Limb-Girdle Muscular Dystrophy Clinical Presentation

Clinical presentation is most often with progressive, symmetrical, predominantly proximal weakness. Distal predominant presentations may be seen in some LGMD types. Variable associated systemic features  or other organ system involvement may be noted and is often useful in identification of LGMD type.

Autosomal recessive LGMD

All patients have a history of progressive, proximal muscle weakness. Described below are the major distinguishing characteristics.

• LGMD2A (calpainopathy; LGMDR1 Calpain-3; 15q15)

  • LGMD2A is likely the most common autosomal recessive LGMD, accounting for up to 30% of all recessive cases. In some areas, including the Basque region of Spain (where a founder mutation is identified), LGMD2A accounts for almost 80% of all cases of LGMD. In other areas, it is quite rare; for example, it accounts for only 6% of LGMD cases in Denmark.

  • Recently patients carrying a single pathogenic variant in the CAPN3 have been reported, indicating a proportion of dominant inheritance. ^[10]

  • About two thirds of patients present at 8–15 years of age (range of 2–40 years).

  • The most typical presentation is of symmetrical weakness due to scapular-humeral-pelvic weakness, which may be similar to the presentation of facioscapulohumeral dystrophy, but without facial weakness. LGMD2I may also have a similar phenotype.

  • Muscle weakness is predominant in the axial muscles of trunk and proximal lower limb. Hip-girdle weakness is most prominent in the gluteus maximus and hip adductors. Along with abdominal weakness, this leads to a wide-based, lordotic gait.

  • Relatively spared muscles include flexor carpi, triceps surae, tibialis posterior and anterior and the sternocleidomastoid.

  • The combination of scapular winging, severe weakness of hip adductors and elbow flexors, normal respiratory function, and contractures has specificity for LGMD2A. ^[11] Contractures are usually mild and predominate in the Achilles tendon.

  • Atrophy is often prominent.

  • Progression tends to be slow, and wheelchair use begins 11–28 years after the onset of symptoms. Men may show earlier onset and faster progression than women.

  • The clinical course varies widely among and within families. Age of onset and age at loss of independent ambulation varies between different mutations.

  • Atypical presentations include a severe Duchenne-like course, exercise-induced stiffness and myalgia before the onset of weakness, and early and clinically significant contractures (especially of the ankles, elbow, and neck) similar to those of Emery-Dreifuss muscular dystrophy.

  • Presentation with asymptomatic hyperCKemia has been reporte in up to 10% of cases.

  • Facial and cardiac involvement have not been reported.

• LGMD2B (dysferlinopathy; LGMDR22 Dysferlin; 2p13)

  • LGMD2B is also a common cause of autosomal recessive LGMD, accounting for about 20% of cases in the Brazilian population. However, in some populations (eg, Cajun, Arcadian groups), it accounts for about 40% of cases.

  • Several phenotypes can occur: Miyoshi myopathy, anterior tibial myopathy, LGMD, and an axial myopathy. A study from France showed 25% with Miyoshi myopathy, 25% with LGMD, and 35% with a combination. ^[12] Different phenotypes can occur in the same family.

  • With each phenotype, presentation usually occurs at 15–35 years, but it can be as early as 10 years. There are also rare cases of late presentation after age 70 years.

  • In the limb-girdle presentation, pelvic and femoral muscles are affected first, with the proximal portions of the arms becoming weak later.

  • With Miyoshi myopathy, the presentation includes gastrocnemius weakness and difficulty with toe walking. The forearm muscles are weak and atrophic, with sparing of intrinsic hand muscles. As the disease progresses, these 2 modes of presentation usually become indistinguishable.

  • The most common phenotype (35% of patients) has a mixed picture, with both proximal and distal weakness. Asymmetry may be present. The patient's gait is unique, with a waddling component combined with inability to raise his or her heels off the ground.

  • A few families have been reported with an anterior tibial myopathy. ^[13] Progressive weakness involves wrist and finger flexor weakness and biceps. Rare cases present with paraspinal (axial) myopathy. ^[14]

  • Interestingly, up to 50% of patients diagnosed with dysferlinopathy report a high degree of physical activity and good muscle prowess before the onset of symptoms. ^[15]

  • The disease slowly progresses, and patients are usually confined to a wheelchair 10–30 years after the onset of weakness.

  • Rare cases present with distal leg pain or swelling with or without weakness or with asymptomatic hyperCKemia.

  • Misdiagnosis as polymyositis can occur since inflammation can be present on muscle biopsy.

• Sarcoglycanopathies (LGMD2C–2F; LGMDR3–R6)

  • In general, sarcoglycanopathies tend to cause a severe Duchenne-like phenotype, but mild Becker-like phenotypes have been described. Overall, these diseases account for about 20–25% of all LGMDs, but they are overrepresented among severe cases. LGMD2D (α-sarcoglycan [adhalin]) accounts for 40% of the sarcoglycanopathies, LGMD2C and 2E (γ-sarcoglycan and β-sarcoglycan) each account for about 23% and LGMD2F (δ-sarcoglycan) accounts for 14% of cases in the Brazilian population.

  • Onset is usually at ages 6–8 years, but onset at or before 2 years and as late as the teens (or even adulthood) has been reported.

  • Some delay in motor milestones is not uncommon.

  • Weakness affects the hip and abdominal and shoulder musculature. Scapular winging is more common in LGMD2C-2F than in Duchenne muscular dystrophy.

  • Hypertrophy of the calf is common, and the tongue muscles may become enlarged.

  • Progression tends to be more rapid than that of other LGMDs, with loss of ambulation usually at 12–16 years but can be as early as 10 years. Patients with a late onset tend to have a more slowly progressive course.

  • Recently, patients with mild forms of alpha-sarcoglycanopathy have been identified using next-generation sequencing (NGS) targeted gene panels, indicating that milder forms may be underdiagnosed. ^[16]

  • Intelligence is normal.

  • Cardiomyopathy is reported in about 30% of cases and is most common with LGMD2E or 2F.

  • Progressive weakness leads to restrictive lung disease and hypoventilation and the need for ventilatory assistance.

  • Death can occur as early as in the second decade of life, although some patients live into adulthood without respiratory assistance.

• LGMD2G (LGMDR7 Telethonin; 17q12)

  • LGMD2D is a rare cause of LGMD, with significant phenotypic variability between and within families.

  • The typical age of onset is the first to second decade of life. Presentation in infancy with a congenital muscular dystrophy phenotype has been described. ^[17]

  • Weakness is predominantly proximal, but one half of patients may present with foot drop and anterior compartment atrophy (leg), and nearly all eventually develop distal leg weakness. Gluteal and thigh atrophy may be prominent. ^[18]

  • Calf hypertrophy occurs in about 50%, but some patients have calf atrophy that may resemble Miyoshi myopathy (LGMD2B).

  • Wheelchair confinement occurs in the third to fourth decade.

  • Cardiomyopathy occurs in about 50%. Presentation with an isolated, dilated cardiomyopathy has been described.

• LGMD2H (LGMDR8 TRIM32; 9q33)

  • LGMD2H has been observed mostly in the Hutterite people of Manitoba. A few non-Hutterites also have been shown to have LGMD2H and have a more variable phenotype. ^[19]

  • This disease is allelic with sarcotubular myopathy (see Congenital Myopathies).

  • Wide phenotype heterogeneity is reported.

  • Onset is usually in the second to third decades of life, with limb-girdle weakness and a waddling gait. The proximal arm muscles and the distal leg muscles are involved late.

  • Back pain and fatigue are common.

  • Progression is slow, with continued ambulation until around 50 years of age or later.

  • Other features can include neck flexor weakness, facial weakness, scapular winging, respiratory insufficiency, ankle contractures, and cramps. 

  • Asymptomatic affected individuals with hyperCKemia have been reported. 

• LGMD2I (fukutin-related proteinopathy; LGMDR9 FKRP; 19q13)

  • LGMD2I may be a fairly common cause of autosomal recessive LGMD, causing 11% of all cases in Brazil and 38% of cases in Denmark.

  • The disease is allelic with congenital muscular dystrophy 1C (MDC 1C). (See Congenital Muscular Dystrophy.)

  • The presentation of patients with a mutation in fukutin-related protein (FKRP) gene can vary from severe congenital muscular dystrophy to mild, late-onset LGMD.

