Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
  • Desmin myopathy: Distinct filamentopathy caused by mutations in the desmin gene

    2 July 2018

    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 July 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

    2 July 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.

  • Two cases of oculopharyngeal muscular dystrophy (OPMD) with the rare PABPN1 c.35G>C; p.Gly12Ala point mutation.

    2 July 2018

    Oculopharyngeal muscular dystrophy is a neuromuscular disease usually presenting in the 5th or 6th decades of life with a dominant inheritance pattern. In almost all cases the cause of the disease is the expansion of a DNA repeat sequence containing GCG and GCA codons in exon 1 of the PABPN1 gene from 10 to between 12 and 17 repeats. However one case has been previously reported without the gene expansion but instead with a c.35G>C missense mutation converting a glycine codon to an alanine and resulting in a sequence of 13 contiguous alanine codons, thus mimicking the effect of the common expansion mutation. Here we report two further cases of OPMD caused by the c.35G>C point mutation. Clinical and pedigree data indicate the usual OPMD dominant inheritance pattern.

  • When the patient fails to respond to treatment: myasthenia gravis.

    2 July 2018

    Myasthenia gravis is one of the most satisfying neurological disorders to treat. There are few other conditions in which therapeutic intervention can take a patient from being bed-bound and ventilated to normality. Most patients present with less severe symptoms, but even mild extraocular muscle weakness can be profoundly disabling. The standard therapeutic approach is successful for most patients, which can make the non-specialist neurologist somewhat blasé about its management. However, panic can set in when the standard approach fails. Failure is often the result of incorrect diagnosis, or inappropriate use of first-line treatments. This article outlines the main reasons for failure and gives advice on alternative therapeutic strategies.

  • Myotonic dystrophy: practical issues relating to assessment of strength.

    2 July 2018

    BACKGROUND: Myotonic dystrophy type 1 is a slowly progressive multisystem disease in which skeletal muscle involvement is prominent. As novel physical and pharmacological treatments become available, it is crucial to be able to measure their efficacy accurately. METHODS: 158 consecutive patients with myotonic dystrophy were assessed annually in a specialist muscle clinic. Strength was measured using both the Medical Research Council (MRC) scale and a hand-held dynamometer. Dynamometer readings were obtained from 108 normal subjects (controls). RESULTS: The movements showing the greatest rate of change in strength were ankle dorsiflexion and pinch grip. Both of these showed a decline of only 0.06 points/year on the MRC scale. Using a hand-held dynamometer, a change in strength of 1.18 kgN/year for women and 1.61 kgN/year for men was detected. CONCLUSIONS: The MRC scale is unsuitable for detecting the small changes in strength seen in a slowly progressive disease such as myotonic dystrophy. Dynamometry provides a simple alternative that can give meaningful data over the duration of a typical clinical trial.

  • Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I.

    2 July 2018

    Mutations in the gene encoding fukutin-related protein cause limb-girdle muscular dystrophy 2I. In this multicenter retrospective analysis of 38 patients, 55.3% had cardiac abnormalities, of which 24% had developed cardiac failure. Heterozygotes for the common C826A mutation developed cardiac involvement earlier than homozygotes. All patients initially improved while receiving standard therapy. Independent of cardiac status, forced vital capacity was below 75% in 44.4% of the patients. There was no absolute correlation between skeletal muscle weakness and cardiomyopathy or respiratory insufficiency. These complications are a primary part of this specific type of limb-girdle muscular dystrophy, with important implications for management.

  • Normal in vivo skeletal muscle oxidative metabolism in sporadic inclusion body myositis assessed by 31P-magnetic resonance spectroscopy.

    2 July 2018

    Sporadic inclusion body myositis (s-IBM) is a chronic inflammatory myopathy of unknown pathogenesis. The common findings of ragged red fibres, cytochrome c oxidase-negative fibres and multiple mitochondrial DNA deletions in the muscle of patients with s-IBM have suggested that a deficit of energy metabolism may be of pathogenic relevance. To test this hypothesis we used 31P magnetic resonance spectroscopy to assess in vivo skeletal muscle mitochondrial function in the calf muscles of 12 patients with definite s-IBM. Eleven patients showed multiple mitochondrial DNA deletions in skeletal muscle and 67% showed ragged red fibres and/or cytochrome c oxidase-negative fibres. T1-weighted MR images showed increased signal intensity in the calf muscle of all patients except one. The involvement of calf muscle was confirmed by 31P magnetic resonance spectroscopy of resting muscle, which disclosed abnormalities in metabolite ratios in all patients. However, muscle oxidative metabolism assessed during recovery from exercise was normal in patients with s-IBM, as maximum rates of mitochondrial ATP production and post-exercise ADP recovery rates were within the normal range in all cases. We conclude that muscle mitochondrial abnormalities are a secondary process and unlikely to play a significant role in the pathogenesis of s-IBM.

  • Spontaneous intracranial hypotension.

    2 July 2018

    The clinical features and radiological appearances of spontaneous intracranial hypotension are described in three patients and the medical literature is reviewed. Awareness of this condition and its differentiation from more sinister meningitic processes is important to avoid unnecessary invasive investigations and to allow prompt diagnosis and effective treatment.

  • A mitochondrial encephalomyopathy. A combined 31P magnetic resonance and biochemical investigation.

    2 July 2018

    A 15-year-old girl presented with recurrent encephalopathic episodes, epilepsy, myopathy and chronic lactic acidosis. A muscle biopsy revealed the presence of ragged red fibres and mitochondria with paracrystalline inclusions. Biochemical studies on freshly isolated skeletal muscle mitochondria demonstrated a deficiency of NADH-CoQ reductase activity. Investigation of her gastrocnemius muscle at rest by phosphorus nuclear magnetic resonance displayed a reduced phosphocreatine concentration with elevated levels of inorganic phosphate and ADP. Abnormalities were also apparent in her brain spectrum. It is therefore possible that the mitochondrial defect present in skeletal muscle is also being expressed in the brain.