Publications by authors named "Renata S Scalco"

20 Publications

  • Page 1 of 1

Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls.

N Engl J Med 2021 07;385(5):427-435

From the Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston (B.T.D.); the Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (R.M., G.B.), and the Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa (C.B.) - both in Italy; the Department of Developmental Neurology, Medical University of Gdańsk, Gdańsk, Poland (M.M.-B.); the Paediatric Gait Analysis Service of New South Wales, the Children's Hospital at Westmead and the University of Sydney, Sydney (K.R.); the Department of Pediatrics, Peking University First Hospital, Beijing (H.X.), and Children's Hospital of Fudan University, Shanghai (Y.W.) - both in China; the Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo (E.Z.); the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust, London (G.B.), Roche Products, Welwyn Garden City (M.E.-K.), and the Muscular Dystrophy UK Oxford Neuromuscular Centre, the Department of Paediatrics, University of Oxford, Oxford (L.S.) - all in the United Kingdom; Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute, Pirogov Russian National Research Medical University, Moscow (D.V.); Pharma Development, Safety (M.G.), Product Development Medical Affairs - Neuroscience and Rare Disease (K.G., P.F.), and Pharma Development Neurology (R.S.S.), F. Hoffmann-La Roche, and Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel (O.K., H.K.) - both in Basel, Switzerland; the Division of Child Neurology, Centre de Références des Maladies Neuromusculaires, the Department of Pediatrics, University Hospital Liege, University of Liege, Liege, Belgium (L.S.); and I-Motion, Institut de Myologie, Assistance Publique Hôpitaux de Paris, Hôpital Armand Trousseau, Paris (L.S.).

Background: Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies pre-messenger RNA splicing and increases levels of functional SMN protein in blood.

Methods: We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA.

Results: A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure.

Conclusions: In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482.).
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http://dx.doi.org/10.1056/NEJMoa2102047DOI Listing
July 2021

Risdiplam, the First Approved Small Molecule Splicing Modifier Drug as a Blueprint for Future Transformative Medicines.

ACS Med Chem Lett 2021 Jun 28;12(6):874-877. Epub 2021 Jan 28.

pRED, Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.

Not too long ago, the concept of selectively targeting mRNA with small molecules was perceived as a formidable scientific challenge. The discovery of small molecule splicing modifiers and the development of risdiplam for the treatment of spinal muscular atrophy (SMA) have firmly established proof of concept for this exciting new platform and transformed a scientific curiosity into a viable technology to target disease. Today, several approaches to target mRNA with small molecules, supported by biophysical and screening methods, are in place to deliver new drugs with high therapeutic relevance.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201486PMC
June 2021

Risdiplam in Type 1 Spinal Muscular Atrophy.

N Engl J Med 2021 03 24;384(10):915-923. Epub 2021 Feb 24.

From the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London (G.B.), Roche Products, Welwyn Garden City (M.E.-K.), and the Muscular Dystrophy UK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford (L.S.) - all in the United Kingdom; the Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (G.B., R.M.), and the Pediatric Neurology Institution, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS, Rome (E.M.); the Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston (B.T.D.); the Department of Neurology, Stanford University, Palo Alto, CA (J.W.D.); Centre de Référence des Maladies Neuromusculaires, Queen Fabiola Children's University Hospital, Université Libre de Bruxelles, Brussels (N.D.), the Neuromuscular Reference Center, Universitair Ziekenhuis Gent, Ghent (N.D.), and the Division of Child Neurology, Centre de Références des Maladies Neuromusculaires, Department of Pediatrics, University Hospital Liege and University of Liege, Liege (L.S.) - all in Belgium; the Division of Pediatric Neurology, University Children's Hospital Basel (A.K.), Pharma Development Safety (M.G.), Product Development Medical Affairs-Neuroscience and Rare Disease (K.G., P.F.), and Pharma Development Neurology (R.S.S.), F. Hoffmann-La Roche, and Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel (O.K., H.K., T.S.), Basel, and Pediatric Neurology, Inselspital, University of Bern, Bern (A.K.) - both in Switzerland; the Discipline of Physiotherapy, Faculty of Medicine and Health, University of Sydney, Sydney (K.R.); and I-Motion, Hôpital Armand Trousseau, Paris (L.S.).

