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

LGMD2E (β-sarcoglycan). Thirteen Class III studies were reviewed.^{e17,e23,e24,e40,e43,e144,e156,e164,e213,e219,e228-e230} β-Sarcoglycanopathy was reported in patients of Turkish, Italian, East Indian, Tunisian, white Brazilian, and African-Brazilian descent.^{e17,e23,e24,e40,e228,e229} The age at onset was 8–20 years (mean 6.9 years).^e17,e40,e213 Clinical features varied, including mild proximal muscle weakness (pelvic > shoulder girdle) in 6/12 patients and asymptomatic hyperCKemia with calf hypertrophy in 2/12 patients in one study, but a severe DMD-like picture was noted in 30%–70% of cases across reports.^{e23,e24,e213,e228} Loss of ambulation and wheelchair dependence was variable and seen in childhood or early adulthood.^e23,e40,e229 Patients may have calf hypertrophy^{e24,e213,e228} or scapular winging.^e24 Spinal scoliosis and Achilles contractures were rare.^e229 The type and severity of cardiac involvement varied across studies. Normal cardiac function was reported in some studies.^{e24,e213,e228} However, cardiomyopathy was apparent by echocardiogram in some studies.^e40,e43,e230 One patient died at age 21 of cardiac arrest in one series.^e23 Respiratory function was stated to be normal in all 12 patients in the Turkish study, although details were not mentioned.^e228 However, some patients developed ventilatory failure over time.^{e43,e156,e213}

CK levels were elevated 2–110 times normal (mean 14 times) across studies.^e17,e23,e213 Muscle imaging in one patient revealed severe fatty atrophy of the shoulder and pelvic girdle.^e144 Muscle biopsies revealed typical dystrophic features along with variable immunohistochemical staining to the sarcoglycans. A complete absence of immunohistochemical staining tended to be associated with earlier onset in one study^e17 and more severe phenotype in 2 studies.^e213,e219

LGMD2F (δ-sarcoglycan). Eight Class III studies were reviewed.^{e17,e23,e40,e43,e44,e213,e219,e231} Two of these studies had only one patient with LGMD2F each because they studied sarcoglycanopathies as a whole, but they were included because of the rarity of the disorder.^e17,e213 The Brazilian studies^{e23,e43,e219,e231} appear to describe the same patients, with a few additional patients in the later papers, and are reviewed together. The ethnicity of the described patients was East Indian, white Brazilian, and African-Brazilian.^e23,e40 The age at onset was 4–10 years.^{e17,e23,e213,e231} Eight of 9 patients had a severe DMD-like presentation with onset in early childhood and wheelchair dependence between 11 and 16 years. One patient was ambulatory for short distances at 19 years.^e23,e231 Two patients, one aged 13 years and the other aged 17 years, also had a DMD-like presentation with cardiac involvement (one presymptomatic cardiomyopathy and pulmonary hypertension, one dilated cardiomyopathy). Respiratory involvement was noted in both patients (one mild, FVC 76%; one moderate, FVC 54%).^e43 CK levels were elevated 5–24 times normal, with a 100-fold elevation in one case.^{e23,e40,e43,e213} Immunohistochemical analysis revealed total absence of all sarcoglycans in 3 patients and absence of α-, β-, and δ-sarcoglycan with partial deficiency of γ-sarcoglycan staining in one patient.^e44,e219
LGMD2G (telethonin). Three Class III studies were reviewed.^{e23,e232,e233} The family described in one of the studies^e23 was also included in another study.^e232 The initial description by the same authors was cross-referenced to obtain details of phenotype. Twelve patients from 3 Brazilian families were described. Onset was between 2 and 15 years. Patients had lower extremity distal-greater-than-proximal or proximal-greater-than-distal weakness. In the upper extremities, the weakness was more proximal than distal. Progression of the disease varied within families. Calf hypertrophy was seen in all affected patients of one family. CK levels were elevated from <10 to 30 times normal. Cardiac involvement was noted in 3/6 affected members of one family; the type of involvement was not specified. Muscle biopsy was remarkable for abundant rimmed vacuoles in 2 families.^e233
LGMD2H/TRIM32/sarcotubular myopathy. Four Class III studies were reviewed.^e234-e237 The initial families were of Hutterite descent.^e234,e237 The age at onset ranged from birth to the seventh decade of life. Most affected individuals had a limb-girdle pattern of weakness. Facial weakness, scapular winging, calf hypertrophy, Achilles contractures, neck flexor weakness, and exercise-induced myalgias were noted in a few patients (2/5,^e234 2/4,^e235 1/4^e236); neck flexors were weak and tendo Achilles contractures were noted in 2/4 patients.^e234-e236 Peripheral neuropathy with slowed nerve conduction velocity was seen in 3/5 patients in one study.^e235 ECG in 9 patients showed right bundle branch block in 2.^e235,e236 Respiratory function was normal in 1/4 patients and FVC was reduced to 41% in 1/4 patients.^e236

