Michael G Hanna

University College London, Londinium, England, United Kingdom

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Publications (332)1843.57 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The diagnosis of inclusion body myositis (IBM) can be challenging as it can be difficult to clinically distinguish from other forms of myositis, particularly polymyositis (PM). Recent studies have shown frequent presence of autoantibodies directed against cytosolic 5'-nucleotidase 1A (cN-1A) in patients with IBM. We therefore, examined the autoantigenicity and disease specificity of major epitopes of cN-1A in patients with sporadic IBM compared with healthy and disease controls. Serum samples obtained from patients with IBM (n=238), PM and dermatomyositis (DM) (n=185), other autoimmune diseases (n=246), other neuromuscular diseases (n=93) and healthy controls (n=35) were analysed for the presence of autoantibodies using immunodominant cN-1A peptide ELISAs. Autoantibodies directed against major epitopes of cN-1A were frequent in patients with IBM (37%) but not in PM, DM or non-autoimmune neuromuscular diseases (<5%). Anti-cN-1A reactivity was also observed in some other autoimmune diseases, particularly Sjögren's syndrome (SjS; 36%) and systemic lupus erythematosus (SLE; 20%). In summary, we found frequent anti-cN-1A autoantibodies in sera from patients with IBM. Heterogeneity in reactivity with the three immunodominant epitopes indicates that serological assays should not be limited to a distinct epitope region. The similar reactivities observed for SjS and SLE demonstrate the need to further investigate whether distinct IBM-specific epitopes exist. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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    ABSTRACT: We present follow up data on the original case of 'zebra body myopathy' published by Lake and Wilson in 1975. Pathological features in a second biopsy performed at the age of 29 years included a wide variation in fibre size, multiple split fibres, excess internal nuclei and endomysial connective tissue, rimmed vacuoles, accumulation of myofibrillar material and large 'wiped out' areas lacking stain for oxidative enzymes. The presence of nemaline rods and actin-like filaments in addition to small zebra bodies suggested ACTA1 as a candidate gene. This has been confirmed by the identification of a novel c.1043T.p.Leu348Gln mutation, which probably occurred de novo. This case illustrates that the myopathy associated with zebra bodies is part of the spectrum of myopathies associated with the ACTA1 gene. It also highlights that accumulation of actin filaments is not confined to severe neonatal ACTA1 cases and that progression of weakness can occur in congenital myopathies, as the patient is now wheelchair bound and can only stand with the aid of a walking frame. Copyright © 2015 Elsevier B.V. All rights reserved.
    Neuromuscular Disorders 02/2015; DOI:10.1016/j.nmd.2015.02.003 · 3.13 Impact Factor
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    ABSTRACT: A previous study showed that, in carriers of the apolipoprotein E (APOE) genotype ε3/ε3 or ε3/ε4, the presence of a very long (VL) polyT repeat allele in "translocase of outer mitochondrial membrane 40" (TOMM40) was less frequent in patients with sporadic inclusion body myositis (sIBM) compared with controls and associated with a later age of sIBM symptom onset, suggesting a protective effect of this haplotype. To further investigate the influence of these genetic factors in sIBM, we analyzed a large sIBM cohort of 158 cases as part of an International sIBM Genetics Study. No significant association was found between APOE or TOMM40 genotypes and the risk of developing sIBM. We found that the presence of at least 1 VL polyT repeat allele in TOMM40 was significantly associated with about 4 years later onset of sIBM symptoms. The age of onset was delayed by 5 years when the patients were also carriers of the APOE genotype ε3/ε3. In addition, males were likely to have a later age of onset than females. Therefore, the TOMM40 VL polyT repeat, although not influencing disease susceptibility, has a disease-modifying effect on sIBM, which can be enhanced by the APOE genotype ε3/ε3. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neurobiology of Aging 01/2015; DOI:10.1016/j.neurobiolaging.2014.12.039 · 4.85 Impact Factor
  • Pietro Fratta, Michael G Hanna
    The Lancet Neurology 01/2015; 14(1):13-4. DOI:10.1016/S1474-4422(14)70239-X · 21.82 Impact Factor
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    ABSTRACT: Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. Ongoing developments include: genetic studies that may provide insights regarding the pathogenesis of IBM, improved histopathological markers, the description of a new IBM autoantibody, scrutiny of the diagnostic utility of clinical features and biomarkers, the refinement of diagnostic criteria, the emerging use of MRI as a diagnostic and monitoring tool, and new pathogenic insights that have led to novel therapeutic approaches being trialled for IBM, including treatments with the objective of restoring protein homeostasis and myostatin blockers. The effect of exercise in IBM continues to be investigated. However, despite these ongoing developments, the aetiopathogenesis of IBM remains uncertain. A translational and multidisciplinary collaborative approach is critical to improve the diagnosis, treatment, and care of patients with IBM.