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies pre-messenger RNA splicing and increases levels of functional SMN protein.

Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds.

Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study.

Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).
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http://dx.doi.org/10.1056/NEJMoa2009965DOI Listing
March 2021

Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC).

Orphanet J Rare Dis 2020 11 24;15(1):330. Epub 2020 Nov 24.

Copenhagen Neuromuscular Center, Section 6921, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark.

Background: The European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) was launched to register rare muscle glycogenoses in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases through workshops and websites. A network of twenty full and collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. After approximately 3 years of data collection, the data in the registry was analysed.

Results: Of 282 patients with confirmed diagnoses of muscle glycogenosis, 269 had McArdle disease. New phenotypic features of McArdle disease were suggested, including a higher frequency (51.4%) of fixed weakness than reported before, normal CK values in a minority of patients (6.8%), ptosis in 8 patients, body mass index above background population and number of comorbidities with a higher frequency than in the background population (hypothyroidism, coronary heart disease).

Conclusions: The EUROMAC project and registry have provided insight into new phenotypic features of McArdle disease and the variety of co-comorbidities affecting people with McArdle disease. This should lead to better management of these disorders in the future, including controlling weight, and preventive screening for thyroid and coronary artery diseases, as well as physical examination with attention on occurrence of ptosis and fixed muscle weakness. Normal serum creatine kinase in a minority of patients stresses the need to not discard a diagnosis of McArdle disease even though creatine kinase is normal and episodes of myoglobinuria are absent.
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http://dx.doi.org/10.1186/s13023-020-01562-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687836PMC
November 2020

Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy.

Ann Clin Transl Neurol 2021 01 24;8(1):54-65. Epub 2020 Nov 24.

Neuro-Ophthalmology Center, Ophthalmology Department, IRCCS Istituto Auxologico Italiano, Milan, Italy.

Objective: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU.

Methods: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study.

Results: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment.

Interpretation: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam.
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http://dx.doi.org/10.1002/acn3.51239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818230PMC
January 2021

Creation and implementation of a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC registry).

Orphanet J Rare Dis 2020 10 15;15(1):187. Epub 2020 Oct 15.

Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, and Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron 119, 08035, Barcelona, Catalonia, Spain.

Background: International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders.

Results: Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients.

Conclusion: EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level.
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http://dx.doi.org/10.1186/s13023-020-01455-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558742PMC
October 2020

Results of an open label feasibility study of sodium valproate in people with McArdle disease.

Neuromuscul Disord 2020 09 16;30(9):734-741. Epub 2020 May 16.

UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, United Kingdom. Electronic address:

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy. Animal model studies indicate that sodium valproate (VPA) can increase expression of phosphorylase in skeletal muscle affected with McArdle disease. This study was designed to assess whether VPA can modify expression of brain phosphorylase isoenzyme in people with McArdle disease. This phase II, open label, feasibility pilot study to assess efficacy of six months treatment with VPA (20 mg/kg/day) included 16 people with McArdle disease. Primary outcome assessed changes in VOpeak during an incremental cycle test. Secondary outcomes included: phosphorylase enzyme expression in post-treatment muscle biopsy, total distance walked in 12 min, plasma lactate change (forearm exercise test) and quality of life (SF36). Safety parameters. 14 participants completed the trial, VPA treatment was well tolerated; weight gain was the most frequently reported drug-related adverse event. There was no clinically meaningful change in any of the primary or secondary outcome measures including: VOpeak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. Although this was a small open label feasibility study, it suggests that a larger randomised controlled study of VPA, may not be worthwhile.
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http://dx.doi.org/10.1016/j.nmd.2020.04.009DOI Listing
September 2020

RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, auto-inflammation, recurrent infections, skeletal, and cardiac myopathy-Four additional patients and a review of the current literature.

