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

    12 December 2017

    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.

    28 January 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.

    10 January 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.

    15 February 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 February 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.

    15 February 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.

    28 January 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.

  • Myopathies in the adult patient

    20 November 2017

    Primary muscle disorders (myopathies) are rare, even within a neurology clinic. It has been estimated that there are about 70,000 people in the UK (population ∼62 million) with a peripheral neuromuscular disorder, with about one-half of them having a myopathy. A fundamental distinction is between acquired and inherited myopathies. Currently, a majority of the former will respond to removal of the cause or specific treatment, such as immunosuppression, whereas despite the hopes of 'genetic engineering' the majority of the latter have no specific treatment, although appropriate interventions can greatly improve both morbidity and mortality. For the latter group, genetic counselling issues are of fundamental importance. All of these diseases are best managed by a multidisciplinary team led by a clinician with a specific interest in neuromuscular disease. Many individual myopathies are extremely rare and will not be seen by most neurologists during their careers. The tyro cannot be expected necessarily to identify these rarities, but should have the generic skills to be able to recognize the broad nature of the problem and to refer on as appropriate. However, it would be indefensible to miss a treatable disorder such as myositis, and they should certainly be aware of the major clinical features and management issues of the more common disorders, notably myotonic dystrophy and those with multisystemic manifestations such as the mitochondrial cytopathies. © 2012 Elsevier Ltd. All rights reserved.

  • Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene.

    12 December 2017

    Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280-amino-acid protein containing four LIM domains and a single zinc-finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery-Dreifuss muscular dystrophy, or an early onset myopathy with reducing bodies. It has been proposed that the phenotypic variability is related to the position of the mutation within the FHL1 gene. Here, we report on three British families with a heterogeneous clinical presentation segregating a single FHL1 gene mutation and haplotype, suggesting that this represents a founder mutation. The underlying FHL1 gene mutation was detected by direct sequencing and the founder effect was verified by haplotype analysis of the FHL1 gene locus. A 3-bp insertion mutation (p.Phe127_Thr128insIle) within the second LIM domain of the FHL1 gene was identified in all available affected family members of the three families. Haplotype analysis of the FHL1 region on Xq26 revealed that the families shared a common haplotype. The p.Phe127_Thr128insIle mutation in the FHL1 gene therefore appears to be a British founder mutation and FHL1 gene screening, in particular of exon 6, should therefore be indicated in British patients with a broad phenotypic spectrum of X-linked muscle diseases.

  • Does cytosine-thymine-guanine (CTG) expansion size predict cardiac events and electrocardiographic progression in myotonic dystrophy?

    2 February 2018

    OBJECTIVE: To assess whether the size of the cytosine-thymine-guanine (CTG) expansion mutation in myotonic dystrophy predicts progression of conduction system disease and cardiac events. DESIGN: Longitudinal study involving ECG and clinical follow up over (mean (SD)) 4.8 (1.8) and 6.2 (1.9) years, respectively, of patients stratified by CTG expansion size (E0 to E4). PATIENTS: 73 adult patients under annual review in a regional myotonic dystrophy clinic. Patients were grouped into E0/E1 (n = 25), E2 (n = 34), and E3/E4 (n = 14). RESULTS: The proportion of patients with a QRS complex > 100 ms at baseline increased with the size of the CTG expansion (EO/E1, 4%; E2, 12%; E3/E4, 36%; p = 0.02). This trend was more pronounced at follow up (E0/E1, 4%; E2, 21%; E3/E4, 57%; p = 0.0004). The rate of widening of the QRS complex (ms/year) was similarly related to the size of the mutation (EO/E1, 0.4 (1.3); E2, 1.4 (2.5); E3/E4, 1.5 (1.6); p = 0.04). First degree atrioventricular block was present in 23% of patients at baseline and 34% at follow up, with no significant relation to expansion size. Seven patients suffered a cardiac event during follow up (sudden death in two, permanent pacemaker insertion in three, chronic atrial arrhythmia in two), of whom six were in CTG expansion group E2 or greater. Patients who experienced a cardiac event during follow up had more rapid rates of PR interval increase (9.9 (11.1) v 1.6 (2.9) ms/year; p = 0.008) and a trend to greater QRS complex widening (3.6 (4.5) v 0.9 (1.5) ms/year; p = 0.06) than those who did not. CONCLUSIONS: Larger CTG expansions are associated with a higher rate of conduction disease progression and a trend to increased risk of cardiac events in myotonic dystrophy.