| Limb-girdle muscular dystrophy |
| Classification and external resources |
| Specialty |
neurology |
| ICD-10 |
G71.0 |
| ICD-9-CM |
359.1 |
| OMIM |
159000 159001 607801 603511 602067 608423 609115 253600 253601 253700 608099 604286 601287 601954 254110 607155 608807 609308 611307 611588 607439 606822 |
| DiseasesDB |
32189 |
| MedlinePlus |
000711 |
| eMedicine |
neuro/189 |
| MeSH |
D049288 |
| GeneReviews |
- Limb-Girdle Muscular Dystrophy Overview
- Calpainopathy
- Dysferlinopathy
|
|
[edit on Wikidata]
|
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.
It is similar to but distinct from Duchenne muscular dystrophy and Becker's muscular dystrophy.
Contents
- 1 Presentation
- 2 Symptoms
- 3 Prognosis
- 4 Diagnosis
- 5 Genetics
- 6 Treatment
- 7 Prevention
- 8 Research
- 9 List of limb-girdle muscular dystrophies
- 10 References
- 11 External links
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.
Symptoms of limb-girdle muscular dystrophy vary widely, but most commonly are muscle weakness and atrophy, myoglobinuria, myotonia, elevated serum CK, and, in ~20% of cases, cardiomyopathy.
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.[1]
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. The specific dermatomes affected can be demonstrated clinically, and although lower limb deep tendon reflexes and plantar reflex are lost, abdominal reflexes are preserved.
Symptoms
A person with LGMD generally has difficulty walking, going both up and down stairs and raising from a chair or a squatting position. 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.[2] Eventually the ability to walk/run deteriorates. It is advised that someone with the disorder not put themselves in situations of potential peril. For example, walking on floors that have even the slightest incline can cause the individual to lose balance and fall. It is not recommended for someone with the disease to walk on terrain which is not stable such as ice or other slippery surfaces to avoid a severe injury. This is mainly due to the fact that LGMD weakens the leg muscles so an individual with LGMD would be more inclined to fall than someone who does not suffer from the disorder. At times, heart palpitation can occur.[3]
Prognosis
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.[3] 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.
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".[4]
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".
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.
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.[5] 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.
Prevention
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.[3]
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.
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".[6]
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.
| Family |
Inheritance |
Type |
OMIM |
Gene |
Locus |
Characteristics |
| LGMD1 |
autosomal dominant |
LGMD1A |
159000 |
TTID |
|
|
| LGMD1B |
159001 |
LMNA |
|
|
| LGMD1C |
607801 |
CAV3 |
|
|
| LGMD1D |
603511 |
DNAJB6 |
|
|
| LGMD1E |
601419 |
DES |
|
|
| LGMD1F |
608423 |
TNPO3[7] |
7q32.1–q32.2 |
|
| LGMD1G |
609115 |
HNRPDL |
4q21 |
|
| LGMD1H |
613530 |
|
3p25.1–p23 |
|
| LGMD2 |
autosomal recessive |
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 |
|
|
| LGMD2Q |
613723 |
PLEC1 |
|
|
References
- ^ MedlinePlus Encyclopedia Limb-girdle muscular dystrophies
- ^ http://www.healthline.com/galecontent/limb-girdle-muscular-dystrophy-1#2
- ^ a b c "Health Guide: Limb-Girdle Muscular Dystrophies". New York Times.
