A 61-year-old woman with a five-year history of progressive muscle weakness and atrophy had a muscle biopsy characterized by a combination of dystrophic features (necrotic fibers and endomysial fibrosis) and mitochondrial alterations [ragged-red cytochrome c oxidase (COX)-negative fibers].
Sequencing of the whole mtDNA, assessment of the mutation load in muscle and in accessible non-muscle tissues, and single fiber polymerase chain reaction (PCR).
Muscle mitochondrial DNA (mtDNA) sequencing revealed a novel heteroplasmic mutation (m.4403G>A) in the gene (MTTM) that encodes tRNAMet. The mutation was not present in accessible non-muscle tissues from the patient or 2 asymptomatic sisters.
The clinical features and muscle morphology in this patient are very similar to those described in a previous patient with a different mutation, also in MTTM, which suggests that mutations in this gene confer a distinctive “dystrophic” quality. This may be a diagnostic clue in patients with isolated mitochondrial myopathy.
mtDNA; tRNAMet; de novo mutation; mitochondrial myopathy; dystrophic features; late-onset weakness
Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD).
A cross-sectional analysis of clinical data from a multi-institutional, international CINRG DMD Natural History Study of 340 DMD patients aged 2 to 28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%.
231 participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47/174), and it was significantly associated with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P>0.68). In patients with cardiomyopathy, 57 % (27/47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15/127) of patients without cardiomyopathy.
Echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort.
cardiomyopathy; Duchenne muscular dystrophy; glucocorticoid; echocardiogram; natural history
Small-amplitude, short-duration motor unit action potentials are non-specific findings seen in myopathies and neuromuscular junction (NMJ) disorders. NMJ studies (repetitive nerve stimulation and single-fiber electromyography) can determine if such findings are related to NMJ abnormalities but are not considered routinely in atypical cases.
Medical records of 338 patients with confirmed NMJ disorders were reviewed to identify cases with a clinical or electrodiagnostic impression of myopathy during initial evaluation. A history of muscle biopsy with findings that did not support a myopathic process was required for inclusion.
Four patients met the inclusion criteria. NMJ studies were abnormal in all cases. One patient had elevated acetylcholine receptor antibodies. Three patients were antibody negative: 2 demonstrated immunotherapy responsiveness, and 1 had a Rapsyn mutation.
NMJ disorders may mimic myopathies, and NMJ studies should be performed to clarify so-called “myopathic” electromyographic findings to avoid unnecessary testing and delayed diagnosis.
action potentials; electromyography; myasthenia gravis; neuromuscular junction disorders; repetitive nerve stimulation
We quantified sub-maximal torque regulation during low to moderate intensity isometric hip flexion contractions in individuals with stroke and the associations with leg function.
10 participants with chronic stroke and 10 controls performed isometric hip flexion contractions at 5%, 10%, 15%, 20%, and 40% of maximal voluntary contraction (MVC) in paretic, non-paretic, and control legs.
Participants with stroke had larger torque fluctuations (coefficient of variation, CV), for both the paretic and non-paretic legs, than controls (P<0.05) with the largest CV at 5% MVC in the paretic leg (P<0.05). The paretic CV correlated with walking speed (r2 =0.45) and Berg Balance Score (r2=0.38). At 5% MVC, there were larger torque fluctuations in the contralateral leg during paretic contractions compared with the control leg.
Impaired low-force regulation of paretic leg hip flexion can be functionally relevant and related to control versus strength deficits post stroke.
force fluctuations; force regulation; hip flexors; stroke; steadiness
Modulation of transforming growth factor-β (TGF-β) signaling to promote muscle growth holds tremendous promise for the muscular dystrophies and other disorders involving the loss of functional muscle mass. Previous studies have focused on the TGF-β family member myostatin and demonstrated that inhibition of myostatin leads to muscle growth in normal and dystrophic mice. We describe a unique method of systemic inhibition of activin IIB receptor signaling via adeno-associated virus (AAV)-mediated gene transfer of a soluble form of the extracellular domain of the activin IIB receptor to the liver. Treatment of mdx mice with activin IIB receptor blockade led to increased skeletal muscle mass, increased force production in the extensor digitorum longus (EDL), and reduced serum creatine kinase. No effect on heart mass or function was observed. Our results indicate that activin IIB receptor blockade represents a novel and effective therapeutic strategy for the muscular dystrophies.
activin IIB receptor; adenoassociated virus; gene therapy; muscular dystrophy; transforming growth factor-β
Skeletal muscles that are under the influence of tetanus toxin show an exaggerated reflex response to stretch. We examined which changes in the stretch reflex may underlie the exaggerated response.
