A new disease allele for the p.C30071R mutation in titin causing hereditary myopathy with early respiratory failure

Hereditary myopathy with early respiratory failure is an autosomal dominant myopathy caused by mutations in the 119th fibronectin-3 domain of titin. To date all reported patients with the most common mutation in this domain (p.C30071R) appear to share ancestral disease alleles. We undertook this study of two families with the p.C30071R mutation to determine whether they share the same haplotype as previously reported British families or whether the mutation arose as a de novo event. We sequenced the 119th fibronectin-3 domain in these two probands and flanking polymorphisms associated with the British haplotype in hereditary myopathy with early respiratory failure. A family of Indian descent had a haplotype that was not compatible with the British shared haplotype. Cloning of the 119th fibronectin-3 domain in this patient demonstrated polymorphisms rs191484894 and novel noncoding variant c.90225C>T on the same allele as the mutation, which is distinct from previously reported British families. This proves that the p.C30071R mutation itself (rather than the haplotype containing this mutation) causes hereditary myopathy with early respiratory failure and suggests its independent origin in different ethnic groups.     

Usefulness of pulmonary function tests and blood gases in acute neuromuscular respiratory failure

Background and purpose: Define the usefulness of pulmonary function tests (PFT) and arterial blood gases (ABG) in patients admitted to the ICU with acute neuromuscular respiratory failure (NMRF). Methods: We reviewed 76 patients admitted to an ICU at Mayo Clinic (Rochester) between 2003 and 2009 with acute NMRF defined as need for mechanical ventilation (MV) because of primary impairment of the peripheral nervous system. Poor functional outcome was defined as a modified Rankin score >3. Results: Median age was 65 years. The most frequent diagnosis was myasthenia gravis (25 patients); 54% of patients had no known neuromuscular diagnosis before admission, and 11% had no specific diagnosis at discharge. Median MV time was 16 days; 14% of patients died during hospitalization, and 63% were severely disabled at discharge. Maximal expiratory pressure ≤30 cm H₂O and maximal inspiratory pressure (MIP) worse than ?28 cm H₂O before MV were associated with need for invasive MV for longer than 7 days (P = 0.02). Indicators of chronic respiratory acidosis (low pH, high pCO₂, and high HCO₃) before MV were associated with in‐hospital death and poor functional outcome, but mostly in patients with progressive, untreatable neuromuscular diagnoses. Conclusions: In patients with primary acute NMRF, bedside PFT and ABG before MV can be used to predict evolution and outcome. Lower MIP and MEP portend prolonged MV and are more useful than forced vital capacity. Presentation with chronic respiratory acidosis is associated with high risk of in‐hospital mortality and severe disability, especially in patients without treatable diagnoses.     

Neuromuscular transmission defects in myopathies: Rare but worth searching for

Introduction: Decremental responses in repetitive nerve stimulation have been reported in a few hereditary myopathies. We examined the frequency of decrement in a cohort of myopathy patients. Methods: We reviewed all patients referred for myopathy who underwent repetitive nerve stimulation between January 2007 and May 2017. We included patients with decrement (>10%) and either a pathological or molecular diagnosis of myopathy. Results: Among 157 patients with myopathies, 4 patients had decrement (2 hydroxychloroquine-associated vacuolar myopathy, 1 centronuclear myopathy, and 1 distal myopathy). One hydroxychloroquine-associated vacuolar myopathy patient also had inflammatory myopathy. Pyridostigmine improved weakness in the centronuclear myopathy patient, but not in the distal myopathy patient. No patient with an acquired myopathy received pyridostigmine. Conclusions: Despite the rare occurrence of decrement in myopathy, its presence may urge consideration of pharmacological intervention. Muscle Nerve 59:475–478, 2019     

Acute mitochondrial myopathy with respiratory insufficiency and motor axonal polyneuropathy

