Evidence-based Guideline: Diagnosis and Treatment of Limb-Girdle Muscular Dystrophy

Clinical Questions 2, 3, and 4 are addressed together in the following section because they evaluate different aspects of the phenotype of LGMD: 2. In patients with muscular dystrophy, what is the association between specific clinical features, degree of CK elevation, and subtypes of these disorders? 3. In patients with LGMD or distal muscular dystrophy, what is the association between specific muscle biopsy features and subtypes of these disorders, in particular rimmed vacuoles, inflammation, and inclusions? 4. How often do patients with muscular dystrophy and its specific subtypes have significant respiratory abnormalities (FVC <50% predicted), cardiac abnormalities (EF <50%, evidence of hypertrophic cardiomyopathy or generalized wall motion abnormality, arrhythmias, conduction defects), or bone loss (osteoporosis or bone mineral density 2.5 SD below peak bone mass, osteopenia or bone mass of 1.0–2.5 SD below peak bone mass)?

We did not include EDMD3 and EDMD4 due to SYNE1/nesprin-1 and SYNE2/nesprin-2 mutations because there was not enough evidence for a detailed assessment of phenotypes. No studies were available evaluating bone loss in LGMD.

LGMD1A (myotilin). This is discussed in the section on MFM.
LGMD1B (lamin A/C). There were 47 Class III studies.^{e12,e15,e16,e75-e118} Mutations in the LMNA gene result in diverse phenotypes, including LGMD1B, AD-EDMD, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibuloacral dysplasia, Hutchinson-Gilford progeria syndrome, restrictive dermopathy, and a form of dominant-intermediate Charcot-Marie-Tooth syndrome (CMT). Phenotypic variability has been reported even in kinships with the same mutation.^e95,e96,e103 Onset was congenital to adult life (fifth decade) with humeroperoneal (AD-EDMD) and limb-girdle phenotypes.

The AD-EDMD phenotype was characterized by proximal muscle weakness in the upper extremities with preferential involvement of humeral muscles, both proximal and distal weakness in the lower extremities, elbow and ankle contractures, and spine rigidity (cervical > thoracic and lumbar). Of note, in some series contractures were seen only late in the disease course or not at all, which is different than X-linked EDMD, in which contractures are invariably present early in the disease course.^{e75,e81,e88,e106,e116,e118} Occasional patients had pseudohypertrophy of the calves or scapular muscles. Atrophy was appreciated in humeral muscles (biceps > triceps) and below the knees, particularly in the medial gastrocnemius.^e75 Scoliosis of the thoracic spine was also noted in addition to rigidity. Scapular winging was uniformly seen and was correlated with the severity of weakness.^e75

The LGMD phenotype was characterized by proximal leg-greater-than-arm weakness, but often with preferential involvement of humeral muscles. Again, flexion contractures of elbows and Achilles tendons were usually minimal or developed late in the course.^{e106,e116,e118} Cardiac abnormalities (arrhythmias, conduction defects, and dilated cardiomyopathy) were common and may be the only presenting feature of laminopathy. Pacemakers or intracardiac defibrillators were commonly implanted because of arrhythmias and the risk of sudden cardiac death. Cardioembolic stroke occurred because of associated arrhythmias. Many patients also required cardiac transplantation because of congestive heart failure (CHF) from dilated cardiomyopathy.

CK levels were normal or slightly elevated—most series had a CK average of <5 times the upper limit of normal (ULN). EMG usually revealed nonspecific myopathic features. MRI/CT demonstrated fatty infiltration in the posterior compartment of the thigh and calves.^e80 The medial gastrocnemius and soleus appeared to be preferentially involved in laminopathies in some studies, even in patients who had only cardiac abnormalities without muscle weakness clinically.^e77,e84,e85 However, other studies have found both the lateral and the medial gastrocnemius to be involved equally.^e80 In both AD-EDMD and LGMD1B phenotypes, other muscles that were involved included the glutei, quadriceps, adductor magnus, and hamstrings.^e77,e106 One study attempting to differentiate AD-EDMD and Bethlem/Ullrich myopathies (collagen VI disorders), which can also be associated with contractures, found that the quadriceps were relatively spared and the hamstrings were more severely involved in AD-EDMD.^e80 Muscle biopsies revealed nonspecific myopathic features (e.g., variability in fiber size with or without necrotic and regenerating muscle fibers and increased endomysial connective tissue). One series reported endomysial inflammation in young children who were initially felt to have an inflammatory myopathy.^e106 Biopsies have shown normal or reduced immunostaining for lamin A/C^e79,e81,e83 and laminin beta-1.^e90 Rare rimmed vacuoles were reported.^e78 On EM, nuclear alterations in about 10% of the preserved muscle fibers with peripheral heterochromatin loss or detachment from the nuclear envelope and interchromatin texture alterations have been reported.^e113