  • The LGMD phenotype is variable. Patients can have a severe Duchenne-like presentation with delay in motor milestones, hypotonia, and severe proximal weakness. Progression to wheelchair by the teenage years and restrictive respiratory failure (even when patients are ambulant) is common. Like in Duchenne muscular dystrophy, treatment with corticosteroids may improve strength. The most common presentation is with a Becker-like onset with normal early motor milestones. An adult-onset form occurs at 11–40 years of age and is slowly progressive.

  • While cognitive impairment is universal in patients with congenital muscular dystrophy due to mutations in FKRP, it is absent or only mild in patients with LGMD2I. Neuropsychological testing shows mild impairment in executive functions and visuospatial planning, without substantial impairment in global and logic IQ, suggesting involvement of frontal and posterior parietal lobes. MRI abnormalities are heterogenous and, when present, always mild, varying from normal-to-mild white matter abnormalities, ventriculomegaly, cerebellar atrophy, and enlarged subarachnoid space. No structural brain abnormalities are noted. There is no correlation between MRI findings and cognitive abnormalities or mutation type. ^[20]

  • In a large study in Denmark, 2 groups of patients could be delineated based on genotype-phenotype correlations. Of the 38 patients studied, 27 (71%) had a homozygous mutation (826C>A), while 11 (29%) had a compound heterozygous mutation. ^[21]

    • The patients with a homozygous mutation had a later onset (mean of 18 y) and slower progression than patients with a compound heterozygous mutation. Only 15% lost the ability to ambulate by their mid 40s. Presentation with exertional myoglobinuria, calf hypertrophy and cardiomyopathy were all more common than in patients with a compound heterozygous mutation.

    • The patients with a compound heterozygous mutation had an earlier onset (mean of 5 y) and more rapid progression. All lost the ability to ambulate by their mid 20s. Tongue hypertrophy, more severe respiratory failure, contractures, and spine abnormalities were more common than in patients with a homozygous mutation.

  • Another large series from Norway found 88 patients (of 326) from 69 families with a mutation in FKRP (prevalence of ≥1 case in 54,000). ^[22] Seventy-six of these patients were homozygous for the 826C>A mutation, with a generally milder phenotype and a significantly later onset (age 14 y) than the patients with a heterozygous mutation (age 6.1 y). Other common features included difficulty with walking, running, or climbing as the presenting complaint and progression to involve arm weakness. About 20% used a wheelchair and 20% needed ventilatory support at the time of evaluation, about 25 years after onset.

  • Myoglobinuria (27%) and myalgia or cramps (60%) are common, ^[23] as can be isolated hyperCKemia. ^[24]

  • Cardiac involvement can occur in up to 60% of patients with LGMD2I as measured by reduced left ventricular ejection fraction. ^[25] There is no clear correlation between severity of cardiac disease and severity of muscle disease. Severely abnormal ejection fraction can occur in about 10% of patients and may cause symptomatic congestive heart failure. Rhythm abnormalities are not present.

• LGMD2J (LGMDR10 Titin; 2q24)

  • LGMD2J onset is at approximately 10–30 years, although one patient presented with weakness in infancy. ^[26] Proximal weakness progresses slowly, and tibialis anterior weakness may develop.

  • Wheelchair confinement usually occurs within 20 years, but some patients are ambulant past 60 years.

  • Occasional asymmetric presentation may be noted. Face is spared.

  • This disease is allelic, with the much more common presentation of tibial muscular dystrophy (TMD), sometimes called Finnish distal myopathy, the most common muscle disease in Finland. Some family members may have LGMD2J while others may have a TMD phenotype.

  • TMD presentation is usually in the fourth decade, with tibialis anterior weakness, which may be asymmetric. After many years, proximal weakness may develop. Less common manifestations include onset with proximal weakness, upper limb involvement, generalized weakness in childhood, persistent focal/asymmetric weakness, and mild bulbar/facial weakness.

  • The disease is also allelic with dilated cardiomyopathy 1G, autosomal recessive congenital myopathy with lethal cardiomyopathy, and hereditary myopathy with early respiratory involvement.

• LGMD2K (MDDGC1; LGMDR11 POMT1; 9q34)

  • The disease is allelic with Walker-Warburg syndrome and mutations in POMT1 cause approximately 20% of Walker-Warburg syndrome cases. (See Congenital Muscular Dystrophy.)

  • The age of onset is 1–6 years; later onset may be noted.

  • LGMD2K is characterized by severe proximal muscle weakness with slow progression. Contractures and scoliosis may be present.

  • Clinical phenotype is inversely correlated with POMT1 activity.

  • Results of ophthalmologic and funduscopic examinations, including electroretinography, are normal.

  • Facial dysmorphic features and mental retardation may occur, though brain MRIs are normal in LGMD2K.

• LGMD2L (LGMDR12 ANO5; 11p14)

  • LGMD2L was originally described in French-Canadian families ^{[27, 28]} but was later described in British, German, and Chinese patients as well. ^{[29, 30]}   

  • Anoctaminopathy is one of the most common adult muscular dystrophies in Northern Europe.

  • Age of onset is usually between early 20s and 50 years (mean 34 years).

  • Females may show less severe phenotype.

  • Common presentation is with proximal shoulder and pelvic girdle weakness. Walking difficulties or standing on the toes is often the presenting complaint. There is often asymmetric quadriceps, hamstring, biceps, brachioradialis, or calf weakness and atrophy. Muscle pain is common. Scapular winging may occur in up to a third of patients.

  • Facial weakness, hand weakness, and contractures are uncommon.

  • Progression is slow, and walking is retained. Cardiac and respiratory function is normal.

  • Asymptomatic hyperCKemia may be noted.

  • This disease is allelic with distal myopathy MMD3, which presents with calf weakness. Proximal thigh, biceps, and proximal weakness may develop later and may be asymmetric. While patients can present with features more typcial of LGMD2L or MMD3, with progression, phenotypes overlap and merge into a more homogenous picture.MRI - predominant fatty degeneration of the gluteus minimus muscle and of the posterior segments of the thigh and calf muscles with sparing of the gracilis muscle.

• LGMD2M (LGMDR13 Fukutin; 9q31)

  • The disease is allelic with Fukuyama congenital muscular dystrophy and most mutations in fukutin result in a severe phenotype.

  • Rare cases of LGMD2M have been described due to a mutation in the fukutin gene. ^{[31, 32, 33]}

  • Patients usually present with hypotonia or delayed motor milestones before age 2 years. Progression is moderate, with proximal greater than distal weakness affecting the legs more than the arms, but walking is maintained through the first decade. Joint contractures and calf hypertrophy may be present.

  • Other features include mild facial weakness, tongue hypertrophy, and contractures.

  • Some of these children have worsening weakness during febrile illnesses, and like boys with Duchenne muscular dystrophy, their weakness improves with steroids.

  • Most children had normal intelligence but a few had low IQs. Structural brain abnormalities in in the posterior fossa or cortex may be noted.

• LGMD2N (LGMDR14 POMT2; 14q24)

  • The disease is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).

  • 16 cases have been described with a LGMD phenotype. ^{[34, 35]}

  • Presenting symptoms include delayed motor milestones, difficulties in walking, exercise related muscle pain. Clinically, hip and knee flexors and extensors are maximally affected.

  • Cognitive impairment and learning difficulties are common. Structural brain abnormalities may be evident on MRI, and include ventricular enlargement, periventricular hyperintensities, and frontal.

  • On MRI, most affected muscles include hamstrings followed by paraspinal and gluteal muscles.

  • Calf hypertrophy and scapular winging have been noted.

  • Muscle biopsy may show inflammatory changes.

• LGMD2O (LGMDR15  POMGnT1; 1p32)

  • This disease is allelic with muscle-eye-brain disease (see Congenital Muscular Dystrophy).

  • Rare cases are described with a LGMD phenotype. Calf hypertrophy has been noted

• LGMD2P (LGMDR16 DAG1; 3p21)

  • Rare families have been reported with delayed walking, proximal more than distal weakness with slow progression, calf or thigh hypertrophy, occasional Achilles joint contracture, greatly elevated CK, and moderate-to-severe mental retardation. ^[36]

  • Brain MRI is normal

  • α -dystroglycan staining is reduced on muscle immunohistochemistry

• LGMD2Q (LGMDR17 Plectin 1f; 8q24)

  • This disease is allelic with congenital muscular dystrophy with familial junctional epidermolysis bullosa (see Congenital Muscular Dystrophy).

  • Rare families have been reported with LGMD phenotype without skin manifestations. ^[37] Onset is in early childhood, with slow progression of proximal more that distal weakness.

  • Rare ocular involvement and hypertrophic gastrocnemius has been described.

