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

LGMD2P (α-dystroglycan). One Class IV study^e277 reported a 16-year-old Turkish female with LGMD. The clinical features were reported in an earlier study.^e278 The patient was born of consanguineous parentage. Age at onset was 3 years with unsteady gait and difficulty climbing stairs. Waddling gait and Gower maneuver were seen at age 10, with microcephaly, increased lumbar lordosis, mild calf hypertrophy, and ankle contractures. Facial weakness or muscle atrophy was not noted. Proximal muscle weakness was observed. Intellectual developmental delay was noted, and IQ at age 16 was 50. CK levels were elevated >10 times at 4,133 U/L and cranial MRI was normal. Muscle biopsy revealed a reduction of α-dystroglycan on immunohistochemistry. The initial description of the patient also reported 8 patients from 7 families with reduced α-dystroglycan expression on muscle biopsy, all characterized by LGMD with onset in the first decade, severe cognitive impairment, and normal brain MRI, but genetic confirmation was not available.^e278
LGMD2Q (muscular dystrophy associated with epidermolysis bullosa [plectin-1]). Thirty articles were reviewed. Most of these were case reports or small case series of up to 4 patients and were included in this guideline because of the rarity of the disorder.^e279-e308 This has recently been designated LGMD2Q and is also considered a form of congenital myasthenia.^{e279,e282,e293,e303,e306} The disorder has been described in several ethnicities, including Dutch, Australian, Japanese, Hispanic, Italian, British, German, and Austrian patients. The characteristic feature was epidermolysis bullosa, in which patients develop blistering of the skin and mucous membranes, usually noted at birth or shortly after. Nail dystrophy was also present. Later in life a progressive muscular dystrophy develops. The onset of dystrophy varied from infancy to as late as the fourth decade, presenting with either hypotonia in the neonatal period, developmental delay, or slowly progressive weakness in late childhood or adulthood. The muscle weakness was described in only a few cases and was in a limb-girdle distribution, with the lower extremity involved more severely.^e292,e302 Ptosis and ophthalmoplegia as well as facial weakness were described in a few cases.^e283,e292 Dental caries, scarring alopecia, urethral strictures, pyloric atresia, esophageal strictures, respiratory distress, and, rarely, cardiomyopathy were associated features. The frequency of these features was difficult to determine given descriptions of individual cases. CK levels were elevated to varying degrees from <10 times to >10 times normal. Muscle biopsy showed myofiber nuclei in subsarcolemmal rows or clusters. Type I fiber predominance was seen in a few cases. Oxidative stains showed irregular distribution of activity. Myofibrillar disarray and Z-disk streaming were seen on EM. Immunohistochemistry showed loss of sarcolemmal and trace sarcoplasmic activity of the antibody to the rid domain of plectin-1 in type I fibers, whereas type II fibers retained activity. Antibody to the last 50 C-terminal residues of plectin was absent in the sarcoplasm and showed only slight immunoreactivity in both type I and type II fibers in one study.^e293
BMD. We reviewed 3 Class I studies^e309-e311 and 54 Class III studies.^{e65,e66,e68,e156,e208,e312-e360} Bushby et al.^e311 is reviewed along with Bushby and Gardner-Medwin^e309 and Bushby et al.^e310 because the former is an earlier report of the same cohort. In a 2-part Class I natural history study of 67 patients with BMD,^e309,e310 the age at onset ranged from 10 months to 38 years, with a mean of 11.2 years. Four patients (6%) with genetic confirmation were asymptomatic. Six of 67 (18%) used a wheelchair (mean age of wheelchair dependency was 37.6 years). Those patients with mutations involving exons 45–47 had prolonged ambulation. Myalgias occurred in 27%, calf pain in 81%, and myoglobinuria in 2%. IQ testing was done in only 6 patients and was noted to be in the low-average range, with verbal performance score discrepancy. Most patients (87.9%) attended a mainstream school, but 6.8% attended a school for those with a learning disability and 3.4% a school for those with a physical disability. ECG was abnormal in 14/34 patients tested. The abnormalities included incomplete right bundle branch block (9 patients), Q waves in V4-6 and aVF (5 patients), left ventricular hypertrophy (4 patients), tall R waves in the right chest leads (3 patients), and nonspecific T-wave abnormalities (3 patients). FVC, measured in 41 patients, was generally reduced compared with the expected change for FVC in a comparable normal population. Serum CK levels ranged from 630 to 35,000 U/L, with a mean of approximately 5,200 U/L (>10 times normal).

The 54 Class III studies are summarized here.^{e65,e66,e68,e156,e208,e312-e360} Symptom onset occurred from early childhood to late adulthood. The pattern of weakness, when present, was proximal-greater-than-distal, with legs more affected than arms. Some patients manifested with only myalgias or episodic myoglobinuria.^{e315,e331,e357,e358} Most patients had calf hypertrophy; contractures were late and first appreciated at the ankles. Variability in the severity of the clinical phenotype was seen even within families harboring the same mutation.^e330

