Limb–girdle muscular dystrophies (LGMD) are muscular dystrophies that affect skeletal muscles, mostly proximal (hips and shoulder muscles). They are caused by a mutation in a gene encoding a protein, which is specific to each subtype. LGMD inheritance is autosomal. This is in contrast to Duchenne or Becker muscular dystrophies, which are caused by a mutation in the DMD gene located on the X chromosome [1]. Some LGMD forms are dominant, and others are recessive.

For example, LGMD 1A is characterized by a mutation in the MYOT gene, responsible for myotilin synthesis ^[2][3][7,8] which cross-links actin filaments and controls sarcomere assembly ^[4][9]. However, this disease is not included in the new classification by Straub et al. (2018) because the weakness is distal and does not affect proximal muscles ^[5][6]. In fact, the most frequent phenotype is a late-onset distal myopathy affecting ankles, feet or calves ^[6][10]. Cases of respiratory insufficiency or cardiac failure are also reported ^[7][11].

LGMD 1B is caused by mutations in the LMNA gene coding for Lamin A/C ^[8][12]. This in turn causes alterations in the nuclear envelope in fibroblasts ^[9][13]. Straub et al. (2018) do not consider this myopathy as an LGMD because it is associated with cardiac arrhythmia ^[5][6]. It is therefore not included in the new nomenclature since the main effect is not exerted on proximal muscles.

LGMD 1C occurs due to mutations in the CAV3 gene ^[10][14], causing a caveolin-3 deficiency associated with skeletal muscle weakness due to impaired mitochondrial form and function ^[11][15]. This pathology was excluded from the new classification due to the muscle rippling and myalgia ^[5][6]. A recent Korean study showed that the phenotype is variable, being mild for some patients and more severe for others. HyperCKemia is found in all patients, whereas myopathic features are less frequent and can occur as ankle contracture, calf hypertrophy, exercise intolerance, or muscular cramps ^[12][16].

LGMD 1D (now LGMD D1) is characterized by a mutation in the DNAJB6 gene, which encodes for a co-chaperone protein implicated in sarcomeric protein maintenance and aggregation ^[13][17]. Patient muscle magnetic resonance imaging (MRI) shows fat infiltration, and biopsies show an increased number of internal nuclei and rimmed vacuoles ^[14][18]. The affected muscles are both proximal and distal; the lower and proximal limbs are affected most severely, while the effects are mild in the distal and upper ones.

LGMD 1E occurs due to mutations in the DES gene encoding for desmin ^[15][19]. A mutation in this protein can lead to desmin aggregate formation and/or to the development of an irregular muscle fibre shape ^[16][20]. LGMDs are not considered in the new classification because of distal weakness and cardiomyopathy ^[5][6]. Desminopathy shows fatty replacement in semitendinosus, gastrocnemius and soleus MRI. The typical phenotype is characterized by distal weakness, but facial and bulbar weakness were also reported ^[17][21]

LGMD 1F (now LGMD D2) is associated with mutations in the TNPO3 gene coding for transportin 3 ^[18][22]. This protein function is still being studied, but abnormalities in sarcomeric assembly have been observed via patient biopsies ^[19][23]. The age of onset and severity of phenotype have a high variability. Typically, however, a pelvic lower girdle weakness is noticed first, followed by the atrophy of the axial muscle and shoulder girdle. MRI also shows fatty replacement of fibres in pelvic and thigh muscles. Biopsy results show rimmed vacuoles and enlarged nuclei ^[20][24].

LGMD 1G (now LGMD D3) is caused by a defect in the heterogenous nuclear ribonucleoprotein D-like (hnRNPDL) protein ^[21][25] and patient muscles show rimmed vacuoles ^[22][26]. The protein has been shown to regulate transcription and alternative splicing ^[23][27].

LGMD 1H is another autosomal dominant type of LGMD with an alteration in a gene situated in chromosome 3 (3p23–p25). However, it remains unassociated with a specific protein ^[24][28] and therefore cannot be classified as an LGMD since all the characteristics one are not fulfilled ^[5][6].

