Limb–girdle muscular dystrophy

Limb–girdle muscular dystrophy
Specialty	Physical medicine and rehabilitation
Frequency	0.0023% (United Kingdom)

Limb-girdle muscular dystrophy (LGMD) or Erb's muscular dystrophy is a genetically and clinically heterogeneous group of rare muscular dystrophies. It is characterised by progressive muscle wasting which affects predominantly hip and shoulder muscles.LGMD has an autosomal pattern of inheritance and currently has no known cure.

Classification(List of LGMD)

The "LGMD1" family is autosomal dominant, and the "LGMD2" family is autosomal recessive.Limb-girdle muscular dystrophy is explained in terms of gene, locus,OMIM and type as follows:

Family	Inheritance	Type	OMIM	Gene	Locus
LGMD1	autosomal dominant	LGMD1A	Template:OMIM2	TTID
		LGMD1B	Template:OMIM2	LMNA
		LGMD1C	Template:OMIM2	CAV3
		LGMD1D	Template:OMIM2	DNAJB6
		LGMD1E	Template:OMIM2	DES
		LGMD1F	Template:OMIM2	TNPO3	7q32.1–q32.2
		LGMD1G	Template:OMIM2	HNRPDL	4q21
		LGMD1H	Template:OMIM2		3p25.1–p23
LGMD2	autosomal recessive	LGMD2A	Template:OMIM2	CAPN3
		LGMD2B	Template:OMIM2	DYSF
		LGMD2C	Template:OMIM2	SGCG
		LGMD2D	Template:OMIM2	SGCA
		LGMD2E	Template:OMIM2	SGCB
		LGMD2F	Template:OMIM2	SGCD
		LGMD2G	Template:OMIM2	TCAP
		LGMD2H	Template:OMIM2	TRIM32
		LGMD2I	Template:OMIM2	FKRP
		LGMD2J	Template:OMIM2	TTN
		LGMD2K	Template:OMIM2	POMT1
		LGMD2L	Template:OMIM2	ANO5
		LGMD2M	Template:OMIM2	FKTN
		LGMD2N	Template:OMIM2	POMT2
		LGMD2O	Template:OMIM2	POMGNT1
		LGMD2Q	Template:OMIM2	PLEC1

Symptoms/signs

The symptoms of an individual with Limb-girdle muscular dystrophy (LGMD) generally has difficulty walking, going both up and down stairs and raising from a chair. Difficulty bending over and falling on a regular basis are also common. Difficulty lifting certain objects is also a common presentation of LGMD as well as difficulty holding your arms out or above your head. Eventually the ability to walk/run deteriorates.

Presentation

2

The disease inevitably gets worse over time, although progression is more rapid in some patients than others. Eventually the disease can affect other muscles such as the ones located in the face. The disease commonly leads to dependence on a wheelchair within twenty to thirty years of symptom onset, but there is high inter-patient variability, with some patients maintaining mobility.

The muscle weakness is generally symmetric, proximal, and slowly progressive.In most cases, pain is not present with LGMD, and mental function is not affected.LGMD can begin in childhood, adolescence, young adulthood or even later, the age of onset is usually between 10 and 30. Both genders are affected equally, when limb-girdle muscular dystrophy begins in childhood the progression appears to be faster and the disease more disabling. When the disorder begins in adolescence or adulthood the disease is generally not as severe and progresses more slowly.There is no sensory neuropathy or autonomic or visceral dysfunction at presentation.

Genetics

LGMD is typically an inherited disorder, though it may be inherited as a dominant or recessive genetic defect. The result of the defect is that the muscles cannot properly form certain proteins needed for normal muscle function. Several different proteins can be affected, and the specific protein that is absent or defective identifies the specific type of muscular dystrophy. Among the proteins affected in LGMD are α, β, γ and δ sarcoglycans. The sarcoglycanopathies could be possibly amenable to gene therapy.

Diagnosis

A muscle biopsy will show the presence of muscular dystrophy, and genetic testing is used to determine which type of muscular dystrophy a patient has. A consortium of LGMD Family Foundations (http://www.lgmd-diagnosis.org/about-the-sponsors) are offering free genetic sequencing for patients in the United States with muscle weakness (http://lgmd-diagnosis.org). The Jain Foundation (http://www.jain-foundation.org/) is an organization that helps patients become genetically diagnosed and has created an online tool for physicians called "ALDA (http://jain-foundation.org/lgmd-subtyping-tool/)," which predicts the LGMD subtype, saving time and money by avoidance of sequencing each LGMD by suggesting which are the most likely. ALDA is also now connected to the LGMD-diagnosis.org program and physicians are automatically offered the chance to apply for free genetic sequencing for eligible patients.Currently a "CHIP" is being developed by an organization called "NMD CHIP".

The project is designing chips for the diagnosis of mutations already known to cause Duchenne / Becker muscular dystrophies (DMD/BMD), limb girdle muscular dystrophies (LGMD), congenital muscular dystrophies (CMD), and hereditary motor-sensory neuropathies or Charcot-Marie-Tooth neuropathies (CMT). These diagnostic chips are described as "known-gene chips".