A mild decrease in IQ on average and learning problems were seen in some patients. In a study of neuropsychological testing of 28 patients, 5 had an IQ less than 70 and 13 had an IQ between 70 and 85. The mean IQ was 87.8 (SD 14.8).^e318 Another study reported normal IQ (mean 95.6) in 23 patients. However, in 17 males who were tested, a high prevalence of learning abnormalities was noted (reading problems in 21%, spelling in 32%, arithmetic in 26%).^e352 A third study of 28 patients with BMD revealed borderline MR in only one patient and a mean IQ of 85.9.^e335 Dilated cardiomyopathy with reduced EF occurred in 4% to more than 70%, depending on the duration of illness.^{e66,e156,e312,e315,e316,e319,e321,e322,e324,e328-e330,e332,e334,e337,e340,e341,e345,e347,e359,e360} In the largest series (98 patients), more than 40% developed a cardiomyopathy.^e315 In addition, nonspecific ECG abnormalities were seen in the majority of patients.^{e312,e313,e321,e328,e333,e340,e341,e346-e348,e356,e357} There was a wide range of CK levels, from slightly to markedly elevated. Muscle biopsies usually revealed reduced immunostaining for dystrophin, but Western blot was more sensitive and demonstrated reduced size or amount of dystrophin.^{e66,e315-e317,e320,e321,e331} Abnormal immunostaining to sarcoglycans has also been observed.^e343,e347
Females manifesting with dystrophinopathy. Sixteen Class III studies were reviewed.^{e65,e328,e356,e357,e361-e372} Hoogerwaard et al.^e366 and Hoogerwaard et al.^e367 describe the same cohort of patients and are reviewed together. Symptom onset was reported to be between ages 2 and 48 years.^{e357,e361-e363,e366,e368,e370,e372} Patients manifested most frequently with muscle pains with or without a limb-girdle pattern of weakness; 30%–75% had noticeable calf hypertrophy. Asymmetric weakness was noted in 3/15 patients in one study.^e370 In one study, 1 of 5 patients had tight heel cords. Weakness could be severe as in DMD or mild like BMD.^{e65,e356,e358,e361,e362,e364,e368,e371,e372} In a 10-year study of 197 carriers (152 DMD, 45 BMD), 9 DMD (5.9%) and 3 BMD (6.6%) carriers presented with mild calf pseudohypertrophy and 4 DMD carriers (2.6%) had marked proximal wasting and weakness.^e369 Normal cardiac status was observed in 15 (45.5%) of the 33 carriers aged between 5 and 15 years but in only 16 (9.8%) of the 164 carriers older than 15 years (p < 0.001). On the other hand, clinically evident myocardial damage was found in 5 (15.1%) of the 33 carriers aged between 5 and 15 years but in 73 (44.5%) of the 164 carriers older than 15 years (p < 0.001). The authors concluded that cardiac involvement in carriers of DMD/BMD is more frequent with increasing age.^e369 In another study, 30 of 264 carriers (11%) to 5 of 15 carriers (33%) of DMD/BMD mutation (not necessarily manifesting carriers) had dilated cardiomyopathy on echocardiography; 50/164 (30.5%) had evidence of hypertrophic cardiomyopathy and 7/186 (4%) had arrhythmia of some type on ECG.^{e328,e365,e369,e370} CK levels were only slightly to markedly elevated to >10 times normal.^{e65,e356,e361-e364,e368,e371,e372} Immunohistochemistry on muscle biopsies usually revealed a mosaic pattern for dystrophin.^{e356,e357,e362,e363,e371,e372} A few studies reported preferential inactivation of the putative X chromosome carrying the normal dystrophin allele in most, but not all, affected females.^{e362,e363,e372}
X-linked Emery-Dreifuss muscular dystrophy/EDMD-X1 (emerin). Twelve Class III studies were reviewed and are summarized here.^{e81,e373-e383} There was a wide range in age at onset or detection, varying from 14 months to 62 years across the various studies. European, Japanese, and North American kindreds were described. Gradually progressive weakness and atrophy were most typically described in a humeroperoneal pattern, although pelvifemoral distribution of weakness was also described in some families and scapular winging was not infrequent.^{e81,e376,e378} Most patients remained ambulatory into late adulthood.^e81,e378 Rigidity of the spine with an exaggerated lumbar lordosis and contractures at the elbows and Achilles tendon were characteristic features, but inter- and intrafamilial phenotypic variation was frequent; contractures occurred in some patients in the absence of muscle weakness.^{e376,e377,e380,e383}

Cardiac arrhythmias were an important and prominent clinical feature. Conduction disturbances were common, particularly sinus node dysfunction with varying degrees of atrioventricular block progressing to atrial standstill, or paralysis.^{e81,e373,e375,e376,e378,e381,e383} Notably, conduction abnormalities did not correlate with the severity of skeletal muscle involvement and were described in several patients without any associated myopathic features, including symptomatic nonsustained ventricular tachycardia in 2 patients.^e381 A large percentage of patients among studies required permanent pacemaker implantation: 10/12,^e373 3/3,^e375 15/23,^e81 3/5,^e377 4/4,^e381 and 7/7,^e383 for a combined reported incidence of 42/54 (77.8%). Cardiac conduction abnormalities presented at an early age; pacemaker implantation occurred at a mean age between 20 and 35 years in various studies (range 15–42 years).^{e81,e373,e375-e377} Female carriers were also found to have a high incidence of cardiac conduction abnormalities, increasing with increasing age: 6/34 (18%) overall, 1/29 below the age of 59 years, increasing to 5/5 over the age of 60 years.^e373 Pacemaker requirement was reported in 2/34 (6%),^e373 2/9 (22%),^e383 and 3/5 (60%)^e81 female carriers. Thromboembolic stroke was reported in 4 patients.^e81,e383 Sudden cardiac death was reported in 2 studies, including 5/23 subjects (22%) in one long-term follow-up study^e373 and 3/33 subjects (9%) in 2 families,^e383 occurring at mean ages of 47 years^e373 and 34.7 years,^e383 respectively (range 27–67 years).

In contrast to the severe conduction abnormalities, CHF was not a clinical feature of emerinopathy, and echocardiography was often found to be normal.^{e81,e375,e376} However, abnormalities were not infrequent; characteristically, atrial abnormalities, particularly of the right atrium, predominated.^{e377,e378,e383} In a 5-year longitudinal study,^e377 1/5 patients showed right atrial enlargement (RAE) at the outset whereas 4/5 were normal; over the follow-up period, 2 more patients developed RAE. All 3 patients with RAE progressed to biatrial enlargement with early left ventricular enlargement by 5 years; only one patient had LVEF reduced to 45%. Another study revealed RAE in 7/7 (100%) and biatrial enlargement in 2/7 (29%) but no cardiomyopathy.^e383 In one series examining left ventricular function by echocardiography, 6/23 patients (26%) had LVEF <50% and 3 of these had severe LVEF compromise (<35%); 2 were asymptomatic.^e378

