If your child has been diagnosed with a rare inherited genetic disease, you may ask the question as to what the healthcare services are doing to find a cure, or, perhaps to prevent such diseases in the future.  In general your GP and hospital consultant will not of have heard of Niemann-Pick disease or have any experience in treating it, they may however, help by conducting a search on their medical databases or the internet.  This search will provide some detail of the disease itself but it is unlikely that you will learn a great deal about what research is being carried out.  You may receive a referral to a metabolic specialist paediatrician and receive information about patient support groups such as the NPDG (UK).

There is no directed programme of research in the UK for Niemann-Pick diseases or for any of the many hundreds of similar conditions affecting our population.  Research into any of these diseases relies on interest being taken by a professional in a diagnostic laboratory or an academic working within a university.  As a parent you would find it difficult to identify researchers and even more difficult to penetrate the healthcare authorities to discuss your concerns.

The NPDG (UK) can help you in a number of ways by providing information on a range of topics including research.  Over the years that the Charity has been in existence a working knowledge has been built up relating to the research that is taking place, its status and where it is happening.  A summary of the research status together with appropriate references is provided for a variety of users ranging from parents, perhaps having little knowledge of the science behind the disease, to interested professionals in different specialisations.  Much of the information is, by necessity, of a technical nature. Please refer to the Glossary for definitions of the terms used.

The Niemann-Pick Diseases - Background

In the early part of the 20th century a German doctor, Dr Albert Niemann described the clinical presentation of children with the disease, but at that time little was known regarding the cellular or molecular explanation.  It was not until 1958 that the disease presentations were classified into type A, B and C.  In 1966 types A and B were identified with a lysosomal enzyme, acid sphingomyelinase.  Type C, which in turn was further sub classified into types D, E and possibly others, remained the subject of investigation, mainly by the National Institute of Health near Washington, USA.  Although NPC could be diagnosed through clinical, histological and biochemical means, it was not until 1997 that the genetic link was made which accounted for most of the NPC cases and is identified as NPC1.  Subsequently, a further link was made with a second gene, NPC2, which accounted for most of the remainder.  Some patients diagnosed with the disease remain to be accounted for.  All known types of Niemann-Pick disease are acquired through autosomal recessive inheritance.

Niemann-Pick Type A/B

Research Status

Although originally thought to be separate diseases, it is now established that types A and B have a single genetic cause, mutations which result in a clinical and cellular phenotypic spectrum ranging from mild to very severe.  The principal, traditionally understood difference between type A and B was that type B patients had no neurological involvement.  Emerging evidence suggests that the division may not be a clear cut as this and that there are intermediate cases.

The disease is caused by mutations in the ASM gene on chromosome 11 which lead to defective function of the gene product, acid sphingomyelinase (ASM) enzyme.  This lysosomal enzyme catalyses the breakdown of sphingomyelin to phosphocholine and ceremide.  The disruption in enzyme function results in accumulation of substrate within lysosomes which in turn, results in lesions to organs and tissue.  It has been suggested that a more descriptive name for the disease is ASM deficiency rather than the legacy name of Niemann-Pick A/B.

As a lysosomal enzyme defect, type A/B is one of more than 40 other similar genetic diseases resulting in pathological storage problems.  The molecular cause is well understood although much remains to be learned about the various ways in which different tissue and organs are affected and, how these effects relate to specific mutations.

Treatment Potential

Designing treatment for NP Type A presents a major challenge as the central nervous system (CNS) is involved in addition to other organs and tissues of the body.  In addition, survival time is short and diagnosis can be delayed.  Even if an effective treatment were to be available and could be administered soon after birth, damage may already have progressed beyond the possibility of rescue.  The recessive nature of the disease allows no warning for the affected firstborn child.

The disease could be a candidate for gene or stem cell therapy and also small molecule intervention. 

The outlook for NP Type B is much more optimistic.  Although ASM is impaired, there is sufficient activity to confer protection within the CNS.  This not only provides the patient with time, but also allows consideration of enzyme replacement therapy (ERT) which has been shown to be efficacious in a number of other, similar conditions.  A Phase 1 trial using ERT started late 2006.

References

1. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick Disease.  Journal of Inherited Metabolic Disease, 12 July 2007.  Schuchmann.
2. A Phase 1, Single-Center, Single Dose, Dose Escalation Study of Recombinant Human Acid Sphingomyelinase (RHASM) in Adults with Acid Sphingomyelinase Deficiency (ASMD).

Niemann-Pick Type C

Research Status

NPC has been difficult to classify due to the highly variable clinical presentation, age of onset and rate of progression.  Following the discovery of the gene in 1997, it became clear that the subdivision previously allocated, C, D E were in fact traceable to mutations on the NPC1 gene on chromosome 18.  A small group, less than 5% of patients, could not be accounted for by NPC1 gene defects and were subsequently traced to a gene on chromosome 14 already designated HE1.  This gene is now also known as NPC2.  A further small group, diagnosed with the disease by clinical and cellular phenotype, have not as yet been found to have mutations in either the NPC1 or the NPC2 genes.  This raises the possibility that other genes may contribute to the pathway in which NPC1/2 operate.  The function of the protein product of NPC1 remains elusive and is the subject of much investigation.  The protein is thought to be a membrane bound transporter operating in the endosomal/lysosomal (E/L) recycling pathway.  Defects in the NPC2 protein result in very similar clinical and cellular phenotypes and this suggests that the proteins operate in the same pathway.  NPC2 has been shown to be a lysosomal protein that binds and transports cholesterol.

Treatment Potential

Being recessive, the disease strikes without warning with symptoms becoming evident soon after birth or, after many years have elapsed.  In the early onset cases, even assuming a cure was available and diagnosis occurred soon after birth, it is not clear whether damage sustained prior to birth would permit rescue.  The situation is similar to type A.  In the cases of later, juvenile or young adult onset, diagnosis may take many years as symptoms are often slow to develop and awareness of genetic disease in the medical community is low.  A tragic consequence of late onset is that other children may have been born to the family who have also inherited the disease.  In later onset cases, neurological aspects progressively dominate as populations of neurons are destroyed.

Although there is currently no cure for the disease, treatment with gene transfer, stem cell therapy or small molecule intervention, offer potential for the future.  Substrate reduction therapy (SRT) is an example of the latter technology, the use of which has been successfully demonstrated with NPC mice.  A Phase II trial using a small molecule, miglustat, has been progressing for over 2 years on both adults and children.

References

1. Biochemica et Biophysica Acta.  Molecular and Cell Biology of Lipids.  Volume 1685, Issue 1-3, 11 October 2004.  This provides a review of research and the history of the disease.
2. Marc P, latest report on trial.
3. www.parseghian.org.  This is the website of the Ara Parseghian Medical Research Foundation.  This family Foundation is based in Tucson, Arizona and raises funds for research into NPC.
4. www.nnpdf.org.  This is the website of the US based charity, The National Niemann-Pick Disease Foundation.  This Charity operates in a similar way to the NPDG(UK) and raises funds for research, provision of support to families and information.
5. www.ncbi.nlm.nih.gov/omim.  This is a website operated by the US National Institutes of Health and is a source of a great deal of information.  Ongoing publication abstracts can be found by selecting Pubmed and the disease of interest.