Publications by authors named "Michael G Hanna"

216 Publications

Iterative Reanalysis of Hypertrophic Cardiomyopathy Exome Data Reveals Causative Pathogenic Mitochondrial DNA Variants.

Circ Genom Precis Med 2021 May 10. Epub 2021 May 10.

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London & Barts Heart Centre, St. Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom.

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http://dx.doi.org/10.1161/CIRCGEN.121.003388DOI Listing
May 2021

Annual Renal Ultrasound May Prevent Acute Presentation With Acetazolamide-Associated Urolithiasis.

Neurol Clin Pract 2021 Feb;11(1):e40-e42

MRC Centre for Neuromuscular Diseases (KJS, VV, NJ, SH, DF, MGH, ELM), Queen Square Institute of Neurology, UCL and National Hospital for Neurology and Neurosurgery; and Neurogenetics Unit (RS), National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

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http://dx.doi.org/10.1212/CPJ.0000000000000761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101321PMC
February 2021

VPS13D bridges the ER to mitochondria and peroxisomes via Miro.

J Cell Biol 2021 May;220(5)

Departments of Neuroscience and of Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT.

Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In yeast, the outer mitochondrial membrane GTPase Gem1 is an accessory factor of ERMES, an ER-mitochondria tethering complex that contains lipid transport domains and that functions, partially redundantly with Vps13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro was linked to mitochondrial dynamics but not to lipid transport. Here we show that Miro, including its peroxisome-enriched splice variant, recruits the lipid transport protein VPS13D, which in turn binds the ER in a VAP-dependent way and thus could provide a lipid conduit between the ER and mitochondria. These findings reveal a so far missing link between function(s) of Gem1/Miro in yeast and higher eukaryotes, where Miro is a Parkin substrate, with potential implications for Parkinson's disease pathogenesis.
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http://dx.doi.org/10.1083/jcb.202010004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077184PMC
May 2021

A form of muscular dystrophy associated with pathogenic variants in JAG2.

Am J Hum Genet 2021 May 15;108(5):840-856. Epub 2021 Apr 15.

Centre de Référence Neuromusculaire and Paediatric Neurology Department, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, 1020 Brussels, Belgium.

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.
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http://dx.doi.org/10.1016/j.ajhg.2021.03.020DOI Listing
May 2021

Longitudinal observational study investigating outcome measures for clinical trials in inclusion body myositis.

J Neurol Neurosurg Psychiatry 2021 Apr 13. Epub 2021 Apr 13.

Queen Square Centre for Neuromuscular Diseases, University College Hospitals NHS Foundation Trust, London, UK

Objective: To describe decline in muscle strength and physical function in patients with sporadic inclusion body myositis (IBM).

Methods: Manual muscle testing (MMT), quantitative muscle testing (QMT) and disability scoring using the IBM Functional Rating Scale (IBMFRS) were undertaken for 181 patients for up to 7.3 years. The relationship between MMT, QMT and IBMFRS composite scores and time from onset were examined using linear mixed effects models adjusted for gender and age of disease onset. Adaptive LASSO regression analysis was used to identify muscle groups that best predicted the time elapsed from onset. Cox proportional hazards regression was used to evaluate time to use of a mobility aid.

Results: Multilevel modelling of change in percentage MMT, QMT and IBMFRS score over time yielded an average decline of 3.7% (95% CI 3.1% to 4.3%), 3.8% (95% CI 2.7% to 4.9%) and 6.3% (95% CI 5.5% to 7.2%) per year, respectively. The decline, however, was not linear, with steeper decline in the initial years. Older age of onset was associated with a more rapid IBMFRS decline (p=0.007), but did not influence the rate of MMT/QMT decline. Combination of selected muscle groups allowed for generation of single measures of patient progress (MMT and QMT factors). Median (IQR) time to using a mobility aid was 5.4 (3.6-9.2) years, significantly affected by greater age of onset (HR 1.06, 95% CI 1.04 to 1.09, p<0.001).

Conclusion: This prospective observational study represents the largest IBM cohort to date. Measures of patient progress evaluated in this study accurately predict disease progression in a reliable and useful way to be used in trial design.
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http://dx.doi.org/10.1136/jnnp-2020-325141DOI Listing
April 2021

Uniparental isodisomy of chromosome 2 causing MRPL44-related multisystem mitochondrial disease.