CK levels ranged from normal to mildly elevated (<3 times normal) and were noted to peak during adolescence and then decline in adulthood. In a study of 33 obligate female carriers, CK levels were normal in 100%.^{e81,e374-e376,e379} Muscle imaging revealed variable involvement of posterior leg muscles, most severely affecting semimembranosus muscles in the thigh and soleus and medial gastrocnemius in 5/5 patients.^e381 Immunohistochemistry on muscle biopsies revealed absent or markedly reduced emerin staining.^{e81,e377,e379,e382,e383} One study found absence of emerin staining on immunohistochemistry of buccal epithelial cells in 3/3 affected males and reduced amounts of nuclear staining in female carriers.^e381 Immunocytochemistry on skin biopsies demonstrated absence of emerin staining, whereas immunoblotting of peripheral blood cells showed absence or reduced intensity of the emerin band.^e382 Muscle biopsies in 2 cases from one family showed rimmed vacuoles and tubulofilamentous inclusions typical of inclusion body myopathy.^e379

EDMD-X2/scapuloperoneal myopathy (four-and-one-half LIM1 protein or FHL1).

Eleven Class III studies were reviewed.^e384-e394 Pedigrees included German, Italian-American, Austrian, Croatian, British, Japanese, and northern European. The age at onset showed a wide range, from infancy^e389 to the eighth decade,^e392 but most commonly occurred between childhood and middle age.^{e387-e391,e393} The clinical phenotypes included limb-girdle weakness,^{e387,e388,e390,e393} anterior tibial weakness with early foot drop,^e385,e392 scapuloperoneal weakness,^{e385,e388,e390} and rigid spine syndrome.^{e384,e386,e390,e394} Prominent biceps atrophy was noted in 2 studies.^e391,e393 Athletic hypertrophic appearance was seen in some cohorts, especially early in the course of the disease.^{e384,e388,e390} Scapular winging was noted to be common^e385,e388 but more often was not reported. Dysphagia and dysarthria were rare.^{e386,e387,e392} Extremity contractures^{e384,e386-e388} and neck contractures were common.^{e384,e386,e388,e390,e392,e393} Some patients had a cardiomyopathy.^{e384,e386,e387,e390} Severe respiratory failure was seen in many patients,^{e386,e388,e390} particularly early-onset patients.^e387

CK levels were normal or elevated to <10 times normal.^{e384,e387,e388,e390,e392,e393} Muscle biopsies frequently showed reducing bodies and cytoplasmic bodies.^{e384,e386,e387,e392,e394} Two reports found cytoplasmic bodies without reducing bodies.^e384,e388 FHL1 immunostaining was used in several studies and noted to be positive for reducing bodies.^{e384,e387,e390-e392}
Myofibrillar myopathies. The term myofibrillar myopathies (MFMs) is used to describe a group of muscular dystrophies that share specific, common morphologic features on muscle biospy.^e395,e396 On light microscopy these abnormalities are best appreciated on the modified Gomori trichrome stains, in which the abnormal fibers harbor an admixture of amorphous, granular, or hyaline deposits that vary in shape and size and are dark blue or blue red in color. Many abnormal fiber regions, especially the hyaline structures, are devoid of or have diminished oxidative enzyme activity. Some hyaline structures are intensely congophilic. Some muscle fibers harbor small rimmed vacuoles. EM shows that disintegration of the myofibrils begins at the Z-disk, followed by accumulation of degraded filamentous material in various patterns, aggregation of membranous organelles and glycogen in spaces vacated by myofibrils, and degradation of dislocated membranous organelles in autophagic vacuoles. Immunostaining reveals ectopic accumulation of multiple proteins, including myotilin, αB-crystallin, desmin, dystrophin, sarcoglycans, caveolin, neural cell adhesion molecule, plectin, gelsolin, ubiquitin, filamin C, Bag3, and others. One study reported differences between the distinct MFM subgroups: the consistent presence of “rubbed-out” fibers in desminopathies and αB-crystallinopathies, an elevated frequency of vacuoles in ZASPopathies and myotilinopathies, and the presence of a few necrotic fibers in myotilinopathy patients.^e397

In a separate study, the same group of authors reported that EM findings in desminopathies and αB-crystallinopathies were very similar and consisted of electron-dense granulofilamentous accumulations and sandwich formations; they differed in the obvious presence of early apoptotic nuclear changes in αB-crystallinopathies.^e398 ZASPopathies were characterized by filamentous bundles (labeled with the myotilin antibody on immune-EM) and floccular accumulations of thin filamentous material. Tubulofilamentous inclusions in sarcoplasm and myonuclei in combination with filamentous bundles were characteristic for myotilinopathies. Rather than reiterating the hallmarks above in each of the subsequent MFM subtypes, we note that each of these disorders shows the characteristic MFM features on biopsy.

Myotilin (LGMD1A). Nine Class III studies were reviewed.^e9,e399-e406 The age at onset was 18–79 years with limb-girdle or distal limb weakness. Asymmetric muscle weakness and atrophy were frequently noted across studies. Scapular winging was not reported. Dysarthria was found in 4/16 affected individuals of a single kinship who were assigned as having LGMD1A^e402 and in the most-affected family members of another large kinship^e401; another patient had hypernasal speech.^e403 Ten of 16 in the initial report^e407 (cross-referenced in Hauser et al.^e402), 1/5,^e9 and 4/13^e403 patients had tight heel cords. Cardiac abnormalities were seen in 3/5,^e9 2/13,^e403 1/24,^e406 and 1/12^e400 patients. Respiratory failure was present in 3/13,^e403 3/24,^e406 and several affected family members of a large kinship.^e401

Serum CK levels were normal to <10-fold elevated. Muscle-imaging studies revealed involvement of the medial gastrocnemius, soleus, hip adductors, and biceps femoris with fatty/fibrous replacement and edema; the semitendinosus was relatively spared.^{e399,e400,e403,e405,e406} Muscle biopsy showed features of MFM. Myofiber necrosis and inflammatory infiltrates were also seen occasionally.^{e9,e399,e403,e406}