LGMD 1I (now LGMD D4) is caused by dominant mutations in the CAPN3 gene, encoding for calpain 3. Research shows that missense mutations lead to a milder phenotype and null mutations to increased phenotype severity ^[25][29]. Fat infiltration int the affected muscles (thigh adductors and semimembranosus, but also calf gastrocnemius and soleus) is also noticed in MRI and happens before the deterioration of muscle function ^[26][30].

Bethlem myopathy (now LGMD D5) is now also classified as an LGMD and can be caused by a dominant mutation in COL6A1, COL6A2 or COL6A3 genes, encoding for the Collagen 6 protein that plays a role in extracellular matrix structure and muscle regeneration ^[5][6]. This myopathy also causes there to be a higher fat fraction in the muscles, especially in the psoas major ^[27][31], and recent authors have suggested that this be used as an MRI diagnosis tool. Other MRI patterns also indicate this pathology, such as a “target sign” located in the rectus femoris or a “sandwich sign” in the vastus lateralis ^[28][32].

As for autosomal recessive limb–girdle muscular dystrophies, LGMD 2A (now LGMD R1) is caused by recessive mutations in CAPN3, a gene encoding for calpain 3 ^[29][33], which could regulate the sarcomere ^[30][34]. The dominant form is also described above as LGMD 1I/D4.

LGMD 2B (LGMD R2) is associated with mutations in the DYSF gene that impairthe synthesis of dysferlin, a protein responsible for sarcomere stability and muscular repair ^[31][35]. The posterior thigh and leg muscles are the most affected areas and show a progressive fat fraction increase, which is accentuated when patients become non-ambulant ^[32][36]. Two-thirds of patients have a diamond-shaped bulge on their quadriceps when in action ^[33][37].

LGMD 2C (LGMD R5) is caused by mutations in the SGCG gene, which synthetizes the γ-Sarcoglycan protein. This protein is part of the DAP complex and plays a role in the cytoskeleton extracellular matrix link ^[34][4]. The phenotype severity varies in siblings with the same mutation and is not related to the age of onset ^[35][38]. The phonotype is considered severe when patients lose ambulation before 13 years of age.

LGMD 2D (LGMD R3) is also caused by a mutation in a gene of the sarcoglycan complex: the SGCA gene responsible for the synthesis of the α-Sarcoglycan protein. The main signs include pelvic girdle weakness, fatty replacement, and atrophy of the vastus intermedius, semimembranosus and biceps femoris muscles ^[36][39].

LGMD 2E (LGMD R4) is associated with a mutation in the SGCB gene, related to the β-Sarcoglycan protein. The phenotype is a weakness and fatty replacement in: Latissimus dorsi, spine extensors, abdominal belt, glutei, adductors, and various thigh muscles ^[37][40].

LGMD 2F (LGMD R6) is caused by a mutation in the SGCD gene coding for the δ-Sarcoglycan protein. The phenotype is variable, but generally involves a progressive atrophy of proximal muscles and high serum creatine kinase. Some patients also present cardiomyopathy ^[38][41].

LGMD 2G (LGMD R7) is related to mutations in the TCAP gene encoding for telethonin, which plays a role in myofibrillogenesis in interaction with titin in the sarcomeric Z-disk ^[39][40][42,43]. The first sign of this is generally thigh muscle weakness progressively also affecting calf muscles via fatty infiltration in the glutei, hip and thigh muscles ^[41][44].

LGMD 2H (LGMD R8) is known for mutations in the TRIM32 gene, which codes for the tripartite motif-containing protein 32 responsible for the movement of Ca²⁺ in skeletal muscles ^[42][45]. Patients present calf hypertrophy and weakness. Their muscles contain fibres of various size, small vacuoles, and increased numbers of internal nuclei ^[43][46].

LGMD 2I (LGMD R9) is caused by mutations in the FKRP gene, coding for fukutin-related protein. This protein is necessary for the glycosylation of α-dystroglycan ^[44][47]. Muscle biopsies show different fibre modifications: some are hypertrophic, while others are split, hyaline, rounded or necrotic ^[45][48].

