Limb–girdle muscular dystrophy

By definition, all limb-girdle muscular dystrophies (LGMD) cause progressive proximal weakness, Usually, the hip girdle is the first area to exhibit weakness, Eventually the disease can affect other muscles such as the ones located in the face. By definition, LGMDs primarily affect skeletal muscles, • Secondary muscular mitochondrial impairment == Genetics ==

LGMD is a genetic and heritable disorder, due to one of many genetic mutations of proteins involved in muscle function. All currently identified LGMDs have an inheritance pattern that is dominant or recessive, although the definition of LGMD allows for diseases with more complicated inheritance patterns to be classified as LGMD. Pathogenic mutations are mostly in coding regions, but non-coding causative variants were also reported. In Euroasia, CAPN3 mutations are the most common cause of LGMD. However, in northern Europe, mutations in FKRP are also very common. HMG CoA Reductase homozygous mutation leads to a form of LGMD that may respond to treatment with the downstream metabolite mevalonolactone in the cholesterol synthesis pathway. ==Diagnosis==

Limb-girdle muscular dystrophy can be diagnosed 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). • High CK levels (10–150 times normal) • MRI can indicate different types of LGMD. • EMG can confirm the myopathic characteristic of the disease. • Electrocardiography (cardiac arrhythmias in LGMD1B can occur) Types The "LGMD D" family is autosomal dominant, and the "LGMD R" family is autosomal recessive. Dystrophinopathies, including Duchenne muscular dystrophy, Becker muscular dystrophy, and manifesting dystrophinopathy in female carriers, can present similarly to LGMD. Facioscapulohumeral muscular dystrophy can appear similarly, especially when it spares the facial muscles. Also in the differential are Emery–Dreifuss muscular dystrophies, Pompe disease, later-onset congenital myasthenic syndromes, and proximal-predominant hereditary motor neuropathies. ==Treatment==

Few studies corroborate the effectiveness of exercise for limb–girdle muscular dystrophy. Studies have shown that exercise can, in fact, damage muscles permanently due to intense muscle contraction. 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, show some improvement. ==Prognosis==

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. ==Epidemiology==

The minimum prevalence of limb–girdle muscular dystrophy, as a group, likely ranges from 2.27–10 per 100,000 (1:44,000 to 1:10,000). The prevalence of individual LGMDs, as studied in the United States, in descending order, are those due to mutation of 1) calpain, 2) dysferlin, 3) collagen VI, 4) sarcoglycans, 5) anoctamin 5, and 6) fukutin-related protein. In Euroasia CAPN3 mutations are the most common cause of LGMD, however, in northern Europe mutations in FKRP are also very common. It is difficult to calculate the worldwide prevalence of even the most common LGMD types, due to the founder effect causing varying prevalence by region. The less common types are very rare, often only described is limited regions of the world. ==History==

The term 'limb-girdle muscular dystrophy' was published in 1954, describing a group of heterogeneous conditions that clinicians noticed to be distinct from Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. The genetics of LGMDs began to be understood in the late 1900s, which led the European Neuromuscular Centre (ENMC) to establish a consensus on the classification of LGMDs in 1995. The classification scheme at that time denoted autosomal dominant LGMDs as 'LGMD1' and autosomal recessive LGMDs as 'LGMD2.' A letter was appended to the names of LGMDs according to the order of discovery of the causal genetic mutation. As LGMD2Z was established, the question arose of what letter to assign the next discovered LGMD2. With this issue, among other motives, the ENMC established a new consensus on the classification and definition of LGMD in 2017. With the new definition, several diseases were removed from the LGMD category: ==Research==

There is a variety of research underway targeted at various forms of limb-girdle muscular dystrophy. Among the treatments thought to hold promise is gene therapy, which is the delivery of genetic material, often a copy of a healthy gene, into cells. According to a review by Bengtsson et al., some success with AAV-mediated gene therapies (for different disorders) has increased interest in researchers, with CRISPR/Cas9 and exon-skipping helping these therapeutic goals along. Limb-girdle muscular dystrophies have 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. According to a review by Straub, et al., several research issues need to be addressed: the rareness of the disease, poor understanding of the mechanism of LGMD R, and absence of patient cohorts, all contributing to the lack of biomarkers for LGMD. The review states that animal models for LGMD R have been used to analyze therapeutic medications. Also, although 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. ==See also==