Symptoms of all forms of Niemann-Pick disease are variable - no single symptom should be used to include or exclude a diagnosis of Niemann-Pick disease. A person in the early stages of the disease may exhibit only a few of the symptoms. Even in the later stages of the disease, not all symptoms may be present.

Types A and B are both caused by the same enzymatic deficiency, a lack of a substance called ASM-acid sphingomyelinase, but represent different extremes in terms of clinical prognosis. Lack of ASM causes build up of sphingomyeline in certain cells and causes damage to the central nervous system, liver, and lungs. Between these two types, many variations exist with different levels of clinical symptoms.

In Niemann-Pick Type A, symptoms begin in the first few months of life and may include:

• feeding difficulties
• abdominal distension
• may present with jaundice in infancy and progressive liver failure
• progressive loss of early motor skills
• a ‘cherry red spot’ in the eye (visible only by special exam)
• enlarged liver and/or spleen

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.

Niemann-Pick Type B is bio chemically similar to Type A, but the symptoms are more variable. Abdominal enlargement may be detected in early childhood but there is almost no neurological involvement, such as loss of motor skills. Growth may be slow and some patients may develop repeated respiratory infections. The underlying reason for the dramatic difference in the two forms of the disease is not really understood and, at present, it is not possible to accurately predict the severity of the disease by enzyme testing.

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.

Niemann-Pick Type C is an extremely rare disease that affects multiple body systems and has variable onset and progression over a course of years. It is perhaps not surprising that in past decades it has frequently been misdiagnosed or even undetected at presentation in primary care. Even now that direct biochemical and genetic tests are available, diagnosis can be challenging. This highlights the need for increased awareness of this disease, and for effective referral to specialist care for patients who are suspected of having the condition.  Niemann-Pick disease 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
• an enlarged spleen and/or liver
• difficulty with upward and downward eye movements (Vertical Supranuclear Gaze Palsy)
• unsteadiness of gait, clumsiness, problems in walking ("ataxia")
• difficulty in posturing of limbs ("dystonia")
• slurred, irregular speech ("dysarthria")
• learning difficulties and progressive intellectual decline ("dementia")
• sudden loss of muscle tone which may lead to falls ("cataplexy")
• tremors accompanying movement and, in some cases, seizures

How is the Diagnosis of Niemann-Pick Type C Made?
Type C Niemann-Pick is initially diagnosed by taking a small piece of skin ("skin biopsy"), growing the cells ("fibroblasts") in the laboratory, and then studying their ability to transport and store cholesterol. The transport of cholesterol in the cells is studied by measuring conversion of the cholesterol from one form to another ("esterification"). The storage of cholesterol is assessed by staining the cells with a compound ("filipin") which glows under ultraviolet light. It is important that both of these tests be performed, since reliance on one or the other may lead to the diagnosis being missed in some cases.

Diagnosis can also be made on DNA analysis if the mutations in the affected child are known. This can be done fairly simply on a blood test but is only carried out in a few specialist centres. There is one common mutation and about 50% of those affected carry one copy of this. Unfortunately there are over 250 other known mutations, often individual to families and these may be difficult to find. Pre-natal testing is available for NPC; cells can be grown from samples taken at around 11 weeks of pregnancy (CVS) or an amniotic fluid specimen can be analysed in the 16th to 20th week of pregnancy. Unfortunately it may take several weeks for the cells to grow. If the DNA mutations are known, this process is much quicker.

Carrier Testing

An important issue to be addressed by families affected by Niemann-Pick Diseases or many other serious inherited diseases is that of carrier testing. In the case of Niemann-Pick diseases the issue is whether any one else in your own, or, your partners family has inherited a copy of the defective gene. As these diseases are classified as autosomal recessive conditions, it is implicit that having one defective copy of the gene will have little, or no noticeable affect on the individual.

There are wider issues surrounding carrier testing and it is helpful to be aware of these in coming to a decision on whether or not to pursue this course of action in a family. Professional advice should be sought from a genetic counsellor before coming to a decision on testing. This can be arranged through your local GP or hospital consultant but our Clinical Nurse Specialist at the Willink, Jackie Imrie, will also assist.

