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The Jennifer Trust for Spinal Muscular Atrophy

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An Overview of
Spinal Muscular Atrophy

By Jenny Versnel

Research Support Officer,
The Muscular Dystrophy Group
of Great Britain and Northern Ireland
Proximal SMA is an autosomal recessive disorder with onset in childhood that results in the loss of motor neurones and as a consequence there is accompanying muscle atrophy. This is the most frequent form of SMA. Classification is based on the age of onset and the severity of the disease with three types: Type I (severe), Type II (intermediate), and Type III (mild). The SMA defect has been mapped to the region of chromosome 5q13.

The critical region in 5q13 contains several genes including the Survival Motor Neurone Gene (SMN), the Neuronal Apoptosis Inhibitory Protein gene (NAIP) and the p44 gene. Deletion of NAIP and p44 is observed more often in severe SMA but there is no evidence that these genes play a direct role in the pathology of the disease. NAIP may offer a protective effect to the motor neurones but further research needs to be done in this area before there is any certainty.

There are two copies of the SMN gene, a centromeric copy (SMNcen) located centrally on the chromosome and a telomeric copy (SMNtel) located near the tip of the chromosome. The SMN protein is the product of the SMN genes and is found in the cytoplasm and the nucleus. The nuclear form is located in structures called gems. It is thought that it is the telomeric copy of the SMN gene that plays a major role in disease determination as in over 90% of patients (irrespective of disease severity), there are deletions in both copies of SMNtel.

In addition to SMNtel, the number of copies of the SMNcen gene is thought to play a major role. It is now possible to determine the number of copies of SMNcen and the severity of the disease has been shown to correlate very well with the number of copies of SMNcen. The number of copies would affect the amount of SMN protein produced, i.e. the less the protein the more severe the disease.

SMN protein levels and gem numbers (nuclear form) correlate well, with low gem numbers being found in SMA Type I patients and higher numbers in Types II and III.The number of copies of the SMNcen gene may vary on each allele further complicating the inheritance pattern. An allele is one of a pair or multiple forms of a gene located at the same locus (position) on homologous chromosomes. This may help explain why we see children with differing severity in one family. One sibling may have inherited an allele with several copies of the SMNcen gene and have a milder form than a sibling who inherits an allele with a low copy number of the SMNcen gene.

In summary, the severity of the disease appears, at present, to be a combination of the following factors : -

  1. The deletion of both SMNtel genes
  2. The copy number of the SMNcen gene, the more copies the less the severity, and
  3. The occurrence of gene conversion leading to additional copies of SMNcen thereby reducing the severity of the disease.

Unfortunately this is not the final picture as the disease can not be unequivocally explained by the above. Patients have presented with a typical SMA but on analysis have been found to have two copies of the SMNtel gene, although this is a rare event. There is also an adult form of SMA and an autosomal dominant form which do not clearly fit into the above pictiure. There may well be additional factors that play a role and scientists world wide are collaborating to try to explain fully the disease mechanism.

Carrier testing.

Carrier testing is being set up in the UK, but is as yet not available. It is performed in some United States laboratories. It is based on the fact that if there is a homozygous deletion of SMNtel (i.e. 0 copies of the gene) then you have a 95% chance of being a carrier. Conversely if you perform a carrier test and find two copies of SMNtel there is a 90% chance of not being a carrier. There is, however, a small error rate involved.

Current status of therapeutic trials.

At present there are no clinical trials outside the USA. There have been a couple of small Phase I trials using growth factors which proved unsuccessful due to the fact that the patient's body formed antibodies to the growth factor. As a consequence the growth factor would be destroyed in any future contact and Phase II trials never took place.

There is a small trial on the use of Riluzole for SMA Type I patients which began in the USA in April 1998. Results from this will take at least another year but it is thought unlikely to have any benefit.

Gabapentin trial in the USA :
The European Neuromuscular Centre (ENMC) drew up the protocols for this trial and have thus been involved. However, no patients from Europe will be included in this study unless initial results are positive. Clinicians and scientists in Europe think it unlikely that Gabapentin will work, but one positive thing from this trial is that the protocols set up for therapeutic trials will have been tested and, if future trials are planned, these can be implemented.

Gabapentin and Riluzole are glutamate inhibitors which are hypothesised to play a role in Motor Neurone Disease but there is no proven link with SMA.

I have just attended the ENMC workshop on SMA in the Netherlands and it was very encouraging to see scientists and clinicians coming together and collaborating to try to elucidate the mechanisms involved. This type of collaborative research can only benefit families.

What follows will give you an idea of what key scientists are working on in the field of SMA (European and a few Americans). Those listed here are only those who were present, or mentioned, at the ENMC meeting in April 1998. If you feel that there is another project which might be included on this list, please e-mail it to the page editor for consideration.

SMA work in the United Kingdom.
Professor Kay Davies' laboratory
This is a three year project entitled the "Molecular Analysis of SMA". Professor Davies is well known for her excellent scientific contributions and one of the aims of this project has been to establish a relationship between the deletions and the severity of the disease. It was Professor Davies' work which demonstrated the importance of gene conversion events. She is also running another project on SMA.
Professor G. Vrbova's laboratory
There is a critical time period in the development where the motor neurones and muscles are dependent on the functional interaction with each other for survival. Professor Vrbova and her team are disrupting neuromuscular interaction during the early postnatal period to try to determine the critical stage for neuromuscular interaction.
 
SMA work in France.
Dr J. Melki's laboratory
Here they are studying the structure and organisation of the SMN gene. They are also looking at the role of the p44 gene as well as different forms of mutations that are occuring in the disease.
Dr S. Lefevre . .
. . was responsible for the identification of the SMN gene in 1995 and is looking at the correlation between severity and SMN protein level in SMA as well as the structure and organisation of the SMN gene. She is also working on a mouse model for SMA.
 
SMA work in Germany
Prof K. Zerres, Dr S. Rudnik-Schoneborn and Dr B. Wirth . .
. . have been very involved in the clinical and genetic correlations of SMA and have studied large numbers of patients and their families. They have very detailed information on these patients which is very helpful in the analysis of the disease mechanisms.
Prof H. Goebel's laboratory
Here they are studying apoptosis-related (cell death) proteins in skeletal muscle.
 
SMA work in The Netherlands
Dr H. Scheffer and Dr J.M. Cobben . .
. . are involved in prenatal prediction of SMA and carrier testing.
 
SMA work in Italy
Dr C. Brahe
Her group is studying the SMN gene and mutations in the gene. They are also interested in Adult Onset SMA and have collected data on their patients for analysis.
 
SMA work in Canada
Dr A. MacKenzie's laboratory
Here they are primarily involved in the study of the NAIP gene and its role in SMA.
 
SMA work in the United States of America
Dr A. Burghes' laboratory
Here their interests lie in the SMN gene and its protein, genotype/phenotype correlations and mouse models. They have also developed a carrier test.
There is a new page on this site outlining a research breakthrough from Dr Burghes' laboratory.
Dr T. Gilliam's laboratory
This laboratory has contributed to the construction of genetic and physical maps across several human chromosomes with the specific goal of mapping, cloning and identifying human disease genes. They have been involved in the mapping and characterisation of the genes for SMA.
Dr T. Munsat's laboratory
This laboratory is involved in the current trial of Gabapentin for SMA.
Please note that this is not a complete listing of those working in the field of SMA.

Back to the index.
Author : Jenny Versnel, Research Support Officer, The Muscular Dystrophy Group of Great Britain and Northern Ireland.

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First published by The Jennifer Trust for Spinal Muscular Atrophy : 18th May 1998

Latest update : 1st february 2000