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Tasca G.,Don Carlo Gnocchi Onlus Foundation | Penttila S.,University of Tampere | Giglio V.,Center for Neuromuscular Diseases | Ottaviani P.,Instituto Dermopatico dellImmacolata | And 4 more authors.
Neuromuscular Disorders | Year: 2012

Laing distal myopathy is an autosomal dominant disease due to mutations in the gene encoding for the human slow-β myosin heavy chain, MYH7. Most reports describe it as a mild, early onset myopathy with involvement usually restricted to foot extensors, hand finger extensors and neck flexors, and unspecific findings on muscle biopsy. We identified the first two Italian families with Laing distal myopathy, harboring two novel mutations in the MYH7 gene and performed clinical, neurophysiological, pathological, muscle MRI and cardiological investigations on affected members from the two families. Subjects from one family presented a moderate-severe phenotype, with proximal together with distal involvement and even loss of ambulation at advanced age. One patient displayed atypical muscle biopsy findings including cytoplasmic bodies and myofibrillar myopathy-like features. Affected members from the second family shared a very mild phenotype, with weakness largely limited to long toe and foot extensors and/or late onset. No patient showed any sign of heart involvement. Our study significantly broadens the clinical and pathological spectrum of Laing distal myopathy. We suggest that MYH7 screening should be considered in undiagnosed late-onset distal myopathy or cytoplasmic body myopathy patients. © 2012 Elsevier B.V.


Gardiner A.R.,Reta Lila Weston Laboratories | Gardiner A.R.,Center for Neuromuscular Diseases | Dale R.C.,University of Sydney | Kurian M.A.,University College London | And 18 more authors.
Neurology | Year: 2012

Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/ IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence ofmigraine and HMwith PKD/IC, and the association ofmutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders. © 2012 American Academy of Neurology.


Efthymiou S.,University College London | Efthymiou S.,Center for Neuromuscular Diseases | Manole A.,University College London | Manole A.,Center for Neuromuscular Diseases | And 2 more authors.
Current Opinion in Neurology | Year: 2016

Purpose of review Neuromuscular diseases are clinically and genetically heterogeneous and probably contain the greatest proportion of causative Mendelian defects than any other group of conditions. These disorders affect muscle and/or nerves with neonatal, childhood or adulthood onset, with significant disability and early mortality. Along with heterogeneity, unidentified and often very large genes require complementary and comprehensive methods in routine molecular diagnosis. Inevitably, this leads to increased diagnostic delays and challenges in the interpretation of genetic variants. Recent findings The application of next-generation sequencing, as a research and diagnostic strategy, has made significant progress into solving many of these problems. The analysis of these data is by no means simple, and the clinical input is essential to interpret results. Summary In this review, we describe using examples the recent advances in the genetic diagnosis of neuromuscular disorders, in research and clinical practice and the latest developments that are underway in nextgeneration sequencing. We also discuss the latest collaborative initiatives such as the Genomics England (Department of Health, UK) genome sequencing project that combine rare disease clinical phenotyping with genomics, with the aim of defining the vast majority of rare disease genes in patients as well as modifying risks and pharmacogenomics factors. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Brady S.,Center for Neuromuscular Diseases | Godfrey R.,Brunel University | Scalco R.S.,Center for Neuromuscular Diseases | Quinlivan R.M.,University College London
BMJ Case Reports | Year: 2014

Despite the majority of patients with McArdle disease reporting symptoms including fatigue, cramps and episodes of myoglobinuria from early childhood, diagnosis is often delayed by several decades. Additionally, many individuals with rhabdomyolysis remain undiagnosed. The occurrence of symptoms during exercise, particularly isometric muscle contraction such as heavy lifting, is well known in McArdle disease. However, isometric muscle contraction that occurs with emotion is not recognised as exercise and may be missed as a trigger for rhabdomyolysis, potentially leading to a delay in diagnosis. Three patients are presented here, all with symptoms from childhood including episodes of rhabdomyolysis induced by tense emotional situations without physical exertion; two patients reported recurrent episodes while watching rather than playing football. The remaining patient developed rhabdomyolysis during a heated argument. These patients' histories emphasise the risk from sustained isometric muscle contraction that occurs in emotive situations for patients with McArdle disease. Copyright 2014 BMJ Publishing Group. All rights reserved.


Brady S.,Center for Neuromuscular Diseases | Melath S.,Northwick Park Hospital | Scalco R.S.,Center for Neuromuscular Diseases | Penn H.,Northwick Park Hospital
BMJ Case Reports | Year: 2014

A 35-year-old Afro-Caribbean woman presented with dyspnoea, urticarial rash and myalgia 1 month after treatment for a community-acquired respiratory tract infection. Investigations revealed raised antisynthetase antibodies, lung fibrosis and an inflammatory myopathy. The patient was diagnosed with antisynthetase syndrome (ASS) and started on immunosuppressive medication. Despite treatment she died 4 weeks after presentation from a fulminant cardiomyopathy. ASS is a rare condition and is not typically associated with a cardiomyopathy. This case report intends to raise awareness that cardiomyopathy is a potentially fatal complication of ASS. Copyright 2014 BMJ Publishing Group. All rights reserved.


