DNAJB6 myopathy: A vacuolar myopathy with childhood onset

Introduction: DNAJB6 mutations cause an autosomal dominant myopathy that can manifest as limb‐girdle muscular dystrophy (LGMD1D/1E) or distal‐predominant myopathy. In the majority of patients this myopathy manifests in adulthood and shows vacuolar changes on muscle biopsy. Methods: Clinical, electrophysiological, pathological, and molecular findings are reported. Results: We report a 56‐year‐old woman, who, like 3 other family members, became symptomatic in childhood with slowly progressive limb‐girdle muscle weakness, normal serum creatine kinase (CK) values, and myopathic electromyographic findings. Muscle biopsy showed vacuolar changes and congophilic inclusions, and molecular analysis revealed a pathogenic mutation in the DNAJB6 gene. Differences and similarities with previously described cases are assessed. Conclusions: Childhood‐onset of DNAJB6 myopathy is more frequent than previously believed; congophilic inclusions may be present in the muscle of these patients. Muscle Nerve 49:607–610, 2014     

LAMA2‐related myopathy: Frequency among congenital and limb‐girdle muscular dystrophies

Introduction: Muscular dystrophy caused by LAMA2‐gene mutations is an autosomal recessive disease typically presenting as a severe, early‐onset congenital muscular dystrophy (CMD). However, milder cases with a limb‐girdle type muscular dystrophy (LGMD) have been described. Methods: In this study, we assessed the frequency and phenotypic spectrum of LAMA2‐related muscular dystrophy in CMD (n = 18) and LGMD2 (n = 128) cohorts identified in the last 15 years in eastern Denmark. The medical history, brain‐MRI, muscle pathology, muscle laminin‐α2 expression, and genetic analyses were assessed. Results: Molecular genetics revealed 2 pathogenic LAMA2 mutations in 5 of 18 CMD and 3 of 128 LGMD patients, corresponding to a LAMA2‐mutation frequency of 28% in the CMD and 2.3% in the LGMD cohorts, respectively. Conclusions: This study demonstrates a wide clinical spectrum of LAMA2‐related muscular dystrophy and its prevalence in an LGMD2 cohort, which indicates that LAMA2 muscular dystrophy should be included in the LGMD2 nomenclature. Muscle Nerve 52: 547–553, 2015     

A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients

FHL1, BAG3, MATR3 and PTRF are recently identified myopathy genes associated with phenotypes that overlap muscular dystrophy. TCAP is a rare reported cause of muscular dystrophy not routinely screened in most centres. We hypothesised that these genes may account for patients with undiagnosed forms of muscular dystrophy in Australia. We screened a large cohort of muscular dystrophy patients for abnormalities in FHL1 (n = 102) and TCAP (n = 100) and selected patients whose clinical features overlapped the phenotypes previously described for BAG3 (n = 9), MATR3 (n = 15) and PTRF (n = 7). We found one FHL1 mutation (c.311G>A, p.C104Y) in a boy with rapidly progressive muscle weakness and reducing body myopathy who was initially diagnosed with muscular dystrophy. We identified no pathogenic mutations in BAG3, MATR3, PTRF or TCAP. In conclusion, we have excluded these five genes as common causes of muscular dystrophy in Australia. Patients with reducing body myopathy may be initially diagnosed as muscular dystrophy.     

Fukutin gene mutations in an Italian patient with early onset muscular dystrophy but no central nervous system involvement

Hypoglycosylation of α‐dystroglycan characterizes a subgroup of muscular dystrophies of variable severity, including Fukuyama congenital muscular dystrophy. We found fukutin gene mutations in a 4.5‐year‐old Italian patient, with reduced α‐dystroglycan expression, dystrophic features on muscle biopsy, hypotonia since birth, mild myopathy, but no brain involvement. Mutations in the fukutin gene can be associated with much milder phenotypes than classical Fukuyama congenital muscular dystrophy, and, although rare, can occur in non‐Japanese. Muscle Nerve, 2009     

Isokinetic assessment of trunk muscles in facioscapulohumeral muscular dystrophy type 1 patients