H-reflexes were obtained from the tibialis anterior (TA) and flexor digitorum brevis (FDB) muscles in rats 7 days after intramuscular injection of tetanus toxin into the TA.
We found effects of the toxin on the threshold, amplitude, and duration of H-waves from the TA. The toxin inhibited rate-dependent depression in the FDB between the stimulation frequencies of 0.5–50 HZ and when a conditioning magnetic stimulus applied to the brain preceded a test electrical stimulus delivered to the plantar nerve.
Tetanus toxin increased the amplitude of the H-wave and reduced the normal depression of H-wave amplitude that is associated with closely timed stimuli, two phenomena that could contribute to hyperactivity of the stretch reflex.
H-reflex; rate-dependent depression; presynaptic inhibition; rat; stretch reflex; transcranial magnetic stimulation; tetanus toxin
Quantitative ultrasound can measure skeletal muscle pathology. We investigated whether inexperienced evaluators could accurately obtain and analyze ultrasound images.
Two examiners underwent a 20-minute training session before obtaining ultrasound images of several limb muscles in 21 healthy boys and 19 boys with Duchenne muscular dystrophy (DMD). Gray scale levels (GSLs) of muscle and subcutaneous fat were then measured by 2 analysts: a trained research assistant and a radiologist. We compared results between examiners and analysts.
Interrater reliability of muscle GSLs was high between examiners (ICC ≥ 0.85) and analysts (ICC ≥ 0.84). As anticipated, GSLs were higher in dystrophic than in healthy muscles (P < 0.001). Fat GSLs were less reliable (ICC = 0.5–0.89) than muscle and increased with age and body size.
GSLs from ultrasound images of healthy and dystrophic skeletal muscle, but not from subcutaneous fat, can be obtained reliably and can be analyzed by inexperienced evaluators with minimal training.
children; Duchenne muscular dystrophy; muscle; myopathy; quantitative ultrasound
Genitourinary (GU) health among patients with Duchenne and Becker muscular dystrophies (DBMD) has not been explored using population-based data.
Medical records of 918 males ascertained by the Muscular Dystrophy Surveillance, Tracking, and Research Network were reviewed for documentation of GU-related hospitalizations and prescribed medications. Percentages of males who received these medical interventions were calculated, hazard ratios (HR) and 95% confidence intervals (CI) were estimated for associations with sociodemographics (study site, race/ethnicity), symptoms (early-versus late-onset, ambulation status, scoliosis), and treatments (respiratory support, steroids).
Among the 918 males, 81 (9%) had a GU condition; voiding dysfunction (n=40), GU tract infection (n=19), and kidney/ureter calculus (n=9) were most common. A Kaplan-Meier curve produced a cumulative probability of 27%. Cox regression showed GU conditions were more common when males were non-ambulatory (HR=2.7, 95% CI=1.3-5.6).
These findings highlight increased awareness of GU health and multidisciplinary care of DBMD patients.
male urogenital diseases; Duchenne muscular dystrophy; Becker muscular dystrophy; neuromuscular diseases; epidemiology
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in a constellation of problematic symptoms and a high patient and caregiver burden. Multidisciplinary care includes rehabilitation interventions that have the goal of assisting people to teach their fullest potential despite the presence of a disabling disease. Given the progressive nature of ALS, the clinician must be aware of the expected disease trajectory and apply appropriate interventions at each stage. This review will present rehabilitation strategies that can be utilized to maximize patient independence, function, safety, and quality of life, and to minimize disease-related symptoms. The role of bracing, exercise, assistive devices, and adaptive equipment will be discussed. At each disease stage, an experienced rehabilitation team is well positioned to make a significant impact on the life of ALS patients.
braces; exercise; multidisciplinary care; physical therapy; rehabilitation
The correlation of markers of disease severity among brothers with Duchenne or Becker muscular dystrophy has implications for clinical guidance and clinical trials.
Sibling pairs with Duchenne or Becker muscular dystrophy (n = 60) were compared for ages when they reached clinical milestones of disease progression, including ceased ambulation, scoliosis of ≥ 20°, and development of cardiomyopathy.
The median age at which younger brothers reached each milestone, compared with their older brothers ranged from 25 months younger for development of cardiomyopathy to 2 months older for ceased ambulation. For each additional month of ambulation by the older brother, the hazard of ceased ambulation by the younger brother decreased by 4%.