Mol Biol Rep 2021 Mar 19;48(3):2093-2104. Epub 2021 Mar 19.

MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.

Mutations in nuclear-encoded protein subunits of the mitochondrial ribosome are an increasingly recognised cause of oxidative phosphorylation system (OXPHOS) disorders. Among them, mutations in the MRPL44 gene, encoding a structural protein of the large subunit of the mitochondrial ribosome, have been identified in four patients with OXPHOS defects and early-onset hypertrophic cardiomyopathy with or without additional clinical features. A 23-year-old individual with cardiac and skeletal myopathy, neurological involvement, and combined deficiency of OXPHOS complexes in skeletal muscle was clinically and genetically investigated. Analysis of whole-exome sequencing data revealed a homozygous mutation in MRPL44 (c.467 T > G), which was not present in the biological father, and a region of homozygosity involving most of chromosome 2, raising the possibility of uniparental disomy. Short-tandem repeat and genome-wide SNP microarray analyses of the family trio confirmed complete maternal uniparental isodisomy of chromosome 2. Mitochondrial ribosome assembly and mitochondrial translation were assessed in patient derived-fibroblasts. These studies confirmed that c.467 T > G affects the stability or assembly of the large subunit of the mitochondrial ribosome, leading to impaired mitochondrial protein synthesis and decreased levels of multiple OXPHOS components. This study provides evidence of complete maternal uniparental isodisomy of chromosome 2 in a patient with MRPL44-related disease, and confirms that MRLP44 mutations cause a mitochondrial translation defect that may present as a multisystem disorder with neurological involvement.
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http://dx.doi.org/10.1007/s11033-021-06188-1DOI Listing
March 2021

Mitochondrial DNA Analysis from Exome Sequencing Data Improves Diagnostic Yield in Neurological Diseases.

Ann Neurol 2021 Mar 11. Epub 2021 Mar 11.

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.

A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently exhibit neurological manifestations that overlap with other nervous system disorders. However, mitochondrial DNA (mtDNA) is not routinely analyzed in standard clinical WES bioinformatic pipelines. We reanalyzed 11,424 exomes, enriched with neurological diseases, for pathogenic mtDNA variants. Twenty-four different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26063DOI Listing
March 2021

Cardiolipin, Mitochondria, and Neurological Disease.

Trends Endocrinol Metab 2021 Apr 24;32(4):224-237. Epub 2021 Feb 24.

Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK. Electronic address:

Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS) where they modulate membrane fluidity, electric signal transduction, and synaptic stabilization. Abnormal lipid profiles reported in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), are further support for the importance of lipid metablism in the nervous system. Cardiolipin (CL), a mitochondria-exclusive phospholipid, has recently emerged as a focus of neurodegenerative disease research. Aberrant CL content, structure, and localization are linked to impaired neurogenesis and neuronal dysfunction, contributing to aging and the pathogenesis of several neurodegenerative diseases, such as AD and PD. Furthermore, the highly tissue-specific acyl chain composition of CL confers it significant potential as a biomarker to diagnose and monitor the progression in several neurological diseases. CL also represents a potential target for pharmacological strategies aimed at treating neurodegeneration. Given the equipoise that currently exists between CL metabolism, mitochondrial function, and neurological disease, we review the role of CL in nervous system physiology and monogenic and neurodegenerative disease pathophysiology, in addition to its potential application as a biomarker and pharmacological target.
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http://dx.doi.org/10.1016/j.tem.2021.01.006DOI Listing
April 2021

Applying genomic and transcriptomic advances to mitochondrial medicine.

Nat Rev Neurol 2021 Apr 23;17(4):215-230. Epub 2021 Feb 23.

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.

Next-generation sequencing (NGS) has increased our understanding of the molecular basis of many primary mitochondrial diseases (PMDs). Despite this progress, many patients with suspected PMD remain without a genetic diagnosis, which restricts their access to in-depth genetic counselling, reproductive options and clinical trials, in addition to hampering efforts to understand the underlying disease mechanisms. Although they represent a considerable improvement over their predecessors, current methods for sequencing the mitochondrial and nuclear genomes have important limitations, and molecular diagnostic techniques are often manual and time consuming. However, recent advances in genomics and transcriptomics offer realistic solutions to these challenges. In this Review, we discuss the current genetic testing approach for PMDs and the opportunities that exist for increased use of whole-genome NGS of nuclear and mitochondrial DNA (mtDNA) in the clinical environment. We consider the possible role for long-read approaches in sequencing of mtDNA and in the identification of novel nuclear genomic causes of PMDs. We examine the expanding applications of RNA sequencing, including the detection of cryptic variants that affect splicing and gene expression and the interpretation of rare and novel mitochondrial transfer RNA variants.
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http://dx.doi.org/10.1038/s41582-021-00455-2DOI Listing
April 2021

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

Neurology 2021 03 17;96(12):e1595-e1607. Epub 2021 Feb 17.

