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  • Myopathies

    20 November 2017

  • Myopathies

    20 November 2017

  • The causes of stroke in the young.

    16 February 2018

    In a group of 75 patients under the age of 45 years with stroke, ischaemic cerebral infarction was diagnosed in 60 patients and primary intracerebral haemorrhage in 15. Trauma was found to be the commonest identifiable predisposing factor to cerebral infarction, being present in 13 cases (22%). Migraine was the second most commonly identified predisposing factor while atheroma and hypertension were infrequent. Such a high frequency of preceding trauma has not previously been described, perhaps because it is not generally appreciated that the delay between the traumatic event and subsequent stroke may be considerable. The diagnostic management of young stroke patients is considered with particular reference to the indications for specialized cardiac and neuroradiological investigations.

  • Desmin myopathy: Distinct filamentopathy caused by mutations in the desmin gene

    20 November 2017

    Intermediate filaments are 10 nm structures that interact with actin and microtubules to form the cytoskeletal scaffolding of the cells. They share a common structure of a dimer with 2 alpha helical chains intertwined in a coiled-coil highly conserved rod structure. In the muscle, intermediate filaments constitute 1% of the total proteins and include lamin A/C, emerin, desmin, paranemin, nestin, vimentin, peripherin and possibly syncoilin. Together with various proteins associated with them, such as plectin and αB crystalline, the intermediate filaments play a fundamental role in the structural resilience of the myofibres. A group of neuromuscular diseases that selectively affect intermediate filaments, has now emerged that can be collectively called "filamentopathy". The prototypic filamentopathy causing myopathy is the one due to mutations in the desmin gene (desmin myopathy); others may be due to defects in nuclear intermediate filaments such as lamin A/C and emerin, causing dilated cardiomyopathy or Emery-Dreifuss muscular dystrophy; and still others due to mutations in plectin or αB crystallin causing myofibrillar myopathy, as discussed later. The prototypic filamentopathy affecting nerves is the one due to mutations in gigaxonin that results in an axonal neuropathy; the prototypic filamentopathy affecting skin is caused by mutations in the keratin gene. Finally, mutations in neurofilament subunits may lead to motor neuron cell death.

  • An unusual metabolic myopathy: a malate-aspartate shuttle defect.

    2 February 2018

    Studies on a 27-year-old man with a 3-year history of exercise-induced muscle pain, passage of red urine and elevated serum creatine kinase are described. Histological examination of a biopsy from quadriceps revealed non-specific myopathic changes with occasional clusters of subsarcolemmal mitochondria. The phosphorylase stain was normal. Phosphorous nuclear magnetic resonance (NMR) spectroscopy studies of gastrocnemius and flexor digitorum superficialis muscles showed no abnormalities at rest. During aerobic exercise there was an abnormally rapid decrease in phosphocreatine concentration but the pH remained within the normal range. There was a build-up of phosphomonoester (probably glucose 6-phosphate), usually indicative of a block in glycolysis. However, a primary defect in the glycolytic pathway seemed unlikely because muscle acidified normally during ischaemic exercise. Recovery from exercise was unusual in that phosphocreatine resynthesis and inorganic phosphate disappearance followed similar prolonged time courses (in control subjects the rate of inorganic phosphate disappearance was about twice as fast as the rate of phosphocreatine resynthesis). The transport of inorganic phosphate into the mitochondria appeared to be delayed. These slow recovery data suggested that oxidative metabolism was impaired. However, with all substrates tested, isolated muscle mitochondria had rates of oxygen uptake that were similar to control values, thereby ruling out a primary defect in mitochondrial respiration. A system involving several mitochondrial transport systems, the malate-aspartate shuttle, was measured. The activity in the patient's isolated mitochondria was less than 20% of the activity present in samples from control subjects. This patient is the only one so far reported with a defect involving the malate-aspartate shuttle system.

  • Long-term observational study of sporadic inclusion body myositis

    28 January 2018

    We describe a long-term observational study of a large cohort of patients with sporadic inclusion body myositis and propose a sporadic inclusion body myositis weakness composite index that is easy to perform during a clinic. Data collection from two groups of patients (Paris and Oxford) was completed either during a clinic visit (52), or by extraction from previous medical records (48). One hundred and thirty-six patients [57 males, 61 (interquartile range 55-69) years at onset] were included. At the last visit all patients had muscle weakness (proximal British Medical Research Council scale < 3/5 in 48, distal British Medical Research Council scale < 3/5 in 40, swallowing problems in 46). During their follow-up, 75 of patients had significant walking difficulties and 37 used a wheelchair (after a median duration from onset of 14 years). The sporadic inclusion body myositis weakness composite index, which correlated with grip strength (correlation coefficient: 0.47; P < 0.001) and Rivermead Mobility Index (correlation coefficient: 0.85; P < 0.001), decreased significantly with disease duration (correlation coefficient:-0.47; P < 0.001). The risk of death was only influenced by older age at onset of first symptoms. Seventy-one (52) patients received immunosuppressive treatments [prednisone in 91.5, associated (in 64.8) with other immunomodulatory drugs (intravenous immunoglobulins, methotrexate or azathioprine) for a median duration of 40.8 months]. At the last assessment, patients who had been treated were more severely affected on disability scales (Walton P=0.007, Rivermead Mobility Index P=0.004) and on the sporadic inclusion body myositis weakness composite index (P=0.04). The first stage of disease progression towards handicap for walking was more rapid among patients receiving immunosuppressive treatments (hazard ratio=2.0, P=0.002). This study confirms that sporadic inclusion body myositis is slowly progressive but not lethal and that immunosuppressive treatments do not ameliorate its natural course, thus confirming findings from smaller studies. Furthermore, our findings suggest that immunosuppressant drug therapy could have modestly exacerbated progression of disability. The sporadic inclusion body myositis weakness composite index might be a valuable outcome measure for future clinical trials, but requires further assessment and validation. © 2011 The Author.