Rajakulendran S.,University College London | Tan S.V.,National Hospital for Neurology and Neurosurgery | Hanna M.G.,National Hospital for Neurology and Neurosurgery | Hanna M.G.,Center for Neuromuscular Diseases
Practical Neurology | Year: 2010

'Ion channelopathies' have emerged in the past decade as a new cause of several neurological diseases. These Mendelian disorders are caused by mutations in genes that encode ion channel subunits and are often characterised by paroxysmal attacks of brain or muscle dysfunction, interspersed with periods of clinical normality. Andersen-Tawil syndrome is one of the rarest and is characterised clinically by the triad of periodic paralysis, cardiac dysrhythmias and skeletal abnormalities. Mutations in a potassium channel gene, KCNJ2 which encodes the potassium channel, Kir2.1, underlie the disorder. Here, the authors describe a patient and review the clinical spectrum and genetic features of the disorder.


Maurer K.,University of Zürich | Maurer K.,University College London | Bostock H.,University College London | Bostock H.,Center for Neuromuscular Diseases | And 2 more authors.
Journal of the Peripheral Nervous System | Year: 2012

Little information is available on the pH sensitivity of the excitability properties of mammalian axons. Computer-assisted threshold tracking in humans has helped to define clinically relevant changes of nerve excitability in response to hyperventilation and ischaemia, but in vivo studies cannot directly differentiate between the impact of pH and other secondary factors. In this investigation, we applied an excitability testing protocol to a rat saphenous skin nerve in vitro preparation. Changes in extracellular pH were induced by altering pCO 2 in the perfusate, and excitability properties of large myelinated fibres were measured in the pH range from 6.9 to 8.1. The main effect of protons on nerve excitability was a near linear increase in threshold which was accompanied by a decrease in strength-duration time constant reflecting mainly a decrease in persistent sodium current. In the recovery cycle, late subexcitability following 7 conditioning stimuli was substantially reduced at acid pH, indicating a block of slow but not of fast potassium channels. Changes in threshold electrotonus were complex, reflecting the combined effects of pH on multiple channel types. These results provide the first systematic data on pH sensitivity of mammalian nerve excitability properties, and may help in the interpretation of abnormal clinical excitability measurements. © 2012 Peripheral Nerve Society.


PubMed | Northwick Park Hospital and Center for Neuromuscular Diseases
Type: | Journal: BMJ case reports | Year: 2014

A 35-year-old Afro-Caribbean woman presented with dyspnoea, urticarial rash and myalgia 1month after treatment for a community-acquired respiratory tract infection. Investigations revealed raised antisynthetase antibodies, lung fibrosis and an inflammatory myopathy. The patient was diagnosed with antisynthetase syndrome (ASS) and started on immunosuppressive medication. Despite treatment she died 4weeks after presentation from a fulminant cardiomyopathy. ASS is a rare condition and is not typically associated with a cardiomyopathy. This case report intends to raise awareness that cardiomyopathy is a potentially fatal complication of ASS.


PubMed | King's College and Center for Neuromuscular Diseases
Type: Journal Article | Journal: Practical neurology | Year: 2016

The anatomical localisation of brainstem syndromes is the domain of the clinical neurologist, though MRI has made an encyclopaedic knowledge of neuroanatomy less crucial. Isolated pontine syndromes comprise 20% of the brainstem lacunar syndromes. Typical presentations such as pure motor hemiparesis and ataxic hemiparesis are easily recognisable but atypical syndromes, particularly when bilateral, may present with puzzling signs. We discuss a patient with an unusual acute bilateral brainstem syndrome, in whom MRI was contraindicated. We use the relevant neuroanatomy to support the likely diagnosis of bilateral caudal pontine tegmentum infarction due to occlusion of a single paramedian pontine tegmental perforating artery.


PubMed | Brunel University, University College London and Center for Neuromuscular Diseases
Type: | Journal: BMJ case reports | Year: 2014

Despite the majority of patients with McArdle disease reporting symptoms including fatigue, cramps and episodes of myoglobinuria from early childhood, diagnosis is often delayed by several decades. Additionally, many individuals with rhabdomyolysis remain undiagnosed. The occurrence of symptoms during exercise, particularly isometric muscle contraction such as heavy lifting, is well known in McArdle disease. However, isometric muscle contraction that occurs with emotion is not recognised as exercise and may be missed as a trigger for rhabdomyolysis, potentially leading to a delay in diagnosis. Three patients are presented here, all with symptoms from childhood including episodes of rhabdomyolysis induced by tense emotional situations without physical exertion; two patients reported recurrent episodes while watching rather than playing football. The remaining patient developed rhabdomyolysis during a heated argument. These patients histories emphasise the risk from sustained isometric muscle contraction that occurs in emotive situations for patients with McArdle disease.

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