From the Department of Neurology (A.A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Medical Research Council Centre for Neuromuscular Diseases (M.G.H., P.M.M.) and Institute of Neurology, Department of Neuromuscular Diseases & Centre for Rheumatology (P.M.M.), University College London; Department of Rheumatology & Queen Square Centre for Neuromuscular Diseases (P.M.M.), University College London Hospitals NHS Foundation Trust; Department of Rheumatology (P.M.M.), Northwick Park Hospital, London North West University Healthcare NHS Trust, UK; Department of Neurology (U.A.B.), Leiden University Medical Center, Netherlands; National Institute for Health Research Manchester Biomedical Research Centre (H.C.), Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, UK; Department of Internal Medicine and Clinical Immunology (O.B.), Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France; Novartis Healthcare Pvt. Ltd. (K.A.K), Hyderabad, India; Novartis Pharmaceuticals (M.W., D.A.P.), East Hanover, NJ; Novartis Pharma AG (L.B.T., A.A.S-T.), Basel, Switzerland; Department of Neurology (T.E.L.), The Johns Hopkins University School of Medicine, Baltimore, MD; Institute for Immunology & Infectious Diseases (M.N.), Fiona Stanley Hospital, Murdoch University and Notre Dame University, Perth; Department of Neurology (C.L.), Royal North Shore Hospital, New South Wales; Calvary Health Care Bethlehem (K.A.R.), Caulfield South, Australia; Department of Neurology (M.d.V), Amsterdam University Medical Centre, the Netherlands; Department of Medicine (D.P.A.), University of Miami, FL; Department of Neurology (R.J.B., M.M.D.), University of Kansas Medical Center, Kansas City; Department of Neurology (J.A.L.M.), Newcastle upon Tyne Hospitals NHS Foundation Trust, UK; Department of Neurology (J.T.K.), The Ohio State University Wexner Medical Center, Columbus; Neuromuscular Research Center (B.O., N.C.J.), UC Davis School of Medicine, Sacramento, CA; Department of Neurology (P.V.d.B.), University Hospital Saint-Luc, University of Louvain, Brussels; Neuromuscular Reference Centre, Department of Neurology (J.B.), Antwerp University Hospital; Institute Born-Bunge (J.B.), University of Antwerp; Department of Neurology (J.L.d.B.), Ghent University Hospital, Belgium; Department of Neurology (C.K.), Oregon Health & Science University, Portland; Department of Neurology (W.S.D.), Massachusetts General Hospital, Neuromuscular Diagnostic Center and Electromyography Laboratory, Boston; Department of Neurology (M.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Università Cattolica del Sacro Cuore (M.M.), Rome, Italy; Department of Neurology (S.P.N.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (H.H.J.), University Hospital and University of Zurich, Switzerland; Department of Neurosciences (E.P.), University of Padova School of Medicine; Fondazione IRCCS Istituto Neurologico Carlo Besta (L.M.), Milan; Unit of Neurology and Neuromuscular Disorders (C.R.), Azienda Ospedaliera Universitaria Policlinico G Martino, University of Messina; Center for Neuromuscular Diseases (M.F.), Unit of Neurology, ASST Spedali Civili and University of Brescia, Italy; Nerve and Muscle Center of Texas (A.I.S.), Houston; Neuromuscular Research Center (K.S.), Phoenix, AZ; Department of Neurology (N.A.G.), ALS & Neuromuscular Center, University of California Irvine, Orange; Department of Neurology (M.M.-Y.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (S.Y.), Kumamoto University Hospital; Department of Neurology (N.S.), Tohoku University Hospital, Miyagi; Department of Neurology (M.A.), Tohoku University School of Medicine, Sendai; Department of Neurology (M.K.), Nagoya University Hospital, Aichi; Department of Neurology (H.M.), Osaka City General Hospital; Wakayama Medical University Hospital (K.M.); Tokushima University Hospital (H.N.); Department of Neuromuscular Research (I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; RTI Health Solutions (C.D.R., V.S.L.W.), Research Triangle Park, NC; Copenhagen Neuromuscular Center (J.V.), Rigshospitalet, University of Copenhagen, Denmark; and UCB (L.Z.A.), Bulle, Switzerland. H.N. is currently affiliated with the Department of Neurology, Kanazawa Medical University, Ishikawa, Japan. B.O. is currently affiliated with the Department of Neurology, Mayo Clinic, Jacksonville, FL.

