ability for the therapy to cross the blood brain barrier to reach  affected cells in the central nervous system (CNS), and potential immune response to the viral vector. The NPC1 gene is very large, it spans more than 47 kilobases (kb) and  contains 25 exons;[9] in comparison, the Survival Motor Neuron 1(SMN1) for SMA spans approximately 20kb and contains 9 exons[10]. For the therapy to cross the blood brain barrier to reach the affected CNS cells, intrathecal injection would be necessary which brings additional risks for treatment  in addition to the risks associated with utilizing viral vectors such as off-target effects, toxicity, and immune responses.

The prognosis for Niemann-pick disease type C is generally poor, with patients often experiencing significant neurological deterioration and reduced lifespan. Early diagnosis and intervention are key to managing the disease and improving the quality of life for affected individuals.

Article by Kathy Clark, RN, BSN, CMCN, RIT, Vice President, Director of Managed Care. For more information about how this may affect your plan, please contact your Summit ReSources care specialist. The following sources were used as reference material for this article:

[1] NORD. Niemann Pick Disease Type C. https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/ Accessed 09.03.2025

[2] Burton BK, Ellis AG, Orr B, Chatlani S, Yoon K, Shoaff JR, Gallo D. Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States. Mol Genet Metab. 2021 Sep-Oct;134(1-2):182-187. doi: 10.1016/j.ymgme.2021.06.011. Epub 2021 Jul 1. PMID: 34304992.

[3] Vanier, M.T. Niemann-Pick disease type C. Orphanet J Rare Dis 5, 16 (2010). https://doi.org/10.1186/1750-1172-5-16

[4] NORD. Niemann Pick Disease Type C. https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/ Accessed 09.03.2025

[5] Jan M, Akbar HM, Ashfaque M, Khan ML, Talha M, Haque MA. FDA approval of Miplyffa and Aqneursa: A dual breakthrough for the treatment of Neimann-Pick disease type C. Alzheimers Dement (N Y). 2025 Feb 24;11(1):e70029. doi: 10.1002/trc2.70029. PMID: 39995598; PMCID: PMC11848562.

[6]FDA Approves First Treatment for Niemann-Pick Disease, Type C. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-niemann-pick-disease-type-c . Accessed 09/03/2025.

[7] FDA Approves New Drug to Treat Niemann-Pick Disease, Type C. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-niemann-pick-disease-type-c  Accessed 09/03/2025.

[8] Curant Health Selected By IntraBio as the Exclusive Specialty Pharmacy for AQNEURSA™ (levacetylleucine), the First Stand-Alone Therapy for Niemann-Pick Disease Type C. https://finance.yahoo.com/news/curant-health-selected-intrabio-exclusive-133000400.html Accessed 09/03/2025.

[9]NPC INTRACELLULAR CHOLESTEROL TRANSPORTER 1; NPC.  https://omim.org/entry/607623#:~:text=Morris%20et%20al.,the%20coding%20and%20intronic%20sequences. Accessed 09/03/2025.

[10] Burglen, L., Lefebvre, S., Clermont, O., Burlet, P., Viollet, L., Cruaud, C., Munnich, A., Melki, J. Structure and organization of the human survival motor neurone (SMN) gene. Genomics 32: 479-482, 1996. https://www.sciencedirect.com/science/article/abs/pii/S0888754396901470?via%3Dihub Accessed 09/03/2025.