• LGMD2R (excluded from new classification)

  • Rare patients have been reported with a limb girdle phenotype. ^[38] Features include onset in the second or third decade with slowly progressive proximal and facial weakness. Scapular winging or respiratory involvement may be present. Scoliosis or scapular winging have been reported.

  • Cardiac symptoms are common, including conduction block and cardiomyopathy.

• LGMD2S (LGMDR18 TRAPPC11; 4q35)

  • Rare patients have been reported with childhood onset of slowly progressive proximal weakness, which involves arms more than legs. ^[39] Facial weakness, scapular winging, and myalgias are occasionally noted.

  • There is mild-to-moderate intellectual disability and an infantile-onset hyperkinetic choreiform movement disorder.

  • Seizures, ataxia, and ocular abnormalities can occur.

• LGMD2T (LGMDR19 GMPPB; 3p21)

  • Rare patients have been reported with a wide range of symptom onset (and severity) from birth to the mid 30s. ^{[40, 41]}

  • Proximal limb girdle weakness with slow progression is seen in all subjects. A preferential involvement of paraspinal and hamstring muscles may be noted.

  • Additional features can include cramps, calf hypertrophy, rhabdomyolysis, mild cognitive impairment, epilepsy, and cardiac conduction defects.

  • A more severe phenotype with congenital muscular dystrophy and associated brain and eye abnormalities has been described as in other muscular dystrophies with mutations in genes responsible for glycosylating α-dystroglycan. (see Congenital Muscular Dystrophy).

• LGMD2U (LGMDR20 ISPD; 7p21)

  • Rare patients have been reported with childhood onset (1–12 years) of proximal weakness. ^{[42, 43]}

  • Progression is slow and ambulation is often lost in teenage years, although a few patients were walking in their 40s and 50s.

  • Cardiomyopathy may be present.

  • Cognition and MRI are normal in the majority.

  • Other features can include myoglobinuria, cramps, scapular winging, and calf hypertrophy.

  • A more severe phenotype with congenital muscular dystrophy and associated brain and eye abnormalities has been described as in other muscular dystrophies with mutations in genes responsible for glycosylating α-dystroglycan. (see Congenital Muscular Dystrophy). Phenotypic variability may be noted in the same family.

• LGMD2V (excluded from new classification; see Type II Glycogen Storage Disease (Pompe Disease)

  • Late-onset Pompe disease may present as LGMD.

• LGMD2W (excluded from new classification)

  • Single family described.

  • Childhood onset, severe weakness.

  • Other features include macroglossia and calf hypertrophy.

  • Cardiomyopathy developed in the 30s.

• LGMD2X - Popeye domain–containing 1 (POPDC1); blood vessel epicardial substance (BVES) mutation (excluded from new classification)

  • ​One multigenerational family with 3 affected members is reported. ^[44]

  • Onset of slowly progressive proximal weakness in mid-adulthood.

  • Syncope due to AV-block in all family members may manifest before weakness.

• LGMD2Y - Torsin A-interacting protein 1 (TOR1AIP1) (excluded from new classification)

  • One family described.

  • Onset in first decade.

  • Rigid spine and distal contractures.

  • Cardiomyopthy and respiratory failure.

• LGMD2Z (LGMDR21 POGLUT1; 3q13)

  • Onset in the third decade with limb girdle weakness.

  • Progressive with scapular winging, wheelchair confinement, and respiratory insufficiency.

• LGMDR22 (COL6A2; 21q22)

  • Childhood onset.

  • Progressive contractures.

• LGMDR23 (LAMA2; 6q22)

  • Variable onset, early onset tends to be severe, late onset shows slow progression.

  • Neurological manifestations (epilepsy, leukoencephalopathy, globus pallidi signal changes, neuropathy).

  • Associated dilated cardiomyopathy.

• LGMDR24 (POMGNT2; 3p22)

  • Three Japanese patients described.

  • Early onset proximal weakness.

  • Calf hypertrophy.

  • Intellectual impairment.

Autosomal dominant LGMD

Autosomal dominant LGMD is less common than autosomal recessive LGMD, accounting for about 10% of all cases. In general, patients with autosomal dominant LGMD have a later onset and slower course than those of autosomal recessive LGMD. Creatine kinase (CK) elevations are also not as great in autosomal dominant LGMD as in autosomal recessive LGMD.

• LGMD1A (myotilinopathy, also Myofibrillar myopathies; excluded from the new classification)

  • Onset varies from young adulthood to the mid-70s.

  • Presentation is often with distal weakness causing foot drop, but can also be distal and proximal or just proximal, but progresses to clinically significant proximal and distal weakness in all patients.

  • The progression is slow, with late loss of ambulation or, rarely, respiratory insufficiency.

  • Dysarthria and facial weakness may be present.

  • Cardiomyopathy or arrhythmia is noted in 50%.

  • Neuropathy noted in more than 50% may account for distal weakness.

• LGMD1B (laminopathy, allelic with autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy; excluded from the new classification).

  • Onset can be from childhood (< 10 y) to mid-30s.

  • LGMD1B results in proximal weakness with slow progression.

  • Distal limb and facial weakness may be late manifestations.

  • Cardiac disease begins by the 30s–50s and affects two thirds of patients. Atrioventricular (AV) block progresses from first degree to complete. Dilated cardiomyopathy and ventricular arrhythmias may also be present.

• LGMD1C (caveolinopathy; excluded from the new classification)

  • Predominant symptoms may be rippling-muscle disease, which presents as mechanical or activity-induced, electrically silent muscle contraction that moves laterally in wavelike fashion across the muscle. Myoedema, or mounding of the muscle after percussion, may be observed. Patients may also have proximal weakness, muscle hypertrophy, or myalgias.

  • Onset is usually in the first or second decade, but it may manifest into early adulthood. Presentation is usually with proximal weakness but can also be with distal weakness. Progression is slow to moderate and may be variable within families.

  • Rhabdomyolysis has been reported. ^[45]

  • Calf hypertrophy affects some patients.

  • Adults usually remain ambulant.

• LGMD1D (DNAJB6 mutation; LGMDD1 DNAJB6; 7q36)

  • Nomenclature is confusing and some classify this as LGMD1E. 

  • Usually adult onset with slow progression, although a few patients with childhood onset and respiratory involvement have been described.

  • Limb-girdle muscle weakness with waddling gait is common. Predominant distal weakness may occur.

  • The rectus femoris, sartorius, and the anterolateral group of lower leg and upper limb muscles are relatively preserved until the late stage.

  • Cardiac arrhythmia and cardiomyopathy are noted in all patients beginning 1–2 decades after weakness and may lead to sudden death.

• LGMD1E (Desmin (DES) mutation ^[46] ; excluded from the new classification)

  • This was formerly reported as LGMD1D.

  • Several families have been reported with onset of weakness in their early 20s–60s. ^{[47, 48]} Most have proximal weakness, although distal weakness can predominate. Legs are usually affected more than arms.

  • Progression is slow, with most patients remaining ambulant into late life.

  • Dysphagia may be preset.

  • Serum CK is elevated.

  • No cardiomyopathy is noted.

• LGMD1F (LGMDD2 TNPO3; 7q32)

  • One large family has been described. ^[49]

  • Onset is from the first year of life to the mid-50s.

  • Proximal weakness is noted early, with distal weakness as a late finding. Scapular winging may be noted.

  • Patients with a young onset may have rapid progression and require use of a wheelchair by their 20s–30s. They may also have facial and respiratory weakness and/or spinal deformity.

• LGMD1G (LGMDD3 HNRPDL; 4q21)

  • Onset in third to fourth decade.

  • Asymptomatic carriers reported.

  • Weakness may begin in proximal upper limbs or lower limbs.

  • Cataract.

  • Distal contractures.

• LGMD1H (excluded from new classification)

  • Single family described.

  • Variable onset and severity.

  • Progressive proximal muscle weakness affecting both the upper and lower limbs.

• LGMD1I (LGMDD4 Calpain-3; 15q15)

  • Similar syndrome to LGMD2A (calpainopathy), but milder.

  • Later age of onset (mid-30s).

  • Milder weakness, but similar pattern (proximal leg [glutei/hamstring], paraspinal, medial gastrocnemius).

  • Myalgia in 50%.

  • CK may be markedly elevated.

• LGMDD5 (Bethlem 1; COL6A1: 21q22; COL6A2: 21q22; COL6A3: 2q37)

  • Allelic with Bethlem myopathy, Ullrich Scleroatonic muscular dystrophy

  • Variable age of onset. Early onset may present with fetal hypotonia. Onset in seventh decade has been reported.