Background: Mitochondrial myopathies (MMs) are mainly presented with chronic muscle weakness and accompanied with other syndromes. MM with acute respiratory insufficiency is rare. Aims: To reveal the clinical, pathological and molecular characteristics of a life-threatening MM. Methods: Muscle biopsy and enzyme staining were performed in skeletal muscles. Mitochondrial DNA (mtDNA) sequencing was analyzed and heteroplasmy were quantified by pyrosequencing. Results: All three patients had tachycardia, acute lactic acidosis, dyspnea and sudden severe muscle weakness. Two patients had calf edema and abdominal pain, and one had a heart attack. Electromyography in two patients showed dramatically decreased axonal amplitudes of motor nerves. Muscle biopsies showed ragged red fibers and dramatic mitochondrial abnormality. A mtDNA m.3243A>G mutation was identified in Patient 1 (mutation load: 29% in blood and 73% in muscle) and Patient 3 (79% in blood and 89% in muscle). A mtDNA m.8344A>G mutation was found in Patient 2 (mutation load 80.4% in blood). Conclusion: MM characterized by lactic acidosis, respiratory failure and acute motor axonal neuropathy is life threatening.     

Management of the child with weakness

With increased life expectancy associated with improved respiratory care and research advances in pediatric neuromuscular diseases leading to clinical trials involving potential curative treatments, the goal in the care of the child with weakness is to optimize survival and quality of life. The care of the child with weakness includes management of motor dysfunction because of weakness, orthopedic complications of contractures and scoliosis, and comorbid complications specific to each neuromuscular disease. Optimal holistic integrative care of the multisystemic problems of such patients is best provided by the collaborative efforts of health care providers of an interdisciplinary team.     

Idiopathic adult‐onset nemaline myopathy presenting with isolated respiratory failure

Idiopathic adult‐onset nemaline myopathy is a rare condition of unknown etiology that usually presents with proximal weakness. This case study reports a 60‐year‐old woman who presented with isolated type 2 respiratory failure secondary to bilateral hemidiaphragm weakness. A left vastus medialis muscle biopsy examined under light microscopy revealed appearances typical of nemaline myopathy. Electron microscopy confirmed the presence of nemaline rods in most muscle fibers, thus establishing idiopathic adult‐onset nemaline myopathy as the cause of her respiratory failure. Our patient's presentation highlights the importance of considering neuromuscular weakness as a cause of respiratory failure. Unless appropriate tests are performed—including a muscle biopsy, if indicated—specific neuromuscular diseases are easily missed. This can lead to inappropriate counseling and treatment. Muscle Nerve 39: 406–408, 2009     

Respiratory motor function in individuals with centronuclear myopathies

Introduction: Individuals with X‐linked myotubular myopathy (XLMTM) and other centronuclear myopathies (CNMs) frequently have profound respiratory insufficiency that requires support early in life. Still, few quantitative data exist to characterize respiratory motor function in CNM. Methods: We evaluated the reliance upon mechanical ventilation (MV), ventilatory kinematics, unassisted tidal volumes, and maximal respiratory pressures in 14 individuals with CNMs, including 10 boys with XLMTM. Results: Thirteen participants required full‐time, invasive MV. Maximal inspiratory pressures were higher in subjects who breathed unsupported at least 1 hour/day as compared with 24‐hour MV users [33.7 (11.9–42.3) vs. 8.4 (6.0–10.9) cm H₂O, P < 0.05]. Years of MV dependence correlated significantly with MEP (r = ?0.715, P < 0.01). Conclusions: Respiratory function in CNMs may be related to deconditioning from prolonged MV and/or differences in residual respiratory muscle strength. Results from this study may assist in evaluating severe respiratory insufficiency in neuromuscular clinical care and research. Muscle Nerve 53: 214–221, 2016     

Maximal voluntary ventilation in myasthenia gravis

Assessment of respiratory muscle weakness is important at all stages of myasthenia gravis. The maximal voluntary ventilation (MVV) is an objective dynamic method for measuring the working capacity of respiratory muscles. The clinical value of this method was studied in 24 newly diagnosed patients with myasthenia gravis, classified according to Osserman criteria (grades I, IIa, and IIb). The MVV values were normal in group I, whereas a characteristic "myasthenic pattern" of decremental respiratory volumes was demonstrated during MVV in group IIa and IIb patients, with or without dyspnea. Despite some limitations and lack of specificity, MVV may be a valuable tool in the assessment of respiratory dysfunction in patients with myasthenia gravis. Muscle Nerve, 27: 715-719, 2003     

Phrenic nerve conduction studies in patients with chronic obstructive pulmonary disease