As mentioned, mutations involving lamin A/C have also been associated with dominant-intermediate CMT (not reviewed in this manuscript),^e119 and some patients have signs of both a myopathy and a neuropathy on EMG and muscle biopsy.^e93
LGMD1C (caveolin-3). Thirteen Class III studies were reviewed.^e120-e132 Patients have been reported from the United Kingdom, Italy, Spain, Sweden, and Japan.^{e120-e122,e130,e132} Age at symptom onset ranged from 5–81 years. The clinical phenotypes varied. Intrafamilial variation was not uncommon, and patterns of involvement included proximal arm and leg weakness, distal weakness, rippling muscle disease, or asymptomatic hyperCKemia. Prominent muscle cramps (spontaneous, postexercise, or myalgias) were noted in most patients.^e120-e122 In 3 studies, distal hand weakness and atrophy was noted in 9/23 patients.^{e121,e122,e132} In one series, 3 of 10 patients presented with toe walking but did not have distal leg weakness.^e121 Rippling muscle disease was the sole manifestation of caveolinopathies in several families. One series reported generalized percussion-induced rapid contractions (PIRCs) in the face, neck, and extremities as a constant feature, but actual rippling muscles were seen less frequently (12/19).^e131 In a study of 23 patients from a large Swedish family, all except 2 presented with muscle stiffness.^e130 Percussion-induced muscle mounding and PIRCs were noted in all 23 patients, muscle rippling in 12, calf hypertrophy in 9, and generalized hypertrophy in 2, whereas weakness was not observed. Rhabdomyolysis and myoglobinuria were rarely noted (1/10 patients in one study, 4/19 in another).^e121,e131 Most patients, even when asymptomatic, exhibited calf hypertrophy.^e120,e121 Six of 7 in one family had pes cavus.^e122 Scapular winging, facial weakness, and rigid spine were not seen. Mild contractures were seen in one study (finger flexor and hamstrings in 2/10 patients).^e121

CK levels were elevated 3–30 times above normal.^{e120-e122,e130} Four of 7 patients in one family had asymptomatic hyperCKemia (2 patients subsequently developed weakness in the hands 2 decades later).^e122 Rare patients with cardiac involvement have been described, although clinical cardiac manifestations are distinctly uncommon.^e123,e124 Muscle biopsies were normal or mildly myopathic or dystrophic, without specific diagnostic features.^e121 Reduced staining for caveolin-3 on the sarcolemma on immunohistochemistry has been reported.^{e121,e122,e130,e132}

LGMD1D (DNAJB6). The nomenclature of LGMD1D and LGMD1E has been confusing in the literature. AD LGMD linked to chromosome 7q36 has been termed LGMD1D as well as LGMD1E. In this guideline, we refer to 7q36-linked LGMD with mutations in the DNAJB6 protein as LGMD1D. Three Class III studies were reviewed.^e133-e135 Two studies describe the same Finnish families and are reviewed together.^e133,e134 One of the studies^e134 also includes 2 Italian families and 2 US families, whereas the third^e135 describes 2 families from the US (ethnicity not mentioned). Disease onset was in the third to sixth decade, except for 2 US patients from different families with onset at ages 14 and 18 years. All patients had moderate to severe proximal muscle weakness in the lower extremities; often the quadriceps was relatively preserved compared to the hamstrings.^e135 Proximal upper extremity weakness was absent or milder than lower extremity weakness. In one study, distal lower extremity weakness involving the posterior compartment more than the anterior compartment was noted in all 9 families.^e134Another study reported one family in which 3 affected members had distal muscle atrophy and weakness in the legs as well as the arms and mild to moderate proximal weakness.^e135 Some patients had heel cord contractures. Cardiorespiratory involvement was notably absent.