  • Spontaneous improvement may occur after birth and around puberty. Many become wheelchair bound by the seventh decade.

  • Distal or proximal contractures. 

  • Muscle pain and cramps may be noted.

  • Respiratory and cardiac involvement may occur in minority

    muscle.

  • Hypertrophy is not reported.

Typical clinical features to distinguish the main LGMDs are often most helpful early in the disease.

• LGMD1A: Dysarthria and swallowing difficulty are common. Distal weakness may be present.

• LGMD1B: Frequent cardiac complications include cardiomyopathy and arrhythmia and there may be a family history of sudden cardiac death. Respiratory complications and contractures are common.

• LGMD1C: Patients may present with myalgias, rippling muscles, or asymptomatic elevations of CK levels. Calf hypertrophy and toe walking may be prominent. Weakness is proximal and distal.

• LGMD2A: Onset often in second decade of life. Patients have prominent atrophy of the periscapular muscles, biceps, gluteus maximus, thigh adductors, and hamstring muscles, with sparing of the hip abductors, sartorius, and gracilis. Presentation may be with toe walking. Contractures are common, in which case the disease needs to be differentiated from LGMD1B, Emery-Dreifuss muscular dystrophy, Bethlem myopathy, and laminin-α2 deficiency. This is a common cause of marked hyperCKemia or asymptomatic hyperCKemia.

• LGMD2B: Patients may have early weakness and/or atrophy of the gastrocnemius (might be detected only on MRI), inability to walk on toes, waddling gait, atrophic distal biceps, and spared periscapular and deltoid muscles. Childhood onset is rare, with often sudden onset in the late teens or early 20s most common. CK can be markedly elevated. Misdiagnosis as polymyositis is not uncommon.

• LGMD2C-2F: Patients may have Duchenne- and/or Becker-like weakness but with additional involvement of the periscapular muscles causing scapular winging. Muscle hypertrophy is common, especially of the calf and tongue muscles. Mental development is normal. Cardiomyopathy may be present in some. Respiratory complications are common. CK often markedly elevated. Contractures and scoliosis maybe present.

• LGMD2G: Patients may have initial anterior tibial weakness causing foot drop or a typical LGMD phenotype.

• LGMD2H: Patients may have a late onset, slow progression, and facial weakness. No cardiac symptoms are present, but mild ECG changes may be noted. This form is reported almost exclusively in the Hutterite population.

• LGMD2I: This form has a widely variable spectrum with prominent muscle hypertrophy and cardiomyopathy (Duchenne-like). Respiratory complications are common. Patients may have prominent tongue hypertrophy and severe weakness and wasting of upper arms, neck flexors, and axial muscles; these features can help in distinguishing this disease from Duchenne muscular dystrophy.

• LGMD2J: This is a severe LGMD described in the Finnish population. Distal muscles are affected as the disease progresses. No facial weakness is noted.

• LGMD2K: This may present with global delay. Mental retardation and microcephaly may be present.

• LGMD 2L: Adult onset common. Males more severely affected.  Gastrocnemius atrophy and weakness is common. Asymmetry may be prominent. Gradual progression with myalgias and exercise intolerance. CK often markedly elevated.    

• LGMD2N: This may preset with global delay.

Specific clinical aspects of LGMD subtypes: ^[4]

• Autosomal dominant LGMD: Rare, adolescent to late adult onset (LGMD 1B-1D may have childhood onset), mild weakness, normal to mildly elevated CK (except LGMD1C), rare exercise intolerance or rhabdomyolysis (except LGMD1C) 

• Autosomal recessive LGMD: Common, childhood to young adult onset, moderate to severe weakness, mild to highly elevated CK, common exercise intolerance or rhabdomyolysis

• LGMDs with cardiac involvement: α-dystroglycanopathies, sarcoglycanopahies, myofibrillar myopathies, laminopathy (and other nuclear envelope proteins), LGMD1C (caveolinopathy), LGMDs with respiratory involvement: α-dystroglycanopathies, sarcoglycanopathies, myofibrillar myopathies, LGMD2V (acid maltase deficiency)

• LGMDs with distal weakness (anterior compartment); myofibrillar myopathies

• LGMDs with distal weakness (posterior compartment); LGMD2B (dysferlinopathy) LGMD2L (anoctaminopathy)

• LGMDs with calf hypertrophy; α-dystroglycanopathies, sarcoglycanopathies, LGMD1C (caveolinopathy)

• LGMDs with scapular winging: α-dystroglycanopathies, sarcoglycanopathies, LGMD2A (calpainopathy), myofibrillar myopathies, LGMD2B (dysferlinopathy), LGMD2L (anoctaminopathy), laminopathy (and other nuclear envelope proteins)

• LGMDs with early/prominent contractures: laminopathy (and other nuclear envelope proteins, LGMD2A (calpainopathy), sarcoglycanopathies 

• LGMDs with brain involvement: (α-dystroglycanopathies) LGMD2I, LGMD 2K, LGMD 2M, LGMD2N, LGMD 2O, LGMD 2P, LGMD2S, LGMD2T, LGMD2U, LGMD2Z

• LGMDs with onset in the first decade: LGMD2C-F, LGMD 2H, LGMD2J, LGMD2K, LGMD2M, LGMD2N, LGMD2O

• LGMDs with onset in second decade: LGMD2A, LGMD2G, LGMD2I, LGMD1B, LGMD1C, LGMD1E, LGMD1F

• LGMDs with onset in adulthood: LGMD2B, LGMD2L, LGMD1A, LGMD1D

• LGMDs with eye involvement: α-dystroglycanopathies, HNRPDL

• LGMD with liver involvement: TRAPPC11

• KGMD with skin involvement: PLEC1

• LGMDs with myotonic /discharges on Electromyography ( EMG) : LGMD1A, LGMD1D, LGMD1E

Myofibrillar myopathies (MFM)

Myofibrillar myopathies, (previously called desmin-storage myopathies because desmin was the first protein found and is the most consistent protein in the aggregates that are characteristic of these disorders) refers to a group of hereditary myopathies with homogeneous morphological features.

The relative frequency of mutations is unknown, but desminopathy is likely the most common and αβ-crystallinopathy is the least common. However, in more than half of patients with a myofibrillar myopathy, the causative gene mutation is unknown.

Age at onset varies from 7–77 years, with a mean of 54 years, except for patients with mutations in selenoprotein N who have onset at birth and the 1 described patient with a lamin A/C mutation who presented at age 3 years. Patients with desminopathy often present in early adulthood, while patients with myotilinopathy and filaminopathy often present after age 50 years.

Clinically, this group of disorders is heterogeneous, with slowly progressive weakness affecting the proximal and distal muscles in most patients, but about 25% present with distal predominant weakness (common in myotilinopathy), and 25% present with only proximal weakness (common in filaminopathy). They are included in this article because some mutations are in the same genes that cause LGMD phenotypes.

Muscle MRI may help to distinguish distinct subtypes. ^[50] In patients with desminopathy, the semitendinosus was as least equally affected as the biceps femoris and the peroneal muscles were never less involved than the tibialis anterior. In patients with myotilinopathy, the adductor magnus was more affected than the gracilis and the sartorius was as least equally affected as the semitendinosus. In patients with filaminopathy, the biceps femoris and semitendinosus were at least equally affected as the sartorius, the medial gastrocnemius was more affected than the lateral gastrocnemius and the semimembranosus was more affected than the adductor magnus.

Rare findings include the following:

• Facial weakness

• Asymmetric weakness

• Severe atrophy

• Respiratory failure, which may be severe or at presentation

• Contractures

• Distal sensory deficits (neuropathy diagnosed in about 20%)

Cardiac disease (especially common in desmopathy) may be present either as cardiomyopathy or arrhythmias and conduction block, and is present in about 50%.

Specific mutations include the following:

• Desminopathy (MFM1): Onset is generally in the 20s or 30s with slow progression. Patients often present with distal weakness that progresses proximally, but limb-girdle, scapuloperoneal, and distal weakness combined with proximal weakness have all been described. Inter- and intrafamilial variability exists. Those with autosomal recessive disease may have an early onset. Cardiac disease (cardiomyopathy or atrioventricular conduction abnormalities) occurs in about 60% and may follow or precede myopathy, may be isolated, and may be severe. Respiratory failure may be severe and may be present at presentation. Facial and bulbar weakness may occur late. About 75% of patients eventually need assistance with ambulation.

