limb–girdle muscular dystrophy limb–girdle muscular dystrophy limb–girdle muscular dystrophy (lgmd) is a genetically heterogeneous group of rare muscular dystrophies that share a set of clinical characteristics. it is characterised by progressive muscle wasting which affects predominantly hip and shoulder muscles. lgmd usually has an autosomal pattern of inheritance. it currently has no known cure or treatment. limb–girdle muscular dystrophyother nameserb's muscular dystrophyprotein myot (also known as ttid one of the many genes whose mutations are responsible for this condition)specialtyneurology, neuromuscular medicinesymptomspelvic muscle weaknessdurationlifelongtypes32 typescausesgenetic mutationsdiagnostic methodgenetic testing, and possibly muscle biopsydifferential diagnosismuscular dystrophies: duchenne, becker, facioscapulohumeral, emery-dreifuss; pompe disease; congenital myasthenic syndrome; motor neuropathytreatmentoccupational therapy,speech therapy and physical therapyfrequency2.27-10 per 100,000 signs and symptoms by definition, all limb girdle muscular dystrophies (lgmd) cause progressive proximal weakness, meaning weakness of the muscles on or close to the torso that worsens over time. explicitly, lgmd preferentially affects muscles of the hip girdle, thigh, shoulder girdle, and/or upper arm. the muscle weakness is generally symmetric. usually, the hip girdle is the first area to exhibit weakness, manifesting as difficulty walking, going up and/or down stairs, rising from a chair, bending at the waist, or squatting. because of these difficulties, falling can occur frequently. weakness of the shoulder girdle can make lifting objects, or even elevating the arms, difficult or impossible. rate of progression varies between patients. eventually, the abilities to run and walk can deteriorate. the disease commonly leads to dependence on a wheelchair within years of symptom onset, although some patients maintain mobility. eventually the disease can affect other muscles such as the ones located in the face. by definition, lgmds primarily affect skeletal muscles, although cardiac muscle can be affected to a lesser degree in select subtypes, which can cause palpitations there can be significant variability in disease features and severity between lgmd subtypes, and even within any given lgmd subtype. additional possible presentations include: pseudohypertrophy muscle hypertrophy respiratory muscle problems low back discomfort distal muscle problems winged scapula 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 the various molecules involved in muscle function and implicated in lgmd 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. 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). 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: high ck levels(x10-150 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. limb–girdle muscular dystrophy is explained in terms of gene, locus, omim and type as follows: lgmd subtypes nameinheritanceold nameomimgenegene also implicated in:notes lgmd d1 dnajb6-relatedautosomal dominantlgmd1d 603511dnajb6 lgmd d2 tnp03-relatedlgmd1f 608423tnpo3 lgmd d3 hnrnpdl-relatedlgmd1g 609115hnrpdl lgmd d4 calpain3-relatedlgmd1i 618129capn3lgmd r1also referred to as "autosomal dominant calpainopathy." lgmd d5 collagen 6-relatedbethlem myopathy dominant 158810col6a1, col6a2, col6a3congenital muscular dystrophy, lgmd r22 lgmd r1 calpain3-relatedautosomal recessivelgmd2a 253600capn3lgmd d4also referred to as "autosomal recessive calpainopathy." lgmd r2 dysferlin-relatedlgmd2b 253601dysfmiyoshi myopathy type 1 (mmd1 - 254130).a dysferlinopathy lgmd r3 α-sarcoglycan-relatedlgmd2d 608099sgcasarcoglycanopathies lgmd r4 β -sarcoglycan-relatedlgmd2e 604286sgcb lgmd r5 γ -sarcoglycan-relatedlgmd2c 253700sgcg lgmd r6 δ-sarcoglycan-relatedlgmd2f 601287sgcd lgmd r7 telethonin-relatedlgmd2g 601954tcap lgmd r8 trim 32-relatedlgmd2h 254110trim32 lgmd r9 fkrp-relatedlgmd2i 607155fkrpcongenital muscular dystrophyan α-dystroglycanopathy lgmd r10 titin-relatedlgmd2j 608807ttncongenital myopathy lgmd r11 pomt1-relatedlgmd2k 609308pomt1congenital muscular dystrophyan α-dystroglycanopathy lgmd r12 anoctamin5-relatedlgmd2l 611307ano5miyoshi myopathy type 3 (mmd3 - 613319) lgmd r13 fukutin-relatedlgmd2m 611588fktncongenital muscular dystrophyan α-dystroglycanopathy lgmd r14 pomt2-relatedlgmd2n 607439pomt2congenital muscular dystrophyan α-dystroglycanopathy lgmd r15 pomgnt1-relatedlgmd2o 606822pomgnt1congenital muscular dystrophyan α-dystroglycanopathy lgmd r16 α-dystroglycan-relatedlgmd2p 613818dag1congenital muscular dystrophyan α-dystroglycanopathy lgmd r17 plectin-relatedlgmd2q 613723plec1 lgmd r18 trappc11-relatedlgmd2s 615356trappc11 lgmd r19 gmppb-relatedlgmd2t 615352gmppbcongenital muscular dystrophyan α-dystroglycanopathy lgmd r20 ispd-relatedlgmd2u 616052ispdcongenital muscular dystrophyan α-dystroglycanopathy lgmd r21 poglut1-relatedlgmd2z 617232poglut1 lgmd r22 collagen 6-relatedbethlem myopathy recessivecol6a1, col6a2, col6a3congenital muscular dystrophy, lgmd d5 lgmd r23 laminin α2-relatedlaminin α2-related muscular dystrophy 156225lama2congenital muscular dystrophy lgmd r24 pomgnt2-relatedpomgnt2-related muscular dystrophy 618135pomgnt2congenital muscular dystrophyan α-dystroglycanopathy lgmd r25lgmd2xpopdc1 lgmd r26popdc3 lgmd r27jag2 lgmd r(number pending)pyroxd1 lgmd criteria for a disease entity to be classified as an lgmd, the following criteria must be met: genetic, with an identifiable inheritance pattern such as autosomal dominant, autosomal recessive, digenic, or polygenic. relatively selective to skeletal muscle predominantly proximal muscle involvement independent walking is achieved at one point in life elevated serum creatine kinase muscle fiber loss dystrophic changes in muscle histology degenerative changes on medical imaging end-stage pathology seen in the most affected muscles described in at least two unrelated families differential many diseases can manifest similarly to lgmd. 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 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. 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. additionally individuals can follow management that follows: occupational therapy respiratory therapy speech therapy neutralizing antibody to myostatin should not be pursued the sarcoglycanopathies could be possibly amenable to gene therapy. 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). lgmd is the fourth most common muscular dystrophy, after the dystrophinopathies, myotonic dystrophies, and facioscapulohumeral muscular dystrophy. 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 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: diseases previously classified as lgmd until the 2017 consensus on lgmd criteria current nameold nameomimgenelocusreason for exclusion myofibrillar myopathylgmd1a 159000ttiddistal weakness emery–dreifuss muscular dystrophy (edmd)lgmd1b 159001lmnaedmd phenotype and significant cardiac involvement rippling muscle diseaselgmd1c 607801cav3mainly characterized by muscle rippling and pain myofibrillar myopathylgmd1e 601419desdistal weakness and significant cardiac involvement not confirmedlgmd1h 6135303p25.1–p23still not established as a disease research 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 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) have 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., there are several research issues that 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 lack of biomarkers for lgmd. the review goes on to state 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.