J Inherit Metab Dis 2020 09 16;43(5):1002-1013. Epub 2020 Apr 16.

Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.
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http://dx.doi.org/10.1002/jimd.12234DOI Listing
September 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

The need for biochemical testing in beta-enolase deficiency in the genomic era.

JIMD Rep 2019 Nov 3;50(1):40-43. Epub 2019 Sep 3.

MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery London UK.

Glycogen storage disease type XIII (GSDXIII) is a very rare inherited metabolic myopathy characterized by autosomal-recessive mutations in the gene resulting in muscle β-enolase deficiency, an enzymatic defect of the distal part of glycolysis. Enzyme kinetic studies of two patients presenting with exertion intolerance and recurrent rhabdomyolysis are reported. Next generation sequencing confirmed patient 1 was homozygous for p.E187K in , while patient 2 was homozygous for p.C357Y. variants pathogenicity was confirmed by functional studies in skeletal muscle. p.E187K caused extremely low total enolase activity. p.C357Y was associated with a higher level of residual activity but kinetic studies showed a lower maximum work rate ( ). This study illustrates that GSDXIII may be caused by either null mutations leading to β-enolase deficiency or by mutations that alter the enzyme's kinetic profile. This study highlights the importance of carrying out functional studies as part of the diagnostic process following the identification of variants with next generation sequencing.
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http://dx.doi.org/10.1002/jmd2.12070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851005PMC
November 2019

A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms.

Brain 2018 12;141(12):3308-3318

MRC Centre for Neuromuscular Diseases, Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.

Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle paralysis associated with low serum potassium. Muscle fibre inexcitability during attacks of paralysis is due to an aberrant depolarizing leak current through mutant voltage sensing domains of either the sarcolemmal voltage-gated calcium or sodium channel. We report a child with hypokalaemic periodic paralysis and CNS involvement, including seizures, but without mutations in the known periodic paralysis genes. We identified a novel heterozygous de novo missense mutation in the ATP1A2 gene encoding the α2 subunit of the Na+/K+-ATPase that is abundantly expressed in skeletal muscle and in brain astrocytes. Pump activity is crucial for Na+ and K+ homeostasis following sustained muscle or neuronal activity and its dysfunction is linked to the CNS disorders hemiplegic migraine and alternating hemiplegia of childhood, but muscle dysfunction has not been reported. Electrophysiological measurements of mutant pump activity in Xenopus oocytes revealed lower turnover rates in physiological extracellular K+ and an anomalous inward leak current in hypokalaemic conditions, predicted to lead to muscle depolarization. Our data provide important evidence supporting a leak current as the major pathomechanism underlying hypokalaemic periodic paralysis and indicate ATP1A2 as a new hypokalaemic periodic paralysis gene.
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http://dx.doi.org/10.1093/brain/awy283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262219PMC
December 2018

Resistance Exercise Training in McArdle Disease: Myth or Reality?

Case Rep Neurol Med 2018 30;2018:9658251. Epub 2018 Sep 30.

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

McArdle disease is a metabolic myopathy mainly characterised by symptom onset during physical activities or isometric muscle contraction. Resistance (also termed strength) training is a type of physical exercise focusing on the use of resistance (e.g., lifting weights) to induce muscular contraction, which builds muscle mass and strength. Historically people with McArdle disease were advised to avoid resistance exercises and any other form of physical activity involving high mechanical loads such as prolonged isometric contraction. Paradoxically, a clinical trial exploring the benefits of strength training in this patient population was published. The theory supporting strength training relied on the use of the ATP molecule and the creatine phosphate (ATP-phosphocreatine system) as energy sources for skeletal muscles. Here, we report two patients with McArdle disease who performed weight training at local gyms. A single set of repetitions lasted for maximum 10 seconds with minimum of 30 seconds of rest period in between sets of exercises. Benefits of this type of training included improvement in quality of life and amelioration of McArdle disease symptoms. We provide further safety evidence of this type of exercise in people with McArdle disease. We emphasise the importance of using a specific protocol developed for people affected by this condition.
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http://dx.doi.org/10.1155/2018/9658251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186374PMC
September 2018

Retinopathy Associated with Biallelic Mutations in PYGM (McArdle Disease).