• αβ-crystallinopathy (MFM2): Onset varies from early to mid adulthood. Patients present with proximal more often than distal weakness. They may also present with respiratory failure. Patients may have neuropathy, cardiac failure, conduction abnormality, and congenital posterior polar cataracts.

• Myotilinopathy (MFM3): The first mutations described were in 2 patients with an LGMD phenotype (see LGMD1A). Since then, several patients have been found with a myofibrillar myopathy. Onset is usually in mid-to-late adulthood. Most patients present with distal greater than proximal weakness, often with early foot drop. Neuropathy occurs in about 50%. Cardiomyopathy affects about 50%. Dysarthria, joint contractures and myalgias are present in about 33%. One family with spheroid body myopathy, a congenital myopathy, has been found with a mutation in the myotilin gene.

• Z-band alternatively spliced PDZ motif-containing protein (ZASPopathy) (MFM4): Onset is at age 44-73 years, and patients most often present with distal more than proximal weakness, though proximal weakness can occur alone. Cardiac disease occurs in about 25% of patients and may be the presenting or predominant feature. Neuropathy affects approximately 45% of patients. Mutations are allelic with Markesbery distal myopathy, and dilated cardiomyopathy +/- isolated noncompaction of left ventricular myocardium.

• Filamin C (γ-filamin) myopathy (MFM5): Age at onset is 24-57 years, with proximal greater than distal weakness. Respiratory failure occurs in about 50% of patients. Neuropathy affects about 40%. Cardiac disease may be present in up to 33%.

• BCL2-associated athanogene 3 (BAG3) myopathy (MFM6): Age of onset is from childhood to early teens with proximal and distal weakness with progression that often causes respiratory failure and wheelchair dependency. ^{[51, 52]} Other features include contractures, scoliosis, and rigid spine. Peripheral neuropathy may be present. Cardiomyopathy is common and often severe, requiring transplantation in some patients.

• Selenoprotein N myopathy: Selenoprotein N mutations were originally found in patients with congenital muscular dystrophy with rigid spine syndrome or minicore congenital myopathy. A study has shown that some patients with Mallory-body desmin-related myopathy also have a mutation in the selenoprotein N gene. Onset is at birth with hypotonia as well as axial and proximal weakness. Contractures and scoliosis are common and cardiac disease may occur. Death or the need for ventilatory support occurs before adulthood due to progressive respiratory failure.

• Laminopathy: Besides presenting with a limb girdle phenotype (see LGMD1B), a case was described with a myofibrillar myopathy. The patient presented at age 3 years with difficulty running and at age 5 years was noted to have limb-girdle weakness.

Autosomal recessive LGMD

LGMD2A is caused by mutations in the calpain-3 gene (CAPN3) that encodes a Ca2+-dependent nonlysosomal cysteine protease. The calpain-3 isoform is a homodimer that is abundant in skeletal muscle. More than 450 distinct pathological mutations have been identified so far. Many types of mutations have been found including nonsense mutations leading to stop codons, missense mutations often leading to decreased catalytic activity of calpain-3, splice site mutations, and small deletions or insertions.

• In general, null mutations give rise to phenotypes more severe than those due to missense mutations.

• CAPN3 (p94) is a member of the calpain family of intracellular, soluble cysteine proteases, most of which have calcium-dependent activation (CAPN3 is not calcium-activated). It is expressed almost exclusively in muscle and is anchored by titin at the M-line and N2 line (within the I-band of the sarcomere).

• CAPN3 is involved in cleavage and/or breakdown of several proteins, particularly those involved in assembly and scaffolding of myofibrillar proteins including titin, vinculin, C-terminal binding protein 1, and filamin C.

• CAPN3 also has thiol-dependent proteolytic activity directed against the skeletal muscle ryanodine receptor (RyR). RyR is a Ca2+-release channel, and lack of regulation of RyR by CAPN3 may play a role in skeletal muscle dysfunction.

• Mutations in the CAPN3 gene can lead directly to loss of proteolytic activity or to secondary loss of activity due to its loss of anchorage with titin. The loss of proteolytic activity may lead to reduced cleavage of cytoskeletal and myofibrillar proteins, decreased ubiquitination, and proteasome-mediated degradation, accumulation of damaged proteins that then accumulate within muscle.

• How the absence of CAPN3 triggers an initial event that leads to metabolic reprogramming in the muscle is not entirely understood at this time. There is evidence that the metabolic adjustment triggered by the absence of CAPN3 in muscle results in an aberrant regeneration; AMPK pathway activation has been shown to play an essential role. ^[53]

• Dysregulation of Ca2+ metabolism has also been implicated to play an important role in the pathogenesis of LGMD2A. ^[54]

• Biopsy pathology is typically dystrophic, sometimes characterized by frequent lobulated fibers.

• Of patients with LGMD2A, 20%–30% exhibit normal CAPN3 protein levels as measured by Western blotting. ^[55]

• On muscle biopsy, CAPN3 can be visualized by using Western blots but not muscle immunohistochemistry. Correlation between the degree of deficiency and the clinical phenotype can be total, partial, or (in rare cases) nonexistent. Expression of dystrophin and the sarcoglycans is normal. Expression of dysferlin can be reduced.

LGMD2B is caused by mutations on chromosome 2 in the dysferlin gene.

• More than 300 mutations have been identified, most commonly missense, nonsense, small deletions, and splice-site mutations.

• The type of mutation is not correlated with the phenotype, ie, LGMD versus Miyoshi distal myopathy. Both phenotypes have been described in the same family with identical mutations.

• Dysferlin protein is a large membrane protein with sequence analogy to the nematode protein fer-1, and is a member of the ferlin family of proteins, which are all involved in calcium-dependent membrane fusion. Dysferlin protein has been localized to the sarcolemma, the T-tubule system, and cytoplasmic vacuoles. ^[56] Dysferlin is thought to be involved in the docking and fusion of intracellular vesicles to the sarcolemma during injury-induced membrane repair by interacting with other dysferlin molecules and other proteins. Some of these proteins include annexins A1 and A2 (phospholipid binding proteins), caveolin-3 (LGMD1C), calpain-3 (LGMD2A), the dihydropyridine receptor within the T-tubule system, and AHNAK (desmoyokin, a protein involved in cell membrane differentiation and repair). Dysfunction of dysferlin may lead to impaired muscle membrane repair as well as delayed myoblast fusion and maturation.

• Ultrastructural studies have shown small sarcolemmal defects, replacement of the plasma membrane by multiple layers of vesicles, and small subsarcolemmal vacuoles, all suggesting that dysferlin is likely required for maintaining the structural integrity of the muscle fiber plasma membrane, and plasma membrane injury is an early event in the pathogenesis of dysferlinopathy.

LGMD2C–2F are caused by mutations in the sarcoglycan genes.

• LGMD2C is caused by a mutation on chromosome 13 in the γ-sarcoglycan gene.

• LGMD2D is caused by a mutation on chromosome 17 in the α-sarcoglycan (adhalin) gene.

• LGMD2E is caused by a mutation on chromosome 4 in the β-sarcoglycan gene.

• LGMD2F is caused by a mutation on chromosome 5 in the δ-sarcoglycan gene.

• Missense and nonsense mutations are the most common for all the sarcoglycanopathies, though with γ-sarcoglycanopathies (LGMD2C), small or large deletions are also common.

• Sarcoglycan protein complex is a transmembrane complex that is part of the large dystrophin glycoprotein complex. The core of the complex is made up of the β and δ subunits with weaker binding of the α and γ subunits. This complex likely does not bind directly to dystrophin, but binds to the dystroglycan complex which in turn binds to dystrophin. The sarcoglycan complex also binds strongly to sarcospan as well as to α-dystrobrevin and filamin.

• The function of the sarcoglycan complex is unknown, but it likely stabilizes the dystrophin glycoprotein complex. In the absence of the sarcoglycan complex, binding of dystrophin to β-dystroglycan and binding of β-dystroglycan to α-dystroglycan are weakened.

• The sarcoglycan complex may also play a role in cell signaling based on the following evidence. It may act as a receptor since it has cysteine bonds, common in other receptors, although no substrate has been identified. ATPase activity occurs in α-sarcoglycan. The sarcoglycan complex binds α-dystrobrevin, which in turn binds to syntrophin, which binds nNOS and voltage-gated sodium channels.

• Muscle biopsy usually shows a dystrophic pattern of muscle-fiber necrosis and regeneration similar to that observed in Duchenne muscular dystrophy.

