Diagnostic impact of myotonic discharges in myofibrillar myopathies

Introduction: In patients with myofibrillar myopathies (MFM), myotonic discharges have occasionally been detected by needle electromyography (EMG). Nevertheless, this peculiar type of spontaneous repetitive discharge has not attracted special interest in the genetically heterogeneous MFMs. Methods: EMG features were analyzed in 6 patients with genetically confirmed MFM (n = 1 MYOT, n = 1 DES, n = 2 ZASP, n = 2 FLNC). Results: Fibrillation potentials, positive sharp waves, and myotonic discharges were found in all 6 patients, and complex repetitive discharges were found in 5. Myotonic discharges were detected in approximately 50% of the analyzed muscles independent of the site, including distal (3/6), proximal limb (4/6), and paravertebral muscles (3/6). Clinical myotonia could not be elicited in any patient. Conclusions: Myotonic discharges appear to be part of the electrodiagnostic characteristics of myofibrillar myopathy. Along with other appropriate clinical and histological findings, the presence of myotonic discharges supports the diagnosis of myofibrillar myopathy. Muscle Nerve 47: 845–848, 2013     

A novel MYH7 mutation with prominent paraspinal and proximal muscle involvement

Laing distal myopathy (LDM) is caused by mutations in the MYH7 gene, and known to have muscle weakness of distal limbs and neck flexors. Through whole exome sequencing, we identified a novel p.Ala1439Pro MYH7 mutation in a Korean LDM family. This missense mutation is located in more N-terminal than any reported rod domain LDM mutations. In the early stage of disease, the present patients showed similar clinical patterns to the previously described patients of LDM. However, in the later stage, fatty replacement and atrophy of paraspinal or proximal leg muscles was more severely marked than lower leg muscles, and asymmetric atrophies were observed in trapezius, subscapularis and adductor magnus muscles. Distal myopathy like LDM showed marked and predominant fatty infiltrations in paraspinal or proximal leg muscles with marked asymmetry. These observations expand the clinical spectrum of LDM with the MYH7 mutation.     

Thigh muscle stiffness assessed with magnetic resonance elastography in hyperthyroid patients before and after medical treatment

PURPOSE: To measure the stiffness of the vastus medialis (VM) in hyperthyroid patients before and after treatment. MATERIALS AND METHODS: A total of five healthy euthyroid patients and five hyperthyroid patients were tested using magnetic resonance elastography (MRE), which involves the induction of shear waves in the thigh muscles using a pneumatic driver at 90 Hz. RESULTS: Among the pretreatment hyperthyroid cohort a lower stiffness was found when the muscle was relaxed (2.11 +/- 0.61 kPa) compared the stiffness following treatment of hyperthyroidism (5.52 +/- 1.52 kPa), which was accompanied by an improvement in the contractile function of the VM. Pretreatment muscle stiffness was also less than that of age matched healthy volunteers (4.56 +/- 0.40 kPa). The behavior of the waves was sensitive to the stage of this myopathy and to the amount of free thyroxine (FT4). CONCLUSION: The MRE technique provides a new tool to gain new insights into pathophysiology of thyroid associated and other muscle diseases and their response to treatment.     

Recessive MYH7-related myopathy in two families

Myopathies due to recessive MYH7 mutations are exceedingly rare, reported in only two families to date. We describe three patients from two families (from Australia and the UK) with a myopathy caused by recessive mutations in MYH7. The Australian family was homozygous for a c.5134C > T, p.Arg1712Trp mutation, whilst the UK patient was compound heterozygous for a truncating (c.4699C > T; p.Gln1567*) and a missense variant (c.4664A > G; p.Glu1555Gly). All three patients shared key clinical features, including infancy/childhood onset, pronounced axial/proximal weakness, spinal rigidity, severe scoliosis, and normal cardiac function. There was progressive respiratory impairment necessitating non-invasive ventilation despite preserved ambulation, a combination of features often seen in SEPN1- or NEB-related myopathies. On biopsy, the Australian proband showed classical myosin storage myopathy features, while the UK patient showed multi-minicore like areas. To establish pathogenicity of the Arg1712Trp mutation, we expressed mutant MYH7 protein in COS-7 cells, observing abnormal mutant myosin aggregation compared to wild-type. We describe skinned myofiber studies of patient muscle and hypertrophy of type II myofibers, which may be a compensatory mechanism. In summary, we have expanded the phenotype of ultra-rare recessive MYH7 disease, and provide novel insights into associated changes in muscle physiology.     