Issues to be addressed include:

• Do you wish to know if you are a carrier of a defective gene?
• If you are, what does this mean in terms of your own health?
• How will parents and grandparents react to the knowledge that the defective gene has come from one of them?
• Should more distant relatives or relations that you are no longer in touch with be approached?
• If you are, what will it mean if you are planning to start a family of your own?
• Can your partner be tested?
• Are there wider social considerations or are there any implications regarding your rights and how you are treated by the business world, eg insurance and, more generally, by other organisations.
  Any consideration of carrier testing must take into account the risk context of the disease and, be viewed against other risks we are knowingly or, unknowingly party to in our everyday life. The issues of risk are discussed under the menu heading, ‘Background’. In the cases of families with children affected and diagnosed, it is usual to get the diagnosis confirmed by genetic testing in which case the precise mutations,-there will be two,- will be known. Sometimes the two mutations will be the same, but often they will be different. The parents can also be tested so it can be determined from which side of the family each mutation has come. This makes it a relatively simple matter to check any member of the family as the testing laboratory will know precisely which mutation they are looking for. Mutations are described in two main ways.
• Either as a change in the chromosomal gene sequence (genomic DNA or its RNA transcript) of letters (chemicals A, T, C, G), or
• As a change to the amino acid (20 different types) sequence of the protein which is made from the DNA instructions eg I1061T, the Type C common European mutation, which shows that the normal sequence amino acid I, has been replaced by the amino acid T, at the position 1061 counting from one end, - the amino terminus of the protein.
  The latter method appears to be the most common for any clinical considerations as it is the proteins that carry out the tasks within the cell.

There is no evidence to suggest that carriers of NPA, B or C genes are at any disadvantage in terms of ability or health when compared to the general population. Their lives can be lived normally with no cause for special concern. Possessing the knowledge that you harbour a defective copy of a gene is therefore, the question to be addressed. The situation is not the same as, for example, a carrier of the Parkinson’s gene, or of BRCA1 giving a predisposition to breast cancer, where it is likely that the disease will develop. It may be however, that possessing the knowledge that you are not a carrier of a defective gene might be important to future generations of your family. They will have an awareness and will be better able to predict that their children will be safe from these diseases, rather than be afflicted without warning as is the present situation. The knowledge will allow informed choices to be made.

Reaction of grandparents to gene tests may well pose a problem especially where old fashioned attitudes and a lack of knowledge of genetic inheritance exist. Genetic counselling is an important option in this situation. Grandparents, like parents are not to blame..

A potential problem may arise when an individual who is a carrier decides to start a family. They will be aware of the consequences of NP disease and, will hopefully know that whilst the chances of their partner also having the same defective gene are very low, the impact of having a child with the disease will be very high. Unfortunately as science stands at the moment it is not possible to test partners, therefore genetic counselling will only be able to advise on the risk associated with population risk, which will still be very small

The publication of the human genome sequence and the work that will emerge as a result will have a significant social impact on our lives. The extent of this has yet to be understood, but as ever, knowledge is a two edged sword. Great debates are already underway on ethical issues relating to the choices available to us through genetic science. These debates range from the freedom to choose the sex of a child through to genetic modification to crops aimed at eliminating food shortages. Projects are underway to establish the genetic makeup of whole communities in an attempt to understand the genetic variation existing within communities and how this interacts with environmental factors with regard to incidence of disease. Within these projects, provision has been made collect data on rare genetic diseases. Hopefully this will be of benefit to those carriers and families of patients with NPDs

The implications of having detailed personal genetic knowledge within the society at large has yet to be revealed. One hope is that it will enable the planning of medical services and allow bespoke preventative treatment to be undertaken for individuals and families. A further factor which is the subject of ongoing discussions is that of insurance and how genetic testing may affect this. It is not envisaged that carriers of recessive disease genes will find this a problem, but much relies on the understanding of the insurance industry. This topic has been embraced by government, the insurance industry and patient organisations and there are frequent reports on progress of the discussions. No doubt there will be other issues arising which we are not yet aware.