The ages when siblings reach clinical milestones of disease vary widely between siblings. However, the time to ceased ambulation for older brothers predicts the time to ceased ambulation for their younger brothers.
ambulation; Becker muscular dystrophy; cardiomyopathy; Duchenne muscular dystrophy; scoliosis; sibling features
Pompe disease is a progressive disease that affects skeletal muscles and leads to loss of ambulation. We investigated the activation of the tibialis anterior (TA) in late onset Pompe disease (LOPD) individuals during maximal voluntary contraction (MVC) and evoked involuntary responses.
Four LOPD patients and matched control subjects performed MVC of the TA using dorsiflexion and TA evoked responses. Activation of the TA was recorded with surface EMG.
The Pompe patients exhibited greater power at frequencies below 60 Hz and reduced power above 100 Hz. They exhibited reduced increase in M-wave and prolonged M-wave latency and duration in response to stimulation.
These results provide evidence that LOPD individuals have an altered activation pattern of the TA during maximal contractions. The observed activation pattern may reflect impairments in voluntary command, neuromuscular junction pathology, or compensatory drive due to a reduced number of functional motoneurons.
Pompe disease; Glycogen Storage disease; Skeletal Muscle; Modulation; Motoneuron
Recent studies have provided conflicting data regarding the role of dyslipidemia in amyotrophic lateral sclerosis (ALS). The aim of this study was to determine whether cholesterol level are an independent predictor of survival in ALS.
Cholesterol levels were measured in 427 ALS subjects from three clinical trial databases.
The LDL/HDL ratio did not decrease over time, despite significant declines in body mass index (BMI), forced vital capacity (FVC), and ALSFRS-R. After adjusting for BMI, FVC, and age, the lipid ratio was not associated with survival. There was a “U”-shaped association between BMI and mortality, with the highest survival at 30–35 kg/m2. The adjusted hazard ratio for the linear association between BMI and survival was 0.860 (95% CI 0.80–0.93, P = 0.0001).
We found that dyslipidemia is not an independent predictor of survival in ALS. BMI is an independent prognostic factor for survival after adjusting for markers of disease severity.
ALS; BMI; cholesterol; HDL; LDL; lipid; obesity; survival
Electrodiagnostic features of demyelination are essential for establishing the diagnosis in demyelinating subtypes of Guillain-Barré syndrome (GBS), but they may also occur in disorders that mimic GBS clinically. Information about their frequency in GBS mimics is sparse.
Evaluation of electrodiagnostic features from 38 patients with suspected GBS in whom the diagnosis was later refuted (GBS mimics). Their diagnostic accuracy was analyzed by comparison with NCS from 73 confirmed GBS patients.
Disorders that mimicked GBS clinically at the time of hospital admission included other inflammatory, metabolic, toxic, or infectious neuropathies and spinal cord disorders. The sural sparing pattern was the most specific electrodiagnostic feature for demyelinating GBS.
Common electrodiagnostic abnormalities in early demyelinating GBS do not usually exclude other rare differential diagnoses. An exception to this is the sural sparing pattern described here, which strongly supports the diagnosis of demyelinating GBS.
differential diagnosis; nerve conduction studies; peripheral neuropathy; misdiagnosis; GBS; Guillain-Barré syndrome
Reproducible neurophysiological testing paradigms are critical to multi-center studies of neuropathy associated with impaired glucose regulation (IGR), yet the best methodologies and endpoints remain to be established. This study evaluates the reproducibility of neurophysiologic tests within a multi-center research setting. Twenty-three participants with neuropathy and IGR were studied. Reproducibility of QSART and QST (using the CASE IV system) were determined in a subset of patients at two sessions and calculated from intraclass correlation coefficients (ICC). QST (cold detection threshold ICC 0.80, vibration detection threshold ICC 0.75) was more reproducible than QSART (ICC foot 0.52). Performing multiple tests in one setting did not improve reproducibility of QST. QST reproducibility in IGR patients is similar to other patient groups studied. QSART reproducibility was significantly lower than QST. In this group of patients, the reproducibility of QSART was unacceptable for a secondary endpoint measure in clinical research trials.
neuropathy; impaired glucose tolerance; clinical trials; QSART; QST
To measure and analyze motor unit number estimation (MUNE) values longitudinally in spinal muscular atrophy (SMA).
