Research progress in limb girdle muscular dystrophy


Limb girdle muscular dystrophy (LGMD) is the name given to a group of conditions that causes weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.

Since the condition has many subtypes, the severity, age of onset, and features vary enormously even within the same family. The symptoms may appear at any age and generally worsen with time, although in some cases they remain mild. Weakening of the heart muscle (cardiomyopathy) occurs in some forms and some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing.

About 1,400 people in the UK are affected by a form of LGMD. However about 25 percent of people do not receive a precise genetic diagnosis.

The different forms of LGMD are caused by mutations in many different genes and more than 30 genes are known to be associated with this condition. These genes provide instructions for making proteins that are involved in muscle maintenance and repair. In their absence or when a faulty protein is made due to the genetic mutation the physical integrity of muscle tissue is affected and muscles cannot contract. In some cases the cell signalling, cell membrane repair, or the removal of potentially toxic wastes from muscle cells are impaired.

Some forms of the condition are inherited in a dominant way where one mutated copy of the gene is enough to cause the condition. In other cases the inheritance pattern is recessive. This means that two mutated copies of the gene, one coming from the mother and one from the father, are necessary to cause the condition.

The table below summarises more common types of LGMDs and the genes that cause them.

There are several other forms of the condition not listed on the table. These are very rare and are caused by mutations in several other genes. For more information see our LGMD factsheets.

There are currently no specific therapies or cures for LGMD. Our understanding of the genetic cause and the biology of the condition is in its infancy but is increasing continuously. Some of the challenges in LGMD clinical research are that there are many different genetic causes and some people never get a genetic diagnosis. LGMDs are rare conditions with small numbers of patients dispersed around the world, which makes recruitment for clinical studies more difficult. The progression or natural history of LGMD is also not well understood, which makes it hard to show whether a drug or intervention is having an effect.

Some approaches are focusing on managing the symptoms of the condition rather than the underlying genetic cause. These include non-drug treatments such as physiotherapy and exercise. Corticosteroids have also been investigated as a potential treatment for some limb girdle muscular dystrophies. Some cases of LGMD 2C and LGMD 2F have reported improvements with steroid treatment, but a placebo-controlled study showed that one type of steroid (deflazacort) was not effective in people with LGMD 2B and also had significant side effects. One very small study also reported an improvement in muscle strength after treatment with a compound called rituximab in two patients with LGMD 2B.

There are also potential treatments being developed that target the underlying genetic cause, include exon skipping approaches which might be applicable to LGMD 2B and gene therapy to deliver a functional copy of the defective gene to the muscle. Gene therapy using an adeno-associated virus (AAV) are now in phase 1 safety studies for LGMD 2D and 2B (see Clinical Trials below). Nationwide Children’s Hospital Center for Gene Therapy in Ohio, USA, is leading much of this AAV gene therapy research and have set up a spin-out company that will develop gene therapies for LGMD (read our news story for more information).

In the past, Muscular Dystrophy UK has funded research in the group of Professor Francesco Muntoni to identify new genes causing dystroglycanopathies and biomarkers that help to monitor the progression of LGMD. We have also supported Professor Kate Bushby who identified dysferlin, the gene that is mutated in LGMD 2B.

Currently we are funding one research project that is specific to LGMD. It is based in the Newcastle Muscle Centre, which provides the national LGMD diagnostic and advisory service in the UK.

Professor Volker Straub is using a pioneering genetic technique, called next generation sequencing, to identify new mutations that lead to LGMD. This will provide a genetic diagnosis to a number of people with LGMD and help to improve understanding of the condition.

  • Gene Transfer Clinical Trial for LGMD2D

In this small scale phase I/II study an adeno-associated virus (AAV) will be used to deliver a healthy copy of the alpha-sarcoglycan gene to the muscles of people with LGMD 2D. It is hoped that the gene will be used to produce fully functional alpha-sarcoglycan protein missing in people with LGMD 2D. The study is taking place in the US only and is currently recruiting participants. identifier: NCT01976091

  • Gene Transfer Clinical Trial for LGMD2B

This small scale phase I study will use a harmless AAV virus to deliver a healthy copy of the dysferlin gene to the muscles of people with LGMD 2B. It is hoped that the gene will be used to produce fully functional dysferlin protein missing in people with LGMD 2B. The study is currently recruiting participants in the US. identifier: NCT02710500

  • Clinical Trial of Coenzyme Q10 and Lisinopril

This study aims to test whether Coenzyme Q10 and Lisinopril can be used to prevent or slow down heart problems associated with LGMD 2C-2F and 2I. It is an ongoing phase II/III trial but is enrolling participants by invitation only. identifier: NCT01126697

  •  Resolaris (ATYR1940)

This is an anti-inflammatory drug that might have a beneficial effect for people with LGMD 2B. A phase I/II clinical trial has recently been completed in the US, Denmark and France to test the safety and tolerability of this drug in people with LGMD 2B aged 18-75. The drug was found to be safe and improved the muscle function of seven out of nine participants after 14 weeks of treatment. Read the latest MDUK news story for more information. identifier: NCT02579239

  • Myostatin inhibition

This phase I/II clinical trial is testing to see whether a myostatin blocker called PF-06252616 could help to preserve or improve muscle function in people with LGMD 2I. It is currently ongoing in the US only and is not recruiting participants. identifier: NCT02841267

  • Acceptance and Commitment Therapy for Muscle Disease (ACTMuS)

This clinical study is funded by the National Institute of Health and co-funded by Muscular Dystrophy UK. It is aiming to find out whether a psychological treatment called Acceptance and Commitment Therapy (ACT) can enhance quality of life for people affected by a muscle-wasting condition. ACT is about accepting what is out of your own personal control, while committing to action that will improve your quality of life. This has been shown to be helpful for people with a range of chronic conditions. The ACTMuS study will see if it is also helpful for adults with muscle-wasting conditions, including limb girdle muscular dystrophy. For more information including how to take part, read our news story. identifier: NCT02810028

Last updated September 2017.

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