Objective: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).

Methods: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.

Results: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).

Conclusion: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.

Clinical Trial Registration: Clinicaltrials.gov identifier NCT02573467.

Classification Of Evidence: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.
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http://dx.doi.org/10.1212/WNL.0000000000011626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032371PMC
March 2021

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

EMBO J 2020 12 31;39(23):e105364. Epub 2020 Oct 31.

Department of Pediatrics, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
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http://dx.doi.org/10.15252/embj.2020105364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705457PMC
December 2020

Andersen-Tawil Syndrome Presenting with Complete Heart Block.

J Neuromuscul Dis 2021 ;8(1):151-154

Queen Square Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, and Department of Neuromuscular Diseases, UCL Institute of Neurology, London, UK.

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant neuromuscular disorder due to mutations in the KCNJ2 gene. The classical phenotype of ATS consists of a triad of periodic paralysis, cardiac conduction abnormalities and dysmorphic features. Episodes of either muscle weakness or cardiac arrhythmia may predominate however, and dysmorphic features may be subtle, masking the true breadth of the clinical presentation, and posing a diagnostic challenge. The severity of cardiac involvement varies but includes reports of life-threatening events or sudden cardiac death, usually attributed to ventricular tachyarrhythmias. We report the first case of advanced atrioventricular (AV) block in ATS and highlight clinical factors that may delay diagnosis.
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http://dx.doi.org/10.3233/JND-200572DOI Listing
January 2021

Differential Diagnoses of Inclusion Body Myositis.

Neurol Clin 2020 08;38(3):697-710

Department of Neuromuscular Diseases, Queen Square Centre for Neuromuscular Diseases, University College London, 1st Floor, Russell Square House, 10-12 Russell Square, London WC1B 5EH, UK; Division of Medicine, Centre for Rheumatology, University College London, 1st Floor, Russell Square House, 10-12 Russell Square, London WC1B 5EH, UK. Electronic address:

Inclusion body myositis is a slowly progressive myopathy, characteristically affecting quadriceps and long finger flexors. Atypical presentations do occur, however, and there is overlap with other myopathies, including inflammatory and hereditary etiologies. This article discusses atypical cases and differential diagnoses and considers the role of imaging and histopathology in differentiating inclusion body myositis.
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http://dx.doi.org/10.1016/j.ncl.2020.03.014DOI Listing
August 2020

Skeletal Muscle Channelopathies.

Neurol Clin 2020 08;38(3):481-491

Department of Neuromuscular Diseases, Queen Square Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK. Electronic address:

Skeletal muscle channelopathies are rare genetic neuromuscular conditions that include the nondystrophic myotonias and periodic paralyses. They cause disabling muscle symptoms and can limit educational potential, work opportunities, socialization, and quality of life. Effective therapy is available, making it essential to recognize and treat this group of disorders. Here, the authors highlight important aspects regarding diagnosis and management using illustrative case reports.
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http://dx.doi.org/10.1016/j.ncl.2020.04.003DOI Listing
August 2020

Improving genetic diagnostics of skeletal muscle channelopathies.

Expert Rev Mol Diagn 2020 07 12;20(7):725-736. Epub 2020 Jul 12.

Queen Square Centre for Neuromuscular Diseases and Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL and National Hospital for Neurology and Neurosurgery , London, UK.

Introduction: Skeletal muscle channelopathies are rare inherited conditions that cause significant morbidity and impact on quality of life. Some subsets have a mortality risk. Improved genetic methodology and understanding of phenotypes have improved diagnostic accuracy and yield.