Sixty-two children with SMA types 2 and 3 were observed prospectively for up to 42 months. Longitudinal electrophysiological data were collected, including compound motor action potential (CMAP), single motor unit action potential (SMUP), and MUNE.
Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year, P = 0.009), a mean decrease in SMUP amplitude (−6.32 μV/year, P = 0.10) and stable CMAP amplitude.
The unexpected longitudinal results differ from findings in amyotrophic lateral sclerosis, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA is important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology.
Spinal muscular atrophy; Motor neuron disease; Motor unit number estimation; Compound motor action potential; Electrophysiology
Late-onset Tay-Sachs disease (LOTS) is a lysosomal storage disease caused by deficient Beta-hexosaminidase A activity.
We describe a 53-year-old woman who presented with adult-onset leg weakness, and whose initial diagnosis was progressive muscular atrophy without identifiable etiology. Development of cerebellar ataxia in mid-life prompted reassessment.
Beta-hexosaminidase A quantification assay demonstrated absence of the isozyme. Genetic testing identified compound heterozygous mutations in the HEXA gene, confirming the diagnosis of LOTS.
The phenotypic spectrum of LOTS includes motor neuronopathy, ataxia, choreoathetosis, neuropathy, and psychiatric symptoms in various combinations. This patient highlights the emergence of different clinical features over many years and emphasizes the need to consider LOTS in the differential diagnosis of progressive muscular atrophy.
late-onset Tay-Sachs disease; hexosaminidase; progressive muscular atrophy; ataxia; cerebellum
Acute compartment syndrome (CS) is caused by an elevation of pressure within a muscular compartment which can be caused by numerous factors, including blunt trauma. In this study, we characterized a rodent model of CS-like injury.
Forty male athymic rats received a standardized injury of ischemia and compression to their hindlimbs, while the intracompartmental pressure (ICP) was measured using an implantable transmitter. Tetanic muscle function was evaluated, and histology was performed on the tibialis anterior (TA) muscle.
ICPs were held at 260.70±2.70mmHg during injury. Injured muscles recovered 59% of their total function 4 weeks after injury, and histology showed high levels of edema, inflammation (CD68+), angiogenesis (CD31+), and fibrosis within 72 hours following injury.
We describe a novel CS-like injury model and a novel method to measure ICP which could potentially be used to develop innovative therapies to manage CS injury in humans.
Compartment syndrome; Regeneration; Inflammation; Angiogenesis; Fibrosis
Rodent whisking behavior is supported by the buccal and mandibular branches of the facial nerve, a description of how these branches converge and contribute to whisker movement is lacking.
Eight rats underwent isolated transection of either the buccal or mandibular branch and subsequent opposite branch transection. Whisking function was analyzed following both transections.
Anatomical measurements, and video recording of stimulation to individual branches, were taken from both facial nerves in 10 rats.
Normal to near-normal whisking was demonstrated after isolated branch transection. Following transection of both branches whisking was eliminated.
The buccal and mandibular branches form a convergence just proximal to the whisker-pad, named the “distal pes.” Distal to this convergence, we identified consistent anatomy that demonstrated cross-innervation.
The overlap of efferent supply to the whisker pad must be considered when studying facial nerve regeneration in the rat facial nerve model.
Facial Nerve; Anatomy; Rats; Movement; Vibrissae
We tested the feasibility of using neuromuscular ultrasound for non-invasive real time assessment of diaphragmatic structure and function in a canine model of X-Linked Myotubular Myopathy (XLMTM).
Ultrasound images in 3 dogs (Wild Type WT, n=1; XLMTM untreated, n=1; XLMTM post AAV8-mediated MTM1 gene replacement, n=1) were analyzed for diaphragm thickness, change in thickness with respiration, muscle echogenicity, and diaphragm excursion amplitude during spontaneous breathing.
Quantitative parameters of diaphragm structure were different among the animals. WT diaphragm was thicker and less echogenic than the XLMTM control, whereas the diaphragm measurements of the MTM1-treated XLMTM dog were comparable to the WT dog.
This pilot demonstrates the feasibility of using ultrasound for quantitative assessment of the diaphragm in a canine model. Ultrasonography may potentially replace invasive measures of diaphragm function in canine models and in humans in the future, for non-invasive respiratory monitoring and evaluation of neuromuscular disease.
canine; diaphragm; respiratory failure; ultrasonography; ultrasound
Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA).
Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index.
Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum.
