Congenital muscular dystrophy - 2002

Written by the Research Department at the Muscular Dystrophy Campaign

Congenital muscular dystrophy refers to a group of conditions which share a common muscle pathology but can be distinguished from each other by specific clinical features that are associated with them. There are presently seven forms for which associated genes have been identified, other forms are known to exist but the genes involved have not yet been found. Research advances over the past year have:

• identified the genes involved in three forms of congenital muscular dystrophy
• shown the potential of upregulating a muscle protein known as agrin as a novel strategy to reduce the severity of muscle pathology seen in the animal model of congenital muscular dystrophy, which has a deficiency in merosin (MDC1A)

Advances mean better diagnosis, genetic counseling and management of conditions, which in some cases may be associated with cardiac problems. It is encouraging to see the start of research into potential therapies and although there is still no cure or therapy at present research is moving this goal forward.

Contents:

• Background information
• Classification
• Recent research
• What does this mean for me now and in the future?
• Relevant publications

Background information

Congenital muscular dystrophy refers to a group of muscle disorders with symptoms of muscle weakness and ‘floppiness’ present at birth or within the first six months of life. The overall frequency of this disorder in the UK is approximately one in every 50,000 births.

The conditions are inherited in an autosomal recessive manner which means that both parents carry a faulty gene and have a 25% chance of having an affected child of either sex. In general, the disease is either slowly progressive or non-progressive, contractures are common and involvement of the central nervous system is a component of some forms of congenital muscular dystrophy. Although there is common muscle pathology in the congenital muscular dystrophies, the group is very heterogeneous with each form having specific clinical features associated with it. Over the last few years a lot of effort has gone into identifying the separate categories within the group and locating the gene responsible for each form.

Professor Francesco Muntoni, a Muscular Dystrophy Campaign grantee, has played a major role in this area and has been responsible for two recent gene discoveries, details of which can be found in the research section. Seven genes have been identified so far but it is known that there are at least a dozen more well defined groups which can be separated from each other clinically. The classification of congenital muscular dystrophy has now changed slightly with some forms designated MDC.

Classification

Form of congenital muscular dystrophy: MDC1A ( merosin deficient)
Gene: LAMA2
Protein: Merosin
Chromosome: 6q2

Form of congenital muscular dystrophy: MDC1B (secondary merosin deficiency)
Gene: ?
Protein:
Chromosome: 1q

Form of congenital muscular dystrophy: MDC1C
Gene: FKRP
Protein: Fukutin related protein
Chromosome:

Form of congenital muscular dystrophy: Integrin a7 deficiency
Gene: ITGA7
Protein: Integrin a 7
Chromosome: 12q1

Form of congenital muscular dystrophy: Fukuyama CMD (FCMD)
Gene: Fukutin
Protein: Fukutin
Chromosome: 19q3

Form of congenital muscular dystrophy: congenital muscular dystrophy + Rigid spine (RSMD1)
Gene: SEPN1
Protein: Selenoprotein N
Chromosome: 1p36

Form of congenital muscular dystrophy: Muscle eye brain (MEB)
Gene: OMGnT
Protein:
Chromosome: 1p34

Form of congenital muscular dystrophy: Ulrich congenital muscular dystrophy
Gene: COL6A1, COL6A2, COL6A3,
Protein: Collagen VI, Collagen VI, Collagen VI
Chromosome: 21q2, 21q2, 2q37

As can be seen from the information above, the different classifications differ widely both in the genes associated with them and the proteins these produce. Merosin and integrin a7 are proteins which link proteins on the outside of the cell to ones inside the cell cytoskeleton (scaffolding). The roles and functions of many of the proteins involved in congenital muscular dystrophy still need to be identified and will prove invaluable in understanding the disease process in these disorders.

Recent research

1. Mutations in the KFRP gene cause congenital muscular dystrophy type 1C
In November 2001 Professor Francesco Muntoni published results showing that mutations in the fukutin related-protein (FKRP) gene causes a severe form of congenital muscular dystrophy designated MDC1C. Presentation is:

• with early onset
• inability to walk unaided
• enlarged leg muscles
• secondary reductions of two other proteins implicated in muscular dystrophy

What makes this discovery so interesting is that mutations in the same gene have been found to cause a form of limb-girdle muscular dystrophy, LGMD2I, which means that mutations in the KFRP gene gives rise to two clinically different disorders. This is not the first time a gene has been implicated in two different disorders, it occurred in another form of LGMD (1B) and a form of Emery-Dreifuss muscular dystrophy (EMD-AD). Further research may shed light on a common pathway between some muscle disorders and further our knowledge of how mutations in certain genes result in differing symptoms. This type of information is essential if we are to investigate ways of compensating for these faults.

Reference: Mutations in the Fukutin-Related Protein Gene (FKRP) Cause a Form of Congenital Muscular Dystrophy with Secondary Laminin alpha2 Deficiency and Abnormal Glycosylation of alpha-Dystroglycan.
American Journal of Human Genetics 2001 November

2. Mutations in the SEPN1 gene cause a rare form of congenital muscular dystrohy
In September 2001, Professor Francesco Muntoni published his discovery of a new gene called Selenoprotein N (SEPN1) which is involved in a rare form of congenital muscular dystrohy. This form of the condition is associated with milder symptoms than some other forms of congenital muscular dystrophy but has significant spinal stiffness and frequent scoliosis, which means that night time ventilatory support may be required.