Treatment

Although exercise and physical therapy are advised to maintain as much muscle strength and joint flexibility as possible, there are few studies corroborating the effectiveness of exercise. Physical therapy and exercise may prevent the rapid progression of the disease rather than halt or reverse it. Calipers may be used to maintain mobility and quality of life. Careful attention to lung and heart health is also required. IVIg may increase strength in some forms and prevent progression in others, possibly through the prevention of fibrosis and inflammation without the secondary weakening caused by corticosteroids.

Prognosis

Cardiac muscle

The distal muscles are affected late in LGMD, if at all. The disease typically causes loss of mobility or dependence on a scooter/wheelchair within 20 to 30 years of symptom onset. The various forms of LGMD are highly variable, and can be variable even among persons with the same form of LGMD. In its most severe form, LGMD2C, the symptoms are usually similar to Duchenne Muscular Dystrophy, with individuals losing the ability to walk between ages 10 and 12. In its mildest form, affected individuals have near-normal muscle strength and function.

While LGMD isn't typically a fatal disease, it may eventually weaken the heart and respiratory muscles, leading to illness or death due to secondary disorders. In its most severe form, LGMD2C, lifespans are typically limited to the 20s or early 30s. The mildest forms do not significantly affect lifespan.Because it is a hereditary disorder, there is nothing an individual can do to prevent getting the disease. Because the weakness can affect the heart muscle, it is recommended that a doctor be aware of any heart-related symptoms so a cardiac pacemaker can be implanted to reduce the risk of sudden death due to an abnormal heart rhythm caused from the disease.

Research

There is a variety of research under way targeted at various forms of LGMD. Methods thought to hold significant promise for an effective treatment include "exon skipping" and gene therapy. Several clinical trials are under way and seeking to apply these methodologies to various limb girdle dystrophies.

The results of a Phase I clinical trial of gene therapy for limb-girdle muscular dystrophy type 2C were published in the journal Brain in January 2012. The trial started in December 2006 and has been sponsored by Généthon (the not-for-profit research lab created by the French Muscular Dystrophy Association (AFM) and which is funded almost exclusively by donations from France's annual Telethon). The trial at Pitié-Salpêtriere (AP-HP) is being led by principal investigators Professor Serge Herson (Head of the Department of Internal Medicine 1) and Professor Olivier Benveniste (Institute of Myology). The study's primary objective was to evaluate the safety of local injection of increasing doses of an adeno-associated virus (AAV) vector harboring a "healthy" copy of the gene for gamma-sarcoglycan (the defective protein in this disease). Secondary objectives included the assessment of local and systemic immune reactions and the quality of gene transfer in the injected muscles in terms of efficacy, expression and distribution. The trial's results have just been published and were encouraging. Above all, the injections were well tolerated and not associated with adverse physical or biological effects. Immunohistochemical analysis of injected-muscle biopsy specimens showed ?SGC expression in three out the three patients who received the highest dose. Furthermore, in one of these patients (who had received the highest dose of treatment), a western blot assay revealed that normal protein gamma-sarcoglycan was being expressed in the muscle fibers. Thanks to gene therapy, the missing gamma-sarcoglycan protein was being produced anew. In addition to confirming the treatment's lack of toxicity (the study's primary objective), we were able to make progress in other areas, such as trial logistics, immunological aspects and even the optimal dose for treating a set of muscles efficaciously. This result is especially interesting because it means that we have established the dose threshold above which the treatment becomes efficacious. That’s very rare in a Phase I trial".

Researchers in the US led by Prof. Jerry Mendell have published the results of a gene therapy trial for limb girdle muscular dystrophy type 2D (LGMD2D). Individuals affected by this condition have a fault in their 'alpha-sarcoglycan' gene which contains the instructions for a protein which is essential for muscle function. In this clinical trial three teenagers with LGMD2D had a virus containing a healthy copy of the alpha-sarcoglycan gene injected into a muscle in their foot. Not only was the gene therapy deemed to be safe, a significant amount of alpha-sarcoglycocan protein was produced which persisted for at least three months.

The researchers inserted a healthy copy of the human alpha-sarcoglycan gene into the AAV1 virus along with a molecular 'switch' that would only allow the alpha-sarcoglycan protein to be produced in muscle. This virus was injected into one small muscle in the foot. The same muscle in the other foot was injected with saline (salty water) as a control. Either six weeks (two patients) or 3 months (one patient) after the injection the production of alpha-sarcoglycan protein was assessed.

The muscles injected with the virus strongly produced the alpha-sarcoglycan protein in up to 69% of muscle fibres and was correctly located in the muscle membrane. This in turn restored the structure of a cluster of proteins that is normally found in muscle cells but is missing in muscles that lack alpha-sarcoglycan. This protein cluster is vital for the structure of the muscle fibres.

The results of this phase I clinical trial of gene therapy for LGMD2D are very promising. However, delivery of the gene therapy to the whole body, for example via the blood stream, is required for an improvement in symptoms to be seen in patients. This will be the next step in the development of gene therapy for LGMD2D. Clinical trials will be needed to determine the optimal route of administration, dose and the long term safety of the treatment.The success of the AAV1 virus to deliver the gene to the muscles in this trial also bodes well for the development of gene therapy for other neuromuscular conditions.

External links

• Muscular Dystrophy Association
• LGMD in MDA website
• Dystrophy Type 2B (LGMD2B)
• LGMD2D Foundation: Foundation dedicated to the development of a therapy or cure for LGMD2D