    Current Rheumatology Reports 12/2014; 16(12):477. DOI:10.1007/s11926-014-0477-9 · 2.45 Impact Factor
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    ABSTRACT: Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-m-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 muta-tions in CMT2 were mainly loss-of-function nonsense in the 5 0 region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.
    The American Journal of Human Genetics 11/2014; DOI:10.1016/j.ajhg.2014.10.002 · 11.20 Impact Factor
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    ABSTRACT: Single large-scale mitochondrial DNA (mtDNA) deletions (SLSMDs) are amongst the most frequently diagnosed mtDNA disorders in childhood, yet their natural history remains poorly understood. We report the natural history of a large multicentre cohort of such children.
    Journal of Inherited Metabolic Disease 10/2014; DOI:10.1007/s10545-014-9778-4 · 4.14 Impact Factor
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    ABSTRACT: Mutations in the skeletal muscle channel (SCN4A), encoding the Nav1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects of many of these mutations on channel function have been characterized both in vitro and in vivo. However, little is known about the consequences of SCN4A mutations downstream from their impact on the electrophysiology of the Nav1.4 channel. Here we report the discovery of a novel SCN4A mutation (c.1762A>G; p.I588V) in a patient with myotonia and periodic paralysis, located within the S1 segment of the second domain of the Nav1.4 channel. Using N-ethyl-N-nitrosourea mutagenesis, we generated and characterized a mouse model (named draggen), carrying the equivalent point mutation (c.1744A>G; p.I582V) to that found in the patient with periodic paralysis and myotonia. Draggen mice have myotonia and suffer from intermittent hind-limb immobility attacks. In-depth characterization of draggen mice uncovered novel systemic metabolic abnormalities in Scn4a mouse models and provided novel insights into disease mechanisms. We discovered metabolic alterations leading to lean mice, as well as abnormal AMP-activated protein kinase activation, which were associated with the immobility attacks and may provide a novel potential therapeutic target.
    Brain 10/2014; DOI:10.1093/brain/awu292 · 10.23 Impact Factor
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    ABSTRACT: Laryngospasm is a rare but potentially life-threatening occurrence in infants and usually has infective, allergic, metabolic, or anatomic causes. Underlying genetic conditions are rarely considered. Mutations in SCN4A encoding the voltage-gated sodium channel NaV1.4 have been implicated in a wide spectrum of neuromuscular disorders with variable onset, ranging from a rare form of congenital myasthenic syndrome to both hypokalemic and hyperkalemic forms of periodic paralysis and paramyotonia congenita. Here we report on 3 unrelated patients without family history presenting with recurrent, life-threatening episodes of laryngospasm from the first months of life. Clinical features more typically associated with SCN4A-related disorders such as generalized muscle hypertrophy with clinical or electrical myotonia evolved later in life. All patients were found to be heterozygous for the same SCN4A mutation, c.3917G>A; p.Gly1306Glu. Treatment with carbamazepine resulted in complete abolition of recurrent laryngospasm and alleviated symptoms associated with myotonia and muscle stiffness. We conclude that SCN4A mutations ought to be considered in the differential diagnosis of recurrent infantile laryngospasm because timely institution of treatment can be life-saving.