This form of congenital muscular dystrohy appears to be more common in Turkey and Iran but British patients with mutations in this gene have been found. This is the first time a protein of this type has been implicated in a muscle disorder and this will further our overall understanding of muscle disorders. The discovery suggests a possible link between selenium deficiency and muscular dystrophy but it must be stressed that this is a distinct group of individuals and there is no suggestion that individuals with muscular dystrophy should look at taking selenium supplements. As congenital muscular dystrohy conditions are so different in their presentation, treatment differs for the groups. Identification of this new gene will enable those affected to be better treated and allow families to receive the appropriate genetic counseling.

Reference: Mutations in SEPN1 cause congenital muscular dystrohy with spinal rigidity and restrictive respiratory syndrome. Nature Genetics 2001 Sep 29(1): 17-18

3. The use of an agrin minigene in a mouse model of congenital muscular dystrophy has shown to be effective in reducing the severity of muscular dystrophy symptoms:
Around 40% of children with the classical forms of congenital muscular dystrophy have mutations in the laminin a2 gene (LAMA2) which results in a deficiency of laminin a2 protein, also called merosin protein. This laminin a2 molecule is linked to other proteins that together form a type of scaffold structure. A problem with one molecule can cause the whole complex to be unstable and not be able to perform its function.

The laminins are a family of molecules and one way in which the body tries to compensate for this deficiency is to produce more of another type of laminin but this type of strategy is not effective as other laminins don’t bind as well to the required molecules. Agrin is known to bind the same molecules as laminin a2 so researchers attempted using agrin almost like a bridge to strengthen the structure. An agrin minigene was introduced into the mouse model for this form of congenital muscular dystrophy using gene transfer and results demonstrated a significant improvement in muscle pathology of these mice. At 16 weeks mice with laminin a2 deficiency are normally dead or very weak but mice with the agrin minigene at this stage displayed only mild muscle disease. It is important to note that although the lifespan of these mice increased it did not reach normal levels and the agrin was unable to rescue the damage to the peripheral nerves which is associated with this form of congenital muscular dystrophy.

It is exciting news as it highlights the possibility of reducing muscle disease symptoms but it is still early days when talking about its potential in humans. What are now needed are longer-term studies using these mice models to study things like levels of agrin needed and whether the minigene is sufficient as it was not able to rescue all of the muscle degradation. Pharmacological compounds will also be looked for that may be able to increase naturally occurring levels of agrin without the need for gene transfer. This may avoid any potential immune response problems that could arise if individuals were to be given laminin a2 and their bodies had not previously been exposed to this molecule. In its current form this research does not represent a therapy for humans but it does highlight a novel potential therapeutic approach for this form of congenital muscular dystrophy.

Reference: An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. Nature 2001:Sep 20, 413(6853):302-7.

4. The therapeutic potential of alpha-7-beta-1 integrin in muscular dystrophy:
Researchers in the USA published results in March 2001 demonstrating that animal models that were engineered to lack utrophin and dystrophin (two proteins involved in Duchenne muscular dystrophy) and then given increased levels of alpha-7-beta-1 integrin, the level of severity of muscular dystrophy normally evident in these mice was reduced. This suggested the possible use of this form of integrin in treating several types of muscular dystrophy, including the laminin- and integrin-deficient forms of congenital muscular dystrophy. It is early days and further research is required to determine the levels of integrin required and how this could be achieved – through the transfer of an integrin gene or by finding a drug that is capable of increasing naturally occurring levels within the body. It would also need to be determined in animal models if there are any negative effects when the levels of integrin are increased.

Reference: Enhanced Expression of the alpha7-beta-1 Integrin Reduces Muscular Dystrophy and Restores Viability in Dystrophic Mice. J Cell Biol. 2001 Mar 19;152(6): 1207-18

5. ENMC workshops
The European Neuromuscular Centre based in the Netherlands is an organisation set up to stimulate and facilitate scientific collaboration in neuromuscular disorders throughout Europe. One of its functions is to promote workshops on specific neuromuscular topics and participants (clinicians/researchers working in the field) come together for three days to discuss developments and plan future directives. If you are interested in finding out more about planned workshops or want to view summaries of these events, visit the website at www.enmc.org

In October 2001, Professor Francesco Muntoni led a workshop at the 7th workshop of the international consortium on congenital muscular dystrophy. The meeting focussed on the recent clinical, genetic and biochemical advances that have been made in differentiating three forms of congenital muscular dystrophy (rigid spine syndrome, congenital muscular dystrophy with distal laxity, congenital muscular dystrophy with deficiencies in glycosyltransferases).

Refined diagnostic criteria for these forms of congenital muscular dystrophy were discussed, together with the strategy aimed at arriving at a diagnosis for each condition. In addition management of these conditions, and therapeutic approaches in animal models were discussed with collaborative studies agreed. These workshops are valuable in ensuring that a focussed approach towards the study of a disorder is maintained and that there is not unnecessary duplication of research.

What does this mean for me now and in the future?

Unfortunately there is no cure for congenital muscular dystrophy. However, a precise diagnosis is important in terms of providing genetic counselling and helping the management of the individual conditions, as some forms may have associated respiratory, feeding or cardiac problems. It is exciting to see the emergence in this area of potential therapeutic strategies and although the current research does not represent a therapy it is a step in this direction.

Relevant publications

To order any publications, please email info@muscular-dystrophy.org

1. Muscular Dystrophy Campaign priority update on congenital muscular dystrophy – SEPN1 gene and agrin minigene, November 2001
2. Muscular Dystrophy Campaign priority update on congenital muscular dystrophy – FKRP gene, November 2001
3. Target md – Autumn 2001
4. Glossary of terms
5. Genetics primer - click the link to download the document: Genetics primer (28 kb)


You can download this research review as a Word document: Research review - Congenital muscular dystrophy (364 kb)

Find out more about the condition by visiting the congenital muscular dystrophy section.