Niemann-Pick Type B
Niemann-Pick Type B (NPB) disease is one of a group of metabolic diseases classified as lysosomal storage disorders (LSD’s). Both NPB and Niemann-Pick Type A (NPA) are caused by faults (mutations) in a gene on chromosome 11. To have the disease a person or child will have inherited two faulty genes, one on each chromosome 11. This inheritance pattern is autosomal recessive. The enzyme affected by the gene defects is called acid sphingomyelinase (ASM) and its job is to break down a fatty substance, a lipid, called sphingomyelin (SM). Most proteins of this type are called enzymes and their names often end with 'ase'. SM is a component molecule of cellular membranes. It is made within the cell, transported to its location of use and recycled to a compartment (organelle) within the cell called a lysosome. This organelle breaks down the material, or substrate, sent to it, using ASM. This enzyme, along with many other enzymes, operates with a specific substrate and is contained within the lysosome. Other examples of lysosomal storage disorders are Tay-Sachs, Sandhoff and Gaucher's.
Failure to break down the substrate causes a number of problems. The lysosomes become progressively crammed full of sphingomyelin and swell. This interferes with other substrate breakdown processes taking place within the lysosome. In addition the breakdown products are normally required for reuse elsewhere in the cell and are now in short supply. This has detrimental effects on other operations taking place in the cell. As all cells are affected, deterioration and ultimately, failure of the organs of the body takes place resulting in death. In Type A disease, the clinical affects are apparent at an early stage of life and an affected child will usually die before reaching 5 years. The main feature of this disease type is the severe affect on the brain. Type B appears quite different with most children reaching maturity and adulthood although not without experiencing health problems. There are some reported problems with the brain in some cases but these are few.
If the same gene causes both Type A and Type B disease, why should this be?
Although the exact reasons for such significant difference between Type A and Type B remain to be fully explained, an important factor relates to the types of mutation inherited. Certain mutations appear less aggressive than others. It may be in these instances that the enzyme retains some degree of capability and, this is sufficient to carry out the breakdown of SM although at reduced efficiency. In most cases the residual activity of SM appears sufficient to protect the brain in Type B. Scientists collect data on genetic mutations and try to relate them to clinical symptoms. This process is called genotype/phenotype correlation and is aimed at forecasting the severity and rate of progress of a disease.
How is the diagnosis of Niemann-Pick disease Type B made?
Niemann-Pick Type B disease is diagnosed by measuring the ASM (acid sphingomyelinase) activity in white blood cells. The test can be performed after taking a small blood sample from suspected individuals. While this test will identify persons with Type B (two mutated genes), it is not very reliable for detecting persons who are carriers (only one mutated gene). It is possible to diagnose Type B carriers by DNA testing because the gene containing the blueprint for ASM has been cloned and many of its mutations identified.
Type B - How frequent is this disease?
In the case of Type B and for the purpose of providing an estimate of disease incidence, known cases in the UK amount to approximately 25. In a UK population of say 60,000,000 this gives a figure of 1:5,000,000. Again this is a very rare disease.
Type B is genetically similar to Type A but the symptoms are very variable and usually less aggressive. Abdominal enlargement may be detected in early childhood and can be very large due to storage in the spleen and liver, but there is neurological involvement only in about 10% of cases. Most patients will have some respiratory problems at some stage. Raised cholesterol can be a problem leading to cardiovascular disease. Some patients with NPB also develop bone disease.
What treatment is available?
Recent advances in medical science have brought new hope for the possibility of treatment of Type B. As with most diseases, early diagnosis is helpful, as it allows time to plan for disease management and for those affected to come to terms with the problems associated with the disease. Genzyme, a pharmaceutical firm with experience in lysosomal disorders, are in the process of conducting pre clinical studies on traditional enzyme replacement therapy for Type B patients. Phase 1 is currently underway and preparations are being made for Phase 2, which is expected to begin next year. Meanwhile increased knowledge of Type B from natural history studies have led to more intensive investigations to detect cardiovascular and bone problems early so they can be treated.