LGMD 2J (LGMD R10) is caused by mutations in the TTN gene. This codes for titin, a protein responsible for muscle tension ^[46][49]. Patients have weakened thighs and their muscle biopsy shows rimmed vacuoles containing amyloid accumulation ^[47][50].

LGMD 2K (LGMD R11) and LGMD 2N (LGMD R14) are due to mutations in the POMT1 and POMT2 genes, respectively. These genes allow for the synthesis of protein O-mannosyltransferase 1 and 2, of which co-expression is necessary for O-mannosylation, an important reaction in α-dystroglycan ^[48][51]. LGMD 2J (LGMD R10) shows proximal limbs weakness and cognitive impairment ^[49][52].

LGMD 2L (LGMD R12) is associated with mutations in the ANO5 gene, which encodes for the Anoctamin 5 protein necessary for achieving functional calcium-activated chloride channels in the muscles ^[50][53]. The phenotype is one of prominent asymmetrical quadriceps femoris and biceps brachii atrophy ^[50][53].

LGMD 2M (LGMD R13) is linked to a mutation in the FKTN gene. The fukutin protein also plays a role in the glycosylation of α-dystroglycan ^[51][54]. This LGMD causes proximal muscle weakness in early childhood, with the occurrence of hypotonia and/or hypertrophy. Some patients have ocular problems, cognitive impairment or cardiomyopathy ^[52][55].

LGMD 2N (LGMD R14) is caused by a mutation in the POMT2 gene necessary for the synthesis of protein O-mannosyltransferase 2. The phenotype is generally responsible for walking difficulties and pain during exercise. Hamstrings, paraspinal and gluteal muscles are the first parts of the body affected, leading to a strength reduction in hips as well as knee flexors and extensors. Cognitive impairment is also reported ^[53][56].

LGMD 2O (LGMD R15) is caused by mutations in the POMGnT1 gene, which codes for protein O-mannose beta-1,2-Nacetylglucosaminyltranserase 1. Former POMGNT2-related muscular dystrophy (LGMD R24) was also called Walker–Warburg syndrome or muscle–eye–brain disease and is now categorized as an LGMD since it corresponds to all LGMD new criteria. It is caused by a mutation in the POMGnT2 gene, encoding for protein O-mannose beta-1,2-Nacetylglucosaminyltranserase 2. Both protein O-mannose beta-1,2-Nacetylglucosaminyltranserase 1 and 2 catalyse a modification of α-dystroglycan ^[54][57]. POMGnT1 is necessary for the synthesis of the M1 core glycan structure. MGAT5B is then added to form the M2 core, and the addition of POMGnT2 then transforms it into the M3 core ^[54][57]. LGMD 2O (LGMD R15) patients have proximal limb muscle weakness around puberty. The affected muscles are calves, quadriceps, hamstrings and deltoids. Myopia is also reported among patients ^[55][58].

LGMD 2P (LGMD R16) occurs due to mutations in the DAG1 gene, encoding for dystroglycan, a protein that is part of the dystroglycan complex ^[56][5]. In this case, a proximal muscle weakness is reported along with cognitive impairment ^[57][59].

LGMD 2Q (LGMD R17) occurs when there is a mutation in the PLEC1 gene. This gene encodes for the synthesis of the plectin protein. This has many roles, including cell survival, cell growth, actin organization and T-cell activation ^[56][5]. Progressive limb muscle weakness is reported in deltoids, erector spinae, glutei, biceps femoris and adductor magnus. Some plectinopathies include skin affectation, but case studies do not include skin problems ^[58][60].

LGMD 2R is not classified as an LGMD any longer, and this is caused by a mutation in the DES gene encoding for desmin. Its role is to connect sarcomeres together in order to form myofibrils ^[56][5]. It was rejected from the LGMD category since the weakness it induces is distal, not proximal ^[5][6].

LGMD 2S (LGMD R18) occurs due to mutations in TRAPPC11. This encodes for transport protein particle complex 11, which is responsible for the transport between endoplasmic reticulum and Golgi apparatus ^[56][5]. The onset occurs during school age and the proximal muscle weakness is progressive. The hips are more affected than shoulders and the development of a respiratory restrictive disorder is reported in some patients ^[59][61].