Introduction: The most common etiology of hypercapnic respiratory failure is chronic obstructive pulmonary disease (COPD). However, the differential diagnosis also includes neuromuscular disorders. We studied the specificity of reduced amplitude phrenic nerve compound motor action potential (CMAP) to diagnose neuromuscular disorders. Methods: A group of patients with advanced COPD were recruited prospectively and compared with controls. Phrenic nerve CMAPs were measured bilaterally using supraclavicular surface stimulation and bipolar recording (G1: 5 cm above the xiphoid; G2: 16 cm from G1). Results: A group of 20 patients (15 men) and a group of 29 controls (15 men) were included. Phrenic nerve CMAPs of patients with COPD had significantly longer latency and higher amplitude. Conclusion: Our study demonstrates that patients with hypercapnic respiratory failure and reduced phrenic nerve CMAP amplitude most probably have a neuromuscular disorder affecting the diaphragm and not COPD or another lung disorder. Muscle Nerve 47: 504–509, 2013     

Electromyographic findings in the so-called non-progressive myopathies

Summary Electrophysiological findings in 40 cases of non-progressive myopathies are reported, and compared with a group of 20 cases of Duchenne progressive muscular dystrophy and a control group. In all cases the electrophysiological changes were of the mild s.c. myogenic type.The involvement of proximal and distal muscles was equal without prevalence in proximal muscles as is typical for Duchenne's dystrophy.EMG reexaminations showed a slight progression of the diseases. A peculiar feature of myotubular myopathy was spontaneous activity (fibrillation) in 70% of muscles.A myogenic character of the process of congenital deficiency of muscle innervation with preserved number of motor units is suggested.The study was supported by agreement No. 05-002-1 with N.I.H. Bethesda.     

Hereditary human myopathies in muscle culture

In this article I illustrated the use of regenerating human muscle cultures for studying the hereditary human myopathies. Although some of the data are still controversial, they do point up the great potential of this “in vitro system”. For hereditary myopathies due to developmentally regulated proteins that are expressed only at a more advanced stage of muscle differentiation, the use of highly differentiated nerve-muscle cocultures might contribute significantly to a better understanding of their developmental pathogenesis. More advanced techniques (permanent human muscle cell lines, heterokaryons, myoblast transfer, gene transfer, myogenic conversion of human non-muscle cells, cybrid clones) may provide a great deal of information at molecular level and may also have practical applications in the diagnosis or even in the treatment of hereditary human myopathies.

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Sommario L'Autore illustra l'utilità e i limiti delle colture di muscolo umano nello studio delle miopatie umane ereditarie. In particolare nelle miopatie dovute a difetti di enzimi-specifici muscolari, l'utilizzo di tecniche di cocoltura muscolo-nervo con avanzato grado di maturazione muscolare permette di delucidare i meccanismi molecolari patogenetici di tali malattie. L'uso di avanzate tecniche di biologia molecolare e cellulare, quali linee permanenti, trapianto di mioblasti, trasferimento genico e di mitocondri, oltre che fornire utili informazioni a livello molecolare potranno trovare applicazione, in futuro, persino nella terapia di molte miopatie ereditarie.

     

Vacuolar myopathies in adults with myalgias: Value of paraspinal muscle investigation

We evaluated 4 women with chronic fatigue and myalgias. Two had proximal weakness. All had elevated serum creatine kinase levels, but none was diagnosed with myopathy until electrodiagnostic studies revealed myotonic or complex repetitive discharges predominantly in paraspinal muscles. Histopathology of paraspinal muscles revealed vacuolar myopathies with glycogen storage; biochemical assays revealed phosphorylase deficiency in 1. Since vacuolar myopathies may affect paraspinal muscles more than limb muscles, electromyographic and histopathologic studies of paraspinal muscles may be required for diagnosis. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 1321–1323, 1997     

Hereditary inclusion-body myopathy associated with cardiomyopathy: report of two siblings

Hereditary inclusion-body myopathy (HIBM) or distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive disorder characterized by preferential involvement of distal muscles in the lower extremities, especially the anterior compartment of the legs, with relative preservation of the quadriceps.This is referred to as quadriceps-sparing myopathy. Previous reports have revealed exclusive involvement in skeletal muscles. Herein we describe two siblings with typical HIBM/DMRV. The patients developed exertional dyspnea 20-26 years after disease onset. Echocardiogram revealed a cardiomyopathy in both patients. This is the first report of the association between HIBM/DMRV and cardiomyopathy.