• On immunohistochemistry, dystrophin staining is often slightly reduced, but may be normal (whereas sarcoglycan expression may be mildly reduced in Duchenne-Becker muscular dystrophy). α-sarcoglycan mutations cause absent or reduced α-sarcoglycan staining with preservation of staining for γ-sarcoglycan. Minimal or no staining occurs for β and δ-sarcoglycan. This is the only mutation for which the amount of residual staining (for α-sarcoglycan) and the clinical phenotype are correlated. β- and δ-sarcoglycan mutations usually cause absent staining of the entire sarcoglycan complex.

LGMD2G is caused by mutations on chromosome 17 in the telethonin gene.

• Null mutations have been described in only a few families with a wide range of phenotypic variability.

• Allelic with hereditary cardiomyopathy (CMD 1N & CMH25)

• Telethonin protein (titin-cap protein) is a sarcomeric protein present in the Z disk that binds to titin and several other Z-disk proteins, and is thought to be important in sarcomere assembly. While LGMD2G patients with null mutations do not appear to have a primary defect in myofibril assembly, knock down of titin-cap protein results in decreased expression of several myogenic regulatory factors suggesting that titin-cap protein may function to permit signaling between the contractile apparatus and genes involved in muscle development or maintenance. ^[57]

• Immunofluorescence and Western blot assays may show a telethonin deficiency. Full sequencing testing may be cost-effective in all cases, as the gene is composed only of two small exons.

LGMD2H is caused by mutations on chromosome 9 in TRIM32 (tripartite-motif containing gene 32).

• Most patients have the D487N mutation. Different mutations in TRIM32 have also been found, but all mutations cluster in the NHL domain of TRIM32 protein.

• Mutations in TRIM32 can also cause sarcotubular myopathy (see Congenital Myopathies) and Bardet-Biedl syndrome.

• TRIM32 protein is an E3-ubiquitin ligase that transfers activated ubiquitin residues onto a target protein, tagging the protein for degradation in the proteosome.

• All mutations in the NHL domain result in loss of the self-interacting ability of TRIM32 protein , as well as the loss of interaction of TRIM32 protein with E2N, a muscle-specific protein involved in the ubiquitination process . ^[19] While the disease mechanism is unknown, it is speculated that disruption in the ubiquitination process may lead to protein accumulation and subsequent cell stress and dysfunction.

• On muscle biopsy, no protein accumulations or inclusions have been identified.

LGMD2I (MDDGC5) is caused by mutations on chromosome 19 in the FKRP gene.

• Missense point mutations are the most common mutation. A homozygous Leu276Ileu mutation (826A>C) is particularly common and is present in about 90% of patients. The disease severity correlates with the mutation in the second allele; patients with a homozygous mutation are less severely affected. The most severe phenotype occurs when patients have compound heterozygous mutations for 2 other missense mutations or 1 missense and 1 nonsense mutation. This form is allelic with congenital muscular dystrophy 1C. (See Congenital Muscular Dystrophy.)

• FKRP protein is a putative glycotransferase based on its sequence homology to fukutin. FKRP deficiency causes hypoglycosylation of α-dystroglycan, a component of the dystrophin-associated glycoprotein complex. α-dystroglycan hypoglycosylation is associated with loss of interaction with laminin α2, which in turn results in laminin α2 depletion. ^[58]

• In muscle biopsy, antibodies to the glycosylated portion of α-dystroglycan show reduced staining (and decreased mass on Western blots). Antibodies to laminin-α2 may show reduced staining; however, in mild cases, this is often evident only on Western blots. No consistent relationship is noted  between clinical function and the degree of morphological pathology. 

LGMD2J is caused by mutations on chromosome 2 in the titin gene.

• The most common mutation is an 11-base pair deletion-insertion mutation in the terminal exon. Finnish patients who are homozygous for this titin mutation develop autosomal recessive LGMD2J, while patients with a heterozygous mutation develop autosomal dominant Finnish (tibial) muscular dystrophy.

• Titin protein is the largest protein found in humans. It is important for sarcomeric organization, stretch response, and sarcomerogenesis in myofibrils. It also likely plays a role in the assembly of contractile elements, regulation of the size of the Z disk, and in cell signaling pathways.

• Titin binds caplain-3 in muscle, which may stabilize it from autolytic degradation. Muscle biopsy in patients with LGMD2J shows secondary deficiency of calpain-3. No signal is obtained using autoantibodies to the C-terminus region of titin near the common mutation site. This C-terminus region is important for calpain-3 binding and cell signaling pathways. Muscle biopsy in LGMD2J shows loss of calpain-3.

• Allelic with hereditary cardiomyopathy syndromes (CMD 1G, CMH 9, EOMFC [early onset myopathy with fatal cardiomyopathy]).

LGMD2K (MDDGC1) is caused by mutations on chromosome 9 in the protein O-mannosyltransferase 1 (POMT1) gene.

• LGMD2K is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).

• POMT1 protein is an O-mannosyltransferase that glycosylates α-dystroglycan and disease is likely related to reduced or abnormal glycosylation of α-dystroglycan. POMT enzymatic activity is inversely correlated with severity of clinical phenotype such that patients with a LGMD phenotype have mildly reduced activity and patients with a Walker-Warburg syndrome phenotype have severely reduced activity. ^[59]

• Muscle biopsy shows decreased staining for α-dystroglycan.

LGMD2L is caused by a mutation on chromosome 11 in the ANO5 gene.

• ANO5 encodes a member of the Anoctamin family, comprised of at least 10 proteins all with 8 transmembrane domains. The function of Anoctamin 5 is unknown, but other anoctamins have been recognized to code for calcium-activated chloride channels. ^[28]

• The c.191dupA mutation may be a founder mutation, accounting for the high prevalence in families of northern European descent. ^[29]

• In some biopsies in patients with Anoctamin 5 mutation, there is evidence of sarcolemmal membrane lesions and defective membrane repair. It is hypothesized that similar to mutations in dysferlin, mutations in anoctamin 5 may lead to LGMD due to defects in membrane repair.

LGMD2M (MDDGC4) is caused by mutations on chromosome 9 in the fukutin gene.

• LGMD2M is allelic with Fukuyama congenital muscular dystrophy.

• Fukutin is a putative glycosyltransferase and has sequence homologies to a bacterial glycosyltransferase, but its exact role and enzymatic substrate have not been determined. However, like other glycotransferases, disease is likely related to reduced or abnormal glycosylation of α-dystroglycan.

• Muscle biopsy shows decreased staining for α-dystroglycan.

LGMD2N (MDDGC2) is caused by mutations on chromosome 14 in the POMT2 gene.

• LGMD2N is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).

• POMT2 is an O-mannosyl transferase and is required to form a complex with POMT1 for enzyme activity. Similar to mutations in POMT1, disease is likely related to defective glycosylation of α-dystroglycan.

LGMD2O (MDDGC3) is caused by mutations on chromosome 1 in the POMGnT1 gene.

• LGMD2O is allelic with muscle-eye-brain disease (see Congenital Muscular Dystrophy).

• POMGnT1 is the glycosyltransferase O-mannose β-1,2-N-acetylglucosaminyl-transferase. It catalyzes the transfer of N -acetylglucosamine to the O-linked mannose of glycoproteins, including α-dystroglycan. Like other glycosyltransferase mutations disease is probably related to defective glycosylation of α-dystroglycan.

LGMD2P (MDDGC7) is caused by mutations on chromosome 3 in the DAG1 gene. ^[36]

• DAG1 codes for α -dystroglycan, which is known to be modified by several glycotransfersases and mutations in several of these genes are causes of LGMD or congenital muscular dystrophy.

• In these patients, there is a missense mutation in the DAG1 gene itself.

• A mouse model of this mutation mimics the human disease. The mutation was shown to impair the receptor function of α -dystroglycan by inhibiting post-translational modification by LARGE disease (see Congenital Muscular Dystrophy).

LGMD2Q is caused by mutations on chromosome 8 in the plectin (PLEC1) gene. ^[37]

• Plectin is present in muscle sarcolemma and is thought to be important as a linker of various cytoskeletal proteins, thereby maintaining cell integrity.

• Eight plectin isoforms have been identified. In these families, there was a mutation in the initiation codon for isoform 1f. Plectin expression was reduced in muscle and there was almost no expression of plectin 1f mRNA.

• Allelic with epidermolysis bullosa simplex syndromes (see Epidermolysis Bullosa). 

LGMD2R is caused by a mutation on chromosome 2 in the DES gene.

• This disease is allelic LGMD1D and with myofibrillar myopathy 1 (see below).

• Desmin is important in linking myofibrils to the sarcolemma, nucleus, and mitochondria.