Serum CK levels ranged from normal to 10-fold elevated but averaged about 2–3 times the ULN in most cases. Muscle biopsy in all studies revealed a myopathy with rimmed vacuoles, features suggestive of an MFM in 7/9 families.^e134

LGMD1E (desmin). This is discussed in the section on MFM.
LGMD2A (calpain-3). One Class I^e136 and 36 Class III^{e17,e19,e22-e26,e28,e30,e33,e34,e85,e137-e160} studies were reviewed. Most cases had onset between 5 and 20 years of age. The mean age at onset across studies spanned 9.8–21.8 years,^e138,e149 but the range was broad, from 2–65 years.^e30,e33 Approximately 20%–50% of patients eventually became wheelchair dependent,^{e136,e137,e140,e148} and the mean time from disease onset to loss of ambulation ranged from 9.4–23.6 years.^e140,e148 Onset of weakness occurred in the lower extremities alone in 80%, in the lower and upper extremities in 13%, in the upper extremities alone in 3%, and with isolated hyperCKemia in 4%.^{e25,e148,e150} Hip extensor, hip adductor, and knee flexor muscles were most affected.^{e33,e148,e149,e152,e157,e158} Facial weakness was uncommon; it was reported in less than 5% of cases (4/96 cases).^{e25,e138,e148,e150,e152} Calf hypertrophy was seen in 51/126 (40%) cases.^{e23-e25,e33,e148,e150,e157} However, in the Class I study, calf hypertrophy was described as rare.^e136 Scapular winging often was not present at diagnosis but over time became nearly universal. Overall, scapular winging was present in more than 80% of patients (78/95).^{e24,e33,e34, e150,e152,e157} Dysphagia was not present in any of 51 patients across 3 studies.^{e138,e148,e157} Likewise, dysarthria and hoarseness of voice were seen in none of 20 patients.^e148 Contractures occurred in 25% (18/71) of patients and predominantly affected the ankles.^{e17,e30,e33,e34}

There was essentially no symptomatic cardiac involvement. Across all studies, 9% (17/198) of patients had abnormalities on cardiac testing. In a Class I study, 7/35 patients had ECG abnormalities.^e136 The abnormalities included nonspecific conduction abnormalities in 5/35 patients and repolarization abnormalities in 2/35 patients. No significant abnormalities were found in the 29 patients who underwent echocardiography.^e136 None of the patients in the Class I study had cardiac symptoms. Eight Class III studies evaluated cardiac testing.^{e17,e25,e138,e148,e150,e152,e156,e157} Five percent (8/163) of patients had ECG changes, including premature atrial or ventricular beats, ST segment elevations, atrial fibrillation, atrioventricular conduction block, or bundle branch block^{e25,e150,e156}; 2% (4/163) had abnormalities on echocardiography, including mild anterior cardiac wall dysfunction, mildly impaired left ventricular function, slight diminution of left ventricular contractility, and a left ventricular ejection fraction (LVEF) slightly below 50%.^{e25,e148,e150,e156} Four Class III studies found no abnormalities on ECG or echocardiography.^{e17,e138,e152,e157} Significant respiratory involvement was very infrequent until late in the disease course. Seven percent (8/117) of patients had a restrictive pattern over multiple studies,^{e17,e136,e138,e150,e156,e158} but 12/20 had an FVC reduced to 30%–50% of normal late in the disease course.^e148 Cognitive dysfunction was not reported (0/75 patients).^{e17,e25,e148,e157}

MRI demonstrated fatty and fibrous replacement in the gluteal, hamstring, adductor, soleus, and medial gastrocnemius muscles.^{e85,e144,e149,e152,e155} CK levels were most often more than 10 times the ULN, with a mean of 19 times the ULN and a range of normal to 110 times the ULN. CK levels were elevated >10 times the ULN in 90/146 (62%), 2–10 times the ULN in 50/146 (34%), and were normal in 6/146 (4%).^{e19,e22,e24,e25,e30,e33,e34,e136,e142,e152,e153,e157,e158} On muscle biopsy, lobulated fibers were frequently seen: 33/47 biopsies (70%) on NADH-stained sections.^e25,e26,e148 Rimmed vacuoles and inclusions were not features, but inflammation, including eosinophils, may be seen on some biopsies.^{e30,e140,e150,e160} Western blot analysis of muscle calpain-3 in patients with LGMD2A can show a total or partial deficiency or no deficiency. Furthermore, calpain-3 may be reduced in muscle from patients with LGMD2B and patients with LGMD2J, whereas dysferlin immunostaining may be reduced on muscle biopsies from patients with LGMD2A.^e150 Thus, genetic testing is required to confirm all cases.