- ^ http://www.nmd-chip.eu
- ^ Medicine and Rehabilitation for Limb-Girdle Muscular Dystrophy Treatment & Management ~treatmentPhysical Medicine and Rehabilitation for Limb-Girdle Muscular Dystrophy Treatment & Management at eMedicine
- ^ http://www.pipelinereview.com/index.php/2012011246856/DNA-RNA-and-Cells/Gene-therapy-Encouraging-results-in-a-Phase-I-clinical-trial-in-limb-girdle-muscular-dystrophy-type-2C.html
- ^ Melià MJ, Kubota A, Ortolano S, Vílchez JJ, Gámez J, Tanji K, Bonilla E, Palenzuela L, Fernández-Cadenas I, Pristoupilová A, García-Arumí E, Andreu AL, Navarro C, Hirano M, Martí R (2013) Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene. Brain
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 2A (LGMD2A)
- 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
- LGMD2D Foundation: Foundation dedicated to the development of a therapy or cure for LGMD2D
|
Muscular dystrophy
|
|
| Types |
- Congenital
- dystrophin
- Distal
- Emery-Dreifuss
- Facioscapulohumeral
- Limb-girdle muscular dystrophy
- Myotonic
- Oculopharyngeal
|
|
| National/International Organizations |
- Muscular Dystrophy Association (USA)
- Muscular Dystrophy Canada
- Myotonic Dystrophy Foundation
|
|
| National/International Events |
- MDA Muscle Walk (USA)
- Labor Day Telethon (defunct) (USA/Canada)
- Décrypthon (France)
|
|
| Clinical trials |
|
|
|
Diseases of myoneural junction and muscle / neuromuscular disease (G70–G73, 358–359)
|
|
Neuromuscular-
junction disease |
- autoimmune
- Myasthenia gravis
- Lambert–Eaton myasthenic syndrome
|
|
Myopathy/
congenital myopathy |
Muscular dystrophy
(DAPC) |
| AD |
- Limb-girdle muscular dystrophy 1
- Oculopharyngeal
- Facioscapulohumeral
- Myotonic
- Distal (most)
|
|
| AR |
- Limb-girdle muscular dystrophy 2
- Congenital
- Fukuyama
- Ullrich
- Walker–Warburg
|
|
| XR |
- dystrophin
- Emery–Dreifuss
|
|
|
| Other structural |
- collagen disease
- PTP disease
- adaptor protein disease
- BIN1-linked centronuclear myopathy
- cytoskeleton disease
- Nemaline myopathy
- Zaspopathy
|
|
| Channelopathy |
| Myotonia |
- Myotonia congenita
- Thomsen disease
- Neuromyotonia/Isaacs syndrome
- Paramyotonia congenita
|
|
| Periodic paralysis |
|
|
| Other |
|
|
|
| Mitochondrial myopathy |
|
|
| Other |
|
|
|
|
Inherited disorders of trafficking / vesicular transport proteins
|
|
| Vesicle formation |
| Lysosome/Melanosome: |
- HPS1-HPS7
- Hermansky–Pudlak syndrome
- LYST
|
|
| COPII: |
- SEC23A
- Cranio–lenticulo–sutural dysplasia
|
|
|
|
|
| APC: |
- AP1S2
- X-linked intellectual disability
- AP3B1
- Hermansky–Pudlak syndrome 2
- AP4M1
|
|
|
| Rab |
|
|
| Cytoskeleton |
| Myosin: |
|
|
| Microtubule: |
- SPG4
- Hereditary spastic paraplegia 4
|
|
| Kinesin: |
- KIF5A
- Hereditary spastic paraplegia 10
|
|
| Spectrin: |
|
|
|
| Vesicle fusion |
| Synaptic vesicle: |
- SNAP29
- STX11
- Hemophagocytic lymphohistiocytosis 4
|
|
| Caveolae: |
- CAV1
- Congenital generalized lipodystrophy 3
- CAV3
- Limb-girdle muscular dystrophy 2B, Long QT syndrome 9
|
|
| Vacuolar protein sorting: |
|
|
- DYSF
- Distal muscular dystrophy
|
|
|
|
See also vesicular transport proteins
|
|
|
Cytoskeletal defects
|
|
| Microfilaments |
| Myofilament |
| Actin |
- Hypertrophic cardiomyopathy 11
- Dilated cardiomyopathy 1AA
- DFNA20
- Nemaline myopathy 3
|
|
| Myosin |
- Elejalde syndrome
- Hypertrophic cardiomyopathy 1, 8, 10
- Usher syndrome 1B
- Freeman–Sheldon syndrome
- DFN A3, 4, 11, 17, 22; B2, 30, 37, 48
- May-Hegglin anomaly
|
|
| Troponin |
- Hypertrophic cardiomyopathy 7, 2
- Nemaline myopathy 4, 5
