Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype.

The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15-20 nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset MYH2-myopathy caused by two heterozygous pathogenic variants: c.3331C>T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T>G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient's genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in MYH2-myopathy.

Chronic inflammatory axonal polyneuropathy.

OBJECTIVES: Chronic inflammatory axonal polyneuropathy (CIAP) is defined on the basis of the clinical, electrophysiological and nerve biopsy findings and therapeutic responses of 'immunotherapy responding chronic axonal polyneuropathy (IR-CAP)'. METHODS: The diagnosis of IR-CAP was made when all of three of the following mandatory criterion were met: (1) acquired, chronic progressive or relapsing symmetrical or asymmetrical polyneuropathy with duration of progression >2 months; (2) electrophysiological evidence of axonal neuropathy in at least two nerves without any evidence of 'strict criteria of demyelination'; and (3) definite responsiveness to immunotherapy. RESULTS: Thirty-three patients with IR-CAP showed similar clinical features of chronic inflammatory demyelinating polyneuropathy (CIDP) except 'motor neuropathy subtype'. High spinal fluid protein was found in 27/32 (78%) cases. 'Inflammatory axonal neuropathy' was proven in 14 (45%) of 31 sural nerve biopsies. DISCUSSIONS: IR-CAP could well be 'axonal CIDP' in view of clinical similarity, but not proven as yet. Thus, IR-CAP is best described as CIAP, a distinct entity that deserves its recognition in view of responsiveness to immunotherapy. CONCLUSION: Diagnosis of CIAP can be made by additional documentation of 'inflammation' by high spinal fluid protein or nerve biopsy in addition to the first two diagnostic criteria of IR-CAP.

ACTA1-myopathy with prominent finger flexor weakness and rimmed vacuoles.

Actinopathy is a group of clinically and pathologically heterogeneous myopathies due to mutations in the skeletal muscle sarcomeric α-actin 1-encoding gene (ACTA1). Disease-onset spans from prenatal life to adulthood and weakness can preferentially affect proximal or distal muscles. Myopathological findings include a spectrum of structural abnormalities with nemaline rods being the most common. We report a daughter and father with prominent finger flexors and/or quadriceps involvement. Muscle biopsies revealed rimmed vacuoles in both patients, associated with type 1 fiber atrophy in the daughter, and nemaline rods in the father. Next generation sequencing identified a novel dominant ACTA1 variant, c.149G>A (p.Gly50Asp) in both individuals and no abnormal variants in vacuolar myopathy-associated genes. Our findings expand the clinico-pathological spectrum of actinopathy.

Repetitive nerve stimulation test in myasthenic crisis.

INTRODUCTION: Herein we report our experience with the repetitive nerve stimulation (RNS) test in myasthenia gravis (MG) crisis. METHODS: The various parameters of the RNS tests in 26 patients with MG crisis were analyzed. RESULTS: In 18 (69%) patients, MG crisis is the first manifestation of MG. RNS tests were abnormal in 24 (92%) patients by decrement at low-rate stimulation in any of 4 tested muscles. Three patterns of abnormality were found: MG pattern (decrement at low-rate stimulation) in 23 patients; Lambert-Eaton myasthenic syndrome pattern in 1 patient; and cholinergic crisis pattern in 1 patient. DISCUSSION: During MG crisis, the RNS test can serve as a rapid and sensitive diagnostic tool for MG in a majority of patients. Muscle Nerve 59:544-544, 2019.

Amifampridine phosphate (Firdapse(®)) is effective and safe in a phase 3 clinical trial in LEMS.

OBJECTIVE: We evaluated the efficacy and safety of amifampridine phosphate (Firdapse(®)) for symptomatic treatment in Lambert-Eaton myasthenic syndrome (LEMS). METHODS: Phase 3, randomized, double-blind, study. Patients were treated initially with amifampridine phosphate for 7-91 days, followed by randomization to continue amifampridine phosphate for 14 days or placebo (7-day taper, 7-day placebo). The primary efficacy endpoints were changes from baseline at day 14 in Quantitative Myasthenia Gravis and Subject Global Impression scores. RESULTS: The coprimary efficacy end points and 1 of the secondary efficacy end points were met, showing a significant benefit of aminfampridine phosphate over placebo at Day 14. All 5 primary, secondary, and tertiary endpoints achieved statistical significance at Day 8. Amifampridine phosphate was well tolerated; the most common adverse events were oral and digital paresthesias, nausea, and headache. CONCLUSIONS: This study provides Class I evidence of efficacy of amifampridine phosphate as a symptomatic treatment for LEMS.

Transforming Growth Factor Beta (TGF-ß) Is a Muscle Biomarker of Disease Progression in ALS and Correlates with Smad Expression.

