Diagnosing NPD Types A and B as compared to Type C is occasionally confused, and it is imperative that patients have the diagnosis of NPD performed by individuals experienced in these disorders. The Niemann-Pick Disease Center at the Icahn School of Medicine at Mount Sinai offers the type of expertise required to diagnose and treat NPD while offering support and resources for patients and their families. Our focus continues to be on conducting much-needed research for all who are affected by NPD.
Clinical Symptoms of NPD by Type
Type A NPD: Type A begins in the first few months of life. Symptoms of Type A may include feeding difficulties, a large abdomen within three to six months, and progressive loss of early motor skills. Generally, there is a very rapid decline in the child after 6 months leading to death by two to three years of age.
Type B NPD: Type B varies in its onset and severity. Abdominal enlargement may be detected in early childhood, but not necessarily. The abdominal enlargement may eventually be quite severe in some patients, but remain barely noticeable in others. In general, the abdominal enlargement becomes less noticeable as the patient becomes older. There are usually few neurological problems associated with Type B, and the patients have normal intelligence. Some patients may develop repeated respiratory infections and breathing problems. Type B patients may be a little shorter than their non-affected brothers and sisters. The life expectancy of Type B patients is highly variable depending on the severity of their symptoms.
Type C NPD: Type C usually affects children of school age, but the disease may strike at any time from early infancy to adulthood. Symptoms may include jaundice at or shortly after birth, a large spleen and/or liver, difficulty with upward and downward eye movement,—which is highly suggestive of Type C—clumsiness and problems walking, difficulty in controlling limb movement, slurred, irregular speech, learning difficulties, and other neurological abnormalities. The life expectancy of Type C patients is also variable depending of the severity of the symptoms, but a shortened lifespan is not unusual.
Often, patients, parents, and their physicians tend to suspect cases of NPD by the clinical symptoms displayed, but an accurate diagnosis requires further testing.
Measuring ASM activity: Usually doctors can diagnose NPD Types A and B definitively by measuring the ASM activity in white blood cells using a small blood sample from suspected individuals. They also measure ASM activity in skin cells obtained from patients. In general, Type A and Type B patients have less than 10 percent of the ASM activity in their white blood cells compared to activity in normal individuals. To confirm the enzymatic diagnosis of Types A and B based on reduced ASM activity, doctors test the patient’s DNA.
DNA confirmation: Several alterations or mutations in the ASM gene have been found in some unrelated Type A or Type B patients. The occurrence of these mutations can be tested using DNA obtained from the white blood cells of newly diagnosed patients. However, not all patients will have one of these common ASM mutations, and they may, in fact, have a mutation that is unique to their own family. Therefore, DNA testing alone cannot be used to diagnosis Types A and B definitively. In some rare cases where the enzyme and/or DNA testing results are not conclusive or in clear agreement with the clinical picture, physicians may request to take a small sample of the liver or bone marrow as in a biopsy. They use this sample to identify certain types of cells that are characteristic of NPD.
Identifying carriers: While measuring ASM activity in white blood cells or skin cells is a very reliable method for diagnosing patients with NPD Types A and B, it is not very useful for identifying individuals who carry only one copy of a mutant ASM gene. The only definitive method to identify carriers of Type A or Type B is by doing DNA testing once the mutations in that family have been identified.
Pre-natal testing: It is also possible to diagnose the occurrence of Types A and B in developing fetuses by enzyme and/or DNA testing. Such tests, which should only be performed by highly trained individuals in a hospital environment, are usually performed on pregnant women who have a family history of NPD Type A or Type B and are known to be carriers for the disorder.
Treatment for Types A and B NPD
It is important to recognize that the therapeutic approaches—bone marrow transplantation, enzyme replacement, and gene therapy—while potentially useful for Type B, are unlikely to prevent or reverse the major neurologic complications of Type A. To accomplish this latter goal, more research is necessary to develop methods of delivering higher levels of ASM directly into the brains of Type A patients.
While there are no specific therapies for Types A or B, research on these procedures is ongoing, and the results are encouraging.
Bone marrow transplantation: Results of bone marrow transplants, used in a small number of NPD Type B patients, have been encouraging. In the laboratory setting, bone marrow transplantation in a mouse model of NPD Types A and B corrected many of the non-neurologic disease symptoms in these animals. The effects of this procedure on the neurologic disease, however, were relatively small, consistent with other results suggesting that bone marrow transplantation alone will not have a major impact on the neurologic course of Type A. Bone marrow transplantation is a difficult procedure for patients to undergo, and suitable bone marrow donors will not be available for all individuals. Patients and families considering this treatment should consult with specialists experienced with the procedure.
ASM gene enzyme: To produce large quantities of the human enzyme in the laboratory, the ASM gene is being used for future therapeutic evaluation, such as enzyme replacement therapy. The enzyme has been used to treat the NPD mouse model, and the results have proven to be very encouraging. However, before enzyme therapy can be initiated in human patients, more animal studies are required to evaluate the safety and efficacy of this procedure.
ASM gene therapy: Using gene therapy, the ASM gene itself has been used to make normal ASM directly in cells from NPD Type A and Type B patients, leading to the reduction in sphingomyelin storage. Gene therapy has been undertaken in the NPD mouse model, and again the results have been very encouraging. However, more experimental information is required before such a treatment could be available for human patients.
Schedule a Visit
We encourage all NPD patients to visit our Clinical Research Center (CRC)<link to http://icahn.mssm.edu/research/resources/general-clinical-research-center> at Mount Sinai to get evaluated by our team of NPD experts. Generally, this involves a two- to three-day stay at the GCRC, which is a special unit of the hospital designed for such clinical studies. Hospitalization and other medical costs for these visits are free. For additional information and to schedule a visit, please call
Dana Doheny, MS, CGC at (212) 659-6779.