Facioscapulohumeral muscular dystrophy type 1 is the third most common inherited myopathy. Its severity is proportionate to the loss of microsatellite D4Z4 repetitions, which are below 10. Patients suffer from weakness in facial muscles, shoulder girdles and ankle dorsiflexors. Trunk impairment is reported in few studies. To assess correlation between D4Z4 number of repetitions in facioscapulohumeral muscular dystrophy type 1 patients and trunk extensors and flexors isokinetic peak torque, 48 patients with southern Blot confirmed facioscapulohumeral muscular dystrophy type 1 were enrolled to perform clinical evaluation (Ricci's Clinical Severity Scoring, Berg Balance Scale, Functional Reach Test, timed up-and-go test, six-minute walk test, functional independence measure) and trunk isokinetic assessment. Trunk extensors and flexors isokinetic peak torque at 60°/sec were significantly correlated with number of D4Z4 microsatellite repetitions, sex, weight and age-independent (r = 0.391 [0.121; 0.662], p < 0.006 and r = 0.334 [0.028; 0.641], p < 0.033, respectively). Ricci's Clinical Severity Scoring was significantly correlated to trunk extensors isokinetic peak torque at 60°/sec, sex and weight-independent (r = -0.743 [−0.938; −0.548], p < 0.0001). This study demonstrates moderate correlation between pathologic compression of D4Z4 microsatellite array and trunk extensors isokinetic strength among facioscapulohumeral muscular dystrophy type I patients.     

Camptocormia as presenting manifestation of a spectrum of myopathic disorders

Introduction: Camptocormia is the involuntary flexion of the thoracolumbar spine leading to an abnormal posture. Methods: We retrospectively identified patients with myopathy who manifested with camptocormia and were seen in our neuromuscular clinic. The diagnosis of myopathy was based on myopathic electromyographic changes, often accompanied by 1 or more of the following: elevated creatine kinase (CK); myopathic histopathological findings; and genetic confirmation. Results: Fifty‐two patients were identified; 35 had symptoms limited to camptocormia, but were found to have additional weakness of facial (8 patients), neck (11 patients), and limb muscles (17 patients). CK values were normal or mildly to moderately elevated. MRI/CT of the spine showed paraspinal muscle atrophy and fat replacement. Facioscapulohumeral muscular dystrophy and sporadic inclusion body myositis were the most commonly identified myopathies in this cohort. Conclusions: Despite the difficulty in characterizing the myopathy in patients with camptocormia, a definitive diagnosis was possible in 54% of cases. The pattern of associated extra‐axial weakness may provide clues to the diagnosis. Muscle Nerve 52 : 1008–1012, 2015     

A primigravida with very‐long‐chain acyl‐CoA dehydrogenase deficiency

Introduction: Valosin‐containing protein (VCP) is a ubiquitously expressed, multifunctional AAA‐ATPase protein. Its dominant mutations cause hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) or amyotrophic lateral sclerosis. The pattern of muscle weakness in IBMPFD patients is variable and includes limb‐girdle, scapuloperoneal, distal, or axial distributions. Case Report: We report a 63‐year‐old man with progressive scapuloperoneal weakness, head drop, and hyperCKemia since age 40 years. Electromyography showed myopathic changes and rare myotonic discharges. Muscle biopsy revealed numerous lobulated fibers, few fibers with glycogen accumulation, and rare fibers with polyglucosan bodies. Rimmed vacuoles and congophilic inclusions, often seen in IBMPFD, were absent. VCP sequencing identified a novel heterozygous c. 1160G>A mutation resulting in p.Asn387Ser substitution. Conclusions: Our patient broadens the pathological spectrum of VCP‐myopathy and emphasizes the importance of VCP analysis in patients with scapuloperoneal muscular dystrophy despite the absence of Paget disease, dementia, rimmed vacuoles, or intracellular amyloid deposition. Muscle Nerve 50:295–299, 2014     

Non‐invasive assessment of muscle stiffness in patients with duchenne muscular dystrophy

ABSTRACT: Introduction: Assessment of muscle mechanical properties may provide clinically valuable information for follow‐up of patients with Duchenne muscular dystrophy (DMD) through the course of their disease. In this study we aimed to assess the effect of DMD on stiffness of relaxed muscles using elastography (supersonic shear imaging). Methods: Fourteen DMD patients and 13 control subjects were studied. Six muscles were measured at 2 muscle lengths (shortened and stretched): gastrocnemius medialis (GM); tibialis anterior (TA); vastus lateralis (VL); biceps brachii (BB); triceps brachii (TB); and abductor digiti minimi (ADM). Results: Stiffness was significantly higher in DMD patients compared with controls for all the muscles (main effect for population, P < 0.033 in all cases), except for ADM. The effect size was small (d = 0.33 for ADM at both muscle lengths) to large (d = 0.86 for BB/stretched). Conclusions: Supersonic shear imaging is a sensitive non‐invasive technique to assess the increase in muscle stiffness associated with DMD. Muscle Nerve 51 : 284–286, 2015     