• In these patients, desmin staining in muscle was normal. ^[38] However, ultrastructural abnormalities typical for myofibrillar myopathies such as disruption of myofibrillar organization, formation of myofibrillar degradation products, and aggregation of membranous organelles were not present.

LGMD2S is caused by a mutation on chromosome 4 in the TRAPPC11 gene.

• The TRAPP complex is involved in membrane trafficking.

• Mutations impair the binding of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus. ^[39] There was delayed exit of proteins from the Golgi to the cell surface, and in particular alterations of the lysosomal glycoproteins lysosome-associated membrane protein1 (LAMP1) and LAMP2 support a defect in the transport of secretory proteins as a pathologic mechanism.

LGMD2T (MDDGA14) is caused by a mutation on chromosome 3 in the GMPPB gene.

• LGMD2T is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).
• GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate ^{[40, 41]} . GDP-mannose is required for O-mannosylation of proteins and like other glycosyltransferase mutations disease is probably related to defective glycosylation of α-dystroglycan. 
• Muscle biopsy of affected patients shows reduced glycosylation of α-dystroglycan.

LGMD2U (MDDGA7) is caused by a mutation on chromosome 7 in the ISPD gene

• LGMD2U is allelic with Walker-Warburg syndrome (see  Congenital Muscular Dystrophy).
• ISPD belongs to the glycosyltransferase-A family (as does LARGE) and is required for efficient O-mannosylation of alpha-dystroglycan. ^{[42, 43]}
• Muscle biopsy of affected patietns shows reduced glycosylation of α-dystroglycan.

LGMD2V is caused by a mutation on chromosome 17 in the GAA gene (see Genetics of Glycogen-Storage Disease Type II (Pompe Disease) & Type II Glycogen Storage Disease (Pompe Disease)

• LGMD2V is allelic with Late-onset Pompe disease (glycogen storage disease type 2)
• α-1.4 glucosidase is a lysosomal enzyme that hydrolyzes α-1.4 linkages on carbohydrates.  A mutation causes glycogen accumulation in most tissues. 

LGMD2W is caused by a mutation on chromosome 2 in the LIMS2 gene

• LIMS2 is a component of a complex that mediates multiple protein-protein interactions at adhesion sites between cells and the extracellular matrix and is critical for muscle attachment ^[60] . This complex also functions as a signaling mediator that transmits mechanical signals.
• LIMS2 localizes to sarcomeric Z-disks and costameres in heart and skeletal muscle.
• Patients have reduced staining for pinch2 (alternative name) at Z-disc.

LGMD2X is caused by a mutation on chromosome 6 in the POPDC1 (BVES) gene

• POPDC1 belongs to a group of membrane proteins (popeye domain-containing proteins) that are abundantly expressed in skeletal muscle and heart ^[44] .  
• These proteins bind cAMP and TREK1 (human potassium channel KCNK2) and may have regulatory roles in action potential generation.
• In zebrafish, expression of the homologous mutation caused heart and skeletal muscle phenotypes that resembled those observed in patients.

Autosomal dominant LGMD

LGMD1A is caused by mutations on chromosome 5 in the myotilin gene.

• Several different missense mutations have been identified.

• The term myotilinopathy has been coined because of the overlapping features in patients described as having a LGMD or myofibrillar myopathy and a mutation in the myotilin gene. Furthermore, a large family described as having spheroid body myopathy (see Congenital Myopathies) was recently found to have a mutation in the myotilin gene.

• Myotilin protein is associated with the Z disk and is expressed in skeletal muscle and, to a lesser extent, cardiac muscle. Myotilin protein binds to α-actinin, filamin C, and actin, and it is likely important in stabilizing and anchoring thin filaments to the Z disk during myofibrillogenesis.

• Muscle biopsy shows muscle fiber degeneration/necrosis and nonhyaline or hyaline inclusions that stain positively for multiple proteins (a feature similar to that of other myofibrillar myopathies). Myotilin, dystrophin, neural-cell adhesion molecule (NCAM), desmin, plectin, gelsolin, ubiquitin, and prion protein all are found in the inclusions. Other consistent findings are rimmed or nonrimmed vacuoles, autophagic vacuoles, cytoplasmic or spheroid bodies, and mild evidence of denervation. On electron microscopy, there is Z-disk streaming and sarcomeric disruption.

LGMD1B is caused by mutations on chromosome 1 in the lamin A/C gene.

• Missense and deletion mutations have been reported.

• Mutations in lamin A/C can also cause Emery-Dreifuss muscular dystrophy, quadriceps myopathy, congenital muscular dystrophy with rigid spine, autosomal dominant dilated cardiomyopathy with AV block (or CMD1A, see the Neuromuscular Disease Center), Familial partial lipodystrophy (Köbberling-Dunnigan syndrome), Charcot-Marie Tooth type 2A, mandibuloacral dysplasia, and premature aging syndromes (Hutchinson-Gilford progeria, atypical Werner syndrome).

• No clear genotype-phenotype correlation distinguishes the disorders listed above. Different phenotypes can occur in the same family. One individual can have more than 1 phenotype.

• Lamin A/C is an intermediate filament in the inner nuclear membrane and nucleoplasm of almost all cells. Multiple functions are described, but the pathophysiologic basis for LGMD1B is unknown. Lamin A/C provides mechanical strength to the nucleus; helps to determine nuclear shape; anchors and spaces nuclear pore complexes; is essential for DNA replication and mRNA transcription; and binds to structural components (emerin, nesprin), chromatin components (histone), signal transduction molecules (protein kinase C), and several genetic regulatory molecules.

LGMD1C is caused by mutations on chromosome 3 in the caveolin-3 gene.

• Most are autosomal dominant missense or deletion mutations in the scaffolding region, but a family with autosomal recessive disease has been described. The same mutation can cause different phenotypes (LGMD1C, elevated CK levels, rippling-muscle disease, distal myopathy, hypertrophic cardiomyopathy), even in the same family.

• Caveolins are transmembrane proteins that are the principal component of caveolae. Caveolae are 30- to 60-nm invaginations in cell membranes that can bind several components of signal-transduction pathways and may act as a scaffold, placing members of the pathway in close proximity.

• Caveolin-3 is a muscle-specific caveolin that is localized to the sarcolemma. It interacts with G proteins, a variety of signaling molecules, dystrophin, dystrophin associated proteins, phosphofructokinase, dysferlin, and nitric oxide synthase (nNOS).

• All mutations in caveolin-3 decrease sarcolemmal immunostaining, suggesting that the mutation is due to a loss of function. A dominant negative effect has been noted in which an aberrant protein product forms aggregates that sequester the normal caveolin-3 in the Golgi apparatus. Other effects due to improper caveolin-3 oligomerization and membrane localization result in derangements of the T tubule system, alterations in the sarcolemmal membrane, and the formation of subsarcolemmal vesicles.

• Muscle biopsy shows reduced or absent immunochemical staining for caveolin-3 at the sarcolemma, and this can be used as a screening test before searching for caveolin-3 mutations. In addition, immunochemical staining for dysferlin (caveolin-3 interactions) at the sarcolemma is reduced and the number of caveolae on electron microscopy is also reduced.

LGMD1D (note that some references call this LGMD1E) is caused by a mutation on chromosome 6 in the DES gene. ^[46] See below for myofibrillar myopathy MFM1.  

LGMD1E (note that some references call this LGMD1D) is caused by a mutation on chromosome 7 in the DNAJB6 gene (DNAJ/HSP40 Homolog, subfamily B, Member 6).

• It is a member of the HSP40 family, a class of co-chaperones with a J domain. ^{[47, 48]} These co-chaperones interact with chaperones of the HSP70 family to protect client proteins from irreversible aggregation during protein synthesis or times of cellular stress.

• Mutations have a dominant toxic effect, increasing the half-life of cytoplasmic isoform of DNAJB6 and reducing its protective antiaggregation effect.

• It interacts with BAG3 (See below myofibrillar myopathy MFM6).

• Muscle biopsy shows rimmed vacuolar myopathy. Aggregates contain DNAJB6, TDP-43, and SMI-31

LGMD1F is caused by a mutation on chromosome 7 in the transportin 3 (TNPO3) gene. ^[61]

• Transportin 3 is a member of the importinb super-family that imports proteins into the nucleus, including serine/arginine-rich proteins that control mRNA splicing.

• Muscle biopsy shows variable muscle fiber degeneration, desmin expression in muscle fibers, rimmed vacuoles, and abnormal nuclear morphology.

