Niemann–Pick disease, type C Niemann–Pick disease, type C is associated with NPC1 mutations Classification and external resources Specialty endocrinology ICD-10 E75.2 (ILDS E75.230) ICD-9-CM 272.7 OMIM 257220 601015 607623 607625 DiseasesDB 33390 eMedicine derm/699 MeSH D052556 GeneReviews Niemann-Pick Disease Type C Niemann–Pick type C is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes.
Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade. Symptoms Niemann–Pick type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen (splenomegaly) and liver (hepatomegaly), or enlarged spleen or liver combined (hepatosplenomegaly), but this finding may be absent in later onset cases.
Prolonged jaundice or elevated bilirubin can present at birth. In some cases, however, enlargement of the spleen or liver does not occur for months or years – or not at all. Enlargement of the spleen or liver frequently becomes less apparent with time, in contrast to the progression of other lysosomal storage diseases such as Niemann–Pick disease, Types A and B or Gaucher disease. Organ enlargement does not usually cause major complications.
Progressive neurological disease is the hallmark of Niemann–Pick type C disease, and is responsible for disability and premature death in all cases beyond early childhood. Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia). Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with in turning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, progressive dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor.
In the terminal stages of Niemann–Pick type C disease, the patient is bedridden, with complete ophthalmoplegia, loss of volitional movement and severe dementia. Pathophysiology Niemann–Pick type C is biochemically, genetically and clinically distinct from Niemann–Pick Types A or and B. In Types A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase.
In Niemann–Pick type C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell.
The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes. Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell plasma membranes, which define the cell as a whole and its organelles. It is also the basic building block of steroid hormones, including neurosteroids. In Niemann–Pick type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis.
The accumulation of glycosphingolipids in the nervous system has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically. Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein. Neufeld et al. hypothesized that the accumulation of mannose 6-phosphate receptors (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans Golgi network.
 Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the trans Golgi Network cannot bud and form. Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1.
 Recent 2008 evidence indicates that NPC-1 may play an important role in calcium regulation. Genetics Approximately 95% of Niemann–Pick type C cases are caused by genetic mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene, referred to as type C2. The clinical manifestations of types Niemann–Pick types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes.
The NPC1 gene is located on chromosome 18 (18q11-q12) and was described by researchers at the National Institutes of Health in July 1997. The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. A deficiency of this protein leads to the abnormal buildup of lipids and cholesterol within cell membranes.
The NPC2 gene encodes a protein that binds and transports cholesterol. It has been shown to closely interact with NPC1. "Type D" variant Type D Niemann–Pick has only been found in the French Canadian population of Yarmouth County, Nova Scotia, and is now known to be allelic with Niemann–Pick type C. Genealogical research indicates that Joseph Muise (c. 1679–1729) and Marie Amirault (1684 – c.
1735) are common ancestors to all people with Type D. This couple is the most likely origin for the type D variant. Diagnosis Niemann–Pick type C is diagnosed by assaying cultured fibroblasts for cholesterol esterfication and staining for unesterified cholesterol with filipin. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the NPC1 or NPC2 genes in 80–90% of cases.
This specialized testing is available at Thomas Jefferson University Lysosomal Disease Testing Lab and the Mayo Clinic. Treatment There is no known cure for Niemann–Pick type C, nor is there any FDA-standard approved disease modifying treatment. Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialists in neurology, pulmonology, gastroenterology, psychiatrist, orthopedics, nutrition, physical therapy and occupational therapy.
Standard medications used to treat symptoms can be used in NPC patients. As patients develop difficulty with swallowing, food may need to be softened or thickened, and eventually, parents will need to consider placement of a gastrostomy tube (g-tube, feeding tube). An observational study is underway at the National Institutes of Health to better characterize the natural history of NPC and to attempt to identify markers of disease progression.
Arimoclomol In 2014 the European Medicines Agency (EMA) granted orphan drug designation to arimoclomol for the treatment of Niemann-Pick type C. This was followed in 2015 by the U.S. Food & Drug Administration (FDA). Dosing in a placebo-controlled phase II/III clinical trial to investigate treatment for Niemann-Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016.
 Arimoclomol, which is orally administered, induces the heat shock response in cells and is well tolerated in humans. Hydroxypropyl-beta-cyclodextrin (HPbCD) In April 2009, hydroxypropyl-beta-cyclodextrin (HPbCD) was approved under compassionate use by the U.S. Food and Drug Administration (FDA) to treat Addison and Cassidy Hempel, identical twin girls suffering from Niemann–Pick type C disease.
Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins' chest walls and allow doctors to directly infuse HPbCD into their bloodstreams. Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann–Pick type C mice and feline models.
This is the second time in the United States that cyclodextrin alone has been administered in an attempt treat a fatal pediatric disease. In 1987, HPbCD was used in a medical case involving a boy suffering from severe hypervitaminosis A. On May 17, 2010, the FDA granted Hydroxypropyl-beta-cyclodextrin orphan drug status and designated HPbCD cyclodextrin as a potential treatment for Niemann–Pick type C disease.
On July 14, 2010, Dr. Caroline Hastings of UCSF Benioff Children's Hospital Oakland filed additional applications with the FDA requesting approval to deliver HPbCD directly into the central nervous systems of the twins in an attempt to help HPbCD cross the blood–brain barrier. The request was approved by the FDA on September 23, 2010, and bi-monthly intrathecal injections of HPbCD into the spine were administered starting in October 2010.
On December 25, 2010, the FDA granted approval for HPbCD to be delivered via IV to an additional patient, Peyton Hadley, aged 13, under an IND through Rogue Regional Medical Center in Medford, Oregon. Soon after in March 2011, approval was sought for similar treatment of his sibling, Kayla, age 11, and infusions of HPbCD began shortly after. Both have since begun intrathecal treatments beginning in January 2012.
 In April 2011, the National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), announced they were developing a clinical trial utilizing cyclodextrin for Niemann–Pick type C patients. On September 20, 2011, the European Medicines Agency (EMA) granted HPbCD orphan drug status and designated the compound as a potential treatment for Niemann–Pick type C disease.
On December 31, 2011, the FDA granted approval for IV HPbCD infusions for a fifth child in the United States, Chase DiGiovanni, under a compassionate use protocol. The child was 29 months old at the time of his first intravenous infusion, which was started in January 2012. Due to unprecedented collaboration between individual physicians and parents of children afflicted with NPC, approximately 15 patients worldwide have received HPbCD cyclodextrin therapy under compassionate use treatment protocols.
Treatment involves a combination of intravenous therapy (IV), intrathecal therapy (IT) and intracerebroventricular (ICV) cyclodextrin therapy. On January 23, 2013, a formal clinical trial to evaluate HPβCD cyclodextrin therapy as a treatment for Niemann–Pick disease, type C was announced by scientists from the NIH's National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
A Phase I clinical trial is currently being conducted at the NIH Clinical Center. Other treatments under investigation One drug that has been tried is Miglustat. Miglustat is a glucosylceramide synthase inhibitor, which inhibits the synthesis of glycosphingolipids in cells. It has been shown to delay the onset of disease in the NPC mouse, and published data from a multi-center clinical trial of Miglustat in the United States and England and from case reports suggests that it may ameliorate the course of human NPC.
Several other treatment strategies are under investigation in cell culture and animal models of NPC. These include, cholesterol mobilization, neurosteroid (a special type of hormone that affects brain and other nerve cells) replacement using allopregnanolone, rab overexpression to bypass the trafficking block (Pagano lab) and Curcumin as an anti-inflammatory and calcium modulatory agent. The pregnane X receptor has been identified as a potential target.
 Neural stem cells have also been investigated in an animal model, and clear evidence of life extension in the mouse model has been shown. Low cholesterol diets are often used, but there is no evidence of efficacy. Prognosis The lifespan of patients with NPC is usually related to the age of onset. Children with antenatal or infantile onset usually succumb in the first few months or years of life, whereas adolescent and adult onset forms of Niemann–Pick type C have a more insidious onset and slower progression, and affected individuals may survive to the seventh decade.
Adult cases of NPC are being recognized with increasing frequency. It is suspected that many patients affected by NPC are undiagnosed, owing to lack of awareness of the disease and the absence of readily available screening or diagnostic tests. For the same reasons the diagnosis is often delayed by many years. Research directions Loss of myelin in the central nervous system is considered to be a main pathogenic factor.
Research uses animal models carrying the underlying mutation for Niemann-Pick disease, e.g. a mutation in the NPC1 gene Niemann-Pick type C disease. In this model the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased.MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths. A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.
 Recent neuroimaging studies have shown patients with Niemann-Pick, type C to have a corpus callosum with microstructural abnormalities. Clear reductions in corpus callosum mean thickness and surface area have been shown when compared to age-matched controls. Also, studies using diffusion tensor imaging have shown marked reductions in callosal fractional anisotropy, which suggests architectural abnormalities based on the directional flow of water.