CK levels were normal to 20-fold elevated. The characteristic muscle biopsy feature was many small vacuoles more prominent in type II fibers, although in isolated cases type I fibers had more vacuoles. On EM, the smallest vacuoles were focal dilations of the sarcoplasmic reticulum and coalesced to form larger vacuoles, often with degeneration of their muscle membranes.^e234,e235

LGMD2I/fukutin-related protein (FKRP). Three Class I studies,^e57,e69,e238 one Class II study,^e239 and 27 Class III studies^{e17,e52-e56,e144,e149,e197,e240-e257} were reviewed. LGMD2I is a common cause of LGMD in white populations in northern Europe, Denmark,^e69 Italy,^e17 Germany,^e52,e257 Norway,^e57 and the United Kingdom,^e245 and has also been described in North America, Brazil,^e238 and in families of Tunisian and Bedouin descent. The mean age at onset was 12.7 years in one Class I study^e57 and 20.2 years in another Class I study.^e238 In Class III studies the age at onset ranged from 1.5–54 years, with means ranging from 9–23.2 years.^{e17,e52-e54,e149,e240,e242, e245,e256,e257} Weakness was symmetric and proximal, affecting the legs earlier and more severely than the arms, as reported in 2 Class I studies^e69,e238 and 11 Class III studies.^{e52-e54,e56,e149,e240,e242,e243,e245,e253,e257} In the legs, hip flexion and hip adduction were particularly affected,^{e69,e149,e240} whereas in the arms shoulder adduction^e149,e240 and elbow flexion^e69,e149 were especially affected. Facial weakness was reported in 3/18 in one Class III study^e256 but was not reported in one Class I study and 3 Class III studies.^{e56,e69,e240,e257} No dysarthria or dysphagia was reported, nor atrophy of any specific muscle groups. Scapular winging was noted in 3/20 patients,^e53 6/11 patients,^e240 and 3/7 patients.^e56 Contractures did occur but were not a prominent feature; occasional ankle contractures were reported in 2/7,^e56 2/16,^e245 and 2/27 homozygotes and in 5/11 compound heterozygotes (Class I).^e69 One Class III study reported contractures of the tibialis anterior (17/18), hips (3/18), knees (4/18), and elbows (3/18),^e256 whereas no contractures were observed in other series.^{e240,e242,e243,e257} Calf hypertrophy was common.^{e52-e56,e69,e238,e242,e245,e246,e249,e256,e257} Hypertrophy was also noted in some patients in the brachioradialis,^e54,e245 the thigh,^e256 and the tongue.^{e53-e55,e69,e240,e245,e246,e257}

Dilated cardiomyopathy was common clinically or by echocardiogram.^{e52,e53,e55,e69,e197,e239,e240,e245-e249,e252,e253,e255-e257} One study using cardiac MRI disclosed myocardial fibrosis in 4/7.^e197 In this study, age, muscle strength, ability to ambulate, severity of dystrophic changes on muscle biopsy, and age at symptom onset did not correlate with cardiac involvement. Respiratory dysfunction was common, with a reduced FVC in a restrictive pattern observed in 2 Class I studies^e57,e69 and in 7 Class III studies.^{e17,e53,e55,e56,e240,e243,e245} FVC was reduced 45%/62%/66%/82%/50% of the time,^{e53,e240,e243,e245,e253} often moderately to severely; respiratory support in the form of noninvasive positive pressure ventilation or assisted ventilation was necessary in 20% to 25% of patients in the Class I studies^e57,e69 and in up to 45% of patients in the Class III studies.^{e53,e55,e57,e156,e240,e243,e245,e256} Cognitive dysfunction was not mentioned in most studies, but was specifically noted to be absent in 2.^e53,e242 Formal cognitive testing was performed in 2 studies.^e240,e253 In one, 10/11 patients had normal verbal/written memory, and only 1/11 had a low IQ.^e240 In the second, mild impairment of executive function and visuospatial planning without a global reduction in IQ was common.^e253

