Limb-girdle muscular dystrophy

Last updated
Limb-girdle muscular dystrophy
Other namesErb's muscular dystrophy [1]
Protein MYOT PDB 2KDG.png
Protein MYOT (also known as TTID one of the many genes whose mutations are responsible for this condition)
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
SymptomsPseudohypertrophy [2]
TypesLGMD1 and LGMD2 [3]
Diagnostic method Immunohistochemical dystrophin tests [4]
TreatmentOccupational, speech and physical therapy [5]

Limb-girdle muscular dystrophy or (LGMD) is a genetically and clinically heterogeneous group of rare muscular dystrophies. [6] 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 or treatment. [7] [8]

Contents

Signs and symptoms

The symptoms of an individual with limb-girdle muscular dystrophy (LGMD) generally are great difficulty walking, going both up and downstairs, and raising from a chair. The inability to bend over or squat down is also present. Because of these difficulties, falling can occur on a regular basis. Lifting certain objects, as well as difficulty extending your arms out or above your head, varies from difficult to impossible depending on the severity. Eventually, the ability to walk/run deteriorates. [2] [4]

Further presentations an individual with LGMD might have are:

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 years of symptom onset, but there is high inter-patient variability, with some patients maintaining mobility. [8] [2]

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.[ medical citation needed ]

Genetics

In terms of the genetics LGMD is 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. [3]

Diagnosis

The diagnosis of limb-girdle muscular dystrophy can be done via muscle biopsy, which will show the presence of muscular dystrophy, and genetic testing is used to determine which type of muscular dystrophy a patient has. Immunohistochemical dystrophin tests can indicate a decrease in dystrophin detected in sarcoglycanopathies. In terms of sarcoglycan deficiency there can be variance (if α-sarcoglycan and γ-sarcoglycan are not present then there's a mutation in LGMD2D). [4]

The 2014 Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies indicates that individuals suspected of having the inherited disorder should have genetic testing. Other tests/analysis are: [4] [5]

Types

The "LGMD1" family is autosomal dominant, and the "LGMD2" family is autosomal recessive. [8] Limb-girdle muscular dystrophy is explained in terms of gene, locus, OMIM and type as follows:

FamilyInheritanceType OMIM Gene Locus Notes
LGMD1 autosomal dominant
138pixels Autosomal dominant - en.svg
138pixels
LGMD1A 159000 TTID
LGMD1B 159001 LMNA
LGMD1C 607801 CAV3
LGMD1D 603511 DNAJB6
LGMD1E 601419 DES
LGMD1F 608423 TNPO3 7q32.1–q32.2
LGMD1G 609115 HNRPDL 4q21
LGMD1H 613530 3p25.1–p23
LGMD2 autosomal recessive
Autosomal recessive - en.svg
LGMD2A 253600 CAPN3 Often referred to as "calpainopathy." [10]
LGMD2B 253601 DYSF LGMD with a mutation in this gene, along with Miyoshi Myopathy type 1 (MMD1 - 254130 ) are sometimes called dysferlinopathies. [11]
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

Treatment

Cardiac muscle Glanzstreifen.jpg
Cardiac muscle

There are few studies corroborating the effectiveness of exercise for limb-girdle muscular dystrophy. However studies have shown that exercise can, in fact, damage muscles permanently due to intense muscle contraction. [12] Physical therapy may be required 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 required, corticosteroids in LGMD 2C-F individuals, shows some improvement. [9] Additionally individuals can follow management that follows: [5]

In terms of the prognosis of limb-girdle muscular dystrophy in its mildest form, affected individuals have near-normal muscle strength and function. LGMD isn't typically a fatal disease, though it may eventually weaken the heart and respiratory muscles, leading to illness or death due to secondary disorders. The frequency of limb-girdle muscular dystrophy ranges from 1 in 14,500 (in some instances 1 in 123,000). [6] [8]