We recently identified Smads1, 5 and 8 as muscle biomarkers in human ALS. In the ALS mouse, these markers are elevated and track disease progression. Smads are signal transducers and become activated upon receptor engagement of ligands from the TGF-ß superfamily. Here, we sought to characterize ligands linked to activation of Smads in ALS muscle and their role as biomarkers of disease progression. RNA sequencing data of ALS muscle samples were mined for TGF-ß superfamily ligands. Candidate targets were validated by qRT-PCR in a large cohort of human ALS muscle biopsy samples and in the G93A SOD1 mouse. Protein expression was evaluated by Western blot, ELISA and immunohistochemistry. C2C12 muscle cells were used to assess Smad activation and induction. TGF-ß1, 2 and 3 mRNAs were increased in ALS muscle samples compared to controls and correlated with muscle strength and Smads1, 2, 5 and 8. In the G93A SOD1 mouse, the temporal pattern of TGF-ß expression paralleled the Smads and increased with disease progression. TGF-ß1 immunoreactivity was detected in mononuclear cells surrounding muscle fibers in ALS samples. In muscle cells, TGF-ß ligands were capable of activating Smads. In conclusion, TGF-ß1, 2 and 3 are novel biomarkers of ALS in skeletal muscle. Their correlation with weakness in human ALS and their progressive increase with advancing disease in the ALS mouse suggest that they, as with the Smads, can track disease progression. These ligands are capable of upregulating and activating Smads and thus may contribute to the Smad signaling pathway in ALS muscle.

Asymptomatic vasculitic neuropathy.

INTRODUCTION: We performed a retrospective analysis of the clinical, pathological, and electrophysiological features of 21 cases of Asymptomatic vasculitic neuropathy (AsVN). METHODS: Among 270 patients with biopsy-proven vasculitic neuropathy, we identified 21 (7.8%) who had asymptomatic neuropathy. RESULTS: Of the 21 patients with AsVN, 11 were women and 10 were men. Their mean age was 62.5 years. Referring physicians suspected systemic vasculitis on the basis of clinical and laboratory features, but none of the patients had neuropathy by examination. Screening nerve conduction studies identified neuropathy in all patients, leading us to perform a sural nerve biopsy, which confirmed the diagnosis of vasculitis. Twelve patients had active (type I), 6 had inactive (type II), and 3 had probable (type III) vasculitis. Vasculitis was primary in 10 patients and secondary in 11. CONCLUSIONS: Nerve conduction study is an important tool for identifying AsVN, a subtype of vasculitic neuropathy.

Smads as muscle biomarkers in amyotrophic lateral sclerosis.

OBJECTIVE: To identify molecular signatures in muscle from patients with amyotrophic lateral sclerosis (ALS) that could provide insight into the disease process and serve as biomarkers. METHODS: RNA sequencing was performed on ALS and control muscle samples to identify Smad family members as potential markers of disease. Validation studies were performed in a cohort of 27 ALS patients and 33 controls. The markers were assessed in the G93A superoxide dismutase (SOD)1 mouse at different stages of disease and in a model of sciatic nerve injury. RESULTS: Smad8, and to a lesser extent Smad1 and 5, mRNAs were significantly elevated in human ALS muscle samples. The markers displayed a remarkably similar pattern in the G93A SOD1 mouse model of ALS with increases detected at preclinical stages. Expression at the RNA and protein levels as well as protein activation (phosphorylation) significantly increased with disease progression in the mouse. The markers were also elevated to a lesser degree in gastrocnemius muscle following sciatic nerve injury, but then reverted to baseline during the muscle reinnervation phase. INTERPRETATION: These data indicate that Smad1, 5, 8 mRNA and protein levels, as well as Smad phosphorylation, are elevated in ALS muscle and could potentially serve as markers of disease progression or regression.

Epidemiological features of amyotrophic lateral sclerosis in a large clinic-based African American population.

Our objective was to identify the main clinical and epidemiological features of ALS in a large cohort of African American (AA) patients and compare them to Caucasian (CA) patients in a clinic-based population. We retrospectively identified 207 patients who were diagnosed with ALS based on the revised El Escorial criteria (60 AA and 147 CA subjects). Patients were seen in the Neuromuscular Division at the University Medical Center. We compared epidemiological and clinical features of these two groups, focusing on age of onset and diagnosis, clinical presentation and survival. Results showed that AA patients had a significantly younger age of disease onset (55 years vs. 61 years for CA, p = 0.011) and were diagnosed at an earlier age (56 years vs. 62 years, p = 0.012). In younger ALS patients (< 45 years of age), there was a significant difference in gender frequency, with females predominating in the AA population and males in the CA population (p = 0.025). In a multivariable Cox proportional hazard model, survival rates were not different between the groups. In both groups, survival significantly increased with younger age. In conclusion, AA patients presented at an earlier age, but there was no difference in survival compared to CA patients. A gender reversal occurred in younger ALS patients, with AA patients more likely to be female and CA patients more likely to be male.

Electromyography tests in patients with implanted cardiac devices are safe regardless of magnet placement.

METHODS: We compared the problems or complications associated with electrodiagnostic testing in 77 patients with implanted cardiac devices. Thirty tests were performed after magnet placement, and 47 were performed without magnet application. RESULTS: All electrodiagnostic tests were performed safely in all patients without any serious effect on the implanted cardiac devices with or without magnet placement. A significantly higher number of patient symptoms and procedure changes were reported in the magnet group (P < 0.013). No statistical difference was found in the testing difficulty or ECG changes. CONCLUSION: The magnet group patients had an approximately 11-fold greater risk of symptoms than those in the control group. Our data do not support a recommendation that magnet placement is necessary for routine electrodiagnostic testing in patients with implanted cardiac devices, as long as our general and specific guidelines are followed.