Limb-girdle muscular dystrophy

Limb-girdle muscular dystrophy
Classification and external resources
ICD-10	G71.0
ICD-9	359.1
DiseasesDB	32189
eMedicine	neuro/189
MeSH	D049288

Limb-girdle muscular dystrophy or Erb's muscular dystrophy is an autosomal class of muscular dystrophy that is similar but distinct from Duchenne muscular dystrophy and Becker's muscular dystrophy. Limb-girdle muscular dystrophy encompasses a large number of rare disorders.

Presentation

The term "limb-girdle" is used to describe these disorders because the muscles most severely affected are generally those of the hips and shoulders -- the limb girdle muscles.

Common symptoms of limb-girdle muscular dystrophy are muscle weakness, myoglobinuria, pain, myotonia, cardiomyopathy, elevated serum CK, and rippling muscles.

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 disfunction at presentation. The specific dermatomes affected can be demonstrated clinically, and although lower limb deep tendon reflexes and plantar reflex are lost, abdominal reflexes are preserved.

Prognosis

The distal muscles are affected late in LGMD, if at all. Over time (usually many years), the person with LGMD loses muscle bulk and strength. Eventually, s/he may need a power wheelchair or scooter, especially for long distances. 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.

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.

Diagnosis

A person need to perform "Muscle biopsy" test in order to know whether he has muscular dystrophy or not , "Genetic testing" need to be done in order to find the type of LGMD

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".

A project website has been set up at www.nmd-chip.eu which enables dissemination of information about the project to stakeholders.

Genetics

LGMD is typically an inherited disorder, though it may be inherited as a dominant, recessive, or X-linked genetic defect. The result of the defect is that the muscles cannot properly form the 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 are α, β, γ and δ sarcoglycans. The sarcoglycanopathies could be possibly amenable to gene therapy.

Treatment

Treatment for LGMD is primarily supportive. Exercise and physical therapy are advised to maintain as much muscle strength and joint flexibility as possible. 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.

Research

There is a variety of research underway 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 underway and seeking to apply these methodologies to various limb girdly dystrophies.

GENETHON - LGMD 2C(Gamma-sarcoglycanpathy)

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".

JERRY MENDELL - LGMD 2D(alpha-sarcoglycanpathy)

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.

List of limb-girdle muscular dystrophies

The "LGMD1" family is autosomal dominant, and the "LGMD2" family is autosomal recessive.

Name	OMIM	Location
LGMD1A	159000	TTID
LGMD1B	159001	LMNA
LGMD1C	607801	CAV3
LGMD1D	603511	7q
LGMD1E	602067	6q23
LGMD1F	608423	7q32.1-q32.2
LGMD1G	609115	4q21
LGMD2A	253600	CAPN3
LGMD2B	253601	DYSF
LGMD2C	253700	SGCG
LGMD2D	608099	SGCA
LGMD2E	604286	SGCB
LGMD2F	601287	SGCD
LGMD2G	601954	TCAP
LGMD2H	254110	TRIM32
LGMD2I	607155	FKRP
LGMD2J	608807	TTN
LGMD2K	609308	POMT1
LGMD2L	611307	ANO5
LGMD2M	611588	FKTN
LGMD2N	607439	POMT2
LGMD2O	606822	POMGNT1

External links

• Muscular Dystrophy Association
• LGMD in MDA website
• GeneReviews/NCBI/NIH/UW entry on Limb-Girdle Muscular Dystrophy Overview
• GeneReviews/NCBI/NIH/UW entry on Calpainopathy
• GeneReviews/NCBI/NIH/UW entry on Dysferlinopathy including Miyoshi Distal Myopathy (Miyoshi Myopathy), Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B)
• Healthline for Patients
• Washington University in St. Louis Neuromuscular Section LGMD
• Duke University (Great Clinical Description of LGMD phenotypes
• Glenn Lopate MD for emedicine
• Jain Foundation Inc:Orchestrating a cure for Miyoshi/LGMD2B
• Kurt+Peter Foundation: Raising funds for a cure for LGMD2C