The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges.
clinical trials; motor neuron disease; outcome measures; Rasch analysis; spinal muscular atrophy
Prolonged intravenous immunoglobulin (IVIG) therapy is used for the chronic autoimmune neuropathies chronic idiopathic demyelinating polyneuropathy and multifocal motor neuropathy, but the doses and treatment intervals are usually chosen empirically due to a paucity of data from dose–response studies. Recent studies of the electrophysiology and immunology of these diseases suggest that antibody-induced reversible dysfunction of nodes of Ranvier may play a role in conduction block and disability which responds to immunotherapy more rapidly than would be expected for demyelination or axonal damage per se. Clinical reports suggest that in some cases, the effects of each dose of IVIG may be transient, wearing-off before the next dose is due. These observations lead us to hypothesize that that therapeutic IgG acts by competing with pathologic autoantibodies and that individual patients may require different IgG levels for optimal therapeutic effects. Frequent IVIG dosing and weekly subcutaneous IgG have been tried as ways of continuously maintaining high serum IgG levels, resulting in stabilization of neuromuscular function in small case series. Frequent grip strength and disability measurements, performed by the patient at home and reported electronically, can be used to assess the extent and duration of responses to IgG doses. Individualization of IgG treatment regimens may optimize efficacy, minimize disability, and identify nonresponders. Muscle Nerve 51: 315–326, 2015
CIDP; IVIG; MMN; monitoring; SCIG
The mechanism by which the mERG1a K+ channel increases ubiquitin proteasome proteolysis (UPP) was investigated.
Methods and Results
Atrophic gastrocnemius muscles of hindlimb suspended mice express mERG1a, MuRF1 and MAFbx genes. Electro-transfer of mERG1a into non-suspended mouse muscle significantly decreases muscle fiber size (12.6%) and increases UPP E3ligase MuRF1 mRNA (real time PCR; 2.1 fold) and protein (immunoblot; 23.7%), but does not affect MAFbx E3ligase expression. Neither mERG1a-induced decreased fiber size nor mERG1a-induced increased MuRF1 expression is significantly curtailed by co-expression of inactive HR-FOXO3a, a gene encoding a transcription factor known to induce MAFbx expression by binding directly to its promoter.
The mERG1a K+ channel significantly increases expression of MuRF1 but not MAFbx. We explored this expression pattern by ectopically expressing an inactive FOXO3a and showing that it is not involved in mERG1a-mediated expression of MuRF1. These findings suggest that mERG1a does not modulate MuRF1 expression through the AKT/FOXO pathway.
mERG1a; Skeletal Muscle Atrophy; Ubiquitin Proteasome Proteolysis; MuRF1; MAFbx; Atrogin1
Physical activity plays an important role in preventing chronic disease in adults and the elderly. Exercise has beneficial effects on the nervous system, including at the neuromuscular junction (NMJ). Exercise causes hypertrophy of NMJs and improves recovery from peripheral nerve injuries, whereas decreased physical activity causes degenerative changes in NMJs. Recent studies have begun to elucidate molecular mechanisms underlying the beneficial effects of exercise. These mechanisms involve Bassoon, neuregulin-1, peroxisome proliferator-activated receptor gamma coactivator 1α, Insulin-like growth factor-1, glial cell line-derived neurotrophic factor, neurotrophin 4, Homer, and nuclear factor of activated T cells c1. For example, NMJ denervation and active zone decreases have been observed in aged NMJs, but these age-dependent degenerative changes can be ameliorated by exercise. This review will discuss the effects of exercise on the maintenance and regeneration of NMJs and will highlight recent insights into the molecular mechanisms underlying these exercise effects.
Post-stroke muscle weakness is commonly thought to be the result of a combination of decreased voluntary activation and decreased maximum force generating ability (MFGA). We assessed the ability of muscle volumes obtained using magnetic resonance imaging (MRI) to estimate the MFGA of the plantar flexor muscle group in individuals post-stroke.
MRI was used to measure muscle volume for the plantar flexor muscle group for 17 individuals with post-stroke hemiparesis. A modified burst superimposition test was used to measure MVC and predict the MFGA of the plantar flexors.
While muscle volume obtained via MRI provided information on the overall size of muscle, it overestimated the force generating ability of the paretic plantar flexors.
Results suggest that MRI-derived muscle volume underestimates the functional impairment in individuals post-stroke. Interestingly, the central activation ratio had a strong relationship with the maximum volitional force of contraction.
Magnetic Resonance Imaging; Stroke; Muscle Strength; Plantar Flexors; Electrical Stimulation