Niemann-Pick disease (NPD) is a disorder of fat metabolism that causes abnormalities of the skin, eyes, musculoskeletal system, nervous system, liver, and lymphoid organs. It is named for German pediatricians Albert Niemann (1880-1921) and Ludwig Pick (1898-1935). Six types of the disease have been identified (A, B, C, D, E, and F).
Niemann-Pick disease is inherited through an autosomal recessive trait. The different types of NPD are characterized by an abnormal accumulation of sphingomyelin. A sphingomyelin is any group of sphingolipids (consists of a lipid and a sphingosine) containing phosphorus. It occurs primarily in the tissue of the nervous system.
Some characteristics of Niemann-Pick disease may be common for all types. Common symptoms include jaundice, hepatosplenomegaly (enlargement of the liver and spleen), physical and mental impairment, and feeding difficulties. Symptoms for most types of NPD (A, B, C, and D) are seen in infancy or early childhood.
Alternate names associated with the NPD disorder are lipid histiocytosis, sphingomyelin lipidosis, and sphingomyelinase deficiency.
Niemann-Pick disease is caused by an autosomal recessive genetic trait, therefore the condition will not appear unless a person receives the same defective gene for fat metabolism from each parent. This means that if a person is heterozygous for the trait then they will be a carrier and if they are homozygous then they will show the trait. There is a 25% chance for each pregnancy that the disorder will passed onto the child(ren) if both parents are heterozygous for the trait and a 100% chance if both parents are homozygous for the trait.
The gene for Niemann-Pick disease types A and B has been located on the short arm (p) of chromosome 11. The gene for types C and D has been located on chromosome 18. NPD types C and D are believed to be allelic disorders. This term means that the two types are due to different mutations (a change in building block sequences) of the same gene. Type E is similar to type C and may be a variant form. It is possible that type F is a mild form of type B but there is no supportive research.
Niemann-Pick disease affects males and females equally and has been identified in all races. Type A is the most common form of the disease and is responsible for about 80% of NPD cases.
Types A and B occur mainly in families of eastern European Jewish descent (Ashkenazi). It is estimated that one in 75 may be carriers. Type B is also common in individuals from Tunisia, Morocco, and Algeria. Type C is more common in Spanish-Americans in southern New Mexico and Colorado. As of 2000, it is believed that over 300 people in the United States are affected with type C and an estimated one million worldwide. Type D occurs in French-Canadian descendents from Nova Scotia. Type F has been found to affect people of Spanish descent. It is not clear as to which populations are affected by type E.
Signs and symptoms
This is the infantile or acute form of Niemann-Pick disease. Abnormal accumulation of sphingomyelin is seen in the developing fetus. Sphingomyelin accumulation could represent 2-5% of the total body weight in individuals with type A. Symptoms may progress rapidly and include the following:
- Hepatosplenomegaly. Enlargement of the liver and spleen is due to the low levels of the enzyme sphingomyelinase. This enzyme is required to breakdown sphingomyelin in the body. The decreased levels of this enzyme cause sphingomyelin content of the liver and spleen to be abnormally high. This occurs between the ages of six and 12 months. Accurance of liver enlargement is seen more commonly than that of the spleen.
- Musculoskeletal abnormalities. Degenerative muscle weakness and floppiness may occur due to a decline in motor and intellectual functioning. This is caused by increased accumulation of sphingomyelin in the nervous system. Seizures and muscular spasms may also occur.
- Macula. Pigmentation in the tissue of the eyes may occur. Formation of cherry-red spots may be seen in approximately 50% of patients diagnosed with NPD type A. This is not visible and can only be detected using special instrumentation.
- Additional abnormalities. These include jaundice, fever, and gastrointestinal (GI) problems such as vomiting, diarrhea, and abdominal distention.
This is the chronic form of Niemann-Pick disease. Symptoms progress slowly and begin during infancy or early childhood. Like type A, type B occurs due to a deficiency of the enzyme sphingomyelinase. Neurological involvement is minimal and usually absent. Symptoms are as follows:
- Hepatosplenomegaly. Abnormal enlargement of the liver and spleen occur due to the accumulation of sphingomyelin.
- Macula. The formation of cherry-red spots on the eyes may be seen in some affected individuals.
- Additional abnormalities. These include a slow growth rate and increased incidence of respiratory infections.
