Niemann-Pick Disease Type C
Brief Summary of Disease
Niemann-Pick Disease Type C (NPC) is a progressive and fatal disease resulting in neurological delays beginning in childhood and endured by the individual for the rest of their life.1-2 The disease is characterized by the inability of the body to process cholesterol and lipids inside of cells. NPC is rare in nature, with an incidence of 0.82 cases per 100,000 live births and affects a variety of ethnic backgrounds.3 There is no particular age in which the disease manifests, and NPC affects both males and female equally.3
Etiology & Pathology
The disease manifests as a result of a mutation in either the NCP1 or NCP2, with a majority of individuals affected by the disease carrying a mutation in NPC1.2,4 The exact proteins encoded the NPC1 gene remains unknown. However, it is understood that the proteins play a role in transporting large molecules within cells.2,3 It is hypothesized that a genetic mutation in NCP1 is associated with inadequate levels of these particular transport proteins leading to an abnormal accumulation of cholesterol in nearby tissues, such as the spleen and the liver.2,3 The accumulation of cholesterol and glycosphingolipids - compounds that are made up of both fatty lipids and carbohydrates - are also present in the brain and give rise to the more noticeable cognitive symptoms.2,3
Symptoms
The onset of symptoms related to NPC is classified according to age group: perinatal, early infantile, late infantile, juvenile, and adult.2-5 Symptoms present during the perinatal age group (shortly before or after birth) include the accumulation of fluid in the fetal abdomen, suppression of the flow of bile from the liver resulting in yellowing of the skin, enlargement of the liver and spleen, and lung disease.2 Individuals who survive past the perinatal age group are likely to experience the neurological delays such as difficulty speaking and writing later in life. 2-5
During the infantile period (3 months to 2 years), commonly observed symptoms include a lack of muscle tone, delays in acquiring both mental and physical skills and, the loss of both vertical and horizontal movements (e.g. looking upward and downward).2-5 During the late infantile (2 to 6 years) and juvenile age group (6 to 15 years), impairment in cognitive function can be observed through difficulty with writing, lack of muscle coordination (cerebellar ataxia), difficulties balancing, unsteady gait, difficulty speaking, and difficulty swallowing.2-4 Moreover, at this age, impediments to intellectual ability are discernible which is often misdiagnosed as a learning disability.2,3
The symptoms related to the adult onset of NPC (15 years and older) are similar to the ones present in childhood. However, progression is often slower.2,3 Dystonia, a movement disorder characterized by involuntary muscle contractions, is a common symptom present in adult NPC. The development of tremors which can result in jerking movements is another noticeable symptom in adult NPC.2,4 Nonetheless, NPC is variable and consequently, the symptoms experienced by each individual can differ.
Diagnosis
Diagnosis relies on the observation of the symptoms related to NPC, which is usually obtained through a clinical evaluation and then confirmed by tests.2 To confirm the diagnosis of NPC, physicians conduct laboratory tests to identify the function of the accumulated protein in the patient's body and the presence of mutations in the NPC1 gene, which requires gene sequencing.2-4 Due to the rarity of NPC, there is limited knowledge regarding the diagnosis and treatment of the disease among physicians. A tool recently developed by clinical experts called the Suspicion Index Tool (SIT) attempts to bridge this gap. SIT creates a risk prediction score that is based on specific observations present in the individual (e.g. visceral, neurological, and psychiatric).2 The tool is able to diagnosis individuals regardless of age group, but still requires significant refinement and research to determine whether or not it is effective in practice.2
Prognosis
The average lifespan of an individual living with NPC can vary anywhere from a couple of days to 60 years of age.2 However, quality of life is severely impaired when an individual is diagnosed with NPC as most cases report death occurring between 10 and 25 years of age.2 Quality of life is severely impaired when an individual is diagnosed with NPC. Individuals may have to wear a helmet to protect their skull in the event of a seizure, and a leg brace to reduce the dragging of their feet while they are walking.1 The cognitive impediment can make academics difficult for children dealing with NPC, such as forgetting concepts learned during an entire school year over the course of a summer.1 The frustrations that come along with not remembering how to do basic maths and how to read can make living with NPC especially challenging.1-3
Children
Screening and detection of NPC at an early age will not always improve outcomes, as there is no available cure for the disease.2,3 However, an advantage associated with early detection is the avoidance of misdiagnosing NPC with dementia or psychiatric illnesses, such as schizophrenia, in older adulthood.2,3 It ensures that treatment is focused on specific symptoms of NPC and in turn, creates the most comfortable lifestyle for the patient.2,3
Current Research
Research in the field of NPC has focused on the development of a treatment that could work effectively to slow the progression of the disease, such as the drug miglustat (Zavesca®).2 Researchers hypothesize that miglustat prevents the production of glycosphingolipids, which is one of the molecules known to accumulate in the brain of those with NPC.2 Nonetheless, the efficacy of the drug poses problems and it has not been approved in all countries, which explains the necessity for more investigative therapies.2
In August 2017, Dr. Forbes D. Porter published on a breakthrough regarding treatment of NPC with
Relevant Resources
Canadian Chapter of the National Niemann-Pick Disease Foundation (CCNNPDF)
CCNPDF supports current research surrounding the treatment of NPC and offers services for individuals families who are affected by the disease. The organization promotes awareness of NPC and provides educational information that ensures the correct diagnosis and referral of individuals with NPC.
Works Cited:
1. Hankerson, M. Virginia Beach mom fights for her teen son's life as he struggles with rare disease. The Virginian-Pilot. 2018. Available from https://pilotonline.com/life/parenting/article_e344e207-837d-5220-84d6-aa255941e289.html
2. Niemann Pick Disease Type. National Organization for Rare Disorders. 2017. Available from https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/
3. Melancon S, Clark J, Sirrs SM, et al. Niemann-Pick type C (NPC): Canadian Management Guidelines. 2015. Available from http://www.garrod.ca/wp-content/uploads/NPC-Canadian-Guidelines-June-5-2015.pdf
4. Niemann-Pick Disease Type C. NPUK. 2018. Available from http://www.npuk.org/niemann-pick-disease/niemann-pick-type-c/
5. Evans, W, Hendriksz C. Niemann–Pick type C disease – the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment. BJPsych Bulletin. 2017;41(2):109-114. DOI: 10.1192/pb.bp.116.054072
6. Ory D, Ottinger A, Farhat N, et al. Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1–2 trial. The Lancet. 2017;390:1758-1768. DOI: 10.1016/S0140-6736(17)31465-4
7. Melville A. Intrathecal Therapy May Slow Fatal Niemann-Pick Disease. Medscape. 2017. Available from https://www.medscape.com/viewarticle/884593#vp_2
Cite This Article:
Rivas A, Chan G., Lewis K., Ho J. Niemann-Pick Disease Type C
. Illustrated by Wu W. Rare Disease Review. March 2020.
DOI:10.13140/RG.2.2.23191.52643.