Nonvolitional assessment of tibialis anterior force and architecture during critical illness

Introduction: Contemporaneous measures of muscle architecture and force have not previously been conducted during critical illness to examine their relationship with intensive care unit (ICU)‐acquired weakness. Methods: Ankle dorsiflexor muscle force (ADMF) with high‐frequency electrical peroneal nerve stimulation and skeletal muscle architecture via ultrasound were measured in 21 adult, critically ill patients, 16 at ICU admission. Results: Thirteen patients were measured on 2 occasions. Among these, 10 who were measured at ICU admission demonstrated muscle weakness. Despite significant reductions in tibialis anterior (Δ = ?88.5 ± 78.8 mm², P = 0.002) and rectus femoris (Δ = ?126.1 ± 129.1 mm², P = 0.006) cross‐sectional areas between occasions, ADMF did not change (100‐HZ ankle dorsiflexor force 9.8 [IQR, 8.0–14.4] kg vs. 8.6 (IQR, 6.7–19.2) kg, P = 0.9). Discussion: Muscle weakness was evident at ICU admission. No additional decrements were observed 7 days later despite significant reductions in muscle size. These data suggest that not all ICU weakness is truly “acquired” and questions our understanding of muscle function during critical illness. Muscle Nerve 57 : 964–972, 2018     

Myotonia associated with caveolin-3 mutation

Introduction: Caveolin‐3 is a major component of the caveolae in skeletal and cardiac muscle.Mutations in the caveolin‐3 gene (CAV3) lead to a spectrum of clinical phenotypes including limb‐girdle muscular dystrophy 1C, distal myopathy, rippling muscle disease, isolated hyperCKemia, and cardiomyopathy. Case Report: A 24‐year‐old man with myalgia, muscle stiffness, and fatigue has normal strength and prominent myotonic discharges in the gastrocnemius. He also has epilepsy. He harbors a heterozygous CAV3 mutation, p.V57M. He has no mutations in CLCN1 and SCN4A, and he had normal genetic testing for myotonic dystrophy type 1 and type 2. Conclusions: Mutations in CAV3, and in particular p.V57M in CAV3, previously reported in isolated familial hyperCKemia, can be associated with electrical myotonia. Muscle Nerve 45: 897‐900, 2012     

Muscle Weakness, Paralysis, and Atrophy after Human Cervical Spinal Cord Injury

Muscle weakness and failure of central motor drive were assessed in triceps brachii muscles of individuals with chronic cervical spinal cord injury (SCI) and able-bodied controls. Electrical stimuli were applied to the radial nerve during rest and during triceps submaximal and maximal voluntary contractions (MVCs). The mean forces and integrated EMGs generated by SCI subjects during MVCs were significantly less than those produced by controls (P < 0.01), with 74 and 71% of muscles generating <10% control force and EMG, respectively. There was an inverse linear relationship between the evoked and voluntary forces (n = 32 muscles of SCI subjects) which, when extrapolated to zero evoked force, also showed significant whole muscle weakness for SCI compared to control subjects (P < 0.01). Severe muscle atrophy was revealed which might reflect disuse and/or muscle denervation subsequent to motoneuron loss. Many triceps muscles of SCI subjects showed no force occlusion (n = 41) or were impossible to stimulate selectively (n = 61). Force was always evoked when the radial nerve was stimulated during MVCs of SCI subjects. The force elicited by single magnetic shocks applied to the motor cortex at Cz′ during voluntary contractions of SCI subjects was also inversely related to the voluntary triceps force exerted (n = 18), but usually no force could be elicited during MVCs. Thus central motor drive was probably maximal to these muscles, and the force evoked during MVCs by below-lesion stimulation must come from activation of paralyzed muscle. SCI subjects also had significantly longer mean central nervous system (CNS) conduction times to triceps (P < 0.01) suggesting that the measured deficits reflect CNS rather than peripheral nervous system factors. Thus, the weak voluntary strength of these partially paralyzed muscles is not due to submaximal excitation of higher CNS centers, but results mainly from reduction of this input to triceps motoneurons.     