This type of Niemann-Pick disease occurs due to the inability to breakdown cholesterol. This may lead to a secondary deficiency of acid sphingomyelinase. Studies have shown that there may be two types of NPD type C, NPC1 and NPC2. NPC2 is believed to be caused by a deficiency of HE1 (human epididymis-1), which is a cholesterol-binding protein. NPD type C can occur at anytime between infancy and adulthood but is usually seen in children between the ages of three and 10. The progression of symptoms in NPD type C is slow and the loss of mental and motor function usually occur in early adulthood. Symptoms are as follows:
- Hepatosplenomegaly. The liver and spleen may be moderately enlarged due to the inability to breakdown cholesterol.
- Musculoskeletal. Psychomotor dysfunction, seizures, tremors, and spasticity of the muscles result due to excessive accumulation of cholesterol in the brain. An individual with NPD type C may also exhibit extreme muscle weakness due to emotional excitement and ataxia. Ataxia is the inability to coordinate voluntary muscle movements.
- Eyes. Type C is characterized by vertical gaze palsy. This results in the difficulty or loss of up and down movement. Some individuals may experience opththalmoplegia (loss of muscle ability to move eyes). This is an impaired function of the muscles of the eyes and may cause the eyes to become stuck or fixed in an upward position.
- Additional abnormalities. These include dysarthria and jaundice. Dysarthria is the inability to form and speak words clearly. Jaundice is a yellow discoloration of the skin, eyes, and possibly the mucous membranes.
This is the Nova Scotia variant of Niemann-Pick disease. Like NPD type C, individuals with type D are unable to metabolize cholesterol properly. Individuals with type D do not suffer from a deficiency of acid sphingomyelinase. The symptoms of type D are very similar to type C but vary from case to case.
Many researchers consider this to be a variant form of type C. NPD type E does not usually begin until adulthood and neurological impairment is rare. Symptoms include the following:
- Hepatosplenomegaly. Enlargement of the liver and spleen may occur due to the accumulation of cholesterol.
- Dementia . This is characterized by confusion, disorientation, deterioration of intellectual capacity and function, and impairment of the memory. Dementia is progressive and irreversible.
- Ataxia. Individuals may have an inability to coordinate voluntary muscle movements.
- Opththalmoplegia. Individuals with type E may have an inability to control the muscle movement of the eyes. This may cause the eyes to become stuck in a certain position.
This type of Niemann-Pick disease is characterized by a finding of sea colored blue cells in the blood and/or bone marrow of individuals and therefore may be called sea-blue histocyte disease. It affects people of Spanish descent and may be a mild form of type B. Symptoms may include:
- Hepatosplenomegaly. Abnormal enlargement of the liver and spleen may occur in individuals with NPD type F.
- Cirrhosis. The lobes of the liver may become covered with fibrous tissue (thickened tissue). This fibrous tissue obstructs blood flow through the liver.
- Mild thrombocytopenia. Individuals with NPD type F may suffer from a decrease in the number of platelets found in the blood. Platelets are necessary for coagulation of the blood.
- Macula. Pigmentation in the tissue of the eyes may occur. Individuals may develop a white ring around the maculae of the eyes.
- Hair. Individuals may have an absence of hair in the axillary (armpit) area of the body.
There is no objective diagnostic test for Niemann-Pick disease types D, E, and F. Types A and B are diagnosed through DNA testing or by a blood test. Blood tests for individuals with types A and B will show low levels of the enzyme sphingomyelinase in white blood cells and elevated sphingomyelin and free cholesterol. Type C can be diagnosed by prenatal testing of fibroclastic cells to determine their ability to process and store cholesterol. This is done by testing the amniotic fluid (liquid which bathes and cushions the fetus). Formation of foam cells occurs in all types of NPD and can be determined through a biopsy of bone marrow tissue. Diagnosis of all types is made possible by taking a detailed family history and a thorough examination of the individual.
Symptoms of Niemann-Pick disease may be similar to those of Refsum syndrome (disorder of fat metabolism associated with abnormal accumulation of phytanic acid in the blood and other body tissues), Tay-Sachs disease (disorder found in Eastern European Jewish descendents that results in deterioration of the central nervous system), Sandhoff disease (lipid storage disorder due to a deficiency of the enzyme hexosaminidase), Gaucher's disease (lipid storage disease), and Sialidosis (metabolic disorder due to a deficiency of the enzyme alpha-neuraminidase).
Treatment and management
There is no specific treatment available for any type of Niemann-Pick disease. Individuals are treated on a symptomatic basis. Individuals with NPD types A and B have not benefited from enzyme replacement therapies or organ transplants. Cholesterol lowering drugs and low cholesterol diets are often used for individuals with NPD types C and D. As of 2000, these have not been effective in slowing the progress of types C and D.
Investigational therapies are being tested for types A, B, C, and D. The possibility of treatment by bone marrow transplantation is being tested for types A and B. Studies have also been completed on the use of stem cell (a cell which produces usable tissues) transplantation as treatment for types A and B. Researchers at the National Institutes of Health are studying combinations of cholesterol lowering drugs for treatment of NPD types C and D.
Social and lifestyle issues
Individuals diagnosed with Niemann-Pick disease may want to seek counseling or attend support groups that focus on the psychological, physical, and social issues that may result due to the illness.
Parents may want to seek counseling or attend support groups that focus on the lifestyle changes associated with having a child diagnosed with Niemann-Pick disease.
The prognosis for all types of Niemann-Pick disease varies. In type A, death usually results in early childhood. In individuals with types C and D, death usually results in adolescence or early adulthood. Individuals with type B have a prolonged survival due to the decrease of neurological involvement. The prognosis for types E and F has not been adequately researched.
Affected individuals and their families may want to seek genetic counseling . Pregnant women can receive prenatal testing for NPD type C. Pregnant women that are carriers and have a partner that is a carrier should receive genetic counseling regarding the 25% chance of the child having Niemann-Pick disease.
Early diagnosis is important. Due to advances in medicine, an early diagnosis may increase life expectancy.
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Emery, Alan E. H., MD, and David L. Rimoin, MD, eds. "Sphingomylin Lipidoses (Niemann-Pick disease)." In Principle and Practice of Medical Genetics, Volume 2, New York: Churchhill Livingstone, 1983.
Laith F. Gulli, MD
Tanya Bivins, BS
Niemann-Pick disease (NPD) is a term that defines a group of diseases that affect metabolism and which are caused by specific genetic mutations. Currently, there are three categories of Niemann-Pick diseases: type A (NPD A), the acute infantile form; type B (NPD-B), a less common, chronic, non-neurological form; and type C (NPD-C), a biochemically and genetically distinct form of the disease.
NPD-A is a debilitating neurodegenerative (progressive nervous system dysfunction) childhood disorder characterized by failure to thrive, enlarged liver, and progressive neurological deterioration, which generally leads to death by three years of age. In contrast, NPD-B patients have an enlarged liver, no neurological involvement, and often survive into adulthood. NPD-C, although similar in name to types A and B, is very different at the biochemical and genetic level. People with NPD-C are not able to metabolize cholesterol and other lipids properly within the cells. Consequently, excessive amounts of cholesterol accumulate in the liver and spleen. The vast majority of children with NPD-C die before age 20, and many before the age of 10. Later onset of symptoms usually leads to a longer life span, although death usually occurs by age forty.
Both Niemann-Pick disease types A and B occur in many ethnic groups; however, they occur more frequently among individuals of Ashkenazi Jewish descent than in the general population. NPD-A occurs most frequently, and it accounts for about 85% of all cases of the disease. NPDC affects an estimated 500 children in the United States.
Causes and symptoms
All forms of NPD are inherited autosomal recessive disorders, requiring the presence of an inherited genetic mutation in only one copy of the gene responsible for the disease. Both males and females are affected equally. Types A and B are both caused by the deficiency of a specific enzyme known as the acid sphingomyelinase (ASM). This enzyme is ordinarily found in special compartments within cells called lysosomes and is required to metabolize a certain lipid (fat). If ASM is absent or not functioning properly, this lipid cannot be metabolized and is accumulated within the cell, eventually causing cell death and the malfunction of major organs and systems.
NPD-C disease is a fatal lipid storage disorder characterized by cholesterol accumulation in the liver, spleen, and central nervous system . Mutations in two independent genes result in the clinical features of this disease.
Symptoms of all forms of NPD are variable; no single symptom should be used to include or exclude NPD as a diagnosis. A person in the early stages of the disease may exhibit only a few of the symptoms, and even in the later stages not all symptoms may be present.
NPD-A begins in the first few months of life. Symptoms normally include feeding difficulties, abdomen enlargement, progressive loss of early motor skills, and cherry red spots in the eyes.
NPD-B is biochemically similar to type A, but the symptoms are more variable. Abdomen enlargement may be detected in early childhood, but there is almost no neurological involvement, such as loss of motor skills. Some patients may develop repeated respiratory infections.
