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NORD gratefully acknowledges Forbes D. Porter, MD, PhD, Senior Investigator, Clinical Director, National Institute of Child Health and Human Development, and Simona Bianconi, MD, Clinical fellow, 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.
Niemann-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.
NPC 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 syndrome, juvenile dystonic lipidosis, lipid histiocytosis, and sea blue histiocyte disease. These terms are now considered obsolete.
Many classification systems break down NPC based upon the age of onset of the disorder, often designating forms as perinatal (shortly before and after birth), early infantile (age 3 months to <2 years), late infantile (age 2 to < 6 years), juvenile (age 6< 15 years) and adult (age 15 years and greater). NPC is described as a neurovisceral disorder, or a disorder affecting both the neurological system and various internal organs (viscera) particularly the liver and spleen. Symptoms arise at different times and follow independent progression. Systemic symptoms precede the development of neurological symptoms in most cases. Onset of neurological symptoms is often slow and may occur over time.
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 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. Ascites persists after birth. These infants often have prolonged severe cholestatic liver disease, which refers to the 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) and/or spleen (splenomegaly) may also occur. Lipid-containing cells called 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. Approximately half of these children will recover only to develop neurological symptoms later in childhood, adolescence or adulthood.
When onset is in the early infantile period (2 months to 2 years), affected infants may present with abnormal enlargement of the liver and spleen as the only noticeable symptoms (isolated hepatosplenomegaly) 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 infants 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. Consequently, affected infants or children may blink their eyes, jerk their heads or make abnormal movements in order to compensate for this loss. Eventually, vertical eye movements are lost and, side to side (horizontal) eye movement is affected.
Hearing loss can occur in some individuals with NPC. Affected individuals may develop high frequency sensorineural hearing loss, in which hearing loss is caused by impairment of the auditory nerves to transmit sensory input to the brain. 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 so-called “classic” presentation of NPC is during middle to late childhood. Clumsiness or difficulty in drawing and writing are often noted by teachers and parents. VSGP may be first noticed during this time in the course of a careful neurological examination or if more noticeable by the parents. In some cases, other neurological abnormalities may be the first apparent symptom, specifically cerebellar ataxia, which causes a lack of muscle coordination. Children with cerebellar ataxia often have difficulties with balance and trouble walking (unsteady gait) and may be considered clumsy or fall frequently. Affected children may also experience progressive difficulty speaking (dysarthria) resulting in slurred speech and eventually speech that is unintelligible. 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 breathing in of foreign material 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, a condition characterized by a sudden loss of muscle tone and strength (cataplexy) that can cause a sudden head drop or a weak, rubbery sensation in the legs, or in severe cases collapse. Cataplexy is often caused by strong emotions and in individuals with NPC that emotion is usually laughter (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 occurs in cases with childhood onset (as described above). 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 early on. 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. A schizophrenic-like psychosis may occur in some affected individuals. Adults greater than 30 years of age may experience impairment of executive function (dysexecutive syndrome), which can be 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.
After a long term gradual neurological decline the cause of death is often aspiration pneumonia leading to respiratory failure or intractable epilepsy not responding to medical intervention.
NPC is caused by a mutation in one of two genes, either the NPC1 gene or the NPC2 gene. Approximately 95% of cases are caused by NPC1 mutations. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. 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, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human 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 genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
The NPC1 and NPC2 genes contain instructions for producing (encoding) proteins. The exact function of these proteins is not fully understood and, unlike other lysosomal storage diseases, they are not enzymes. Enzymes are specialized proteins that break down other chemicals in the body. Researchers do know that the protein products of these genes are involved with the movements (trafficking) of large molecules within cells. When these genes are mutated, insufficient levels of functional versions of their protein products are made, which causes the abnormal accumulation of cholesterol in the peripheral tissues of the body as well as the accumulation of cholesterol and glycosphingolipids (complex compounds consisting of fatty material and carbohydrates) within the brain. However, the accumulation of these materials causes the various symptoms of NPC.
NPC affects males and females in equal numbers and can affect individuals of any ethnic background (panethnic). 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.
Symptoms of the following disorders can be similar to those of NPC. Comparisons may be useful for a differential diagnosis.
Differential diagnosis for NPC can vary based upon the age of onset. Newborn and infantile cases can resemble a variety of disorders including alpha-1-antitrypsin deficiency, tyrosinemia, other lysosomal storage diseases including Niemann-Pick disease type A or Gaucher disease, diseases that cause neonatal cholestasis such as idiopathic neonatal cholestasis, and various congenital infections. Childhood onset cases may need to be differentiated from various metabolic disorders including other lysosomal storage diseases, maple syrup urine disease, GM2 gangliosidosis, organic acidemias, attention deficit hyperactivity disorder (ADHD), learning disabilities, dopa-responsive dystonia, Wilson disease, and certain mitochondrial disorders. Adult onset cases may need to be differentiated from Alzheimer disease, frontotemporal dementia, progressive supranuclear palsy, Pick disease (an adult-onset type of frontotemporal dementia unrelated to Niemann-Pick disease), and various psychiatric disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of Niemann-Pick disease type C is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Proper diagnosis of NPC requires physicians to suspect the diagnosis based upon symptoms, whereupon it is necessary to perform appropriate biochemical tests and a skin biopsy. A blood test for NPC is being developed and should soon be readily available. Additionally, many physicians have little or no knowledge of NPC. Consequently, affected individuals and families often face a frustrating delay in diagnosis.
Clinical experts on NPC have developed a Suspicion Index Tool to help physicians unfamiliar with the disorder diagnose NPC (Wraith JE, 2014). This tool creates a risk prediction score based on the specific manifestations present in an individual case, broken down into visceral, neurological, and psychiatric categories. Initially, the tool has proven more effective in diagnosing individuals over the age of 4 than under the age of 4. Further study and refinement of the Suspicion Index Tool is necessary to determine its usefulness in clinical practice.
Clinical Testing and Workup
In individuals suspected of NPC, physicians may take a skin biopsy, which is the surgical removal of a small sample of skin. This skin sample is sent to a laboratory capable of performing biochemical tests that are indicative of NPC. Connective tissue cells known as fibroblasts are obtained from the skin sample and grown in a laboratory (cultured fibroblasts). These cells are studied to see how they handle the chemical conversion or processing of cholesterol (esterification) and they are also stained with a chemical called filipin, which is visible under ultraviolet light. A filipin test can reveal the abnormal accumulation of fatty material in lysosomes. Other tests obtained on the fibroblasts can also rule out other conditions.
Molecular genetic testing can confirm a diagnosis of NPC. Molecular genetic testing can detect mutations in one of the two specific genes known to cause NPC, but is available only as a diagnostic service at specialized laboratories.
A blood-based test has been developed for NPC and should soon be available through specialized diagnostic laboratories.
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 affect child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.
Current treatment is directed toward the specific symptoms that are apparent in each individual. Difficulty swallowing (dysphagia) should be monitored and evaluated regularly, to minimize 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, the implantation of a gastronomy tube may be required. 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 acetylocholine (anticholinergic agents) have been effective in treating dystonia and tremor. Botulinum toxin 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.
The sleep abnormalities observed in NPC are also diverse. Many individuals suffer from poor sleep quality due to fragmented myoclonus during slow wave sleep. In addition total sleep time, REM and slow wave sleep percentage may be decreased. Some individuals may suffer from insomnia which can be linked to underlying psychiatric diseases, such as anxiety or depression. Sometimes, when hypotonia is severe, especially in combination with enlarged adenoids and tonsils there may be disordered breathing with long respiratory pauses during sleep (obstructive sleep apnea). This diagnosis often requires an overnight sleep study. If the obstructive sleep apnea is severe, the patients may need a machine supplying a mild air pressure with a mask to keep the airways open during sleep (positive pressure ventilation). 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.
A controlled study and several anecdotal case reports have shown that miglustat (Zavesca®) may be able to slow or stop the progression of neurological symptoms associated with NPC. Miglustat blocks the creation (biosynthesis) of glycosphingolipids, which is one of the substances that accumulate in the brain of individuals with NPC. The U.S. Food and Drug Administration (FDA) has not approved miglustat for the treatment 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. In the European Union, miglustat under the brand name Zavesca® has been approved for the treatment of progressive neurological manifestations of NPC in both adult and pediatric patients. In Japan, miglustat was approved for the treatment of NPC in 2012 under the brand name, Brazaves®.
ISeveral therapies have been studied or are currently being studied to assess their long-term safety and effectiveness as potential treatments for individuals with NPC. In addition to miglustat, such therapies include curcumin, cyclodextrin, and vorinostat. Curcumin is a component of turmeric, an Indian spice found in some curries. Curcumin has demonstrated some anti-inflammatory effects in regard to NPC. Cyclodextrin are molecules comprising starch and sugar rings that may be able to help brain cells discharge (efflux) cholesterol. Vorinostat is a histone deacetylase inhibitor that has shown some ability to reverse the accumulation of unesterified cholesterol in cells. More research is necessary to determine the long-term safety and effectiveness of such therapies for the treatment of individuals with 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.
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Report last updated: 2014/10/15 00:00:00 GMT+0