Areas Covered: We discuss diagnostic advances since the advent of next-generation sequencing and the role of whole exome and genome sequencing. Advances in genotype-phenotype-functional correlations have improved understanding of inheritance and phenotypes. We outline new phenotypes, particularly in the pediatric setting and consider co-existing mutations that may act as genetic modifiers. We also discuss four newly identified genes associated with skeletal muscle channelopathies.

Expert Opinion: Next-generation sequencing using gene panels has improved diagnostic rates, identified new mutations, and discovered patients with co-existing pathogenic mutations ('double trouble'). This field has previously focussed on single genes, but we are now beginning to understand interactions between co-existing mutations, genetic modifiers, and their role in pathomechanisms. New genetic observations in pediatric presentations of channelopathies broadens our understanding of the conditions. Genetic and mechanistic advances have increased the potential to develop treatments.
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http://dx.doi.org/10.1080/14737159.2020.1782195DOI Listing
July 2020

Managing pregnancy and anaesthetics in patients with skeletal muscle channelopathies.

Neuromuscul Disord 2020 07 28;30(7):539-545. Epub 2020 May 28.

MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.

The skeletal muscle channelopathies are a group of rare diseases and include non-dystrophic myotonia and periodic paralysis. Given their rarity, little has been published on the management of anaesthesia and pregnancy in this cohort despite being important aspects of care. We have conducted a large study of over 70 patients who underwent anaesthesia and 87 pregnancies to investigate the problems encountered following anaesthesia or during pregnancy. This was performed via patient surveys sent out to genetically confirmed channelopathy patients seen at the National Hospital for Neurology and Neurosurgery. Most significantly in our cohort, patients frequently experienced a worsening or precipitation of symptoms during pregnancy (75%) or following anaesthetic (31%). None of our patients developed malignant hyperthermia, although there are confirmed reports of this in patients with periodic paralysis and mutations in RYR1. There was a significantly higher number of miscarriages compared to the normal population. There was no significant difference in antenatal or delivery complications compared to the general population. However, three neonates did have complications, all of whom were found to carry mutations in SCN4A. This study highlights the importance of counselling patients and clinicians for the possibility of worsening symptoms during pregnancy or anaesthesia and the careful management of neonates following delivery.
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http://dx.doi.org/10.1016/j.nmd.2020.05.007DOI Listing
July 2020

Concurrent sodium channelopathies and amyotrophic lateral sclerosis supports shared pathogenesis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 3;21(7-8):627-630. Epub 2020 Jul 3.

Department of Neurology, University College London Hospitals NHS Foundation Trust, London, UK.

Amyotrophic lateral sclerosis (ALS) is an invariably fatal adult-onset neurodegenerative disorder; approximately 10% of ALS is monogenic but all ALS exhibits significant heritability. The skeletal muscle sodium channelopathies are a group of inherited, non-dystrophic ion channel disorders caused by heterozygous point mutations in the gene, leading to clinical manifestations of congenital myotonia, paramyotonia, and periodic paralysis syndromes. We provide clinical and genetic evidence of concurrence of these two rare disorders which implies a possible shared underlying pathophysiology in two patients. We then identify an enrichment of ALS-associated mutations in another sodium channel, , from whole genome sequencing data of 4495 ALS patients and 1925 controls passing multiple testing correction (67 variants,  = 0.0002, Firth logistic regression). These findings suggest dysfunctional sodium channels may play a role upstream in the pathogenesis of ALS in a subset of patients, potentially opening the door to novel personalized medicine approaches.
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http://dx.doi.org/10.1080/21678421.2020.1786128DOI Listing
November 2020

Primary mitochondrial diseases increase susceptibility to bipolar affective disorder.

J Neurol Neurosurg Psychiatry 2020 08 11;91(8):892-894. Epub 2020 Jun 11.

Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, United Kingdom

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http://dx.doi.org/10.1136/jnnp-2020-323632DOI Listing
August 2020

Sodium channel myotonia may be associated with high-risk brief resolved unexplained events.

Wellcome Open Res 2020 12;5:57. Epub 2020 May 12.

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.