Gender differences in contractile and passive properties of mdx extensor digitorum longus muscle

Introduction: Duchenne muscular dystrophy (DMD) is a severe, muscle‐wasting disease caused by mutations in the dystrophin gene. The mdx mouse is the first and perhaps the most commonly used animal model for study of DMD. Both male and female mdx mice are used. However, it is not completely clear whether gender influences contraction and the passive mechanical properties of mdx skeletal muscle. Methods: We compared isometric tetanic forces and passive forces of the extensor digitorum longus muscle between male and female mdx mice. Results: At age 6 months, female mdx mice showed better‐preserved specific tetanic force. Interestingly, at 20 months of age, female mdx muscle appeared stiffer. Conclusions: Our results suggest that gender may profoundly influence physiological measurement outcomes in mdx mice. Gender should be considered when using the mdx model. Muscle Nerve, 2012     

Muscle pathology grade for facioscapulohumeral muscular dystrophy biopsies

Introduction: As we move toward planning for clinical trials in facioscapulohumeral muscular dystrophy (FSHD), a better understanding of the clinical relationship with morphological changes in FSHD muscle biopsies will be important for stratifying patients and understanding post‐therapeutic changes in muscle. Methods: We performed a prospective cross‐sectional study of quadriceps muscle biopsies in 74 genetically confirmed FSHD participants (64 with FSHD type 1 and 10 with FSHD type 2). We compared a 12‐point muscle pathology grade to genetic mutation, disease severity score, and quantitative myometry. Results: Pathology grade had moderate correlations with genetic mutation (rho = –0.45, P < 0.001), clinical severity score (rho = 0.53, P < 0.001), disease duration (rho = 0.31, P = 0.03), and quantitative myometry (rho = –0.47, P < 0.001). We found no difference in the frequency of inflammation between FSHD types 1 and 2. Conclusions: The pathology grade of quadriceps muscle may be a useful marker of disease activity in FSHD, and it may have a role in stratification for future clinical trials. Muscle Nerve 52: 521–526, 2015     

Myoblast implantation in Duchenne muscular dystrophy: The San Francisco study

We evaluated myoblast implantation in 10 boys with Duchenne muscular dystrophy (DMD) and absent dystrophin (age 5–10 years) who were implanted with 100 million myoblasts in the anterior tibial muscle of one leg and placebo in the other. Cyclosporine (5 mg/kg/day) was administered for 7 months. Pre- and postimplantation (after 1 and 6 months) muscle biopsies were analyzed. Force generation (tetanic tension and maximum voluntary contraction) was measured monthly in a double-blind design. There was increased force generation in both legs of all boys, probably due to cyclosporine. Using the polymerase chain reaction, evidence of myoblast survival and dystrophin mRNA expression was obtained in 3 patients after 1 month and in 1 patient after 6 months. These studies suggest a salutary effect of cyclosporine upon muscular force generation in Duchenne muscular dystrophy; however, myoblast implantation was not effective in replacing clinically significant amounts of dystrophin in DMD muscle. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 469–478, 1997.     

Reachable workspace reflects dynamometer‐measured upper extremity strength in facioscapulohumeral muscular dystrophy

Introduction: It is not known whether a reduction in reachable workspace closely reflects loss of upper extremity strength in facioscapulohumeral muscular dystrophy (FSHD). In this study we aimed to determine the relationship between reachable workspace and quantitative upper extremity strength measures. Methods: Maximal voluntary isometric contraction (MVIC) testing of bilateral elbow flexion and shoulder abduction by hand‐held dynamometry was performed on 26 FSHD and 27 control subjects. In addition, Kinect sensor‐based 3D reachable workspace relative surface areas (RSAs) were obtained. Loading (500‐g weight) effects on reachable workspace were also evaluated. Results: Quantitative upper extremity strength (MVIC of elbow flexion and shoulder abduction) correlated with Kinect‐acquired reachable workspace RSA (R = 0.477 for FSHD, P = 0.0003; R = 0.675 for the combined study cohort, P < 0.0001). Progressive reduction in RSA reflected worsening MVIC measures. Loading impacted the moderately weak individuals the most with additional reductions in RSA. Conclusions: Reachable workspace outcome measure is reflective of upper extremity strength impairment in FSHD. Muscle Nerve 52 : 948–955, 2015     

Myoadenylate deaminase deficiency: absence of correlation with exercise intolerance in 452 muscle biopsies