LGMD 2T (LGMD R19) is associated with the GMPPB gene, encoding for the GDP-mannose pyrophosphorylase B protein. Its function is to produce GDP-mannose for the O-mannosylation of α-dystroglycan ^[60][62]. Paraspinal and hamstring muscles are the most affected by this, as seen per MRI, and the phenotype can cause hypotonia, epilepsy, cognitive impairment, cataracts and cardiomyopathy ^[61][63].

LGMD2U (LGMDR20) is related to mutations in the ISPD gene. Its protein is isoprenoid synthase, responsible for glycosylation of α-dystroglycan ^[62][64]. The phenotype includes sural hypertrophy and moderate proximal weakness ^[63][65].

LGMD2V is associated with mutations in the GAA gene. This encodes for α-1,4-Glucosidase, an important protein for lysozyme function ^[56][5]. It is not categorized as an LGMD and is now called Pompe disease ^[64][66]. The phenotype varies from mild to severe, its effects include a progressive proximal muscle weakness, and it can also involve the respiratory or cardiac muscles ^[65][67].

LGMD2W is caused by mutations in the LIMS2 gene, which synthetizes Lim and senescent cell antigen-like domains 2 protein. This protein is involved in cell spreading and migration ^[56][5]. It was only reported in one family and, therefore, cannot be considered an LGMD yet. This is because Straub et al. (2018) consider it an LGMD only when 2 or more unrelated families have the same pathology ^[5][6]. The patients develop and early onset proximal weakness. This includes calf hypertrophy, leading to severe quadriparesis during adolescence. A dilated cardiomyopathy was also reported in both patients ^[66][68].

LGMD2X is related to the BVES gene for blood vessel endocardial substance. This encodes for Popeye domain-containing protein 1 (POPDC1) that is involved in the structure and function of cardiac and skeletal muscle cells ^[56][5]. This myopathy was recently reported in 5 more families, making it part of the LGMDs ^[5][6]. An article from May 2022 classifies LGMD2X as LGMDR25 (OMIM 616812) ^[67][69]. The reported symptoms are exercise-induced myalgia of the thighs and hips, as well as cardiac arrhythmia.

LGMD2Y is associated with mutations in the TOR1A1P1 gene, known for the Torsin 1A-interacting protein 1. This protein serves as a link between the nuclear membrane and lamina during cell division ^[56][5]. It is not considered an LGMD since it has been reported in only one family ^[5][6]. Its symptoms include skeletal muscle weakness and cardiac involvement ^[68][70].

LGMD2Z (LGMDR21) is caused by mutations in the POGLUT1 gene for protein O-glucosyltransferase 1, which is involved in protein transport ^[56][5]. The phenotype induces limb–girdle muscle weakness as well as a decrease in α-dystroglycan glycosylation and fatty replacement in muscles ^[69][71].

Three more myopathies are now considered as LGMDs:

Bethlem myopathy recessive (LGMDR22), caused by mutations in collagen 6 genes COL6A1, COL6A2, and COL6A3, which play roles in the extracellular matrix structure and muscle regeneration ^[5][6]. The phenotype is one of a progressive proximal weakness and ankle contracture. The subtle contracture of the interphalangeal joint is a specific sign of Bethlem myopathy ^[70][72].

Laminin α2-related muscular dystrophy (LGMDR23), associated with mutations in the LAMA2 gene, which is expressed as Laminin α2, a protein involved in myotube stability and apoptosis ^[71][73]. The phenotype is a progressive proximal muscle weakness and accounts for 36% of the patients reported having seizures without an epilepsy-related gene ^[72][74].

POMGNT2-related muscular dystrophy (LGMDR24) occurs due to mutations in the POMGnT2 gene, protein O-linked mannose β-1,4-N-Acetylglucosaminyl-transferase 2, which catalyzes reactions in α-dystroglycan ^[54][57]. The phenotype is one of a progressive proximal lower limb muscle weakness, along with possible ocular problems and cognitive impairment ^[73][75].