Niemann-Pick Type A

Niemann-Pick Type A (NPA) is one of a group of metabolic diseases classified as lysosomal storage disorders (LSD’s). Both NPA and Niemann-Pick Type B (NPB) 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 called 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 NPA, the clinical affects are apparent at an early stage of life and an affected child will usually die before reaching 5 years of age. The main feature of this disease type is the severe affect on the brain.

NPB 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 NPA and NPB 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 NPB. 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 A made?
NP-A is diagnosed by measuring the acid sphingomyelinase (ASM) activity in white blood cells or cultured cells. These are obtained from a small blood sample taken from individuals who are suspected of having the disease. This enzyme test is not reliable at detecting carriers of the condition.   The gene for ASM has now been cloned and many mutations have been identified so it is possible to detect NP-A by DNA testing. The analysis is complex and consequently can take a long time as it is only performed in one or two centres with a research interest

How frequent is this disease?
NPA is known to be pan ethnic and may affect the people of all countries in the world. Until comparatively recently diagnosis was difficult even in countries with advanced medical facilities. Coupled with the problem of deaths of affected children in early infancy, it is likely that any figures on disease incidence were unreliable. Even today when a great deal more is known and awareness of metabolic diseases is much greater, recording and prediction on the incidence of the disease in the general population remains unreliable. It is known that certain population groups have a higher incidence of the disease than others, and this can be accounted for by geographical, religious/cultural reasons.

For the above reasons it is only possible to give estimates of the frequency of the disease and these are related to specific population groups. Information collected on the US Ashkenazi Jewish population indicates a disease incidence of 1:40,000 for NPA. In the UK the pattern of disease is apparently random and very rare. Occurrence of the disease is likely to be in the order of 1:10,000,000. It is believed that there are currently no reported cases of NPA in the UK.

What are the symptoms?
Niemann-Pick Type A begins in the first few months of life. Symptoms may include a combination of those listed below:
• feeding difficulties
• prolonged jaundice
• a large abdomen within 3 to 6 months
• progressive loss of early motor skills
• failure to thrive
• cherry red spot in the eye (not noticeable to parents)
• (generally) a very rapid decline leading to death by two to five years of age

What treatment is available?
There is currently no available treatment for Type A other than symptomatic. Due to storage being evident in early months it is thought that treatment would have to target the newborn child or even be given in utero to be of benefit.

More detailed information is provided under the Research section of the website