CK levels were almost always more than 10-fold elevated, as reported in 2 Class I studies^e69,e238 and 12 Class III studies.^{e17,e52-e55,e240,e242-e245,e251,e257} Episodes of myoglobinuria were reported in 5/14 in one Class III study^e250 and in 7/26 in another.^e253 MRI studies of the legs revealed abnormal signal and fatty infiltration of the psoas, gluteus maximus, and thigh adductors, with relative preservation of the anterior thigh.^{e144,e149,e240} The gracilis and sartorius muscles were involved later and were sometimes spared or even hypertrophied.^e149 MRI studies of the arms revealed abnormalities in the serratus, subscapularis, infraspinatus, and supraspinatus, with relative preservation of the triceps; the deltoids and biceps were either spared or involved later. Muscle biopsies were notable for dystrophic changes, including necrosis, evidence of degeneration and regeneration, variation in fiber size, internal nuclei, and fibrosis.^{e56,e69,e240,e245} Reduced α-dystroglycan immunoreactivity was observed.^{e54,e241,e244,e257} Rimmed vacuoles, inclusions, and inflammation were absent.
LGMD2J/Udd distal myopathy/hereditary myopathy with early respiratory failure (titin). Ten Class III studies were reviewed.^e258-e267 An additional article referenced in Udd^e258 was also reviewed for clinical details.^e268 There are 3 major clinical phenotypes of titinopathies: autosomal recessive LGMD2J, autosomal dominant distal myopathy, and autosomal dominant hereditary myopathy with early respiratory failure (HMERF).
LGMD2J. LGMD2J has been reported mainly in Finnish and French populations.^{e258,e259,e264} Onset of weakness was in the first 3 decades of life, but one Finnish patient was noted to have initial delayed motor milestones that subsequently stabilized, only to develop weakness around age 10 years.^e264 All patients had severe proximal muscle weakness and atrophy involving the pelvifemoral and scapulohumeral muscles, with milder distal weakness (anterior tibial, gastrocnemius, forearm, and hand), and developed severe generalized weakness and wheelchair dependence over the subsequent 20 years. The face was spared, and scapular winging was described in only one patient. Muscle hypertrophy was not noted. One Finnish patient with onset in the early school years died at age 64 years from respiratory failure; no details were provided. At autopsy the heart was normal without signs of heart failure. One of the 7 patients initially described had atrial fibrillation, and another patient had “occasional cardiac arrhythmia.” Echocardiogram performed in 3/7 patients was normal. In contrast to this presentation, an early-onset recessive myopathy with severe cardiomyopathy characterized by delayed milestones and predominantly lower extremity proximal and distal weakness (but also involving proximal upper extremity, trunk, and face weakness and ptosis) has been described in Moroccan and Sudanese patients. In these 5 patients, pseudohypertrophy of the thighs and calves contrasted with atrophy of the upper limbs. Spinal rigidity and moderate joint contractures appeared in the first decade. The muscle disease was mild, but a progressive, severe dilated cardiomyopathy developed in all 5 patients, with rhythm disturbances. Sudden death occurred in 2 at 19.5 and 17.5 years.^e267 CK elevation was usually moderate (3–5 times normal); one patient with >10-fold elevation was reported. Muscle MRI was abnormal in all 22 patients in one study. Eight of the 22 patients had fatty replacement of leg muscles (anterior compartment only in 6, both anterior and posterior compartments in 2). Fourteen patients had both thigh and leg involvement. The hamstrings were uniformly involved: quadriceps in only 3 patients, gracilis in one patient. The lateral leg compartment was usually spared, being involved in only one patient at a late stage of the disease.^e263 Muscle biopsies revealed dystrophic features, and rimmed vacuoles were usually absent or rare.^{e258,e264,e268}
Udd distal myopathy. Distal myopathy due to titin mutations has been described in Finnish, French, and Belgian populations.^{e259-e262,e264} In contrast to the LGMD phenotype due to the same protein defect, the age at onset of distal myopathy is in the fifth to seventh decade of life. The muscle weakness predominated in the anterior tibial leg compartment in all patients, with mild weakness of the pelvifemoral and gastrocnemius muscles in a few patients (6/41 and 2/41). Atrophy of the anterior tibial muscles was noted in 26/41 and of the gastrocnemius in 1/12 patients.^e259,e260 The tibialis posterior and peroneus longus were also mildly weak in one patient.^e262 CK levels were normal or mildly elevated (30%–64%).^{e260,e261,e263} One Belgian patient had CK levels >10 times normal.^e262 Cardiac involvement was absent.^e261 CT scan revealed fatty infiltration in the anterior tibial muscles in 7/9 patients and patchy involvement in the gastrocnemius and pelvic muscles in one patient each.^e258 In one Belgian patient, fatty degeneration of the tibialis anterior and extensor digitorum longus muscles, and to a lesser extent the gluteus medius and minimus muscles, was noted.^e262 Muscle biopsy revealed rimmed vacuoles in 28% of patients in the largest study.^e260
Hereditary myopathy with early respiratory failure. HMERF recently has been reported to be caused by mutations in titin in Swedish^e265 and English^e266 families. The phenotype merges with that of LGMD2J and Udd distal myopathy. Like Udd, it is inherited in an autosomal dominant fashion and has an early predilection for the anterior compartment of the distal lower extremity leading to progressive foot drop. However, it tends to affect patients earlier in adulthood (range 18–71 years) and may affect the proximal muscles (legs greater than arms), as seen in LGMD2J. The majority of patients have prominent calf hypertrophy. Ventilatory muscle weakness gradually develops over time; however, cardiomyopathy is not seen.

