Niemann-Pick Disease
Niemann-Pick Disease (NPD) is a group of genetic lipid storage disorders characterized by the accumulation of sphingomyelin and cholesterol in various organs, including the brain, liver, spleen, and lungs. The disease results from a deficiency of the enzyme sphingomyelinase, which is crucial for lipid metabolism. Symptoms can vary significantly among the different types of NPD, with common manifestations including enlarged liver and spleen, jaundice, respiratory complications, and in severe cases, mental and motor function deterioration. There are several forms of the disease, notably Types A, B, C, and D, with Type A being the most severe and typically leading to early mortality.
Diagnosis often involves genetic testing, but there is currently no cure for NPD. Management focuses on alleviating symptoms, which may include splenectomy or antibiotics for respiratory infections. While some treatments, like enzyme replacement therapy, are being explored, the overall life expectancy for individuals with NPD remains limited. The disease is most prevalent among Ashkenazi Jews, although it can affect individuals from various ethnic backgrounds. Ongoing research aims to develop more effective therapies and interventions to improve quality of life for those affected.
Niemann-Pick Disease
ANATOMY OR SYSTEM AFFECTED: Bones, brain, liver, lungs, nervous system, respiratory system, spleen
DEFINITION: This lipid disease group, resulting from inactive sphingomyelinase and cholesterol-modifying enzymes, causes lipid buildup in the brain and other organs, mental and physical debilitation, and a short life span
CAUSES: Genetic enzyme deficiency
SYMPTOMS: Liver and spleen enlargement; sometimes severe mental damage, loss of motor function, emaciation, jaundice, swollen abdomen, red spots in eyes, breathlessness
DURATION: Chronic and progressive
TREATMENTS: None; enzyme and genetic testing of prospective parents, symptom alleviation through spleen removal or antibiotics
Causes and Symptoms
Niemann-Pick disease (NPD), which consists of several lipid storage diseases, is characterized by an enlarged liver and spleen and the accumulation of fatlike sphingomyelin and cholesterol. Many patients have enlarged spleens and livers soon after birth and develop severe mental damage. In others, symptoms lag; mental damage may not occur, or organ enlargement and mental damage may be postponed. The main forms, types A through C, are attributable to low levels of sphingomyelinase, which normally alters sphingomyelin for use and excretion.
Type A, or infantile NPD, is the most common type. The abdominal organs enlarge, and damage occurs in early infancy. The and liver enlarge by the age of six months, motor function and intellectual capabilities are then lost, and death occurs by four years of age. Patients are emaciated, jaundiced, and have swollen abdomens and cherry-red spots in the macular region of the eye. Large histiocytes (foam cells) abound in the bone marrow, spleen, lymph nodes, adrenal glands, and lungs.
Type B, or juvenile nonneuropathic NPD, is also common. Enlarged abdominal organs develop as quickly as in type A, but no neurological impairment occurs. An enlarged spleen appears first, followed by liver enlargement. Lungs are often so damaged that frequent breathlessness occurs. Abdominal pain is caused by the huge size of the liver, and the patient is susceptible to respiratory infections. Nevertheless, patients with this type of disease reach adulthood in fair health.
Type C, a rarer chronic form, is for approximately two years. Symptoms then develop gradually, accompanied by lost speech and motor coordination and epilepsy. The liver and spleen are smaller than in types A and B. These patients die in their teens.
Type D, a very rare form, is similar to Type C and has only been found in French Canadians in Nova Scotia.
The of Niemann-Pick disease includes abundant foam cells in the spleen, bone marrow, liver, lungs, and lymph nodes. Nervous tissue may be altered similarly. Foam cells contain brown lipofuscin pigment. This and blue to blue-green stained intracellular material leads to an alternate name, sea-blue histiocytes.
The spleen of a patient with NPD is large, pale, and filled with foam cells, though few hematologic changes occur except for late in the disease. The liver of a type A patient is usually about 50 percent larger than normal, while the liver of a type B patient grows so large that it deforms and causes abdominal pain. Foam cells soon fill the liver, although it usually functions adequately. They also fill the lymph nodes, spleen, lungs, and bone marrow. Their number varies with NPD type and duration. In most types, the foam cell-filled adrenal glands, gonads, thyroid, pituitary, and function adequately. However, the brains of type A and C patients drop in weight by 25 to 50 percent and are severely damaged.
The predominant lipid accumulant is sphingomyelin, made of fatty acids joined to substances called sphingosine and phosphocholine. Sphingomyelin content in the spleens of type A, B, and C patients is twenty-five, eighteen, and two to twelve times normal, respectively. A thirtyfold increase of liver sphingomyelin occurs in types A and B. Smaller increases, approximately ten times normal, occur in type C. Also, sphingomyelin levels increase threefold to sevenfold in the lymph nodes of all NPD patients. Cholesterol and other sphingolipids also increase in the tissues of NPD patients. It is believed that lipid increases are causative.
Sphingomyelinase deficiency is greatest in types A and C, in which 4 to 20 percent of normal levels occur. In type C, they are about 50 to 90 percent normal levels. The NPD defect is genetic alteration of sphingomyelinase, yielding mutant enzyme less able to break down sphingomyelin.
Treatment and Therapy
Niemann-Pick disease can be prevented only through the enzymatic and genetic testing of prospective parents. Members of at-risk ethnic groups can be tested for sphingomyelinase in their lymphocytes and muscle cells. Genetic counseling can also be used. The disease is transmitted through an autosomal recessive gene, so both parents must carry the gene to transmit disease. If both parents are carriers of a defective NPD gene, each of their children has a 25 percent chance of having the disease and a 50 percent chance of being an asymptomatic carrier.
There is no cure for Niemann-Pick disease. Therapeutic approaches include spleen removal, which diminishes abdominal pain, but it is not widely used. Patients with lung damage who experience frequent respiratory infections and are treated with antibiotics, but long courses and high doses are required. Bone marrow has been done, with mildly encouraging results for patients with type B, but it is not a common treatment. Some children or teenagers with type C disease have been helped by low-cholesterol diets. However, the life expectancy of patients with NPD has not been prolonged much. Miglustat can help alleviate the nervous system symptoms of type C patients.
Perspective and Prospects
In 1914, Albert Niemann, a German pediatrician, reported an eighteen-month-old Jewish child with huge liver and spleen, swollen lymph glands, and jaundice. The child had poor motor control, could not suckle, and died before age two. Postmortem examination showed large lipid deposits in the liver, spleen, lymph nodes, kidneys, and adrenal glands. The overall symptoms and rapid death suggested a new illness. In the 1920’s, Ludwig Pick studied other cases and named Niemann-Pick disease. NPD, seen in all ethnic groups, is most common in Ashkenazic Jews. Type B patients are often of Spanish ancestry. Type C, which is less common, occurs most in Nova Scotians.
It is believed that enzyme replacement therapy (mostly sphingomyelinase) may ease the lives of NPD victims when an effective methodology for the frequent delivery of purified enzymes is developed and the enzymes are available in sufficient amounts. Recombinant research should contribute greatly. However, such treatment of severe NPD (types A and C) will be difficult because of the need to deliver enzymes to the brain.
Another avenue is transplanting healthy livers and spleens, which is presently done to treat other diseases. The problems are scarce donated organs and difficulty placing them in debilitated NPD patients. Transplantation may prove more promising in the future. Also, researchers have identified animal models and genes that, when defective, contribute to NPD. Understanding these issues may produce successful NPD treatments.
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