Brief resolved unexplained events (BRUEs) have numerous and varied causes posing a challenge to investigation and management. A subset of infants with the neuromuscular disorder sodium channel myotonia, due to mutations in the gene, experience apnoeic events due to laryngospasm (myotonia) of the upper airway muscles that may present as a BRUE. We sought to ascertain the frequency, severity and outcome of infants carrying the G1306E mutation commonly associated with this presentation. We report 14 new cases of individuals with the G1306E mutation from three unrelated families and perform a literature review of all published cases. Infants with the G1306E mutation almost universally experience laryngospasm and apnoeic events. The severity varies significantly, spans both low and high-risk BRUE categories or can be more severe than criteria for a BRUE would allow. At least a third of cases require intensive care unit (ICU) care. Seizure disorder is a common erroneous diagnosis. Apnoeas are effectively reduced or abolished by appropriate treatment with anti-myotonic agents. Probands with the G1306E mutation who are family planning need to be counselled for the likelihood of post-natal complications. There is readily available and extremely effective treatment for the episodic laryngospasm and apnoea caused by this mutation. Proactively seeking clinical evidence of myotonia or muscle hypertrophy with consideration of CK,EMG and genetic testing in high risk BRUEs or more complex apnoeic events may reduce avoidable and prolonged ICU admissions, patient morbidity and potentially mortality.
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http://dx.doi.org/10.12688/wellcomeopenres.15798.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241273PMC
May 2020

Homozygous C-terminal loss-of-function Na1.4 variant in a patient with congenital myasthenic syndrome.

J Neurol Neurosurg Psychiatry 2020 08 2;91(8):898-900. Epub 2020 Jun 2.

Department of Neuromuscular disease, UCL Queen Sqaure Institute of Neurology, London, United Kingdom

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http://dx.doi.org/10.1136/jnnp-2020-323173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115925PMC
August 2020

Multisystem mitochondrial disease caused by a rare m.10038G>A mitochondrial tRNA () variant.

Neurol Genet 2020 Apr 18;6(2):e413. Epub 2020 Mar 18.

Department of Neuromuscular Diseases (O.V.P., A.H., E.B., R.Q., M.G.H., R.D.S.P.), UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, United Kingdom; Wellcome Centre for Mitochondrial Research (S.A.H., R.W.T.), Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne; Neurogenetics Unit (C.E.W.), and Neurometabolic Unit (I.P.H.), The National Hospital for Neurology and Neurosurgery; Division of Neuropathology (A.M.), UCL Queen Square Institute of Neurology; Department of Histopathology (A.M.), Camelia Botnar Laboratory, Great Ormond Street Hospital; and Dubowitz Neuromuscular Centre (R.Q.), Great Ormond Street Hospital, London, United Kingdom.

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http://dx.doi.org/10.1212/NXG.0000000000000413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164964PMC
April 2020

Chronic pain is common in mitochondrial disease.

Neuromuscul Disord 2020 05 29;30(5):413-419. Epub 2020 Feb 29.

Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address:

In the absence of cure, the main objectives in the management of patients with mitochondrial disease are symptom control and prevention of complications. While pain is a complicating symptom in many chronic diseases and is known to have a clear impact on quality of life, its prevalence and severity in people with mitochondrial disease is unknown. We conducted a survey of pain symptoms in patients with genetically confirmed mitochondrial disease from two UK mitochondrial disease specialist centres. The majority (66.7%) of patients had chronic pain which was primarily of neuropathic nature. Presence of pain did not significantly impact overall quality of life. The m.3243A>G MTTL1 mutation was associated with higher pain severity and increased the likelihood of neuropathic pain compared to other causative nuclear and mitochondrial gene mutations. Although previously not considered a core symptom in people with mitochondrial disease, pain is a common clinical manifestation, frequently of neuropathic nature, and influenced by genotype. Therefore, pain-related symptoms should be carefully characterised and actively managed in this patient population.
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http://dx.doi.org/10.1016/j.nmd.2020.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306151PMC
May 2020

Guidelines on clinical presentation and management of nondystrophic myotonias.

Muscle Nerve 2020 10 27;62(4):430-444. Epub 2020 May 27.

Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas.

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.
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http://dx.doi.org/10.1002/mus.26887DOI Listing
October 2020

Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice.

Dis Model Mech 2020 05 26;13(5). Epub 2020 May 26.