 These conclusions suggest that the corpus callosum plays an important role in the disease and should be explored for use as a biomarker of disease progression. Parents of children with NPC are being studied in an attempt to gain insight into the Ebola virus, which uses the protein encoded by NPC1 to enter cells. Researchers have found that mice with one normal copy of the NPC1 gene are more likely to survive Ebola infection than mice with normal two copies of the gene.
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^ Marcus, Amy Dockser (2 November 2014). "Researchers Study Ebola Link to Gene in Rare Disease". Retrieved 12 August 2016 – via Wall Street Journal. External links PubMed v t e (LSD) Inborn error of lipid metabolism: lipid storage disorders (E75, 272.7–272.8) Sphingolipidoses (to ceramide) From ganglioside (gangliosidoses) Ganglioside: GM1 gangliosidoses GM2 gangliosidoses (Sandhoff disease Tay–Sachs disease AB variant) From globoside Globotriaosylceramide: Fabry's disease From sphingomyelin Sphingomyelin: phospholipid: Niemann–Pick disease (SMPD1-associated type C) Glucocerebroside: Gaucher's disease From sulfatide (sulfatidoses leukodystrophy) Sulfatide: Metachromatic leukodystrophy Multiple sulfatase deficiency Galactocerebroside: Krabbe disease To sphingosine Ceramide: Farber disease NCL Infantile Jansky–Bielschowsky disease Batten disease Other Cerebrotendineous xanthomatosis Cholesteryl ester storage disease (Lysosomal acid lipase deficiency/Wolman disease) Sea-blue histiocytosis v t e Medicine Outline History Specialties andsubspecialties Surgery Cardiac surgery Cardiothoracic surgery Colorectal surgery Eye surgery General surgery Neurosurgery Oral and maxillofacial surgery Orthopedic surgery Hand surgery Otolaryngology (ENT) Pediatric surgery Plastic surgery Reproductive surgery Surgical oncology Thoracic surgery Transplant surgery Trauma surgery Urology Andrology Vascular surgery Internal medicine Allergy / Immunology Angiology Cardiology Endocrinology Gastroenterology Hepatology Geriatrics Hematology Hospital medicine Infectious disease Nephrology Oncology Pulmonology Rheumatology Obstetrics and gynaecology Gynaecology Gynecologic oncology Maternal–fetal medicine Obstetrics Reproductive endocrinology and infertility Urogynecology Diagnostic Radiology Interventional radiology Nuclear medicine Pathology Anatomical pathology Clinical pathology Clinical chemistry Clinical immunology Cytopathology Medical microbiology Transfusion medicine Other specialties Addiction medicine Adolescent medicine Anesthesiology Dermatology Disaster medicine Diving medicine Emergency medicine Mass-gathering medicine Family medicine General practice Hospital medicine Intensive-care medicine Medical genetics Neurology Clinical neurophysiology Occupational medicine Ophthalmology Oral medicine Pain management Palliative care Pediatrics Neonatology Physical medicine and rehabilitation (PM&R) Preventive medicine Psychiatry Public health Radiation oncology Reproductive medicine Sexual medicine Sleep medicine Sports medicine Transplantation medicine Tropical medicine Travel medicine Venereology Medical education Medical school Bachelor of Medicine, Bachelor of Surgery Bachelor of Medical Sciences Master of Medicine Master of Surgery Doctor of Medicine Doctor of Osteopathic Medicine MD–PhD Related topics Allied health Dentistry Podiatry Physiotherapy Nanomedicine Molecular oncology Personalized medicine Veterinary medicine Physician Chief physician History of medicine Book Retrieved from "https://en.
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Individuals with NPC can have onset of symptoms at different ages that have been grouped historically as: perinatal (shortly before and after birth), early infantile (3 months to < 2 years), late infantile (2 to < 6 years), juvenile (6 to < 15 years), and adult (15 years and greater). NPC affects neurologic and psychiatric functions, as well as various internal organs (visceral). Symptoms arise at different times and follow independent progression.
Visceral symptoms are more typically seen in individuals presenting at a younger age. Neurologic and psychiatric symptoms often occur slowly over time, and thus feature more prominently in individuals presenting in the later age groups. Because NPC is a highly variable disorder, it is important to note that affected individuals will not have all of the symptoms described below and that every individual case is unique.
Some children will develop severe, life-threatening complications early in life; others have a mild disease that may go undiagnosed well into adulthood. Parents should talk to their child’s physician and medical team about the specific symptoms and overall prognosis. In perinatal NPC, the accumulation of fluid in the fetal abdomen (fetal ascites) may be present and persist after birth. These infants often have prolonged severe interruption or suppression of the flow of bile from the liver (cholestasis).