|
|
| Tropomyosin |
- Hypertrophic cardiomyopathy 3
- Nemaline myopathy 1
|
|
| Titin |
- Hypertrophic cardiomyopathy 9
|
|
|
| Other |
- Fibrillin
- Marfan syndrome
- Weill-Marchesani syndrome
- Filamin
- FG syndrome 2
- Boomerang dysplasia
- Larsen syndrome
- Terminal osseous dysplasia with pigmentary defects
|
|
|
| IF |
| 1/2 |
- Keratinopathy (keratosis, keratoderma, hyperkeratosis): KRT1
- Striate palmoplantar keratoderma 3
- Epidermolytic hyperkeratosis
- IHCM
- KRT2E (Ichthyosis bullosa of Siemens)
- KRT3 (Meesmann juvenile epithelial corneal dystrophy)
- KRT4 (White sponge nevus)
- KRT5 (Epidermolysis bullosa simplex)
- KRT8 (Familial cirrhosis)
- KRT10 (Epidermolytic hyperkeratosis)
- KRT12 (Meesmann juvenile epithelial corneal dystrophy)
- KRT13 (White sponge nevus)
- KRT14 (Epidermolysis bullosa simplex)
- KRT17 (Steatocystoma multiplex)
- KRT18 (Familial cirrhosis)
- KRT81/KRT83/KRT86 (Monilethrix)
- Naegeli–Franceschetti–Jadassohn syndrome
- Reticular pigmented anomaly of the flexures
|
|
| 3 |
- Desmin: Desmin-related myofibrillar myopathy
- Dilated cardiomyopathy 1I
- Peripherin: Amyotrophic lateral sclerosis
|
|
| 4 |
- Neurofilament: Parkinson's disease
- Charcot–Marie–Tooth disease 1F, 2E
- Amyotrophic lateral sclerosis
|
|
| 5 |
- Laminopathy: LMNA
- Mandibuloacral dysplasia
- Dunnigan Familial partial lipodystrophy
- Emery-Dreifuss muscular dystrophy 2
- Limb-girdle muscular dystrophy 1B
- Charcot–Marie–Tooth disease 2B1
- LMNB
- Barraquer–Simons syndrome
- LEMD3
- Buschke–Ollendorff syndrome
- Osteopoikilosis
- LBR
- Pelger-Huet anomaly
- Hydrops-ectopic calcification-moth-eaten skeletal dysplasia
|
|
|
| Microtubules |
| Kinesin |
- Charcot–Marie–Tooth disease 2A
- Hereditary spastic paraplegia 10
|
|
| Dynein |
- Primary ciliary dyskinesia
- Short rib-polydactyly syndrome 3
- Asphyxiating thoracic dysplasia 3
|
|
| Other |
- Tauopathy
- Cavernous venous malformation
|
|
|
| Membrane |
- Spectrin: Spinocerebellar ataxia 5
- Hereditary spherocytosis 2, 3
- Hereditary elliptocytosis 2, 3
Ankyrin: Long QT syndrome 4
- Hereditary spherocytosis 1
|
|
| Catenin |
- APC
- Gardner's syndrome
- Familial adenomatous polyposis
- plakoglobin (Naxos syndrome)
- GAN (Giant axonal neuropathy)
|
|
| Other |
- desmoplakin: Striate palmoplantar keratoderma 2
- Carvajal syndrome
- Arrhythmogenic right ventricular dysplasia 8
- plectin: Epidermolysis bullosa simplex with muscular dystrophy
- Epidermolysis bullosa simplex of Ogna
- plakophilin: Skin fragility syndrome
- Arrhythmogenic right ventricular dysplasia 9
- centrosome: PCNT (Microcephalic osteodysplastic primordial dwarfism type II)
|
|
|
See also: cytoskeletal proteins
|
|
|
Cell membrane protein disorders (other than Cell surface receptor, enzymes, and cytoskeleton)
|
|
| Arrestin |
|
|
| Myelin |
- Pelizaeus–Merzbacher disease
- Dejerine–Sottas disease
- Charcot–Marie–Tooth disease 1B, 2J
|
|
| Pulmonary surfactant |
- Surfactant metabolism dysfunction 1, 2
|
|
| Cell adhesion molecule |
|
IgSF CAM:
|
|
|
|
Cadherin:
|
- DSG1
- Striate palmoplantar keratoderma 1
|
|
- DSG2
- Arrhythmogenic right ventricular dysplasia 10
- DSG4
- DSC2
- Arrhythmogenic right ventricular dysplasia 11
|
|
|
|
Integrin:
|
- cell surface receptor deficiencies
|
|
|
| Tetraspanin |
- TSPAN7
- X-Linked mental retardation 58
- TSPAN12
- Familial exudative vitreoretinopathy 5
|
|
| Other |
- KIND1
- HFE
- HFE hereditary haemochromatosis
- DYSF
- Distal muscular dystrophy
- Limb-girdle muscular dystrophy 2B
|
|
|
See also other cell membrane proteins
|
|