Research

alpha sarcoglycan Left side-normal muscle /right side LGMD2 LGMD2D alpha sarcoglycan.jpg
alpha sarcoglycan Left side-normal muscle /right side LGMD2

There is a variety of research under way targeted at various forms of limb-girdle muscular dystrophy. Among the methods thought to hold promise for treatment include gene transfer therapy, [13] which works by inserting in cells of defective genes with a healthy gene. [14]

According to a review by Bengtsson et al. some success with AAV-mediated gene therapies (for different disorders) have increased interest in researchers, with CRISPR/Cas9 and exon-skipping helping these therapeutic goals along. Limb-girdle muscular dystrophies has many different types which are due to different gene mutations. LGMD2D is caused by a mutation in the α-sarcoglycan gene. Future treatment could be had by gene therapy through recombinant adeno-associated vectors. [15]

Conversely, according to a review by Straub, et al. there are several research issues that need to be targeted, the rareness of the disease, our poor understanding of the mechanism of LGMD2, and absence of patient cohorts, consequently biomarkers for individuals with LGMD2 are lacking. The review goes on to state that animal models for LGMD2 have been used to analyse therapeutic medications. Also adding that while prednisone has been used and has had positive effects on affected LGMD2 individuals there is still no evidence of its effectiveness in trials that are placebo-controlled. [16]

See also

Related Research Articles

Genetic disorder Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

Muscular dystrophy myopathy characterized by progressive skeletal muscle weakness degeneration

Muscular dystrophy (MD) is a group of muscle diseases that results in increasing weakening and breakdown of skeletal muscles over time. The disorders differ in which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Many people will eventually become unable to walk. Some types are also associated with problems in other organs.

Arthrogryposis congenital joint contracture in two or more areas of the body

Arthrogryposis multiplex congenita (AMC), or simply arthrogryposis, describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning "curving of joints".

Becker muscular dystrophy X-linked recessive inherited disorder characterized by slowly progressive muscle weakness of the legs and pelvis

Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. This is caused by mutations in the dystrophin gene, which encodes the protein dystrophin. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, but has a milder course.

Oculopharyngeal muscular dystrophy Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset progressive myopathy characterized by progressive eyelid ptosis, dysphagia, dysarthria and proximal limb weakness

Oculopharyngeal muscular dystrophy (OPMD) is a rare form of muscular dystrophy with symptoms generally starting when an individual is 40 to 50 years old. It can be autosomal dominant neuromuscular disease or autosomal recessive. The most common inheritance of OPMD is autosomal dominant, which means only one copy of the mutated gene needs to be present in each cell. Children of an affected parent have a 50% chance of inheriting the mutant gene.

Fukuyama congenital muscular dystrophy Human disease

Fukuyama congenital muscular dystrophy (FCMD) is a rare, autosomal recessive form of muscular dystrophy mainly described in Japan but also identified in Turkish and Ashkenazi Jewish patients; fifteen cases were first described on 1960 by Dr. Yukio Fukuyama.

Nemaline myopathy is a congenital, hereditary neuromuscular disorder with many symptoms that can occur such as muscle weakness, hypoventilation, swallowing dysfunction, and impaired speech ability. The severity of these symptoms varies and can change throughout one's life to some extent. The prevalence is estimated at 1 in 50,000 live births. It is the most common non-dystrophic myopathy.

Hereditary inclusion body myopathies (HIBM) are a group of rare genetic disorders which have different symptoms. Generally, they are neuromuscular disorders characterized by muscle weakness developing in young adults. Hereditary inclusion body myopathies comprise both autosomal recessive and autosomal dominant muscle disorders that have a variable expression (phenotype) in individuals, but all share similar structural features in the muscles.

Congenital muscular dystrophy human disease

Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges from myopathic to overtly dystrophic due to the age at which the biopsy takes place.