    Pediatrics 10/2014; 134(5). DOI:10.1542/peds.2013-3727 · 5.30 Impact Factor
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    ABSTRACT: Progressive external ophthalmoplegia is a common clinical feature in mitochondrial disease caused by nuclear DNA defects and single, large-scale mitochondrial DNA deletions and is less frequently associated with point mutations of mitochondrial DNA. Peripheral neuropathy is also a frequent manifestation of mitochondrial disease, although its prevalence and characteristics varies considerably among the different syndromes and genetic aetiologies. Based on clinical observations, we systematically investigated whether the presence of peripheral neuropathy could predict the underlying genetic defect in patients with progressive external ophthalmoplegia. We analysed detailed demographic, clinical and neurophysiological data from 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia. Seventy-eight patients (67%) had a single mitochondrial DNA deletion, 12 (10%) had a point mutation of mitochondrial DNA and 26 (22%) had mutations in either POLG, C10orf2 or RRM2B, or had multiple mitochondrial DNA deletions in muscle without an identified nuclear gene defect. Seventy-seven patients had neurophysiological studies; of these, 16 patients (21%) had a large-fibre peripheral neuropathy. The prevalence of peripheral neuropathy was significantly lower in patients with a single mitochondrial DNA deletion (2%) as compared to those with a point mutation of mitochondrial DNA or with a nuclear DNA defect (44% and 52%, respectively; P < 0.001). Univariate analyses revealed significant differences in the distribution of other clinical features between genotypes, including age at disease onset, gender, family history, progressive external ophthalmoplegia at clinical presentation, hearing loss, pigmentary retinopathy and extrapyramidal features. However, binomial logistic regression analysis identified peripheral neuropathy as the only independent predictor associated with a nuclear DNA defect (P = 0.002; odds ratio 8.43, 95% confidence interval 2.24-31.76). Multinomial logistic regression analysis identified peripheral neuropathy, family history and hearing loss as significant predictors of the genotype, and the same three variables showed the highest performance in genotype classification in a decision tree analysis. Of these variables, peripheral neuropathy had the highest specificity (91%), negative predictive value (83%) and positive likelihood ratio (5.87) for the diagnosis of a nuclear DNA defect. These results indicate that peripheral neuropathy is a rare finding in patients with single mitochondrial DNA deletions but that it is highly predictive of an underlying nuclear DNA defect. This observation may facilitate the development of diagnostic algorithms. We suggest that nuclear gene testing may enable a more rapid diagnosis and avoid muscle biopsy in patients with progressive external ophthalmoplegia and peripheral neuropathy.
    Brain 10/2014; DOI:10.1093/brain/awu279 · 10.23 Impact Factor
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    ABSTRACT: Recurrent rhabdomyolysis complicates a number of inherited muscle and metabolic disorders and represents a serious, potentially life-threatening condition which frequently requires critical care. Identification of the underlying genetic cause has traditionally relied upon detailed history and examination findings which subsequently guide the investigative work-up. However, in many cases the causative molecular defect remains undetermined. This study aims to investigate whether utilising next-generation sequencing (NGS) technology early in the diagnostic pathway might offer a rapid, cost-effective tool for the diagnosis of patients with recurrent attacks of rhabdomyolysis when a genetic aetiology is suspected. We have designed a “rhabdomyolysis gene panel” comprised of 48 genes known or predicted to cause rhabdomyolysis using NGS technology. Over 200 patients have been recruited. In addition, array CGH and whole exome sequencing may be used. A pilot study of 53 patients with a panel of sequenced 35 rhabdomyolysis genes using an amplicon based sequencing panel on an Illumina MiSeq was performed. 52 of the first 53 first evaluated patients have a variant in at least 1 gene. 49 patients have heterozygous variants in at least two different genes. We identified 15 cases out of 52 with probable pathogenic mutations using this approach. The pilot study showed that the rhabdomyolysis genetic panel is a potentially useful way to identify genetic alterations in patients with rhabdomyolysis. The high number of symptomatic patients with mutations identified in more than one gene associated with rhabdomyolysis suggests that gene–gene interaction(s) may play an important role. We are currently preparing a new extended panel of 48 genes.
