Niemann-Pick Disease is one of a group of lysosome storage diseases that affect metabolism and that are caused by genetic mutations. The three most commonly recognized forms are Niemann-Pick Types A, B and C. There are approximately 1,200 cases of NPA and NPB world wide with the majority being Type B or an intermediate form. Niemann-Pick Types A and B (NPA and NPB) are caused by the deficiency of a specific enzyme, acid sphingomyelinase (ASM). This enzyme is found in special compartments within cells called lysosomes and is required to metabolize a lipid called sphingomyelin. If ASM is absent or not functioning properly, sphingomyelin cannot be metabolized properly and is accumulated within the cell, eventually causing cell death and the malfunction of major organ systems.
Niemann-Pick Type C (NPC) is very different than Type A or B. Niemann Pick Type C patients are not able to metabolize cholesterol and other lipids properly within the cell. Niemann-Pick Type C disease is very rare and there are about 500 cases diagnosed worldwide. It is believed, however, that the number of people affected by NPC could be higher, but diagnostic difficulties do not allow an accurate assessment of the occurrence rate. NPC has been initially diagnosed as a learning disability, mild retardation, "clumsiness," and delayed development of fine motor skills. It is not uncommon for a family to spend several years seeking a diagnosis before NPC is identified. NPC is always fatal. The vast majority of children die before age 20 (and many die before the age of 10). Late onset of symptoms can lead to longer life spans but it is extremely rare for any person with Niemann Pick Type C to reach age 40.
Pick's Disease is sometimes confused with Niemann-Pick Disease but it is a different disease.
This condition is inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. If both parents are carriers, there is a 25% chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Niemann-Pick.
Type B disease may include signs of hepatosplenomegaly, growth retardation, and problems with lung function including frequent lung infections. Other signs include blood abnormalities such as abnormal cholesterol and lipid levels, and low numbers of blood cells involved in clotting (platelets). People affected by this type of Niemann-Pick disease usually survive into adulthood. Niemann-Pick disease, type B occurs in all populations.
Mutations in the SMPD1 gene cause Niemann-Pick disease, types A and B. This gene carries instructions for cells to produce an enzyme called acid sphingomyelinase. This enzyme is found in the lysosomes (compartments that digest and recycle materials in the cell), where it processes lipids such as sphingomyelin. Mutations in this gene lead to a deficiency of acid sphingomyelinase and the accumulation of sphingomyelin, cholesterol, and other kinds of lipids within the cells and tissues of affected individuals.
Niemann-Pick Type C disease (NPC) is an autosomal recessive, lysosomal storage disease (LSD) that causes progressive deterioration of the nervous system by blocking the movement of cholesterol within cells. The gene that causes the disease, known as NPC1, is located on human chromosome 18 and was announced to the nation by National Institutes of Health scientists in July 1997.
Niemann Pick Type C is a rare disease and strikes an estimated 1:150,000 people, most often very young children. There is no effective treatment for Niemann Pick Type C and the disease is fatal.
Niemann Pick Type C is very different from Niemann-Pick disease types A & B. In types A & B, the main problem in the body is the complete or partial lack of an enzyme called sphingomyelinase. This enzyme breaks down a fatty material called sphingomyelin. When sphingomyelin cannot be broken down, it is stored along with other fats in cells in various organs in the body including the spleen, liver and brain. In Niemann Pick Type C, cholesterol and glycolipids are the materials being stored rather than sphingomyelin. These fats have varied roles in the cell. Cholesterol is normally used to either build the cell, or forms a complex molecule called an ester. In the case of an individual with NPC, there are large amounts of cholesterol that are not used as a building material and also do not form esters. This cholesterol accumulates within the cells throughout the body, but especially in the spleen, the liver and the bone marrow. Unprocessed glycolipids tend to accumulate in the cells in the brain which causes progressive neurological damage.
Niemann Pick Type C has a wide clinical spectrum and a variable age of onset. Classically, children with NPC demonstrate neurological dysfunction with cerebellar ataxia, dysarthria, seizures, vertical gaze palsy, motor impairment, dysphagia, psychotic episodes, and progressive dementia. In general, adolescent and adult onset forms of Niemann Pick Type C have a more insidious onset and slower progression.