The sarcoglycanopathies are a collection of diseases resulting from mutations in any of the five sarcoglycan genes: α, β, γ, δ or ε. The five sarcoglycanopathies are: α-sarcoglycanopathy, LGMD2D; β-sarcoglycanopathy, LGMD2E; γ-sarcoglycanopathy, LGMD2C; δ-sarcoglycanopathy, LGMD2F and ε-sarcoglycanopathy, myoclonic dystonia. The four different sarcoglycan genes encode proteins that form a tetrameric complex at the muscle cell plasma membrane. This complex stabilizes the association of dystrophin with the dystroglycans and contributes to the stability of the plasma membrane cytoskeleton. The four sarcoglycan genes are related to each other structurally and functionally, but each has a distinct chromosome location.

The sarcoglycans are a family of transmembrane proteins involved in the protein complex responsible for connecting the muscle fibre cytoskeleton to the extracellular matrix, preventing damage to the muscle fibre sarcolemma through shearing forces.

Emery–Dreifuss muscular dystrophy muscular dystrophy that chiefly affects muscles used for movement (skeletal) and heart (cardiac) muscle

Emery–Dreifuss muscular dystrophy is a condition that mainly affects muscles used for movement, such as skeletal muscles and also affects the cardiac muscle, it is named after Alan Eglin H. Emery and Fritz E. Dreifuss.

SGCB protein-coding gene in the species Homo sapiens

Beta-sarcoglycan is a protein that in humans is encoded by the SGCB gene.

Delta-sarcoglycan mammalian protein found in Homo sapiens

Delta-sarcoglycan is a protein that in humans is encoded by the SGCD gene.

SGCA protein-coding gene in the species Homo sapiens

Alpha-sarcoglycan is a protein that in humans is encoded by the SGCA gene.

SGCG protein-coding gene in the species Homo sapiens

Gamma-sarcoglycan is a protein that in humans is encoded by the SGCG gene. The α to δ-sarcoglycans are expressed predominantly (β) or exclusively in striated muscle. A mutation in any of the sarcoglycan genes may lead to a secondary deficiency of the other sarcoglycan proteins, presumably due to destabilisation of the sarcoglycan complex. The disease-causing mutations in the α to δ genes cause disruptions within the dystrophin-associated protein (DAP) complex in the muscle cell membrane. The transmembrane components of the DAP complex link the cytoskeleton to the extracellular matrix in adult muscle fibres, and are essential for the preservation of the integrity of the muscle cell membrane.

Myoclonic dystonia dystonia characterized by myoclonic jerks affecting mostly proximal muscles and dystonia, usually torticollis or writers cramp, that typically responds to alcohol and has onset in the first of second decade of life

Myoclonic dystonia or Myoclonus dystonia syndrome is a rare movement disorder that induces spontaneous muscle contraction causing abnormal posture. The prevalence of myoclonus dystonia has not been reported, however, this disorder falls under the umbrella of movement disorders which affect thousands worldwide. Myoclonus dystonia results from mutations in the SGCE gene coding for an integral membrane protein found in both neurons and muscle fibers. Those suffering from this disease exhibit symptoms of rapid, jerky movements of the upper limbs (myoclonus), as well as distortion of the body's orientation due to simultaneous activation of agonist and antagonist muscles (dystonia).

Ullrich congenital muscular dystrophy Ullrich congenital muscular dystrophy (UCMD) is characterized by early-onset, generalized and slowly progressive muscle weakness, multiple proximal joint contractures, marked hypermobility of the distal joints and normal intelligence

Ullrich congenital muscular dystrophy is a form of congenital muscular dystrophy. It is associated with variants of type VI collagen, it is commonly associated with muscle weakness and respiratory problems, though cardiac issues are not associated with this type of CMD. It is named after Otto Ullrich, who is also known for the Ullrich-Turner syndrome.

Anoctamin 5 (ANO5) is a protein that in humans is encoded by the ANO5 gene.