Desmin (LGMD1E). There were 17 Class III studies.^{e400,e405,e406,e408-e421} The myopathy was usually inherited in an autosomal dominant fashion, although sporadic cases were reported. Age at onset ranged from the first to the sixth decade of life. The pattern of muscle weakness was most often distal-greater-than-proximal^{e409,e411-e413,e415,e417,e418} with the earliest manifestation being progressive foot drop, but proximal-greater-than-distal weakness,^e413,e420 proximal and distal weakness,^{e408-e410,e413,e415-e417} and a scapuloperoneal distribution^e413 were also reported. Face and bulbar muscles were affected in some with dysphagia or dysarthria.^{e408,e412,e413,e415-e418,e420} Ventilatory muscle weakness was also common.^{e411,e413,e415,e417,e418} Cardiac involvement was common (40%–100%) across all series, with onset often preceding muscle weakness.^{e400,e406,e408-e410,e412-e418,e420} Onset of cardiac symptoms ranged from the first to the seventh decade of life. The most common cardiac manifestation was cardiac arrhythmia, including atrioventricular conduction block, atrial fibrillation, other tachyarrhythmias, and cardiac conduction defects, and some patients required pacemaker or implantable cardioverter defibrillator implantation. Dilated cardiomyopathy was more frequent than hypertrophic or restrictive cardiomyopathy. In a study of 21 members of a Swedish family, arrhythmogenic right ventricular cardiomyopathy was described in 3, and the authors suggested that the presence of a right ventricular cardiomyopathy (right ventricular dysfunction and tachyarrhythmias of right ventricular origin) was a clue to this disorder.^e421 Sudden death was reported in 3/18 patients, and 2/18 patients underwent cardiac transplantation in one series.^e406

Serum CK levels were normal or only moderately elevated (up to 5 times normal) in the majority of patients.^{e409-e412,e416,e418} Two studies focused on CT/MRI of skeletal muscles.^e400,e405 One study evaluated 19 patients and revealed gluteus maximus greater than gluteus medius or gluteus minimus involvement.^e400 In the thighs, the semitendinosus, sartorius, and gracilis were affected earlier than the adductor magnus, biceps femoris, or semimembranosus. The quadriceps muscles were relatively spared. In the distal legs, the peroneal muscles were affected more than the tibialis anterior, which was affected more than the posterior compartment. The other study evaluated 4 patients^e410 and reported that the iliopsoas, sartorius, gracilis, and semitendinosus were affected in 3 of 4 patients, whereas the biceps femoris was involved in 2 patients and the semimembranosus in one. In the distal legs, the peroneal, tibialis anterior, medial gastrocnemius, and soleus were involved in 3 of 4 patients. Two patients had involvement of the paraspinal muscles and 2 of the shoulder girdle, whereas none had involvement of the humeral muscles in the arms. Another CT study of 4 patients showed the earliest abnormalities in the semitendinosus and sartorius, and later abnormalities in the gracilis muscles at the mid-thigh level and in the peroneal group followed by the anterior tibialis and posterior group at the mid-calf level.^e417 In the later stages of the illness all muscles except for the soleus were replaced by fatty tissue.

αB-Crystallin. Four Class III studies presenting a total of 9 patients were reviewed.^{e400,e422-e424} The age at onset ranged from the 30s to the late 60s. Two patients presented with distal lower limb weakness with asymmetric muscle atrophy; one patient presented with diaphragmatic weakness followed by leg weakness and dysphagia.^e422,e423 Five patients from the same family had dysphagia and dysphonia, and 4 of them had cataracts.^e424 Scapular winging, dysarthria, or contractures were not described. Three patients had cardiomyopathy. Serum CK levels were normal to <10-fold elevated. Muscle-imaging studies showed involvement of gluteus maximus, sartorius, semitendinosus, vastus intermedius, medialis, lateralis, rectus femoris, tensor fasciae latae, adductor magnus, gracilis, and peroneal muscles.
Z-band alternatively spliced PDZ motif-containing protein (ZASP) (Markesbery-Griggs distal myopathy). Four Class III studies were reviewed.^{e72,e400,e406,e425} The age at onset was 27 to 73 years. Patients presented with limb-girdle or distal lower limb weakness. In one study, all 10 patients from a single family had distal leg weakness at onset, followed by atrophy and weakness of the hand muscles and wrist extensors.^e425 In another study of 3 patients, one had distal weakness and 2 had distal-greater-than-proximal weakness.^e400 Likewise, a third study had 5/11 patients with distal-greater-than-proximal weakness; only distal weakness occurred in one patient, only proximal weakness in 2 patients, and both proximal and distal weakness in 3 patients.^e72 One report of 7 patients^e406 also revealed distal-predominant weakness at onset that spread to involve distal and proximal muscles as the disease progressed. Scapular winging, dysphagia, or dysarthria was not noted. Ankle contracture was observed in one of 10 patients (10%) in one study.^e425 Cardiomyopathy was reported in 3 of 11 patients.^e72 Serum CK levels were normal to <10-fold elevated. Muscle MRI showed early involvement of posterior calf muscles, and the soleus muscle was the most affected. In the pelvis, the gluteus minimus was most affected in 3/3 patients. At the thigh level, the posterior compartment (biceps femoris and semimembranosus) was mostly involved, whereas the adductor magnus and gracilis were relatively spared. In the lower legs, one patient presented only with alterations in the soleus and medial gastrocnemius muscle at disease onset; in another case the soleus was most affected, and in the third case all lower leg muscles were involved.^e400 Muscle MRI performed in 2 patients in another study showed considerable involvement of posterior calf muscles.^e425 In another study, the adductor magnus, semimembranosus, vastus medialis, biceps femoris, soleus, and gastrocnemius were most frequently involved.^e406 Five of 11 patients had clinical or biopsy features of an associated neuropathy.^e72
BCL2-associated athanogene 3 (BAG3). Two Class III studies describing 7 patients were reviewed.^e73,e426 One study^e73 reported 2 patients (one age 15 years and one age 11 years) presenting with a history of toe walking, the former since early childhood and the latter since he was a toddler. The third patient presented at age 13 with scoliosis, rigid spine, and easy fatigability. The distribution of weakness was axial and moderately severe, with distal-greater-than-proximal weakness in one patient, moderate proximal weakness in one patient, and severe diffuse weakness in the third patient. One patient had scapular winging. Another patient had hypernasal speech. One patient had knee and ankle contractures. Two patients had restrictive cardiomyopathy, and one had mitral regurgitation. All 3 patients had respiratory involvement. CK levels were 3- to 15-fold elevated. Another study^e426 reported 4 patients from 3 families with weakness starting at ages 5 to 12 years. Two had predominantly proximal muscle weakness, restrictive/hypertrophic cardiomyopathy, and respiratory insufficiency; one developed bilateral pes cavus, neck and sital leg weakness, and restrictive cardiomyopathy with secondary enlargement of both atria, and the other developed restrictive cardiomyopathy, had a heart transplant at age 13 years, and became ventilator dependent. At age 15, he was noted to have predominantly proximal and respiratory muscle weakness.
Filamin C (Williams distal myopathy). Seven Class III studies were reviewed.^{e400,e427-e432} Fischer et al.^e400 described muscle MRI findings of some of the patients previously reported in Kley et al.,^e428 so these 2 studies are reviewed together. Mean age at onset of weakness was early- to mid-40s. The patients presented with a limb-girdle pattern of proximal muscle weakness and atrophy with lower limb predominance; 6 of 31 patients had scapular winging. No dysphagia, dysarthria, hoarse voice, or contractures were noted. In a study of 13 patients from 3 related families, all patients presented with distal upper limb weakness with lower limb involvement upon disease progression.^e431 There was late-onset involvement of respiratory muscles in 14/31 patients, but no details were provided. Cardiac involvement was seen in approximately one-third, including atrial flutter, right bundle branch block, decreased EF, and nonspecific cardiomyopathy. CK elevations were mild (<10-fold). Muscle MRI showed significant sparing of sartorius, gracilis, superficial parts of the quadriceps femoris, and the lateral gastrocnemius. There was involvement of gluteal muscles, semimembranosus, adductor magnus, biceps femoris, and vastus intermedius and medialis. The soleus and medial gastrocnemius were disproportionately involved compared with the lateral gastrocnemius and peroneal muscles. In one study, MRI of a single patient showed marked triceps surae with involvement of other lower leg muscles, with the exception of the posterior tibial muscle.^e431