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's Disease, is a late-onset X-linked progressive neuromuscular disease, which predominantly affects males. The pathological hallmarks of the disease are selective loss of spinal and bulbar motor neurons, accompanied by weakness, atrophy and fasciculations of bulbar and limb muscles. SBMA is caused by a CAG repeat expansion in the gene that encodes the androgen receptor (AR) protein. Disease manifestation is androgen dependent and results principally from a toxic gain of AR function. There are currently no effective treatments for this debilitating disease. It is important to understand the course of the disease in order to target therapeutics to key pathological stages. This is especially relevant in disorders such as SBMA, for which disease can be identified before symptom onset, through family history and genetic testing. To fully characterise the role of muscle in SBMA, we undertook a longitudinal physiological and histological characterisation of disease progression in the AR100 mouse model of SBMA. Our results show that the disease first manifests in skeletal muscle, before any motor neuron degeneration, which only occurs in late-stage disease. These findings reveal that alterations in muscle function, including reduced muscle force and changes in contractile characteristics, are early pathological events in SBMA mice and suggest that muscle-targeted therapeutics may be effective in SBMA.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.042424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272358PMC
May 2020

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches.

Lancet Child Adolesc Health 2020 07 3;4(7):536-547. Epub 2020 Mar 3.

Department of Neuromuscular Diseases, Medical Research Council Centre for Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK; National Hospital for Neurology and Neurosurgery, University College London Hospitals National Health Service Foundation Trust, London, UK.

Voltage-gated sodium channels are essential for excitability of skeletal muscle fibres and neurons. An increasing number of disabling or fatal paediatric neurological disorders linked to mutations of voltage-gated sodium channel genes are recognised. Muscle phenotypes include episodic paralysis, myotonia, neonatal hypotonia, respiratory compromise, laryngospasm or stridor, congenital myasthenia, and myopathy. Evidence suggests a possible link between sodium channel dysfunction and sudden infant death. Increasingly recognised phenotypes of brain sodium channelopathies include several epilepsy disorders and complex encephalopathies. Together, these early-onset muscle and brain phenotypes have a substantial morbidity and a considerable mortality. Important advances in understanding the pathophysiological mechanisms underlying these channelopathies have helped to identify effective targeted therapies. The availability of effective treatments underlines the importance of increasing clinical awareness and the need to achieve a precise genetic diagnosis. In this Review, we describe the expanded range of phenotypes of muscle and brain sodium channelopathies and the underlying knowledge regarding mechanisms of sodium channel dysfunction. We also outline a diagnostic approach and review the available treatment options.
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http://dx.doi.org/10.1016/S2352-4642(19)30425-0DOI Listing
July 2020

In vivo assessment of interictal sarcolemmal membrane properties in hypokalaemic and hyperkalaemic periodic paralysis.

Clin Neurophysiol 2020 04 27;131(4):816-827. Epub 2020 Jan 27.

MRC Centre for Neuromuscular Diseases, Queen Square, Institute of Neurology, UCL, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

Objective: Hypokalaemic periodic paralysis (HypoPP) is caused by mutations of Ca1.1, and Na1.4 which result in an aberrant gating pore current. Hyperkalaemic periodic paralysis (HyperPP) is due to a gain-of-function mutation of the main alpha pore of Na1.4. This study used muscle velocity recovery cycles (MVRCs) to investigate changes in interictal muscle membrane properties in vivo.

Methods: MVRCs and responses to trains of stimuli were recorded in tibialis anterior and compared in patients with HyperPP(n = 7), HypoPP (n = 10), and normal controls (n = 26).

Results: Muscle relative refractory period was increased, and early supernormality reduced in HypoPP, consistent with depolarisation of the interictal resting membrane potential. In HyperPP the mean supernormality and residual supernormality to multiple conditioning stimuli were increased, consistent with increased inward sodium current and delayed repolarisation, predisposing to spontaneous myotonic discharges.

Conclusions: The in vivo findings suggest the interictal resting membrane potential is depolarized in HypoPP, and mostly normal in HyperPP. The MVRC findings in HyperPP are consistent with presence of a window current, previously proposed on the basis of in vitro expression studies. Although clinically similar, HyperPP was electrophysiologically distinct from paramyotonia congenita.

Significance: MVRCs provide important in vivo data that complements expression studies of ion channel mutations.
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http://dx.doi.org/10.1016/j.clinph.2019.12.414DOI Listing
April 2020

Expanding the molecular and phenotypic spectrum of truncating mutations.

Neurol Genet 2020 Feb 7;6(1):e381. Epub 2020 Jan 7.