LGMD2B/Miyoshi myopathy (dysferlin). One Class II study^e161 and 54 Class III studies^{e17,e23,e24,e137,e145,e147,e149,e155,e162-e207} were reviewed. The mean age at onset has been reported as 18.4–31.9 years across reports, with most studies falling between 19 and 23 years. The range for age at onset was 3–60 years, with most studies describing a range of 10–35 years.^{e17,e23,e24,e145,e147,e149,e162-e164,e166-e168,e170,e171,e173- e176,e178,e182,e183,e185,e188-e191,e193,e195,e197,e198,e200-e205} The dysferlinopathies involve 2 principal clinical phenotypes^{e169,e192,e200,e206} that can merge over time.^e167,e168 The Miyoshi phenotype is characterized by distally predominant weakness principally involving the posterior compartment (calf), as described in 17/19 dysferlinopathies,^e162 14/29,^e163 18/25,^e166 21/26,^e147 9/14,^e167 11/36,^e168 4/8,^e177 2/9,^e178 46%,^e188 and in several other series.^{e165,e170,e172,e174-e176} The second phenotype is characterized by a limb-girdle pattern of weakness, accounting for 15/29 dysferlinopathies,^e163 3/25,^e166 8%,^e147 7/9,^e178 23/33 (70%),^e23 22/36 (61%),^e168 40%,^e188 “most” of 37,^e17 and 5/14^e167 in various series. There can be preferential weakness of the biceps in the arms followed by lesser weakness of the deltoid and triceps^{e149,e163,e167,e173,e205}; the weak biceps and relatively preserved deltoid can produce a “deltoid bulge.”^e173 Even in patients presenting with a “limb-girdle” phenotype, the gastrocnemius muscle was still notably atrophic, particularly the medial aspect.^{e23,e167,e168} Rare patients presented with anterior leg (tibialis anterior) weakness and foot drop, occurring in 3/8,^e177 2/19,^e162 2/30,^e188 4 cases in one family,^e207 and 2/11^e203cases. Weakness was commonly asymmetric.^e167,e168 One study described a “diamond on the quadriceps” bulge, affecting 21/31 patients with dysferlinopathy who presented with both the Miyoshi and limb-girdle pattern of weakness.^e170 Calf atrophy was typical,^e189,e195 and atrophy of the anterior shin was sometimes seen.^e195 Calf hypertrophy and pain have been reported early in the course in 5/29,^e163 1/3,^e24 3/14,^e167 5/39,^e23 and 6/21^e173 patients with dysferlinopathy. Partial atrophy of the biceps has been observed in both the Miyoshi and limb-girdle phenotypes,^e189 and selective atrophy of the shoulder girdle muscles producing a “double calf’s head on a trophy” sign has been described.^e195 Scapular winging, dysphagia, dysarthria, and contractures were not reported. Some dysferlinopathy patients can present with asymptomatic hyperCKemia or recurrent myoglobinuria^e192; symptomatic carriers have also been described.

Respiratory and cognitive dysfunction have not been described. Cardiac involvement was uncommon.^{e96,e162,e168,e178,e189,e191,e201,e205} Nonspecific ECG changes have been reported in some patients.^e17,e161 Echocardiography has demonstrated left ventricular hypertrophy or reduced EF in rare patients.^{e17,e161,e204} Subclinical cardiac fibrosis or diastolic dysfunction was reported in a few patients by cardiac MRI.^e197 Cardiac muscle biopsies in 2 patients revealed absence of dysferlin from the sarcolemma with perivascular and interstitial fibrosis.^e204