In a study of a Chinese family with 10 affected members over 4 generations, proximal muscle weakness and atrophy of the lower limbs were noted at the onset; as the disease progressed, all limbs were involved.^e432 The index patient had right bundle branch block and atrial and ventricular premature beats.

In a Class III study originally categorized as the Williams distal myopathy and subsequently confirmed to be due to filamin C mutations,^e429,e430 12 affected members of a single Australian kindred were described with onset of distal upper and lower extremity weakness in early adulthood. Two additional family members were possibly affected. Age at onset varied considerably, but all cases reported onset by the fourth decade of life, and in many cases much younger: 5/27 reported onset in their teens and 4/27 reported onset around age 30 years. The characteristic pattern included early involvement of the distal anterior upper limb (selectively involving forearm pronators and finger flexors) and posterior leg (ankle plantar flexor) muscles, with sparing of the tibialis anterior, even in advanced disease. Muscle pain was a prominent feature. All patients remained ambulatory. None had evidence of cardiac or respiratory muscle involvement. Serum CK levels were either normal (5/8) or mildly elevated (<3 times normal in 3/8 patients). MRI showed widespread involvement of the posterior and lateral leg compartments in 4/7 patients (57%) and was normal in 3/7 patients (43%). In a similarly affected Italian family, the weakness started distally in the hand muscles with hand muscle atrophy and slowly progressed to involve the proximal muscles. Two of the 3 patients had cardiomyopathy.^e430 Muscle biopsies showed features of MFM except for patients in Duff et al.^e430 and Guergueltcheva et al.,^e431 whose biopsies showed nonspecific myopathic changes.
Titin. This is described under the section on LGMD2J/Udd distal myopathy/HMERF.
Hereditary inclusion body myopathies. Autosomal recessive hIBM/Nonaka distal myopathy (GNE). Eleven Class III studies were reviewed.^e433-e443 In addition, another report (Sadeh et al.^e444) before confirmation by genetic testing was also reviewed in conjunction with Mitrani-Rosenbaum et al.^e434 Autosomal recessive hIBM (AR-hIBM) and Nonaka distal myopathy are the same disorder caused by mutations in the gene encoding UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE). AR-hIBM was initially described in Iranian Jews and other Middle Eastern Karaites and Arab Muslims of Palestinian and Bedouin origin, whereas Nonaka distal myopathy was reported in Japanese, Korean, and Chinese families.^e436-e439 The age at onset ranged between the late teens and early 40s.^{e434,e436,e441} The characteristic pattern of muscle involvement was early involvement of the anterior tibial muscles leading to progressive foot drop. Over time, proximal legs could be involved, but there was relative sparing of the quadriceps in comparison to sporadic inclusion body myositis. The extensor muscles in the forearms also become affected, followed by involvement of more proximal arm muscles.^{e434,e436,e441} Mild neck flexor weakness was noted in some patients (number not mentioned), and facial weakness was noted in 2/55 families in one study.^e436 Bulbar and extraocular muscles were spared.^e434 The heart was not typically involved, but dilated cardiomyopathy developed in 2 patients late in their course.^e433

Serum CK levels were normal or mildly to moderately elevated (2- to 6-fold).^e436,e441 Muscle ultrasound of 6 patients demonstrated severe atrophy of the hamstring, anterior tibial, and peroneal muscles with milder quadriceps and gastrocnemius involvement and central atrophy with peripheral sparing; the “myopathic target” was noted in all 6 patients in the hamstrings.^e435 Muscle biopsy demonstrated dystrophic myopathy and rimmed vacuoles. The autophagic vacuoles had nuclear and cytoplasmic 15- to 18-nm filamentous inclusions on EM.^{e437-e439,e441-e443} Perivascular lymphocytic inflammation was described in 1/55 families in one study.^e436

