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 is an inheritable condition, which may be passed on to offspring via autosomal dominant or autosomal recessive patterns of inheritance. It currently has no known cure or treatment.
LGMD may be triggered or worsened in genetically susceptible individuals by statins, because of their effects on HMG-CoA reductase.
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 downstairs, 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. The rate of progression varies between patients. Eventually, the ability 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:
Pseudoathletic appearance (muscle hypertrophy and/or pseudohypertrophy) Respiratory muscle problems Low back discomfort Distal muscle problems 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, Calpain-3 (CAPN3) mutations are the most common cause of LGMD. However, in northern Europe, mutations in Fukutin-related protein (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).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 (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. Limb-girdle muscular dystrophy is explained in terms of the gene, locus, OMIM, and type as follows:
+LGMD subtypes Name Inheritance Old Nameupdate 2012 OMIM Gene Gene also implicated in: Notes LGMD D1 DNAJB6-related Autosomal dominant LGMD1D & LGMD1E DNAJB6 LGMD D2 TNP03-related LGMD1F TNPO3 LGMD D3 HNRNPDL-related LGMD1G HNRPDL LGMD D4 calpain3-related LGMD1I CAPN3 LGMD R1 Also referred to as "autosomal dominant calpainopathy." LGMD D5 collagen 6-related Bethlem myopathy 1 COL6A1, COL6A2, COL6A3 Bethlem myopathy 1 (recessive), LGMD R22; Ullrich congenital muscular dystrophy 1 ?Bethlem myopathy 2616471COL12A1Ullrich congenital muscular dystrophy 2Formerly referred to as "Ehlers–Danlos syndrome, myopathic type" LGMD R1 calpain3-related Autosomal recessive LGMD2A CAPN3 LGMD D4 Also referred to as "autosomal recessive calpainopathy." LGMD R2 dysferlin-related LGMD2B DYSF Miyoshi myopathy type 1 (MMD1 - ). A dysferlinopathy LGMD R3 α-sarcoglycan-related LGMD2D SGCA sarcoglycanopathies LGMD R4 β -sarcoglycan-related LGMD2E SGCB LGMD R5 γ -sarcoglycan-related LGMD2C SGCG LGMD R6 δ-sarcoglycan-related LGMD2F SGCD LGMD R7 telethonin-related LGMD2G TCAP LGMD R8 TRIM 32-related LGMD2H TRIM32 LGMD R9 FKRP-related LGMD2I FKRP Congenital muscular dystrophy An α-dystroglycanopathy LGMD R10 titin-related LGMD2J TTN Congenital myopathy LGMD R11 POMT1-related LGMD2K POMT1 Congenital muscular dystrophy An α-dystroglycanopathy LGMD R12 anoctamin5-related LGMD2L ANO5 Miyoshi myopathy type 3 (MMD3 - ) LGMD R13 Fukutin-related LGMD2M FKTN Congenital muscular dystrophy An α-dystroglycanopathy LGMD R14 POMT2-related LGMD2N POMT2 Congenital muscular dystrophy An α-dystroglycanopathy LGMD R15 POMGnT1-related LGMD2O POMGNT1 Congenital muscular dystrophy An α-dystroglycanopathy LGMD R16 α-dystroglycan-related LGMD2P DAG1 Congenital muscular dystrophy An α-dystroglycanopathy LGMD R17 plectin-related LGMD2Q PLEC1 LGMD R18 TRAPPC11-related LGMD2S TRAPPC11 LGMD R19 GMPPB-related LGMD2T GMPPB Congenital muscular dystrophy An α-dystroglycanopathy LGMD R20 ISPD-related LGMD2U ISPD Congenital muscular dystrophy An α-dystroglycanopathy LGMD R21 POGLUT1-related LGMD2Z POGLUT1 LGMD R22 collagen 6-related Bethlem myopathy 1 158810 COL6A1, COL6A2, COL6A3 Ullrich congenital muscular dystrophy 1; LGMD D5; Congenital myosclerosis (COL6A2) LGMD R23 laminin α2-related Laminin α2-related muscular dystrophy LAMA2 Congenital muscular dystrophy LGMD R24 POMGNT2-related POMGNT2-related muscular dystrophy POMGNT2 Congenital muscular dystrophy An α-dystroglycanopathy LGMD R25 LGMD2X 616812 BVES LGMD R26 n/a 618848 POPDC3 LGMD R27 n/a 619566 JAG2 LGMD R28Myopathy, limb-girdle, adult-onset (MYPLG)620375HMGCR LGMD R(number pending) Myofibrillar myopathy 8 (MFM8) 617258 PYROXD1 Adult-onset Limb–girdle phenotype
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 diagnosis 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
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. 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) CAPN3 (calpain-3), 2) dysferlin, 3) collagen VI, 4) sarcoglycans, 5) anoctamin 5, and 6) FKRP (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:
+Diseases previously classified as LGMD until the 2017 consensus on LGMD criteria Current name Old Name OMIM Gene Locus Reason for exclusion Myofibrillar myopathy 3 (MFM3) LGMD1A609200 MYOT Distal weakness Emery–Dreifuss muscular dystrophy 2, autosomal dominant (EDMD2) LGMD1B 181350 LMNA EDMD phenotype and significant cardiac involvement Rippling muscle disease 2 LGMD1C606072 CAV3 Mainly characterized by muscle rippling and pain Myofibrillar myopathy 1 (MFM1) LGMD1D & LGMD2R DES Distal weakness and significant cardiac involvement Not yet given new nomenclature LGMD1H unknown 3p23–p25.1 "False linkage" Possibly mitochondrial myopathyPompe disease (Glycogen storage disease type 2)LGMD2V232300GAAKnown disease entity, histological changesMuscular dystrophy, autosomal recessive, with cardiomyopathy and triangular tongue (MDRCMTT)LGMD2W616827LIMS2One known familyMuscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures (MRRSDC)LGMD2Y617072TOR1AIP1One known family
Research