One report noted that the most commonly affected muscles on MRI were the semitendinosus (20 of 21 subjects), the peroneus longus (16/21), and the obturator externus (15/21).^e266 In the other series, MRI revealed fatty replacement mainly of the iliopsoas, rectus abdominis, obturatorius, and gluteus minimus muscles. Severely affected muscles in the thighs were the semitendinosus, gracilis, sartorius, vastus lateralis, intermedius, and medialis muscles, whereas the adductor longus muscles were relatively spared. In the lower legs, there was fatty replacement predominantly in the anterior and lateral compartments. Muscle histopathologic features included rimmed vacuoles, eosinophilic inclusions, desmin deposits, and extensive myofibrillar lesions with marked Z-disk alterations on EM resembling those described in MFM; thus, titin mutations of the HMERF phenotype should be added to the differential diagnosis of MFM.

LGMD2K (protein-O-mannosyltransferase 1 or POMT1). One Class III study^e59 evaluated 3 patients with LGMD, ethnicity unspecified. Onset of disease was in infancy in 2 patients and at 3 years in one patient. Details of muscle involvement were not described. Muscle hypertrophy was noted in all 3 patients, but muscles involved were unspecified. Other phenotypes associated with POMT1 mutations in this study included WWS (1), MEB/FCMD (1), and CMD-MR (3). CK levels were elevated >10 times. All patients had microcephaly and intellectual disability (mental retardation). Brain MRI showed minimal white matter changes in one patient and normal results in 2 patients. This study also included one patient with LGMD2K described by the authors previously; the studies were therefore reviewed together.^e244
LGMD2L (anoctamin-5). Four Class III studies were reviewed.^{e61,e269-e271} Earlier reports of these families were also reviewed for clinical details.^e272,e273 The disorder was initially reported in patients of French Canadian, Finnish, or Dutch descent, but subsequently in Australian, Spanish, Italian, German, and Afghan patients. Patients manifested with a limb-girdle pattern of weakness (LGMD2L) or with distal weakness resembling Miyoshi myopathy. The latter has been referred to as Miyoshi myopathy type III (MM3), but these phenotypes often overlap over time. Patients also presented for evaluation of hyperCKemia.^{e61,e269-e271} One study included 7 patients with LGMD2L and 5 patients with distal myopathy.^e269 Another study reported long-term follow-up of 2 patients of Finnish descent with MM3 as reported in the first study.^e270 A third study found 25 patients with ANO5 mutations out of a cohort of 101 patients with recessive LGMD, calf weakness, or hyperCKemia.^e61 The final study reported 4 patients: one with LGMD, one with distal myopathy, one with hyperCKemia, and one with weakness and atrophy of the quadriceps and medial calves.^e271 Age at onset ranged from 20–55 years (mean 34.4 years) in LGMD2L and 20–51 years (mean 36 years) in patients presenting with distal myopathy. Five of 7 patients (71%) with LGMD2L had weakness of the pelvic and scapular girdles. One patient also had mild weakness of the calf muscles and another of the tibialis anterior. One patient had atrophy and weakness of the right biceps brachii and right posterior thigh atrophy on examination initially, despite involvement of lower extremity muscles on MRI, and developed asymmetric hamstring weakness after 2 years.^e61 Asymmetric atrophy of the biceps and quadriceps was noted in many patients across reports. Patients with distal myopathy had early calf weakness with difficulty in toe walking; the calf muscles were noted to be atrophic, often asymmetrically. However, some patients had calf hypertrophy early in the course before atrophy ensued. Atrophy or weakness of the quadriceps was noted in some patients with LGMD and some patients with distal myopathy.^e269-e271 Atrophy was also appreciated later in the course in the biceps and pectorals.^e270

