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Niemann-Pick Disease

Niemann-Pick disease


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.

Treatment team

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.

Clinical trials

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.

A clinical trial with a drug known as Zavesca for NPD type C is underway in the United States and Europe. The drug slowed, but did not stop, the neurological decline when tested on NPD mice.

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.

Special concerns

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): 1255212558.

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): 2551725525.

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): 3256932577.


National Institute of Neurological Disorders and Stroke. NINDS Niemann-Pick Disease Information Page. <> (January 4, 2003).

National Tay-Sachs & Allied Diseases Association (NTSAD). Neimann-Pick Disease. <> (January 4, 2004).


National Niemann-Pick Disease Foundation, Inc. PO Box 49, 415 Madison Ave, Ft. Atkinson, WI 53538. (920) 563-0930 or (877) 287-3672; Fax: (920) 563-0931. <>.

Beatriz Alves Vianna

Iuri Drumond Louro

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Niemann-Pick disease

Niemann-Pick disease (nee-man pik) n. a rare inherited disease of phospholipid metabolism in which sphingomyelin and lecithin accumulate in the bone marrow, spleen, and lymph nodes. It is characterized by enlargement of the liver and the spleen and by physical and mental retardation. [ A. Niemann (1880–1921), German paediatrician; F. Pick (1868–1935), German physician]

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