Department of Neuromuscular Diseases (E. Bugiardini, O.V.P, A.H., H.H., R.Q., M.G.H., R.D.S.P.), UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, United Kingdom; Mitochondrial Medicine Group (E. Bottani, C.B., M.Z.), Medical Research Council Mitochondrial Biology Unit, Cambridge, United Kingdom; Department of Molecular and Translational Medicine (E. Bottani, A.V.), University of Brescia; Medical Genetics and Neurogenetics Unit (S.M., E.L., C.L.), Fondazione IRCCS Istituto Neurologico, "C. Besta," Milan, Italy; Neurogenetics Unit (C.W.), and Neurometabolic Unit (A.L., I.H., A.C.), The National Hospital for Neurology and Neurosurgery; Division of Neuropathology (K.V., J.L.H.), UCL Queen Square Institute of Neurology; and Dubowitz Neuromuscular Centre (R.Q.), Great Ormond Street Hospital, London, United Kingdom.

Objective: To describe the clinical and functional consequences of 1 novel and 1 previously reported truncating mutation.

Methods: Three unrelated probands with mitochondrial encephalomyopathy harboring truncating mutations are reported. Transmitochondrial cybrid cell studies were used to confirm pathogenicity of 1 novel variant, and the effects of all 3 mutations on and complex V structure and function were investigated.

Results: Patient 1 presented with adult-onset cerebellar ataxia, chronic kidney disease, and diabetes, whereas patient 2 had myoclonic epilepsy and cerebellar ataxia; both harbored the novel m.8782G>A; p.(Gly86*) mutation. Patient 3 exhibited cognitive decline, with posterior white matter abnormalities on brain MRI, and severely impaired renal function requiring transplantation. The m.8618dup; p.(Thr33Hisfs*32) mutation, previously associated with neurogenic muscle weakness, ataxia, and retinitis pigmentosa, was identified. All 3 probands demonstrated a broad range of heteroplasmy across different tissue types. Blue-native gel electrophoresis of cultured fibroblasts and skeletal muscle tissue confirmed multiple bands, suggestive of impaired complex V assembly. Microscale oxygraphy showed reduced basal respiration and adenosine triphosphate synthesis, while reactive oxygen species generation was increased. Transmitochondrial cybrid cell lines studies confirmed the deleterious effects of the novel m.8782 G>A; p.(Gly86*) mutation.

Conclusions: We expand the clinical and molecular spectrum of -related mitochondrial disorders to include leukodystrophy, renal disease, and myoclonic epilepsy with cerebellar ataxia. Truncating mutations may exhibit highly variable mutant levels across different tissue types, an important consideration during genetic counseling.
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http://dx.doi.org/10.1212/NXG.0000000000000381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984135PMC
February 2020

Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients.

Brain 2020 02;143(2):452-466

Department of Neurology, Donders Centre for Medical Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands.

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.
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http://dx.doi.org/10.1093/brain/awz410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009512PMC
February 2020

Improving specialised care for neuromuscular patients reduces the frequency of preventable emergency hospital admissions.

Neuromuscul Disord 2020 02 4;30(2):173-179. Epub 2019 Dec 4.

MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, WC1N 3BG London, UK.

Two retrospective audits were undertaken across several hospitals to understand the frequency and preventability of emergency admissions in people with neuromuscular disease (NMD). Following audit 1 (A1), a number of preventable themes emerged on the basis of which recommendations were made to improve quality and co-ordination of care and a network approach was developed to improve awareness and education amongst patients and non-expert professionals. Audit 2 (A2) was undertaken to determine the effect of these measures. The central NHS IT database identified emergency NMD admissions. Case notes were reviewed and audited against pre-agreed criteria. A1 included 576 admissions (395 patients) A2 included 361 admissions (314 patients). Preventable admissions (where an NMD was known) accounted for 63% in A1 and 33% in A2, with more patients followed up at a specialised neuromuscular centre in A2. There were fewer re-admissions in A2 (12%) compared with A1 (25%) and lower mortality (A1: 4.5%, A2: 0.3%). A2 showed a significant rise in patients admitted under the care of neuroscience during the acute admission and fewer preventable ITU admissions. These audits demonstrate a significant impact for both patient care and potential for financial savings following the implementation of recommendations made after A1.
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http://dx.doi.org/10.1016/j.nmd.2019.11.013DOI Listing
February 2020