NORD gratefully acknowledges Forbes D. Porter, MD, PhD, Senior Investigator, Clinical Director; Simona E. Bianconi, MD, Staff Clinician; and An N. Dang Do, MD, PhD, Staff Clinician; National Institute of Child Health and Human Development, Program in Developmental Endocrinology and Genetics, Section on Molecular Dysmorphology, for assistance in the preparation of this report.
SummaryNiemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and other fatty substances (lipids) inside of cells. This leads to the abnormal accumulation of these substances within various tissues of the body, including brain tissue. The accumulation of these substances damages the affected areas. NPC is highly variable and the age of onset and specific symptoms can vary from one person to another, sometimes even among members of the same family. NPC can range from a fatal disorder within the first few months after birth (neonatal period) to a late onset, chronic progressive disorder that remains undiagnosed well into adulthood. Most cases are detected during childhood and progress to cause life-threatening complications by the second or third decade of life. NPC is caused by mutations in the NPC1 gene (NPC type 1C) or the NPC2 gene (NPC type 2C) and is inherited in an autosomal recessive manner.
IntroductionNPC belongs to a larger group of more than 50 disorders known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks. Abnormal functioning of a transport protein leads to the accumulation of cholesterol and other fatty substances in various tissues of the body, including brain tissue. NPC used to be grouped together with two other disorders, named Niemann-Pick disease type A and Niemann-Pick disease type B. However, researchers have determined that the underlying defect in types A and B involves mutations in the SMPD1 gene and deficiency of the enzyme acid sphingomyelinase, which does not occur in NPC. Niemann-Pick disease types A and B are now considered a distinct disorder called acid sphingomyelinase deficiency. NORD has a separate report in the Rare Disease Database on this disorder. Niemann-Pick disease type D is an obsolete term for a condition in a group of individuals in Nova Scotia, Canada who have NPC due to a specific founder mutation of the NPC1 gene. This form is clinically indistinguishable from NPC. Additional terms have been used in the past to describe NPC including DAF (down gaze palsy, ataxia, foam cells) syndrome, juvenile dystonic lipidosis, lipid histiocytosis, and sea blue histiocyte disease. These terms are now considered obsolete.
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.
Individuals with NPC have mutations in one of two genes, NPC1 or NPC2. Approximately 95% of affected individuals have mutations in NPC1. Genes provide instructions for producing proteins that play a critical role in many functions of the body. Mutations in a gene may lead to the production of a protein that has reduced or abnormal functions, or to the absence of the protein. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
Investigators have determined that the NPC1 gene is located on the long arm (q) of chromosome 18 (18q11.2). The NPC2 gene is located on the long arm of chromosome 14 (14q24.3). Chromosomes, present in the nucleus of human cells, carry the genes that contain genetic information for each individual. Human body cells normally have 46 chromosomes, 23 inherited from each parent. Pairs of corresponding chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q.”
Genetic diseases are determined by the combination of the pair of genes for a particular trait received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal (mutated) gene for the same trait from each parent. If an individual receives one normal gene and one mutated gene, the person will be a carrier for the disease, but usually will not show symptoms. For a couple who are both carriers the risk with each pregnancy for them to have an affected child is 25%, a child who is a carrier is 50%, and a child who is unaffected and is not a carrier is 25%. In recessive genetic disorders such as NPC the risk is the same for male and female offspring.
The exact function of the NPC1 and NPC2 proteins is not fully understood. Researchers do know that the protein products of these genes are involved in the movements (trafficking) of large molecules within cells. When NPC1 or NPC2 gene is mutated insufficient levels of functional protein products are made. This causes abnormal accumulation of cholesterol in the peripheral tissues of the body such as the liver and spleen, and accumulation of cholesterol and glycosphingolipids (complex compounds consisting of fatty material and carbohydrates) in the brain. The accumulation of these materials causes the various observable symptoms of NPC.
NPC affects males and females in equal numbers, and can affect individuals of any ethnic background (pan ethnic). NPC is estimated to occur in 1 in 100,000-120,000 live births. However, many cases go misdiagnosed or undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.
Niemann-Pick disease type C is diagnosed based on characteristic symptoms obtained from a thorough clinical evaluation (see under Signs and Symptoms), and confirmed by a variety of specialized tests. Proper diagnosis of NPC requires physicians to suspect the diagnosis based upon symptoms, and to follow up with appropriate laboratory tests to evaluate the function of the protein or the presence of accumulated byproducts (biochemical tests), and to identify mutations in the NPC1 or NPC2 gene (gene sequencing).
Many physicians have little experience with NPC. Thus, affected individuals and families often face a significant delay in diagnosis. Clinical experts on NPC have developed a Suspicion Index Tool to help physicians unfamiliar with the disorder to diagnose NPC (Wraith JE, 2014). This tool creates a risk prediction score based on the specific manifestations present in an individual, broken down into visceral, neurological, and psychiatric categories. The original tool was effective in diagnosing individuals over the age of 4 years. Subsequently the same group derived a version that improved on diagnosing NPC in children younger than 4 years (Pineda M et al, 2016). Further study and refinement of the Suspicion Index Tool is necessary to determine its usefulness in clinical practice.
Clinical Testing and Workup
Traditionally the confirmation of an NPC diagnosis was done by staining the affected individual’s skin cells (fibroblasts) for level of cholesterol accumulation (filipin staining). Testing for the cells’ ability to modify cholesterol (cholesterol esterification test) has also been used for diagnostic purpose. Recently, blood-based testing for biomarkers (oxysterols, lysosphingolipids, bile acid metabolites) and molecular gene sequencing of NPC1 and NPC2 have replaced these traditional methods. Outside of the neonatal period, the combination of biomarkers and gene sequencing has improved the detection rate (sensitivity) and accuracy (specificity) of diagnosing NPC. In cases where the test results are equivocal, experts in the NPC field should be consulted to discuss their interpretation.
Treatment of NPC may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, ophthalmologists, pulmonologists, gastroenterologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling would benefit affected individuals and their families.
Current treatment is directed toward the specific symptoms apparent in each individual. Difficulty swallowing (dysphagia) should be monitored and evaluated regularly for the risk of aspiration. Swallowing difficulties may first be managed by softening solids and thickening liquids. A speech therapist can work with the individual to optimize swallowing function. Eventually, a gastronomy tube may be required to meet adequate caloric needs. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the direct intake of food or medicine.
Seizures often respond, at least partially, to anti-seizure medications (antiepileptics). Eventually, in an advanced stage of the disease, seizures may no longer respond to such medications (refractory seizures). Cataplexy may be treated by specific drugs including tricyclic antidepressants and central nervous system stimulants such as clomipramine, protriptyline or modafinil. Drugs that block the neurotransmitter acetylcholine (anticholinergic agents) have been effective in treating dystonia and tremor. Botulinum toxin injections can be used to treat severe dystonia. Drugs have also been used to treat various psychiatric illnesses, such as antipsychotic medications to treat psychosis and antidepressants to treat mood disorders.
Sleep abnormalities observed in NPC are diverse. Many individuals suffer from poor sleep quality due to fragmented myoclonus during slow wave sleep. Total sleep time, and time spent in different stages of sleep (REM and slow wave) may be decreased. Some individuals may suffer from insomnia which can be linked to underlying psychiatric diseases, such as anxiety or depression. When hypotonia is severe, especially in combination with enlarged adenoids and tonsils, disordered breathing with long respiratory pauses during sleep (obstructive sleep apnea) may occur. This diagnosis often requires an overnight sleep study. If the obstructive sleep apnea is severe, the patients may need a machine supplying continuous positive air pressure (CPAP) with a mask to keep the airways open during sleep. Insomnia and other sleep problems should be treated with melatonin, and if needed nocturnal sedatives.
Various services that may be beneficial to affected patients include an individualized educational plan encompassing physical therapy, speech therapy and occupational therapy. Parents, siblings, and other family members of affected individuals may find support, resources for respite care, and information on NPC through their primary pediatrician and the various professional and parent organizations listed below.
Studies have shown that miglustat (Zavesca®) may be able to slow the progression of neurological symptoms associated with NPC. Miglustat blocks the synthesis of glycosphingolipids, one of the substances that accumulates in the brain of individuals with NPC. The U.S. Food and Drug Administration (FDA) has not approved miglustat for the treatment of individuals with NPC, although the drug is approved for the treatment of another lysosomal storage disease known as Gaucher disease. Miglustat has been used off-label in the U.S. to treat individuals with NPC. Miglustat is available for the treatment of NPC in Australia, Canada, New Zealand, and several countries in Asia, Europe, and South America as Zavesca®, and in Japan as Brazaves®.
NPC affects the processing of cholesterols produced within neurons, and not those outside of the cells. Thus, diets low in fats and cholesterols do not affect the neurological disease course.
Several therapies have been studied or are currently being studied to assess their long-term safety and effectiveness as potential treatments for individuals with NPC. These therapies include vorinostat, 2-hydroxypropyl-β-cyclodextrin (HPBCD), and arimoclomol. HPBCD, specifically VTS270, and arimoclomol are currently in phase 2/3 clinical trials being studied for their effectiveness in treating NPC.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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