Features of cholestasis include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) or spleen (splenomegaly) is present in a high percentage of affected individuals in this age group. Lipid-containing (foam) cells may accumulate in the lungs, resulting in lung disease. Liver and lung disease can progress to cause life-threatening complications during this period.
Surviving individuals will develop neurological symptoms at a later age. In the early infantile period, affected individuals may present with abnormal enlargement of the liver or spleen as the only noticeable symptom (isolated hepato-/splenomegaly), and that may remain the only symptom for many years. In other cases, additional symptoms develop including lack of muscle tone (hypotonia) often by 1 or 2 years of age.
Affected individuals may also experience delays in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development). A characteristic early finding in children with NPC is impairment of the ability to look upward and downward (vertical supranuclear gaze palsy or VSGP). Specifically, affected children lose their ability to rapidly move their eyes up and down.
To compensate, they may blink their eyes, jerk their heads, or make abnormal movements. Eventually, vertical eye movements are lost, and side to side (horizontal) eye movements are also affected. Hearing loss can occur in some individuals with NPC. Affected individuals may develop high frequency sensorineural hearing loss, in which transmission of sensory inputs from the auditory nerves to the brain is impaired.
Up to 74% of individuals develop clinically significant hearing loss in at least one ear. Hearing loss may be the first problem seen in adults. The classic presentation of NPC occurs during middle to late childhood with clumsiness or difficulty in drawing and writing, often noted by teachers and parents. VSGP may be first reported during this time from a careful neurological exam or observations by the parents.
Other neurological abnormalities may be the first apparent symptoms, specifically lack of muscle coordination (cerebellar ataxia). Children with cerebellar ataxia often have difficulties with balance and trouble with walking (unsteady gait). They may fall frequently and be considered clumsy. Affected children may also experience progressive difficulty speaking (dysarthria), resulting in slurred and eventually unintelligible speech.
Children may lose previously acquired speech skills. Difficulty swallowing (dysphagia) may also develop and can become progressively worse, so that modifications such as thickening fluids or using special utensils may be recommended. Eventually a feeding tube may be required to maintain adequate nutrition. The dysphagia can lead to trouble swallowing saliva and other secretions. This may result in the inhalation of foreign materials into the airways and lungs (aspiration pneumonia).
During this time, affected individuals may also develop slowly progressive impairment of intellectually ability (cognitive impairment) that can initially be mistaken for learning disabilities. Furthermore, psychiatric disturbances and the progressive loss of memory and intellectual ability (dementia) can develop. Additional neurologic findings can include drooling, epileptic seizures, and cataplexy.
Cataplexy is characterized by a sudden loss of muscle tone and strength that can cause a sudden head drop, a weak, rubbery sensation in the legs, or in severe cases collapse. Cataplexy is often caused by strong emotions, typically laughter, in individuals with NPC (gelastic cataplexy). Dystonia, a large group of movement disorders, is also common. Dystonia is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures).
Some individuals may develop a tremor marked by rhythmic, jerking movements (myoclonic tremor). Sleep disturbances or irregularities such as narcolepsy or sleep apnea have also been reported. Adolescent or adult onset of NPC may be associated with a similar neurological presentation as in childhood onset. However, the rate of progression is often much slower. Specific manifestations may vary, but can include cerebellar ataxia, dysarthria, dysphagia, cognitive impairment, and other movement disorders such as dystonia or tremor.
VSGP is invariably present, but can be difficult to appreciate initially. Although systemic symptoms are more common in infancy or childhood, they can also occur in individuals with adolescent or adult onset NPC. Isolated splenomegaly may be the presenting symptom in some adolescents or adults. Psychiatric issues that have been described in individuals with adolescent onset of NPC include learning difficulties, behavioral problems, difficulty with expressive language, and attention deficit-hyperactivity disorder.
Psychotic or manic episodes may occur in some affected individuals. Adults greater than 30 years of age may experience impairment of executive functions (dysexecutive syndrome) characterized by problems with complex thinking and reasoning tasks such as difficulty with organization and planning. In some cases, older adults may first be misdiagnosed with dementia or psychiatric illness such as major depression or schizophrenia.
Individuals have been described in the medical literature with other psychiatric manifestations such as obsessive-compulsive disorder, bipolar disorders, and hallucinations. Following a long term gradual neurological decline death often results from aspiration pneumonia and subsequent respiratory failure, or intractable epilepsy not responding to medical intervention.