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From the National Tay-Sachs & Allied Diseases Association, Inc.
In 1914 Albert Niemann, a German pediatrician, described a young child with an enlarged liver and spleen, enlarged lymph glands, swelling and a darkening of the skin of the face. The child had brain and nervous system impairment and died in less than six months, before the age of two. Later, in the 1920's, Luddwick Pick studied tissues after the death of such children and provided evidence of a new disorder, distinct from those storage disorders previously described.
Today, there are three separate diseases that carry the name Niemann-Pick: Type A, Type B and Type C. The majority of the infants affected with the acute infantile form of Niemann-Pick described above (now called Type A) are Ashkenazi Jewish ancestry. The less common Niemann-Pick disease, Type B, a chronic non-neurological form, shows the same ethnic predilection as Type A. It has been estimated that about 1/1000 Ashkenazi Jews is a carrier for one of these forms of Niemann-Pick Disease. Niemann-Pick Type C, a biochemically and genetically distinct form of the disease, does not show this ethnic predilection and occurs with similar frequency in all populations.
Infantile, or Type A, Niemann-Pick Disease occurs most frequently and it accounts for about 85% of all cases of the disease. Its effects begin in the first few months of life; by six months of age feeding difficulties, progressive loss of early motor skills and enlargement of the abdominal organs are usually present. Continued poor feeding causes children to take on a emaciated look accompanied by abdominal distention. Their skin may develop a brownish-yellow discoloration, and about one-third of affected children have a cherry-red spot in the eye similar to that found in children with Tay-Sachs Disease. There is progressive loss of motor and mental function and death usually occurs between two and three years of age.
Type B Niemann-Pick has a more variable course with the first symptoms of disease usually being enlargement of the liver and/or spleen in early childhood. The child experiences progressive organ enlargement, poor growth and susceptibility to chest infections but no nervous system involvement. Many persons with Type B Niemann-Pick survive into adulthood.
Persons with Type C Niemann-Pick, on the other hand, exhibit normal development for two or more years; this is then followed by a slow loss of speech and other nervous system skills. The disease progresses with symptoms of increased clumsiness and lack of coordination, and eventually seizures, and a gradual failure of physical and mental function. Most children with Type C die between the ages of five and fifteen years.
All of these forms of Niemann-Pick Disease show evidence of fatty deposits in one or more organs of the body. Those deposits contain a characteristic lipid called sphingomyelin, along with cholesterol, and they have a foamy, swollen appearance. They are usually found in the liver, spleen and bone marrow cells of affected persons and contribute to the liver and spleen enlargement so characteristic of Niemann-Pick Disease. In Types A and C, deposits also accumulate in cells of the central nervous system, causing damage to the cells and progressive neurological impairment.
Persons with Type A and B Niemann-Pick Disease are missing the enzyme sphingomyelinase which is necessary to metabolize and break down sphingomyelin, a component of cell membranes. Without sphingomyelinase, the sphingomyelin builds up abnormally. The gene for the enzyme sphingomyelinase is located on Chromosome 11, and persons with Type A and Type B Niemann-Pick Disease carry mutations in both copies of the gene, making it impossible for them to make adequate amounts of functional sphingomyelinase. Children with Type A are completely deficient in sphingomyelinase production and make less than 5% of normal levels, while persons with less severe Type B form make 5-10% of the normal levels of sphingomyelinase. Diagnosis of individuals suspected of having Type A or B Niemann-Pick Disease is done by determining that the sphingomyelinase levels in samples of blood are severely depressed.
Persons with Type C Niemann-Pick Disease have approximately normal levels of sphingomyelinase; they do not carry mutations in the sphingomyelinase gene but instead carry mutations in a different gene, located on a different chromosome, which interfere with cholesterol trafficking within the body. This causes cholesterol, and sphingomyelin, to accumulate inside cells and cause disease. Diagnosis of individuals with Type C is more complex but can be carried out in special laboratories.
All forms of Niemann-Pick are autosomal recessive diseases, so they affect both males and females equally. As with Tays-Sachs Disease, the parents of children with Niemann-Pick are carriers and they have a one in four probability with each pregnancy of having an affected child. Prenatal diagnosis for Types A and B by biochemical testing, or, in families with identified mutations, by DNA-based testing, is accurate and reliable. Carrier testing within an affected family should also be considered, especially if the mutations are known. Because the primary molecular defect for Niemann-Pick Type C is still unknown, it is more difficult to do a prenatal diagnosis or to ascertain whether relatives are carriers or not.
From the National Institute of Health in Bethesda, Maryland
Niemann-Pick disease (NP) is an inherited metabolic disorder in which harmful quantities of a fatty substance accumulates in the spleen, liver, lungs, bone marrow, and, in some patients, the brain. The clinical designations applied to NP are somewhat erratic. Patients are currently subdivided into four categories. In the first, called type A, enlargement of the liver and spleen are apparent early in infancy and profound brain damage is evident. These children rarely live beyond 18 months. In the second group, called type B, enlargement of the liver and spleen characteristically occur in pre-teen years. Most of the patients also have pulmonary difficulties, but the brain is not effected. The fatty material that accumulates in types A and B is called sphingolyelin. This lipid is a major component of the membrane of all cells in the body. The metabolic defect in types A and B is insufficient activity so an enzyme called sphingomyelinase that initiates the biodegradation of sphingolyelin that arises for normal cell turnover.
The term NP also includes two other variant forms called types C and D. Patients with these types have only moderate enlargement of their spleens and livers. They have brain involvement that can be extensive leading to inability to look up and down, difficulty in walking and swallowing, as well as progressive loss of vision and hearing. The disorder may appear early in life or its onset may be delayed into the teen years. Both types are characterized by an inability to mobilize cholesterol in the nerve cells in the brain where it accumulates and causes malfunction of these cells. The only difference between these two subtypes is that type D arises in people with a common ancestral background in Nova Scotia.
There is currently no effective treatment for patients with type A. Bone marrow transplantation has been attempted in a few patients with type B, and encouraging results have been reported. Since type B resembles type 1 Gaucher's disease to a considerable degree, one might anticipate that enzyme replacement, and ultimately gene therapy, will eventually be helpful to these patients. Patients with types C and D are frequently placed on a low-cholesterol dietary regimen.
Patients with type A die in infancy. Type B patients may live a comparatively long time, but many require supplemental oxygen because of lung involvement. The life expectancies of patients with types C and D are quite variable. Some patients die in childhood while others appear to be less drastically affected live into adulthood.