Patient

Diagnosis of and Treatment for Types A and B NPD

Diagnosis

Patients, family members, and their physicians usually arrive at the diagnosis of NPD based on the clinical symptoms occurring in affected individuals. Types A and B NPD can almost always be definitively diagnosed by measuring the ASM activity in white blood cells. This measurement can be obtained by taking a small blood sample from suspected individuals. ASM activity can also be measured in skin cells obtained from patients. In general, Types A and B NPD 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 NPD (i.e., reduced ASM activity), DNA testing can be performed. There are several alterations, or mutations, in the ASM gene that have been found in several unrelated Type A or B NPD patients. The occurrence of these mutations can be readily tested for in DNA obtained from the white blood cells of newly diagnosed patients. However, because 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, DNA testing alone cannot be used to diagnosis Types A and B NPD definitively. In some rare cases where the enzyme and/or DNA testing results are not conclusive or in good agreement with the clinical picture, physicians may request to take a small sample (biopsy) of the liver or bone marrow. This sample is used to identify certain types of cells that are characteristic of NPD.

While measuring ASM activity in white blood cells or skin cells is a very reliable method for diagnosing patients with Types A and B NPD, it is not very useful for identifying carrier individuals who carry only one copy of a mutant ASM gene. The only definitive method to identify carriers of Types A or B NPD is by DNA testing once the mutations in that family have been identified.

It is also possible to diagnose the occurrence of Types A and B NPD 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 carried out on pregnant women who have a family history of Type A or B NPD and are known to be carriers for the disorder.

Treatment

At present, there are no specific therapies for Type A or B NPD. Bone marrow transplantation has been attempted in a small number of Type B NPD patients, and the results have been encouraging. Bone marrow transplantation also has been carried out in a mouse model of Type A and B NPD and shown to correct 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 NPD. Bone marrow transplantation also is a difficult procedure for patients to undergo, and suitable bone marrow donors will not be available for all individuals. Thus, patients and families considering this treatment should be sure to consult first with medical experts experienced with this procedure.

The ASM gene also has been used to produce large quantities of the human enzyme in the laboratory for future therapeutic evaluation (i.e., enzyme replacement therapy). Such 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.

Finally, the ASM gene itself has been used to make normal ASM directly in cells from Type A and B NPD patients, leading to the reduction in sphingomyelin storage (i.e., gene therapy). 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.

It is important to recognize that each of these therapeutic approaches (bone marrow transplantation, enzyme replacement, gene therapy), while potentially useful for Type B NPD, is unlikely to prevent or reverse the major neurologic complications of Type A NPD. 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 NPD patients.