Muscle CT^e175,e193 and MRI^{e149,e155,e165,e167,e172,e189,e191,e203} reported preferential involvement of the posterior compartments of the distal and proximal legs. By MRI, the pattern of muscle involvement appeared similar for patients with both the Miyoshi and limb-girdle phenotypes,^e189 with early involvement of the gastrocnemius and thigh adductors. CK levels were typically markedly elevated,^{e17,e162,e165,e167,e168,e171,e172,e173,e175,e177,e178,e182,e183,e185,e189,e191,e193,e200,e201,e204,e205,e206} up to 10–30 times,^e163 23–40 times,^e24 36 times,^e23 20–100 times,^e174 or 15–30 times^e185 the ULN. Muscle biopsies were characterized by dystrophic changes.^{e145,e162- e167,e169,e171,e173,e175,e177,e178,e181,e183,e184,e193,e201,e202,e205-e207} Perivascular and/or endomysial inflammatory infiltrates were common.^{e162,e164,e166,e169,e171,e173,e181,e183,e184,e187-e189,e193,e201,e202} Amyloid deposits were detected by Congo red staining in blood vessel walls and in perimysial connective tissue in one study^e173; 4/6 specimens in a second study also contained sarcolemmal and interstitial amyloid deposits in skeletal muscle.^e200 Absence or reduction of dysferlin by immunofluorescence and/or Western blot staining was characteristic.^{e17,e147,e166-e169,e176,e177,e182,e183,e192,e193,e196,e198,e200-e202} Rimmed vacuoles and inclusions were not a common feature, although a single study described rimmed vacuoles in 4/14 patients with a Miyoshi phenotype.^e188
LGMD2C (γ-sarcoglycan). Two Class I^e208,e209 and 15 Class III^{e17,e23,e41,e43,e210-e220} studies were reviewed. This dystrophy occurs worldwide but may be more common in Roma/Gypsy^e209,e216 and Tunisian populations.^e208,e220 Onset occurred in the early childhood to adult years, but most series had an age at onset in early childhood, with a range of 1–13 years (mean 6.1 years) in one Class I study^e208 and a range of 2–8 years in the other Class I study.^e209 However, other series had slightly later ages of onset, ranging from 2–23 years (mean of ~11 years).^e17,e23 Patients presented with proximal leg weakness greater than proximal arm weakness. Scapular winging, calf hypertrophy, macroglossia, ankle contractures, and scoliosis were common, at least in the Roma populations with the disorder.^e209,e216 Age at loss of ambulation ranged from 11–37 years (mean 16 years) in one Class I study^e208; 81% of patients were wheelchair dependent by age 14 years in the other Class I study.^e209 Normal intelligence was noted in 2 small series.^e41,e215 The largest series of 68 patients with LGMD2C found no patient with clinically relevant cardiomyopathy.^e216 Most small studies reported that patients had normal ECG and echocardiography.^{e41,e210,e218} In one study, ECG and echocardiogram were normal in 2/3 patients and revealed abnormal contraction of the interventricular septum in 1/3^e217; 4/10 patients had dilated cardiomyopathy in another study.^e211 Ventilatory muscle weakness requiring noninvasive ventilation developed in 2/5,^e217 but respiratory function was normal in other small series.^e43,e215 CK levels were elevated 4–100 times normal in most series.^{e17,e23,e208,e211-e213,e216} Muscle biopsies revealed markedly reduced or absent γ-sarcoglycan on immunohistochemistry, whereas immunohistochemistry of other sarcoglycans was more variable (normal or moderately reduced).^{e23,e208,e210,e211,e212,e216,e219}
LGMD2D (α-sarcoglycan). Eighteen Class III studies were reviewed.^{e17,e19,e23,e43,e145,e149,e156,e164,e213,e218,e219,e221-e227} LGMD2D has been described in French, Italian, Moroccan, Algerian, Finnish, German, white Brazilian, and African-Brazilian families.^{e19,e23,e221,e223,e225,e226} Symptom onset occurred at 1–30 years of age (mean 10.5 years). The legs were weaker than the arms. The glutei and hip adductors were involved more than the psoas and the thigh muscles; the quadriceps and hamstrings were involved equally. Distal lower extremity weakness was minimal and, if present, involved the tibialis anterior. In the upper extremity, the deltoids, serratus anterior, trapezius, and latissimus dorsi and rhomboids were involved early. The infraspinatus was affected more than the supraspinatus, and the biceps was involved but less so than the infraspinatus and supraspinatus; the triceps, pronators, and supinator were spared. Trunk extensors were involved but neck flexors only minimally so. Scapular winging, thigh atrophy, and calf hypertrophy were seen in the majority of patients across studies.^{e213,e221,e223} The weakness varied widely in severity, and intra-/interfamilial variation was common. In one study, 4/24 patients lost ambulation before age 16, whereas 9 were ambulatory, 3 of whom were aged 50 or older (age range 6–56 years, mean 34.4 years, although the 2 youngest patients had been followed only 1 and 3 years).^e213 Intellectual development was noted to be normal in all 12 cases in one study.^e226 CK levels were elevated in all patients but varied widely from 2–100 times normal.^{e17,e19,e23,e213,e221,e223,e227}

Symptomatic cardiomyopathy was not common, at least early on. ECG revealed nonspecific abnormalities in a minority of patients.^e156 Echocardiography was usually normal,^e156,e213 although a minority had findings of a dilated cardiomyopathy.^e218,e226

Severe ventilatory muscle weakness has been reported in up to one-third of patients.^e43,e213

CT scan of the lower limbs revealed early involvement of pelvic muscles, especially the glutei and posterior and deep anterior thigh muscles.^e221 The medial femoral muscles were spared in the mildly affected patients. Hypertrophy of rectus femoris, sartorius, and gracilis was observed in a mildly affected patient. Distal muscles were spared except in the severe cases, when the tibialis anterior was involved. Muscle MRI in 2 patients demonstrated more severe involvement of the quadriceps than the posterior thigh muscles, with hypertrophy of the gracilis and sartorius; one of these patients also had changes in the soleus, gastrocnemius, and peroneus longus.^e149 Muscle biopsies revealed variable immunohistochemistry staining of the sarcoglycan complex.^{e219,e225,e226}