    Neuromuscular Disorders 10/2014; 24(s 9–10):801. DOI:10.1016/j.nmd.2014.06.036 · 3.13 Impact Factor
  • Ros Quinlivan, Emma Matthews, Michael G Hanna
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    ABSTRACT: Many neuromuscular disorders require complex multisystem management. This is especially true for the rapidly growing numbers of young adults surviving congenital and childhood onset conditions following improved multidisciplinary care and the routine use of home ventilation. Surveys from the United Kingdom and Netherlands indicate that neuromuscular disorder patients report their services to be at best 'average' and more often 'poor' in quality. Centralization of care to a small number of specialist centres to increase critical mass and thus improve the expertise of clinical teams has been recommended.
    Current Opinion in Neurology 10/2014; 27(5):607-613. DOI:10.1097/WCO.0000000000000132 · 5.73 Impact Factor
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    ABSTRACT: Purpose of review This article reviews recent advances in clinical, genetic, diagnostic and pathophysiological aspects of the skeletal muscle channelopathies. Recent findings Genetic advances include the use of the minigene assay to confirm pathogenicity of splice site mutations of CLC-1 chloride channels and a new gene association for Andersen-Tawil syndrome. Mutations causing a gating pore current have been established as a pathomechanism for hypokalaemic periodic paralysis. Mutations in nonchannel genes, including the mitochondrial mATP6/8 genes, have been linked to channelopathy-like episodic weakness. Advances in diagnostic tools include the use of MRI and muscle velocity recovery cycles to evaluate myotonia congenita patients. Specific neonatal presentations of sodium channel myotonia are now well documented. An international multicentre placebo-controlled randomized clinical trial established that mexiletine is an effective therapy in the nondystrophic myotonias. This is the first evidence-based treatment for a skeletal muscle channelopathy. Recent evidence in mouse models indicated that bumetanide can prevent attacks of hypokalaemic periodic paralysis, but this has not yet been tested in patient trials. Summary Advances in genetic, clinical, diagnostic and pathomechanistic understanding of skeletal muscle channelopathies are being translated into improved therapies. Mexiletine is the first evidence-based treatment for nondystrophic myotonias. Bumetanide is effective in preventing attacks in mouse models of hypokalaemic periodic paralysis and now needs to be tested in patients.
    Current Opinion in Neurology 10/2014; 27(5):583-590. DOI:10.1097/WCO.0000000000000127 · 5.73 Impact Factor
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    ABSTRACT: We studied the extent and nature of renal involvement in a cohort of 117 adult patients with mitochondrial disease, by measuring urinary retinol-binding protein (RBP) and albumin; established markers of tubular and glomerular dysfunction, respectively. Seventy-five patients had the m.3243A>G mutation and the most frequent phenotypes within the entire cohort were 14 with MELAS, 33 with MIDD, and 17 with MERRF. Urinary RBP was increased in 29 of 75 of m.3243A>G patients, whereas albumin was increased in 23 of the 75. The corresponding numbers were 16 and 14, respectively, in the 42 non-m.3243A>G patients. RBP and albumin were higher in diabetic m.3243A>G patients than in nondiabetics, but there were no significant differences across the three major clinical phenotypes. The urine proteome (mass spectrometry) and metabonome (nuclear magnetic resonance) in a subset of the m.3243A>G patients were markedly different from controls, with the most significant alterations occurring in lysosomal proteins, calcium-binding proteins, and antioxidant defenses. Differences were also found between asymptomatic m.3243A>G carriers and controls. No patients had an elevated serum creatinine level, but 14% had hyponatremia, 10% had hypophosphatemia, and 14% had hypomagnesemia. Thus, abnormalities in kidney function are common in adults with mitochondrial disease, exist in the absence of elevated serum creatinine, and are not solely explained by diabetes.Kidney International advance online publication, 10 September 2014; doi:10.1038/ki.2014.297.