Autosomal dominant hIBM with Paget disease and frontotemporal dementia (hIBMPFD) (valosin-containing protein or VCP). Seventeen Class III studies were reviewed and are summarized here.^e445-e461 Pedigrees included Asian, North American, European, Scottish, British, and Australian families. The myopathy was variably associated with Paget disease of bone (PDB), frontotemporal dementia, and more recently motor neuron disease (familial amyotrophic lateral sclerosis [fALS]). There was significant heterogeneity in clinical phenotype and severity both between and within families. Age at onset was variable, but across studies the mean age at onset for myopathy and PDB was 43 years (range late 20s–81 years). Most patients presented with either limb-girdle or scapuloperoneal weakness. A purely distal myopathy affecting lower and upper extremities was reported a Finnish kindred.^e461 Scapular winging and lumbar lordosis were common. Frontotemporal dementia was described in approximately 30%–50% of patients, with onset approximately 10 years after weakness (average age 54 years). PDB tended to occur earlier than in sporadic PDB and was seen with variable frequency, ranging from 29% to 100% in various kindreds; in some patients, PDB was not clinically apparent but was diagnosed by laboratory and radiographic findings. In a British pedigree, dilated cardiomyopathy (4/18 patients), urge incontinence (5/5 patients), and fecal incontinence (4/5 patients) were described.^e451

CK levels were normal or slightly elevated (<10-fold). Elevated blood alkaline phosphatase was found with high frequency among patients with PDB (86% average across the studies [range 57%–100%]). Muscle MRI in 2 studies^e451,e454 showed symmetric fatty degeneration of the quadriceps/hamstrings/glutei and anterior/posterior compartment of the legs. In the upper extremity, MRI showed fatty degeneration of paraspinal, supraspinatus, infraspinatus, and teres minor, and less so biceps, triceps, and deltoid.

Characteristic findings on muscle biopsy included rimmed vacuoles with ubiquitin and VCP-positive cytoplasmic inclusions, although in the larger series these were noted in less than half of biopsies (33%–39%).^{e447,e448,e460} Most biopsies revealed nonspecific myopathic abnormalities as well as neurogenic features of type grouping and angulated fibers. The latter may be due to fALS that can be associated with VCP mutations.^{e447,e448,e460} EM showed paired helical filaments in muscle and in PDB osteoclasts.^e460
Fast myosin heavy chain, MYHC-IIA, IBM3. Five Class III studies were reviewed.^e462-e466 Since some of the Swedish studies^e463,e465 appeared to report the same patients, they were reviewed along with Martinsson et al.,^e466 the original study. This disorder has been reported in Sweden, Finland, and the United Kingdom.^{e463,e464,e466} Age at onset ranged from birth to 40 years.^e463,e464 Myalgia and muscle weakness were the presenting symptoms in 7/15 patients in one family^e463 and were common in the first report of 19 patients as well, although numbers were not provided.^e466 Muscle weakness was predominantly proximal in a limb-girdle distribution. External ophthalmoplegia was a consistent finding in all 19 patients of one family in the initial report. They were found to have a dominant missense mutation, p.E706K,^e466 but ophthalmoplegia was not described in a second report of 8 patients who had different missense mutations in the MYHC-IIA gene. In patients in whom the disease started at birth, congenital joint contractures were seen.^e465,e466 Hand and face weakness were noted in 7/19 patients, and congenital hip dislocation in 4/19.^e466 Mild cervicothoracic kyphoscoliosis was described in 3/15 patients in one study^e463 and 7/19 in the original description of one family.^e466 Finally, one study described 5 patients with nonsense or truncating mutations from 3 families, one from the United Kingdom and 2 from Finland.^e464 Three presented in early childhood; 2 were asymptomatic. All had pronounced ophthalmoplegia, ptosis, and facial muscle weakness. Neck flexors were weak in 3/5, elbow flexors and ankle dorsiflexors were weak in 2, and 3 had joint hypermobility. Serum CK levels were normal in all 3 patients in whom they were checked. Two patients had muscle MRI that showed moderate diffuse fatty degenerative changes in the thigh and medial gastrocnemius. Muscle biopsy in the initial description revealed small and infrequent type II fibers, focal disorganization of the myofibrils, and rimmed vacuoles and inclusion consisting of 15- to 20-nm tubulofilaments.^e466 One muscle biopsy had lobulated fibers and another had central nuclei and minicores in another study of patients with a different missense mutation.^e463 Finally, in patients with the nonsense or truncating mutation, muscle biopsies demonstrated the absence of type II A fibers and myopathic changes.^e464 Thus, different mutations in the MYH-IIA gene appear to have different clinical presentations and muscle biopsy features.
Distal muscular dystrophies/myopathies. Welander distal myopathy. Six Class III studies were reviewed.^{e263,e467-e471} Although most often seen in the Swedish population,^e468 Finnish patients with Welander distal myopathy have also been described.^e471 This myopathy was recently reported to be caused by mutations in the RNA-binding protein described initially as T-cell restricted intracellular antigen (TIA1), now known to be expressed widely.^e472 The age at onset ranged from 24–60 years across studies, with a mean in the third to fourth decade of life.^{e263,e468-e471} The weakness predominantly involved the finger extensors and foot dorsiflexors and often began in either the hands or the legs. All 7 patients had foot dorsiflexor weakness in one study.^e467 All 9 patients in another study had finger extensor weakness, and 7/9 patients had foot dorsiflexor weakness.^e468 In a third study, 2/4 patients had finger extensor weakness, 1/4 had both finger extensor and foot dorsiflexor weakness, and the remaining 1/4 had weakness limited to foot dorsiflexors.^e470 Thenar muscle atrophy was noted in 3/4 patients in one study.^e470 An unusual feature of Welander myopathy is impaired distal sensation^{e468,e469,e471}; however, nerve conduction studies were normal in all patients in one study.^e469

CK levels were normal in 3/4 patients and mildly elevated (<10-fold) in 1/4 patients.^e263,e470 Imaging studies (CT and MRI) revealed fatty infiltration in the tibialis anterior, gastrocnemius, and soleus muscles with relative sparing of the peroneus and tibialis posterior muscles.^{e263,e467,e471} In the proximal leg, the biceps femoris, semitendinosus, semimembranosus, and adductors were involved. Muscle biopsy revealed rimmed vacuoles mainly in atrophic fibers but also less frequently in normal fibers when performed in the distal muscles such as the tibialis anterior.^e468-e471 In contrast, biopsy of a proximal muscle such as the vastus lateralis was normal in 7/7 patients in one study.^e467 EM revealed cytoplasmic 16- to 21-nm filaments associated with the rimmed vacuoles. Other abnormalities included dense collections of Z-disk material or streaming, double Z-disks, honeycomb material, and abnormal mitochondria.^e470 Moderate loss of myelinated nerve fibers was noted in 2/5 patients in one study.^e469

Markesbery-Griggs distal muscular dystrophy. This is discussed in the MFM section under ZASP.
Udd distal muscular dystrophy. This is discussed in the section on LGMD2J and HMERF (titinopathy).
Miyoshi distal myopathy. This is discussed in the sections on LGMD2B (dysferlin) and LGMD2L (anoctamin-5).
Nonaka distal myopathy. This is discussed in the section on AR-hIBM/GNE.
Laing myopathy/MYH7. Eleven Class III studies were reviewed.^e473-e483 Mastaglia et al.^e475 is a follow-up of the kindred described in Laing et al.^e478; these are reviewed together. Disorders caused by myosin heavy chain (MYH7) mutations have been classified into 2 subgroups with distinct clinical and pathologic findings: Laing distal myopathy (LDM) and hyaline body (or myosin storage) myopathy. In LDM, the typical clinical features are of an early-onset distal myopathy, with weakness and atrophy beginning in the first decade and selectively involving the anterior compartment of the lower leg, including ankle and toe dorsiflexors, resulting in foot drop or “hanging big toe.” Weakness progresses slowly, with an average of 10 years before involvement of finger extensors and neck flexors, and later development of proximal extremity weakness.^{e474,e475,e478,e483} Neck flexor weakness is a distinguishing feature from other distal myopathies and was reported in 20%–100% of cases in various series.^{e474,e478,e483} Mild facial weakness was described in up to 70% of patients.^e475,e477 Calf hypertrophy was noted in 11/31 (35%) in the largest cohort of patients.^e477 Scapular winging was observed in 2/9 (22%) and 4/31 (13%) patients in the largest cohorts.^e477,e478 Disabling myalgias were a clinical feature in 33% of 31 patients.^e477 Associated findings of scoliosis, pes cavus, ankle contractures, and lumbar hyperlordosis were variably described in about half of 43 patients reported.^{e474,e476,e477,e483} One of 27 patients had dilated cardiomyopathy,^e477 but this was atypical; a single patient with a syndrome of hypertrophic cardiomyopathy and tibialis anterior hypertrophy was described.^e480 Skeletal muscle CT scans in 7 patients^e477and MRI in 28 patients revealed selective early involvement of the toe extensors, anterior tibialis, and sternocleidomastoids.^{e474,e477,e478,e483} Muscles from the posterolateral lower leg and rectus femoris were affected at very late stages; the gastrocnemius was spared.^e477Across studies, serum CK levels were normal or only slightly elevated (<3 times the ULN).^{e474,e477,e478,e480} Five studies described muscle biopsies in 21 patients^{e474,e477,e478,e480,e483}; these showed variable and often nonspecific myopathic changes, most commonly atrophy and type I fiber grouping. Rimmed vacuoles were typically absent. Myosin immunohistochemistry demonstrated coexpression of slow and fast myosin in type I fibers, highly characteristic of LDM.

Four studies were relevant to myosin storage (hyaline body) myopathy.^{e473,e479,e481,e482} Although phenotypes vary considerably, muscle biopsy findings are characteristic for the disorder. Patients presented from the first to the fifth decade, and the average age at onset ranged from 29–38 years.^e479,e481 Weakness in either a scapuloperoneal or a limb-girdle distribution was described; CK levels were normal or slightly elevated.^{e473,e479,e481,e482} In a British kindred, limb-girdle weakness was associated with hypertrophic cardiomyopathy in 3/3 siblings,^e481 but other patients were reported to have normal echocardiography.^e473,e482 Muscle biopsies from 8/8 individuals revealed subsarcolemmal “hyaline bodies”: discrete, amorphous, eosinophilic material in type I fibers exclusively, staining homogeneous pale pink on hematoxylin & eosin and faint green on Gomori, which stains intensely with antibodies to MHY7.^{e473,e479,e481,e482}

Vocal cord and pharyngeal weakness with distal myopathy (matrin-3). Two Class III studies were reviewed.^e484,e485 Two pedigrees were reported: one white North American and one Bulgarian. Mean age at onset of weakness was 45 years. The clinical phenotype was slowly progressive, beginning with foot drop and distal upper extremity muscle weakness and progressing to involve proximal muscles, frequently associated with dysphagia and dysphonia. One patient from the North American pedigree (37 individuals, 12 who underwent clinical examination) had restrictive ventilatory weakness and low EF. None of the patients in this pedigree had unexplained cardiomyopathy. CK levels were slightly elevated (<10 times normal) in 13/17 cases tested and normal in 4/17. Muscle biopsies showed characteristic subsarcolemmal rimmed vacuoles in 5/7; 2/7 biopsies showed end-stage changes.
Filamin C (Williams distal myopathy). This is discussed in the MFM section on filamin C (Williams distal myopathy).
Nebulin (NEB). Two Class III studies were reviewed.^e486,e487 The first Class III study described 7 patients of Finnish descent from 4 unrelated families with a novel recessively inherited distal myopathy caused by homozygous missense mutations in the nebulin gene.^e486 In the second Class III study, 3 non-Finnish patients from 2 unrelated families were reported to have distal myopathy caused by 4 different compound heterozygous nebulin mutations. Onset was in early childhood, with very slowly progressive weakness and atrophy of ankle dorsiflexors, finger extensors, and neck flexors, initially presenting with foot drop. Delayed motor milestones (walking at 2 years), an elongated face, and lumbar lordosis were reported in 2 children who presented at ages 11 and 13 years with foot drop.^e487 Mild to moderate facial weakness was noted in 6 of 7 patients (86%).

CK levels were normal in 6/7 patients (86%) and slightly elevated in 1/7 patients (14%) in the Finnish study and normal in all 3 patients of non-Finnish descent.^e486,e487 One of 6 patients (17%) demonstrated a low FVC.^e486 Imaging was abnormal in all patients: CT (3/3) and MRI (5/5) of the leg muscles showed fatty degeneration in the anterior compartment of the lower legs.^e486,e487 Muscle biopsies demonstrated nemaline bodies.^e486,e487

Distal myopathy with Kelch-like homologue 9 mutations (KLHL9). One Class III study^e488 reported a German kindred with 10 affected members who had weakness and atrophy of the anterior tibial muscles (age at onset between 8 and 16 years), followed later by atrophy of the intrinsic hand muscles. The disorder was slowly progressive and patients retained the ability to walk until the seventh decade. Ankle contractures were present in all 10 patients. Tendon reflexes were absent in the lower extremities in 2 patients. Reduced sensation in a distal symmetric pattern was noted in 7 patients between the ages of 25 and 67 but not in the younger patients.

CK levels were normal or mildly elevated in 8 patients and moderately elevated (144 U/L) in one. Nerve conduction studies in 2 patients revealed mildly prolonged distal latencies in some motor nerves and reduced sural amplitude in one patient. ECG, echocardiogram, and pulmonary function tests were normal in one patient. MRI of the lower extremity in the index patient showed symmetric fatty atrophy that was most prominent in the semimembranosus, biceps femoris, and vastus intermedius, whereas the vastus lateralis and medialis, sartorius, gracilis, and adductors were preserved. The tibialis anterior, gastrocnemius, and soleus were more affected than the peroneus longus or tibialis posterior. Muscle biopsy in the index case did not reveal vacuoles. There were dystrophic changes and angulated fibers. There was loss of fiber typing on NADH stain. Sural nerve biopsy did not reveal neuropathy. Immunohistochemistry revealed normal expression of dystrophin, caveolin-3, laminin-α2, and sarcoglycan-dystroglycan complex. All patients possessed a heterozygous mutation in the KLHL9 gene encoding a bric-a-brac Kelch protein.

Other disorders. Selenoprotein (SEPN1, rigid spine syndrome). Most studies reviewed discussed the congenital myopathy phenotype of SEPN1 mutations and are not included in this guideline. Two Class III studies are reviewed.^e85,e489 One large Class III study^e489 described the clinical course of SEPN1-related muscular dystrophy in 41 patients. Mean age at onset was 2.7 years and ranged from birth to the second decade. In 19 of 41 patients (46%), the onset was between 6 months and 5 years, with delayed milestones, difficulty running, or falls. Scoliosis or easy fatigability was noted at onset in 3 children between the ages of 6 and 10 years; 2 presented at 7 years with running difficulty and 2 at age 13 years with back stiffness and generalized muscle weakness and atrophy. CK levels were normal in 29/37, minimally elevated in 6/37, and markedly elevated in only 1/37. Rigid spine was noted in 25 patients and scoliosis in 26 with onset between the ages of 1 and 20 years. Nine patients required spinal surgery by age 15 years, and an additional 4 required it by age 20. Joint contractures were present in 26 patients by the age of 10 years and involved the Achilles tendon, elbow, and long finger flexors. Mild right ventricular hypertrophy/pulmonary hypertension was found in only 5 patients. Twenty-seven of 41 patients required nocturnal noninvasive ventilation for reduced FVC. Most patients remained ambulatory; only 6 became wheelchair dependent. MRI in 13 children revealed selective or prominent involvement of the sartorius; no selectivity was noted at the calf level.^e85 Muscle biopsy features included nonspecific myopathic change (5/20), type I fiber predominance (5/20), multiminicores (8/20), and cores (2/20); Mallory bodies were noted in one patient who also had nonspecific myopathy.
Muscular dystrophy with generalized lipodystrophy (cavin-1/polymerase I and transcript release factor [PTRF]. Three Class III studies were reviewed.^e490-e492 The first study reported 5 Japanese patients of nonconsanguineous parentage with PTRF mutations causing a secondary deficiency of caveolin-3.^e490 The second study^e491 reported 15 patients from Oman and one from the United Kingdom. The third study reported 2 Mexican siblings and a Turkish girl with the disorder.^e492 The age range was from the neonatal period to 24 years. All patients had generalized lipodystrophy. Clinical information was incomplete in the second study.^e491 Developmental delay was noted in all 3 patients in one study.^e492 Weakness was present in 12/15 patients in the second study^e491 but not described. In the first study, weakness was distal dominant in 2/5, generalized in one, and absent in the other 2.^e490 Almost all patients had electrically silent percussion-induced muscle mounding, muscle hypertrophy, myalgias, and cramps. Five of the 23 described patients had cardiac arrhythmias, including prolonged QTc syndrome. Sudden death in the teenage years occurred in 4 patients in one study.^e491 Six of 23 patients had hepatosplenomegaly/fatty liver. Across studies, scoliosis was noted in 5 patients, rigid spine in 2, lordosis in one, and contractures (ankle, finger, and other unspecified) in 6. Fifteen patients had congenital hypertrophic pyloric stenosis. Insulin resistance (4 patients across the studies), elevated serum triglycerides (10), acanthosis nigricans (3), and atlantoaxial dislocation (1) were other features. CK levels were elevated in all patients tested, ranging from 542–2,630 IU/L (<10- to >10-fold). Muscle CT scan in one patient revealed hypertrophy of paravertebral and thigh muscles with minimal subcutaneous and abdominal fat.^e490 Reduced immunoreactivity to PTRF antibodies was noted on muscle biopsies. Caveolin-3 immunoreactivity was greatly reduced in the sarcolemma, but cytoplasmic staining was increased in a pattern similar to LGMD caused by caveolin-3 mutations. Immunoblotting revealed absent PTRF bands.^e490