Summary A histochemical assay was routinely performed of myoadenylate deaminase (MAD) in muscle biopsy specimens. MAD was absent in 13 cases, i.e. 2.9% of the specimens. In 10 cases the deficiency was confirmed biochemically. The diagnoses in the 13 patients were: polyneuropathy (n=5), infantile spinal muscular atrophy (n=3), congenital myopathy with type 2 fibre atrophy, facioscapulohumeral myopathy, polymyositis, myotonic dystrophy and hyperornithinaemia with gyrate atrophy of the retina. In contrast, 35 unrelated patients presenting with exercise-related muscle cramps or pains showed normal histochemical MAD activity. The biopsy specimens in all of these patients were essentially normal and in none of them was the diagnosis of a neuromuscular disease made. The results failed to confirm the association of MAD deficiency with aches, cramps and pains or exertional myalgia.     

Decreased surface sialic acid content is a sensitive indicator of muscle damage

Introduction: The glycosylation state of the muscle sarcolemma is crucial for membrane strength and is thereby linked to pathologic conditions. No markers currently exist with sufficient sensitivity to detect muscle damage in biopsy samples. We aimed to determine whether surface sialic acid content is a useful criterion for estimating muscle injury. Methods: Sialic acid content was measured by comparing the fluorescence intensity of muscle sections stained with 2 types of lectins. One binds specifically to nonsialylated sugars, and the other binds to both sialylated and nonsialylated sugars. Results: Sialic acid levels were markedly reduced (60–80%) in muscles from dystrophin‐defective mice, δ‐sarcoglycan–deficient hamsters, merosin‐deficient mice, and patients with muscular dystrophy, when compared with their healthy counterparts. Conclusions: Testing for a marked decrease in sialic acid levels, which is caused by the release of trace amounts of sialidase from damaged muscles, is a sensitive detection method for muscle injury and could be commonly utilized for various subtypes of muscular dystrophy. Muscle Nerve 47:372‐378, 2013     

Muscular adaptations and insulin‐like growth factor‐1 responses to resistance training are stretch‐mediated

Introduction: Modulation of muscle characteristics was attempted through altering muscle stretch during resistance training. We hypothesized that stretch would enhance muscle responses. Methods: Participants trained for 8 weeks, loading the quadriceps in a shortened (SL, 0–50° knee flexion; n = 10) or lengthened (LL, 40–90°; n = 11) position, followed by 4 weeks of detraining. Controls (CON; n = 10) were untrained. Quadriceps strength, vastus lateralis architecture, anatomical cross‐sectional area (aCSA), and serum insulin‐like growth factor‐1 (IGF‐1) were measured at weeks 0, 8, 10, and 12. Results: Increases in fascicle length (29 ± 4% vs. 14 ± 4%), distal aCSA (53 ± 12% vs. 18 ± 8%), strength (26 ± 6% vs. 7 ± 3%), and IGF‐1 (31 ± 6% vs. 7 ± 6%) were greater in LL compared with SL muscles (P < 0.05). No changes occurred in CON. Detraining decrements in strength and aCSA were greater in SL than LL muscles (P < 0.05). Conclusions: Enhanced muscle in vivo (and somewhat IGF‐1) adaptations to resistance training are concurrent with muscle stretch, which warrants its inclusion within training. Muscle Nerve 49 : 108–119, 2014     

Exercise increases utrophin protein expression in the mdx mouse model of Duchenne muscular dystrophy

Introduction: Duchenne muscular dystrophy (DMD) is a lethal genetic disease caused by mutations in the dystrophin gene resulting in chronic muscle damage, muscle wasting, and premature death. Utrophin is a dystrophin protein homologue that increases dystrophic muscle function and reduces pathology. Currently, no treatments that increase utrophin protein expression exist. However, exercise increases utrophin mRNA expression in healthy humans. Therefore, the purpose was to determine whether exercise increases utrophin protein expression in dystrophic muscle. Methods: Utrophin protein was measured in the quadriceps and soleus muscles of mdx mice after 12 weeks of voluntary wheel running exercise or sedentary controls. Muscle pathology was measured in the quadriceps. Results: Exercise increased utrophin protein expression 334 ± 63% in the quadriceps relative to sedentary controls. Exercise increased central nuclei 4 ± 1% but not other measures of pathology. Conclusions: Exercise may be an intervention that increases utrophin expression in patients with DMD. Muscle Nerve 49 : 915–918, 2014