    Kidney International 09/2014; DOI:10.1038/ki.2014.297 · 8.52 Impact Factor
  • Journal of Neurology Neurosurgery & Psychiatry 09/2014; 85(10):e4-e4. DOI:10.1136/jnnp-2014-309236.98 · 5.58 Impact Factor
  • Journal of Neurology Neurosurgery & Psychiatry 09/2014; 85(10):e4-e4. DOI:10.1136/jnnp-2014-309236.30 · 5.58 Impact Factor
  • Journal of Neurology Neurosurgery & Psychiatry 09/2014; 85(10):e4-e4. DOI:10.1136/jnnp-2014-309236.173 · 5.58 Impact Factor
  • E Matthews, M G Hanna
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    ABSTRACT: Myotonia is often a painful and disabling symptom which can interfere with daily motor function resulting in significant morbidity. Since myotonic disorders are rare it has generally proved difficult to obtain class I level evidence for anti-myotonic drug efficacy by performing randomized placebo controlled trials. Current treatment guidance is therefore largely based on anecdotal reports and physician experience. Despite the genetic channel heterogeneity of the myotonic disorders the sodium channel antagonists have become the main focus of pharmacological interest. Mexiletine is currently regarded as the first choice sodium channel blocker based on a recent placebo controlled randomized trial. However, some patients do not respond to mexiletine or have significant side effects limiting its use. There is a clinical need to develop additional antimyotonic agents. The study of Desaphy et al. is therefore important and provides in vitro evidence that a number of existing drugs with sodium channel blocking capability could potentially be repurposed as anti-myotonic drugs. Translation of these potentially important in vitro findings into clinical practice requires carefully designed randomized controlled trials. Here we discuss Desaphy's findings in the wider context of attempts to develop additional therapies for patients with clinically significant myotonia.
    Experimental Neurology 09/2014; 261. DOI:10.1016/j.expneurol.2014.09.003 · 4.62 Impact Factor
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    ABSTRACT: Sporadic inclusion body myositis (sIBM) is the commonest idiopathic inflammatory muscle disease in people over 50 years old. It is characterized by slowly progressive muscle weakness and atrophy, with typical pathological changes of inflammation, degeneration and mitochondrial abnormality in affected muscle fibres. The cause(s) of sIBM are still unknown, but are considered complex, with the contribution of multiple factors such as environmental triggers, aging and genetic susceptibility. This review summarizes the current understanding of the genetic contributions to sIBM and provides some insights for future research in this mysterious disease with the advantage of the rapid development of advanced genetic technology. An international sIBM genetic study is ongoing and whole-exome sequencing will be applied in a large cohort of sIBM patients with the aim of unravelling important genetic risk factors for sIBM.
    Orphanet Journal of Rare Diseases 06/2014; 9(1):88. DOI:10.1186/1750-1172-9-88 · 3.96 Impact Factor
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Publication Stats

4k Citations
1,843.57 Total Impact Points


  • 1998–2015
    • University College London
      • • Department of Molecular Neuroscience
      • • Institute of Neurology
      Londinium, England, United Kingdom
  • 2009–2014
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
    • University of Coimbra
      Coímbra, Coimbra, Portugal
  • 2013
    • University of Pavia
      Ticinum, Lombardy, Italy
    • University of Texas Southwestern Medical Center
      Dallas, Texas, United States
  • 2003–2013
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Dubowitz Neuromuscular Centre (DNC)
      Londinium, England, United Kingdom
    • Ramathibodi Hospital
      Krung Thep, Bangkok, Thailand
  • 2002–2013
    • University College London Hospitals NHS Foundation Trust
      • Department of Neurosurgery (National Hospital for Neurology and Neurosurgery)
      Londinium, England, United Kingdom
    • University of Nottingham
      Nottigham, England, United Kingdom
  • 2001–2013
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 2011–2012
    • University Center Rochester
      • Department of Neurology
      Rochester, Minnesota, United States
  • 2009–2012
    • MRC National Institute for Medical Research
      Londinium, England, United Kingdom
  • 2010
    • Royal Liverpool and Broadgreen University Hospitals NHS Trust
      Liverpool, England, United Kingdom
  • 2000–2009
    • Newcastle University
      • Institute for Ageing and Health
      Newcastle-on-Tyne, England, United Kingdom
  • 2005–2006
    • London Research Institute
      Londinium, England, United Kingdom
    • Louisiana State University Health Sciences Center Shreveport
      Shreveport, Louisiana, United States
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
    • Jaslok Hospital and Research Centre
      Mumbai, Maharashtra, India
  • 1995–2001
    • University of London
      • The School of Pharmacy
      Londinium, England, United Kingdom
    • The Kings College
      Brooklyn, New York, United States
  • 1997
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom