Michael G Hanna

Cleveland Clinic, Cleveland, Ohio, United States

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Publications (261)

  • Dipa L. Raja Rayan · Michael G. Hanna
    [Show abstract] [Hide abstract] ABSTRACT: A case of onset of episodes of weakness in teens, cardiac arrhythmias in childhood and facial dysmorphism. A mutation was found in the potassium channel KCNJ2 consistent with a diagnosis of Andersen-Tawil Syndrome.
    Chapter · Jan 2017
  • Robert D. S. Pitceathly · Shamima Rahman · Michael G. Hanna
    [Show abstract] [Hide abstract] ABSTRACT: A 64 year old woman presenting with ptosis, ophthalmoparesis, fatigue and exercise intolerance with disease onset in the fourth decade and no family history of neurological disease. Muscle biopsy revealed cytochrome-c oxidase deficient and ragged red fibres and Southern blot analysis confirmed multiple mitochondrial DNA deletions due to compound heterozygous POLG mutations.
    Chapter · Jan 2017
  • Dipa L. Raja Rayan · Michael G. Hanna
    [Show abstract] [Hide abstract] ABSTRACT: A case of stiffness from childhood and episodes of transient weakness which in later life to mild proximal weakness. It was associated with muscle hypertrophy and myotonia. Two mutations were found in the chloride channel gene, CLCN1 consistent with a diagnosis of recessive myotonia congenita
    Chapter · Jan 2017
  • Dipa L. Raja Rayan · Michael G. Hanna
    [Show abstract] [Hide abstract] ABSTRACT: A case of inherited episodes of weakness and myotonia from childhood progressing in middle age to fixed proximal weakness. A mutation was found in the sodium channel, SCN4A consistent with hyperkalaemic periodic paralysis.
    Chapter · Jan 2017
  • Conference Paper · Oct 2016
  • Article · Oct 2016 · Neuromuscular Disorders
  • Article · Oct 2016 · Neuromuscular Disorders
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    [Show abstract] [Hide abstract] ABSTRACT: A number of promising experimental therapies for Duchenne muscular dystrophy (DMD) are emerging. Clinical trials currently rely on invasive biopsies or motivation-dependent functional tests to assess outcome. Quantitative muscle magnetic resonance imaging (MRI) could offer a valuable alternative and permit inclusion of non-ambulant DMD subjects. The aims of our study were to explore the responsiveness of upper-limb MRI muscle-fat measurement as a non-invasive objective endpoint for clinical trials in non-ambulant DMD, and to investigate the relationship of these MRI measures to those of muscle force and function.
    Full-text Article · Sep 2016 · PLoS ONE
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor-1 gene (SIGMAR1) and review the phenotypic spectrum of mutations in this gene. Methods: We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations. Results: In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 of SIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1. No other mutations were identified in 16 additional patients with dHMN. Conclusions: We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies.
    Article · Sep 2016 · Neurology
  • Michael Lunn · Michael Hanna · Robin Howard · [...] · Christopher Turner
    [Show abstract] [Hide abstract] ABSTRACT: Neuromuscular diseases have traditionally been overlooked, underdiagnosed and poorly treated when compared with neurological diseases with greater visibility, social impact, or which pose a threat for survival. This chapter provides a comprehensive summary of disorders of peripheral nerve, neuromuscular junction, muscle and the anterior horn cell. Peripheral nerves are bundles of axons, Schwann cells, elaborated myelin and the supporting cellular tissues whose primary purpose is to communicate neural information between the central nervous system (CNS) and peripheral sensory or effector structures. All peripheral nervous system (PNS) axons are ensheathed by Schwann cells and the Schwann cells are, in turn, invested by a continuous layer of basal lamina. Functional or structural abnormalities of the neuromuscular junction (NMJ) interfere with the transmission of neural impulses from motor nerves to muscles. Myasthenic crisis indicates the development of ventilatory failure. The chapter also talks about congenital myasthenic syndromes (CMS), ermatomyositis, polymyositis, necrotising autoimmune myopathy (NAM) and rhabdomyolysis.
    Chapter · Aug 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n=6). Symptoms included myalgia (n=7), exercise intolerance (n=7) and episodes of rhabdomyolysis (n=2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other “typical” features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes.
    Full-text Article · Aug 2016 · Neuromuscular Disorders
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    [Show abstract] [Hide abstract] ABSTRACT: Genetic factors have been suggested to be involved in the pathogenesis of sporadic inclusion body myositis (sIBM). SQSTM1 and VCP are two key genes associated with several neurodegenerative disorders but have yet to be thoroughly investigated in sIBM. A candidate gene analysis was conducted using whole-exome sequencing data from 181 sIBM patients, and whole-transcriptome expression analysis was performed in patients with genetic variants of interest. We identified six rare missense variants in the SQSTM1 and VCP in seven sIBM patients (4.0%). Two variants SQSTM1 p.G194R and the VCP p.R159C were significantly overrepresented in this sIBM cohort compared with controls. Five of these variants had been previously reported in patients with degenerative diseases. The mRNA levels of MHC genes were up-regulated, this elevation being more pronounced in SQSTM1 patient group. We report for the first time potentially pathogenic SQSTM1 variants and expand the spectrum of VCP variants in sIBM. These data suggests that defects in neurodegenerative pathways may confer genetic susceptibility to sIBM and reinforce the mechanistic overlap in these neurodegenerative disorders.
    Full-text Article · Aug 2016 · Neurobiology of Aging
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    [Show abstract] [Hide abstract] ABSTRACT: The genetic information in mammalian mitochondrial DNA is densely packed; there are no introns and only one sizeable noncoding, or control, region containing key cis-elements for its replication and expression. Many molecules of mitochondrial DNA bear a third strand of DNA, known as " 7S DNA, " which forms a displacement (D-) loop in the control region. Here we show that many other molecules contain RNA as a third strand. The RNA of these R-loops maps to the control region of the mitochondrial DNA and is complementary to 7S DNA. Ribonuclease H1 is essential for mitochondrial DNA replication; it degrades RNA hybridized to DNA, so the R-loop is a potential substrate. In cells with a pathological variant of ribonucle-ase H1 associated with mitochondrial disease, R-loops are of low abundance, and there is mitochondrial DNA aggregation. These findings implicate ribonuclease H1 and RNA in the physical segregation of mitochondrial DNA, perturbation of which represents a previously unidentified disease mechanism. RNase H1 | R-loop | mitochondrial DNA | DNA segregation | mitochondrial disease
    Full-text Article · Jul 2016 · Proceedings of the National Academy of Sciences
  • [Show abstract] [Hide abstract] ABSTRACT: Episodic ataxia type 1 (EA1) is an autosomal dominant channelopathy caused by mutations in KCNA1, which encodes the voltage-gated potassium channel, Kv1.1. Eleven members of an EA family were evaluated with molecular and functional studies. A novel c.746T>G (p.Phe249Cys) missense mutation of KCNA1 segregated in the family members with episodic ataxia, myokymia, and malignant hyperthermia susceptibility. No mutations were found in the known malignant hyperthermia genes RYR1 or CACNA1S. The Phe249Cys-Kv1.1 channels did not show any currents upon functional expression, confirming a pathogenic role of the mutation. Malignant hyperthermia may be a presentation of KCNA1 mutations, which has significant implications for the clinical care of these patients and illustrates the phenotypic heterogeneity of KCNA1 mutations.
    Article · Jun 2016 · Neurogenetics
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including LGMD1C, rippling muscle disease, distal myopathy and isolated hyperCKemia. Aims: To present a series of patients with exercise intolerance and rhabdomyolysis caused by mutations in CAV3. Methods: Clinical phenotype, genetic findings, muscle biopsy analysis and immunoblotting are described in eight patients from six families. Results: Symptoms included myalgia (n=7), exercise intolerance (n=6) and episodes of rhabdomyolysis (n=2). A previous heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immuno-labelling in sections was normal in 3/4 patients however, immunoblotting showed more than 50% reduction compared with controls in 5 patients. Conclusion: This case series demonstrated that rhabdomyolysis can be caused by mutations in CAV3 and broadens the phenotypic spectrum of caveolinopathies. Defects in CAV3 should therefore be considered in patients presenting with rhabdomyolysis. Caveolin-3 expression may be normal on immunohistochemical study on sections, but immunoblotting proved to be a more sensitive method to detect reduced caveolin-3.