Symptoms of Niemann-Pick Disease Type C
An individual with NPC usually has some obvious symptoms. Vertical eye gaze palsy (the inability to move the eyes up and down), enlarged liver (hepatomegaly), enlarged spleen (splenomegaly), or jaundice in young children are strong indications that NPC should be considered. It is common for only one or two symptoms to appear in the early stages of the disease. In some cases, however, enlargement of the spleen and/or liver does not occur for months or years. Enlargement of the spleen and/or liver increases slowly with time. This is caused by abnormal storage or accumulation of fatty material including cholesterol within the cells of the organs. This enlargement does not usually cause major complications.
Neurological problems that worsen with time are a major part of Niemann Pick Type C. These can include increased muscle tone, difficulty with muscle coordination and difficulty with balance. This results in body movements that are clumsy or awkward. Feet are often positioned more than shoulder width apart, to assist balance by creating a wide base while standing or walking. Speech is usually slow and slurred. Patients are almost always unable to move their eyes up or down completely without moving their head. This is called vertical supranuclear palsy.
Learning difficulties and loss of intellectual abilities over time are to be expected. A person with NPC may be slow to learn new skills. In a young child there may be a delay in reaching normal developmental milestones. For example s/he may be late in walking, making sounds, or putting words together. An older child may show a decline in abilities at school. Learning can become progressively more difficult. Eventually the child will lose some of the mental skills that s/he once had.
Other neurological problems that may occur as the disease worsens include tremor or shaking with movement, and seizures. Unfortunately, neurological symptoms are progressive. In the final stages, the patient with Niemann Pick Type C is frequently bedridden, has little muscle control and is intellectually impaired.
What Can Be Done for the Person with Niemann-Pick Disease Type C?
Currently, there is no known cure for NPC. There is also no standard treatment that has proven to be effective. However, supportive care may include involvement of specialists in gastroenterology, nutrition, physical and/or occupational therapy, learning and others. Standard medications used to treat seizures, cataplexy (sudden loss of muscle strength), dystonia (abnormal movements or postures due to ongoing muscle contractions) and spasticity (continuous contraction of certain muscles) 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 (feeding tube). Research is underway at the National Institutes of Health with the hope of revealing the underlying defect in NPC, finding a treatment and ultimately finding a cure. For example, a clinical trial of miglustat (trade name Zavesca) is being done in the United States and Great Britain. This medication is a glucosylceramide synthase inhibitor, which means that it blocks one of the metabolic steps that leads to the build up of fats in cells. It has been shown to decrease build up of these glycolipids in cells, but it is not yet know if this will affect the timing of the gradual changes that occur in NPC. Some researchers are also studying the way cholesterol and other fats are moved through cells in order to find ways to reduce storage of cholesterol, while others are looking at the effect of giving a neurosteroid (a special type of hormone that effects brain and other nerve cells) supplement to delay onset of symptoms.
Patients with NPC have mutations in the NPC1 or NPC2 gene (18q11-q12). These proteins are involved in cellular post-lysosomal/late-endosomal transport of cholesterol and glycolipids, and it is likely that deficient translocation of cholesterol from lysosomes to other intracellular membrane sites may play an important role in the pathogenesis of NPC.
If a physician suspects Niemann Pick Type C, a laboratory test is available that detects the abnormal cholesterol processing and storage in fibroblasts (skin cells) grown from a small skin biopsy taken from a person with NPC. The cells are grown in the laboratory, which can take several weeks, and are then tested by cholesterol processing and storage studies or by DNA studies. This sophisticated testing is often conducted at Thomas Jefferson University Lysosomal Disease Testing Lab or the Mayo Clinic.
The support of these theories has considerable evidence using mutant proteins in vitro to determine the buildup of cholesterol in the lysosomes. Researchers have also discovered that the NPC-1 protein may function as a pump of cholesterol.
The overall effect of a malfunction in NPC-1 is that low levels or an absence of the protein lead to the abnormal accumulation of lipids and cholesterol in the cells of people with this condition.