CK levels were elevated 8- to >20-fold. Five patients across the studies had asymptomatic hyperCKemia noted in the fourth decade or later, although one had calf hypertrophy. Echocardiography, ECG, and Holter monitoring were normal in all the patients who were tested across studies.^{e61,e269-e271} No pulmonary abnormalities were noted in one study.^e61 In 2 patients, muscle MRI showed atrophy and fat replacement of the long head of the biceps brachii. Muscles most involved in the legs were the medial gastrocnemius, adductor magnus, hamstrings, tensor fasciae latae, and to a lesser extent the quadriceps, often asymmetrically.^e61,e273 In one of the 2 patients with distal myopathy who were followed long-term, initial muscle MRI at disease duration of 10 years showed fibrofatty degeneration in the gastrocnemius. Subsequent studies revealed similar changes in the soleus and biceps brachii. The other patient with distal myopathy also had asymmetric changes in the adductor magnus, vastus lateralis and intermedius, and tensor fasciae latae.^e270 Muscle biopsies revealed myopathic/dystrophic changes. EM revealed multifocal disruption of the sarcolemmal membrane.^e61,e270

LGMD2M (fukutin). Three Class III studies were reviewed.^{e59,e244,e274} There were only 5 patients from 3 families reported across these studies. The disorder was described in one Israeli family in one study and in the child of Jewish and East Indian parents in another study. The ethnicities in the other cases were unspecified.^e274 The onset of illness was from 4 months to 4 years of age. The phenotype was described as LGMD without intellectual disability (mental retardation) in 2 studies, with lower extremities more affected in 2/3 cases and upper extremities more affected in 1/3 cases. Muscle hypertrophy was described in 4/5 cases in one study, but the muscle group was not specified.^e59 In another study, 2/3 patients had lateral calf hypertrophy.^e274 Unspecified contractures were reported in 2/5 patients.^e59 Cognitive function as defined by IQ was normal in all 5 patients, and brain MRI showed mild hydrocephalus in one patient and normal results in 2 patients. Increased weakness with a febrile illness was reported in 2 patients. All patients had CK levels more than 10 times normal. The muscle biopsy was significant for the presence of inflammation with macrophages, CD8+ lymphocytes, and major histocompatibility complex class I antigen upregulation in 2 cases.^e59,e274
LGMD2N (protein-O-mannosyltransferase 2 or POMT2). Two Class III studies^e59,e244 and one Class IV study^e275 were available. The Class IV study was retained because of the rarity of the disorder. One Class III study was excluded because it reported only patients with MEB and CMD, which are not addressed in this guideline.^e244 The other 2 studies describe only one patient each with LGMD2N.^e59,e275 One patient presented with developmental delay at 18 months and had an LGMD phenotype with learning difficulties at age 20 years.^e59 Hypertrophy was mentioned but not described further. Cardiac evaluation revealed right bundle branch block. The second patient was found to have elevated CK levels incidentally. She had calf hypertrophy. At age 5 years, scapular winging, mild proximal lower extremity weakness, and lordosis were evident. Intellectual development and brain MRI were normal. CK levels were >10 times normal. Cardiac evaluation, not described further, was normal. Muscle biopsy revealed dystrophic changes with inflammatory infiltration of macrophages and lymphocytes.
LGMD2O (protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase or POMGNT1). Two Class III studies^e59,e244 and one Class IV study^e276 were reviewed. Each study described only one patient, but all studies were retained because of the rarity of the disorder.^{e59,e244,e276} Age at onset was 12 years in one case^e59 and 21 in another.^e276 All 3 patients had a limb-girdle pattern of weakness, with neck, hip girdle, and shoulder abductors particularly affected in one.^e276 Hamstrings and deltoids were atrophic; calves and quadriceps were hypertrophic.^e59,e276 Contractures were absent in one patient and were not described in the others.^e59 Cognitive function was normal in all 3 patients. CK levels were elevated >10 times above normal. Cardiac and respiratory involvement were not described. Muscle biopsy in one patient revealed basophilic fibers, some of which were granular, with vacuoles.^e276 In another study, the patient with the more severe CMD phenotype was noted to have a severe reduction in the glycosylation of α-dystroglycan compared with the patient with the milder LGMD phenotype.^e244