    Conference Paper · Mar 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Hypokalamic periodic paralysis (hypoPP) is a muscle channelopathy characterised by episodes of focal or generalised attacks of weakness accompanied by low serum potassium. Treatment of acute attacks is limited to potassium supplement either taken orally or intravenously. Recent animal studies suggested that bumetanide may be useful in treating both acute attacks as well as a preventative agent. Aims: We designed a clinical trial to explore possible efficacy and safety aspects of bumetanide in hypoPP. Method: Randomised double blind placebo controlled phase II clinical trial with a crossover design carried out at the MRC Centre for Neuromuscular Diseases, London, aiming to recruit a total of 12 participants. A focal attack of HypoPP is provoked by exercise in a hand muscle (using the McManis protocol) and participants receive either placebo or bumetanide as a single dose on two different occasions. Electrophysiological measurements are used to assess the severity and the duration of the attack. Results: The results of the first participants are presented. There were no serious adverse events. Vital signs and serum potassium levels were stable over a period of 4 hours after treatment intake in all participants. Outcome measurements are discussed. Conclusions: This is the first time bumetanide is utilised as a treatment option for patients with hypoPP. Interim results indicate that bumetanide is safe to use as a single dose in this patient group. The McManis test, used here as a procedure and an outcome measurement in a clinical trial for the first time, is well tolerated and produces reliable results.
    Conference Paper · Mar 2016
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    Full-text Conference Paper · Mar 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Abnormal protein aggregation is observed in an expanding number of neurodegenerative diseases. Here, we describe a mechanism for intracellular toxic protein aggregation induced by an unusual mutation event in families affected by axonal neuropathy. These families carry distinct frameshift variants in NEFH (neurofilament heavy), leading to a loss of the terminating codon and translation of the 3' UTR into an extra 40 amino acids. In silico aggregation prediction suggested the terminal 20 residues of the altered NEFH to be amyloidogenic, which we confirmed experimentally by serial deletion analysis. The presence of this amyloidogenic motif fused to NEFH caused prominent and toxic protein aggregates in transfected cells and disrupted motor neurons in zebrafish. We identified a similar aggregation-inducing mechanism in NEFL (neurofilament light) and FUS (fused in sarcoma), in which mutations are known to cause aggregation in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, respectively. In summary, we present a protein-aggregation-triggering mechanism that should be taken into consideration during the evaluation of stop-loss variants.
    Full-text Article · Mar 2016 · The American Journal of Human Genetics
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. Methods: Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase. Results: The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form-36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined). Conclusions: DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis. Classification of evidence: These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.
    Article · Feb 2016 · Neurology
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    Susan E. Tomlinson · S. Veronica Tan · David Burke · [...] · Michael G. Hanna
    [Show abstract] [Hide abstract] ABSTRACT: Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P < 0.00007) and depolarizing currents (P < 0.001) in threshold electrotonus. In the recovery cycle, refractoriness (P < 0.0002) and superexcitability (P < 0.006) were increased. Cav2.1 dysfunction in episodic ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development. © 2016 The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
    Full-text Article · Feb 2016 · Brain

Publication Stats

5k Citations


  • 2015
    • Cleveland Clinic
      Cleveland, Ohio, United States
    • University College London
      • Department of Molecular Neuroscience
      Londinium, England, United Kingdom
  • 2013
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2012-2013
    • Newcastle University
      • Institute for Ageing and Health
      Newcastle-on-Tyne, England, United Kingdom
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
    • Royal Free London NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2005
    • Louisiana State University Health Sciences Center Shreveport
      Shreveport, Louisiana, United States
  • 2003
    • Mahidol University
      Siayuthia, Bangkok, Thailand
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 2000
    • University of London
      Londinium, England, United Kingdom