Serial brain imaging analysis of stroke-like episodes in MELAS

We report 2 patients of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and consider the pathophysiology of stroke-like lesions, using magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) on MRI, perfusion imaging on MRI, and 1H magnetic resonance spectroscopy (1H-MRS). In Patient 1, T2-weighted imaging (T2-WI) on MRI at onset and even at 44 days after onset of the stroke-like episode showed high intensity in left parietal, temporal, and occipital lobe lesions. In the temporal lobe lesion, the apparent diffusion coefficient (ADC) at 44 days after onset was higher (average: 1.219x10(-3)mm2/s) than that in a normal region (average: 0.796x10(-3)mm2/s). (1)H-MRS of the left parietal lobe lesion at the same day showed a decrease in N-acetylaspartate/(creatine+phosphocreatine) (NAA/Cr) (0.43) and a peak in lactate. 1H-MRS of the contralateral side at the same day showed NAA/Cr (1.57) and no peak in lactate. Thereafter, ADC gradually decreased and NAA/Cr gradually increased, and the peak in lactate disappeared in the lesion. In Patient 2, T2-WI at onset showed high intensity in bilateral occipital lobe lesions. In the left occipital lobe lesion, ADC at the same day was higher (1.082x10(-3)mm2/s) than that in a normal region (average: 0.841x10(-3)mm2/s). (1)H-MRS of the left occipital lobe lesion at the same day showed a decrease of NAA (3.0mM) and a peak in lactate (13.1mM) (measured by LCModel). In 1H-MRS of the normal left parietooccipital lobe at 4 months before onset, NAA was 7.6mM and there was no peak in lactate (0mM). Perfusion imaging at onset showed high intensity in bilateral occipital lobes, which indicated hyperperfusion in stroke-like lesions. Thereafter, ADC gradually decreased and the peak in lactate partially decreased, and the low concentration of NAA persisted (regardless of the partial recovery) in the lesion. These results suggest that the stroke-like episodes is related to vasogenic edema, hyperperfusion, and neuronal damage. Acute oxidative phosphorylation defect may have a crucial role in the pathophysiology of stroke-like episodes.     

Limited diagnostic value of enzyme analysis in patients with mitochondrial tRNA mutations

We evaluated the diagnostic value of respiratory chain (RC) enzyme analysis of muscle in adult patients with mitochondrial myopathy (MM). RC enzyme activity was measured in muscle biopsies from 39 patients who carry either the 3243A>G mutation, other tRNA point mutations, or single, large‐scale deletions of mtDNA. Findings were compared with those obtained from asymptomatic relatives with the 3243A>G mutation, myotonic dystrophy patients, and healthy subjects. Plasma lactate concentration, maximal oxygen uptake, and ragged‐red fibers/cytochrome c–negative fibers in muscle were also determined. Only 10% of patients with the 3243A>G point mutation had decreased enzyme activity of one or more RC complexes, whereas this was the case for 83% of patients with other point mutations and 62% of patients with deletions. Abnormal muscle histochemistry was found in 65%, 100%, and 85% of patients, respectively, in these three groups. The results indicate that RC enzyme analysis in muscle is not a sensitive test for MM in adults. In these patients, abnormal muscle histochemistry appears to be a better predictor ofMM. Muscle Nerve, 2010     

Facioscapulohumeral muscular dystrophy presenting with isolated axial myopathy and bent spine syndrome

Several subtypes of facioscapulohumeral muscular dystrophy (FSHD) with atypical clinical presentation have been described. We report a new, distinct phenotype with progressive bent spine syndrome solely affecting the paraspinal muscles. Magnetic resonance imaging study of the lumbar spine revealed marked atrophy of the paraspinal muscles. The diagnosis was confirmed by DNA testing, which revealed shortened restriction fragments of the D4Z4 repeat on haplotype A in connection with a positive family history. Muscle Nerve 42:273–275, 2010     

Statin-associated myopathy and its exacerbation with exercise

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are a common and effective treatment for hypercholesterolemia, with a low overall rate of side-effects. The most common complication is some degree of skeletal muscle myopathy, ranging from painless serum creatine kinase elevations to rhabdomyolysis. Unfortunately, the likelihood and/or severity of complications increases with the combination of statin treatment and physical activity. The specific pathways that mediate statin-associated myopathy are unclear, and research directly addressing the exacerbation with exercise is limited. Potential mechanisms include the induction of skeletal muscle fiber apoptosis, alterations in ubiquitin-proteasome pathway activity, mitochondrial dysfunction, and terpenoid depletion. In this review we provide an overview of research that specifically addresses the combination of statin-associated myopathy and physical activity and highlight some deficiencies in the available literature, as well as future directions for this important subset of statin-associated myopathy.     

Collagen XII myopathy with rectus femoris atrophy and collagen XII retention in fibroblasts

Introduction: Mutation in the collagen XII gene (COL12A1) was recently reported to induce Bethlem myopathy. We describe a family affected by collagen XII‐related myopathy in 3 generations. Methods: Systematic interview, clinical examination, skin biopsies, and MRI of muscle were used. Results: The phenotype was characterized by neonatal hypotonia, contractures, and delayed motor development followed by resolution of contractures and a motor performance limited by reduced endurance. DNA analyses revealed a novel donor splice‐site mutation in COL12A1 (c.8100 + 2T>C), which segregated with clinical affection and abnormal collagen XII retention in fibroblasts. MRI disclosed a selective wasting of the rectus femoris muscle. Discussion: COL12A1 mutations should be considered in patients with a mild Bethlem phenotype who present with selective wasting of the rectus femoris, absence of the outside‐in phenomenon on MRI, and abnormal collagen XII retention in fibroblasts. Muscle Nerve 57 : 1026–1030, 2018     

Evidence for a relatively high proportion of DM2 mutations in a large group of Polish patients

Introduction

Myotonic dystrophies (DMs) type 1 (DM1) and type 2 (DM2) are autosomal dominant, multisystem disorders, considered the most common dystrophies in adults. DM1 and DM2 are caused by dynamic mutations in the DMPK and CNBP genes, respectively.