NPD-C usually affects children of school age, but the disease may strike at any time from early infancy to adulthood. Symptoms commonly found are jaundice, spleen and/or liver enlargement, difficulties with upward and downward eye movements, gait (walking) unsteadiness, clumsiness, dystonia (difficulty in posturing of limbs), dysarthria (irregular speech), learning difficulties and progressive intellectual decline, sudden loss of muscle tone which may lead to falls, tremors accompanying movement, and in some cases seizures .
The diagnosis of NPD-A and B is normally clinical, helped by measuring the ASM activity in the blood (white blood cells). While this test will identify affected individuals with the two mutated genes, it is not very reliable for detecting carriers, who have only one mutated gene.
NPD-C is diagnosed by taking a small skin biopsy , growing the cells (fibroblasts) in the laboratory, and studying their ability to transport and store cholesterol. Cholesterol transport in the cells is tested by measuring conversion of the cholesterol from one form to another. The storage of cholesterol is assessed by staining the cells with a compound that glows under ultraviolet light. It is important that both of these tests are performed, as reliance on one or the other may lead to the diagnosis being missed in some cases. NPD-C is often incorrectly diagnosed, and misclassified as attention deficit disorder (ADD), learning disability, retardation, or delayed development.
The treatment team is normally composed of a nutritionist, a physical therapist and/or occupational therapist (walking and balance, motor skills and posturing), a neurologist (seizure medications and neurological assessments), a speech therapist, pulmonologist, a geneticist, a
gastroenterologist, a psychologist, a social worker, and nurses.
No specific definitive treatment is available for patients with any NPD type, and treatment is purely supportive. For NPD-C, a healthy, low-cholesterol diet is recommended. However, research into low-cholesterol diets and cholesterol-lowering drugs do not indicate that these halt the progress of the disease or change cholesterol metabolism at the cellular level.
Recovery and rehabilitation
All types of NPD require continuous family care and medical follow-up. Long-term survival and life quality will vary from patient to patient and seem to be directly related to the nature of the disease (genetic mutation) and the medical support provided.
Enzyme replacement has been tested in mice and shown to be effective for type NPD type B. It has also been used successfully in other storage diseases, such as Gaucher type I. Genzyme Corporation and Mount Sinai Medical Center have announced plans for a clinical trial using enzyme replacement therapy to begin late 2003.
Laboratory studies of neurosteroids have recently shown encouraging results when tested on mice, but more work needs to be done before a clinical trial can be considered.
Patients with NPD-A commonly die during infancy. NPD-B patients may live for a few decades, but many require supplemental oxygen because of lung impairment. The life expectancy of patients with type C is variable. Some patients die in childhood while others, who appear to be less drastically affected, live into adulthood.
All types of NPD are autosomal recessive, which means that both parents carry one copy of the abnormal gene without having any signs of the disease. When parents are carriers, in each pregnancy, there is a 25% risk of conceiving a child who is affected with the disease and a 50% risk that the child will be a carrier.
For NPD-A and B the ASM gene has been isolated and extensively studied. DNA testing and prenatal diagnosis is currently available. Research into treatment alternatives for these types has progressed rapidly since the early 1990's. Current research focuses on bone marrow transplantation, enzyme replacement therapy, and gene therapy . All of these therapies have had some success against NPD-B in a laboratory environment. Unfortunately, none of the potential therapies has been effective against NPD-A.
Takahashi, T., M. Suchi, R. J. Desnick, G. Takada, and E. Schuchman. "Identification and Expression of Five Mutations in the Human Acid Sphingomyelinase Gene Causing Types A and B Niemann-Pick Disease. Molecular Evidence for Genetic Heterogeneity in the Neuronopathic and Non-neuronopathic Forms." The Journal of Biological Chemistry (June 1992): 12552–12558.
Frolov, A., et al. "NPC1 and NPC2 Regulate Cellular Cholesterol Homeostasis through Generation of Low Density Lipoprotein Cholesterol-derived Oxysterols." The Journal of Biological Chemistry (July 2003): 25517–25525.
Choi, H. Y., et al. "Impaired ABCA1-dependent Lipid Efflux and Hypoalphalipoproteinemia in Human Niemann-Pick type C Disease." The Journal of Biological Chemistry (August 2003): 32569–32577.
National Institute of Neurological Disorders and Stroke. NINDS Niemann-Pick Disease Information Page. <http://www.ninds.nih.gov/health_and_medical/disorders/niemann.doc.htm> (January 4, 2003).
National Tay-Sachs & Allied Diseases Association (NTSAD). Neimann-Pick Disease. <http://www.ntsad.org/pages/npick.htm> (January 4, 2004).
Beatriz Alves Vianna
Iuri Drumond Louro