Calpainopathy

Calpainopathy is the most common type of autosomal recessive limb-girdle muscular dystrophy (LGMD). It has a predisposition for affecting the muscles of the hip girdle and shoulder girdle.

References

  1. ↑ Newfoundland, FRCP William Pryse-Phillips MD, FRCP(C) Faculty of Medicine Health Sciences Centre Memorial University of Newfoundland St John's (2009-05-06). Companion to Clinical Neurology. Oxford University Press, USA. p. 579. ISBN   9780199710041.
  2. 1 2 3 4 5 6 7 8 MedlinePlus Encyclopedia Limb-girdle muscular dystrophies
  3. 1 2 Reference, Genetics Home. "limb-girdle muscular dystrophy". Genetics Home Reference. Retrieved 2016-04-22.
  4. 1 2 3 4 "Limb-Girdle Muscular Dystrophy: Practice Essentials, Background, Pathophysiology". August 2018.Cite journal requires |journal= (help)
  5. 1 2 3 Narayanaswami, Pushpa; Weiss, Michael; Selcen, Duygu; David, William; Raynor, Elizabeth; Carter, Gregory; Wicklund, Matthew; Barohn, Richard J.; Ensrud, Erik (2014-10-14). "Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies". Neurology. 83 (16): 1453–1463. doi:10.1212/WNL.0000000000000892. ISSN   0028-3878. PMC   4206155 . PMID   25313375.
  6. 1 2 "Limb-girdle muscular dystrophy".
  7. ↑ "Limb-Girdle Muscular Dystrophy Treatment & Management: Medical Care, Surgical Care, Consultations". August 2018.Cite journal requires |journal= (help)
  8. 1 2 3 4 Pegoraro, Elena; Hoffman, Eric P. (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora JH; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). Limb-Girdle Muscular Dystrophy Overview. Seattle (WA): University of Washington, Seattle. PMID   20301582.update 2012
  9. 1 2 3 4 "Limb-girdle Muscular Dystrophy | Doctor".
  10. ↑ Lasa-Elgarresta, J; Mosqueira-Martín, L; Naldaiz-Gastesi, N; Sáenz, A; López de Munain, A; Vallejo-Illarramendi, A (13 September 2019). "Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with CAPN3 Mutations". International Journal of Molecular Sciences. 20 (18): 4548. doi:10.3390/ijms20184548. PMC   6770289 . PMID   31540302.
  11. ↑ Aoki, Masashi (March 5, 2015). "Dysferlinopathy". GeneReviews.
  12. ↑ Siciliano G, Simoncini C, Giannotti S, Zampa V, Angelini C, Ricci G (2015). "Muscle exercise in limb girdle muscular dystrophies: pitfall and advantages". Acta Myologica. 34 (1): 3–8. PMC   4478773 . PMID   26155063.
  13. ↑ Liaison, Melanie Martinez, Office of Communications and Public. "Limb-Girdle Muscular Dystrophy". www.niams.nih.gov. Retrieved 2016-04-22.
  14. ↑ Reference, Genetics Home. "How does gene therapy work?". Genetics Home Reference. Retrieved 2016-04-23.
  15. ↑ Bengtsson, Niclas E.; Seto, Jane T.; Hall, John K.; Chamberlain, Jeffrey S.; Odom, Guy L. (2016-04-15). "Progress and prospects of gene therapy clinical trials for the muscular dystrophies". Human Molecular Genetics. 25 (R1): R9–R17. doi:10.1093/hmg/ddv420. ISSN   0964-6906. PMC   4802376 . PMID   26450518.
  16. ↑ Straub, Volker; Bertoli, Marta (2016-02-01). "Where do we stand in trial readiness for autosomal recessive limb girdle muscular dystrophies?". Neuromuscular Disorders. 26 (2): 111–125. doi:10.1016/j.nmd.2015.11.012. PMID   26810373. S2CID   23787096. – via ScienceDirect  (Subscription may be required or content may be available in libraries.)

Further reading

Classification
D
External resources
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.