LGMD1G is caused by a mutation on chromosome 4 in the hetrogenous nuclear ribonucleoprotein D-like (HNRPDL) gene. ^[62]

• HNPRDL is a member of the hetrogenous ribonucleoprotein family whose members participate in mRNA biogenesis and metabolism including the splicing of specific exons in pre-mRNA transcripts of muscle related genes.  .
• Muslce biopsy shows muscle fiber necrosis, rimmed vacuoles and perimysial fibrosis.   

LGMD1H is caused by a mutation on chromosome 3 at the 3p25.1-p23 locus; the protein has not yet been identified.

LGMD1I is caused by in-frame deletion on c.643_663del21 in calpain-3 gene.

LGMDD5 is caused by mutations in α1, α2, or α3 subunits of collagen type VI. 

• Allelic disorders include bethlem myopathy, myosclerosis, early-onset dystonia and Ullrich Scleroatonic muscular dystrophy. 

• Collagen VI may play a role in anchoring basement menbranes and stabilizing cells in the extracellular matrix, via interactions with proteoglycans, integrins, and other proteins.

• Mutations may result in lower protein level, misfolded protein, or defective assembly.

Myofibrillar myopathies

Many patients with a clinical and histologic phenotype of myofibrillar myopathy have no known mutation. Myofibrillar myopathy syndromes related to know genetic mutations are described below.

Most mutations are in proteins of the Z-disk or with attachments to the Z-disk. Most are proposed to cause disease by means of a dominant negative effect due to combined wild-type and mutant protein. The pathogenesis of disease is likely due to disrupted Z-disk function, which includes: (1) an attachment site and mechanical link of actin and titin filaments, (2) transmission of force along the myofibril, and (3) an attachment site for intermediate filaments (desmin) that link adjacent sarcomeres with each other and with other cellular organelles.

The common morphologic features of myofibrillar myopathies includes myobrillar disorganization at the Z-disk (Z-disk streaming) followed by accumulation of myofibrillar degradation products and aggregation of many proteins. These proteins include not only cytoskeletal and myofibrillar proteins and intermediate filaments, but also proteins of the ubiquitin-proteasome system, nuclear proteins, chaperones, Alzheimer disease-related proteins, oxidative stress proteins, kinases, and neuronal proteins. ^[63] A proposed molecular pathogenesis includes aggregation of mutant proteins followed by aggregation of other proteins including those of the ubiquitin-proteasome system, which is the main pathway for nonlysosomal protein degradation. Abnormal proteasome function results and may then lead to autophagocytosis, hyaline inclusion body formation, and inflammation, all pathologic hallmarks of the disease.

Desminopathy (MFM1) is caused by mutations on chromosome 2 in the desmin gene and can be either autosomal dominant or autosomal recessive. More than 20 mutations (most nonsense or missense and autosomal dominant) have been identified. Most mutations are located in the α-helical rod domain, which is critically important for filament assembly. Different mutations cause variable phenotypes and also disrupt desmin filaments at various stages of assembly. Pathogenesis is likely due to loss of desmin function or a dominant negative effect related to the accumulation of mutant desmin into toxic aggregates that disrupt cell function and eventually cause cell death.

• Desmin protein is an intermediate filament (IF) protein. In muscle, it is located at the periphery of the Z-disk, under the sarcolemma, and at myotendinous junctions. In cardiac muscle, it is at intercalated disks and Purkinje fibers. Two desmin molecules align head to tail to form a dimer, 2 dimers form a tetramer, 2 tetramers form a protofilament, 2 protofilaments form a protofibril, and 2-6 protofibrils form an IF. IFs can heterodimerize with other IFs or IF-associated proteins. Desmin binds to ankyrin, spectrin, synemin, syncoilin, plectin, and nebulin. IFs form a heteropolymeric lattice to organize the myofibrils and link them to nuclei, mitochondria, and the sarcolemma.

• αβ-crystallinopathy (MFM2) is caused by a mutation on chromosome 11 on the αβ-crystallin gene. Mutations have all been autosomal dominant.

  • αβ-crystallin protein is a small heat-shock protein that forms homo-oligomeric or hetero-oligomeric complexes with αβ-crystallin or other heat-shock proteins. Expression in skeletal and cardiac muscles and in the lens is high. In muscle, the protein is localized to the Z-disk. It binds to unfolded and denatured proteins to suppress nonspecific aggregation, and it protects actin, desmin, tubulin, and a variety of soluble enzymes from stress-induced damage. Mutant proteins are expressed and likely impair this chaperone function by means of dominant negative effect.

Myotilinopathy (MFM3) is caused by mutations on chromosome 5 in the myotilin gene (see LGMD1A). More than 15 families have been described with autosomal dominant or sporadic mutations. The serine-rich exon 2 is a hot spot for mutations. Myotilin protein is expressed in skeletal and cardiac muscle and in peripheral nerves. In muscle, it is expressed at the Z-disk. The protein binds to α-actinin, F-actin and filamin C and likely plays a role in cross-linking actin filaments and is in control of sarcomere assembly.

ZASP (Z-band alternatively spliced PDZ-containing protein) myopathy (MFM4) is caused by mutations on chromosome 10 in the ZASP gene, and is allelic with Markesbery distal myopathy and a form of hereditary dilated cardiomyopathy. In the largest series to date, 3 mutations have been identified in 11 patients with autosomal dominant or sporadic inheritance. ZASP may be a common cause of myofibrillar myopathy (about 15% of patients). ZASP protein is expressed in cardiac and skeletal muscle, binds to α-actinin in the Z-disk, and supports Z-disk structure during contraction.

Filamin C myopathy (MFM5) has been described in 1 German family with an autosomal dominant truncating mutation on chromosome 7 in the filamin C gene. Filamin C protein is expressed in skeletal and cardiac muscle. It is a Z-disk protein that binds actin, sarcoglycans, myotilin, myozenin, and many other proteins. It functions in actin reorganization, signal transduction, and maintenance of membrane integrity during force application.

BCL2-associated athanogene 3 myopathy (MFM6) is caused by a mutation on the BAG3 gene and has been described in a few patients. ^{[51, 52]} The BAG family of proteins bind to HSP70/HSC70 (heat shock proteins that act as chaperones to assist with protein folding and prevent protein aggregation) and are thought to inhibit the activity of these HSPs, thereby promoting protein release. Bag-3 localizes to and co-chaperones the Z disk in skeletal and cardiac muscle. Muscle pathology showed abnormal aggregation of desmin and Bag-3, Z-disc disintegration, and nuclear apoptosis.

Selenoprotein N related myopathy is caused by mutations on chromosome 1 in the selenoprotein N gene. These patients were originally described as having Mallory-body desmin-related myopathy. The term selenoprotein-related myopathy has been proposed to encompass patients with Mallory-body desmin-related myopathy, rigid spine syndrome, and minimulticore disease who have mutations in selenoprotein N. Selenoprotein N is a ubiquitously expressed glycoprotein that localizes to the endoplasmic reticulum and has an unknown function. Increased levels are present in myoblasts, with lower levels in myotubes or mature muscle fibers suggesting a role in early muscle development or in muscle cell proliferation or regeneration.

Laminopathy: Mutations in lamin A/C cause a wide variety of neuromuscular and more complex phenotypes. The pathogenesis is unknown (see LGMD1B).

Muscle biopsy of myofibrillar myopathies

See the list below.

• Light microscopy: Trichrome-stained tissue shows single or multiple areas of blue-red amorphous material described as hyaline structures, cytoplasmic bodies, or inclusions. Abnormal hyaline structures are congophilic and contain many degraded proteins. Oxidative enzymes and ATPase activity is absent in the areas containing inclusions. Rimmed or nonrimmed vacuoles are present in most biopsies. Focal muscle fiber degeneration or inflammation can occur.

• Electron microscopy: Z-disk streaming is an early feature. The main ultrastructural feature of all myofibrillar myopathies is disintegration of the Z disk and replacement of normal structures by homogenous irregular masses of electron dense material and granulofilamentous material. The normal myofibrillar architecture is replaced by fragments of thick and thin filaments and Z-disk material. Autophagic vacuoles contain abnormal sarcomeric proteins and other organelles.

• Immunohistochemical staining: Many proteins can be localized to over 50% of abnormal fibers noted on light microscopy: desmin, αβ-crystallin, myotilin, dystrophin, β-amyloid precursor protein, neural cell adhesion molecule, actin, cell division cycle kinase 2, plectin, and prion protein. Several other proteins are noted in less than 50% of abnormal fibers including α1-antichymotrypsin, gelsolin, ubiquitin, synemin, and nestin.