Ophthalmology 2019 02 11;126(2):320-322. Epub 2018 Oct 11.

UCL Institute of Ophthalmology, University College London, London, UK; Genetics and Medical Retina Services, Moorfields Eye Hospital, London, UK.

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http://dx.doi.org/10.1016/j.ophtha.2018.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347563PMC
February 2019

Atypical periodic paralysis and myalgia: A novel phenotype.

Neurology 2018 01 3;90(5):e412-e418. Epub 2018 Jan 3.

From the MRC Centre for Neuromuscular Diseases (E.M., F.J., R.S.S., D.F., M.P., D.R.R., K.S., H.H., E.H., R.Q., J.L.H., M.G.H.), Department of Molecular Neuroscience, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Neuromuscular Diseases Unit/ALS Clinic (C.N.), Kantonsspital St. Gallen, Switzerland; Neurogenetics Unit (R.S., H.H.) and Department of Neuropathology (J.L.H.), National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Human Genetics Laboratory Genetica (R.S.), Zurich, Switzerland; Genetics Department (R.M.), Viapath, Guy's Hospital, London; Wellcome Trust Centre for Mitochondrial Research (A.S.), University of Newcastle, Framlington Place, Newcastle Upon Tyne, UK; Institute of Pathology (E.H.), Belfast Health and Social Care Trust, Northern Ireland; Department of Neurology (J.P.), John Radcliffe Hospital, Oxford, UK; Departments of Biomedicine and Anesthesia (S.T.), Basel University Hospital, Switzerland; Department of Life Sciences (S.T.), Microbiology and Applied Pathology Section, University of Ferrara, Italy; Department of Paediatric Neurology (H.J.), Neuromuscular Service, Evelina Children's Hospital, St. Thomas' Hospital; and Department of Basic and Clinical Neuroscience (H.J.), Institute of Psychiatry, Psychology and Neuroscience, and Randall Division of Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London, UK.

Objective: To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor () gene mutations.

Methods: Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with related disorders were referred for a tertiary neuromuscular clinical assessment in which they underwent detailed clinical evaluation, including neurophysiologic assessment, muscle biopsy, and muscle MRI. Genetic analysis with next-generation sequencing and/or targeted Sanger sequencing was performed.

Results: Three cases with episodic muscle paralysis or weakness and additional findings compatible with a -related myopathy were identified. The McManis test, used in the diagnosis of PP, was positive in 2 of 3 cases. Genetic analysis of known PP genes was negative. analysis confirmed likely pathogenic variants in all 3 cases.

Conclusions: mutations can cause late-onset atypical PP both with and without associated myopathy. Myalgia and cramps are prominent features. The McManis test may be a useful diagnostic tool to indicate -associated PP. We propose that clinicopathologic features suggestive of -related disorders should be sought in genetically undefined PP cases and that gene testing be considered in those in whom mutations in , and have already been excluded.
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http://dx.doi.org/10.1212/WNL.0000000000004894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791790PMC
January 2018

Clinical, pathological and functional characterization of riboflavin-responsive neuropathy.

Brain 2017 11;140(11):2820-2837

Department of Molecular Neuroscience and Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.
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http://dx.doi.org/10.1093/brain/awx231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808726PMC
November 2017

Calpainopathy with macrophage-rich, regional inflammatory infiltrates.

Neuromuscul Disord 2017 Aug 27;27(8):738-741. Epub 2017 Apr 27.

Division of Neuropathology, UCL Institute of Neurology, Queen Square, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK; MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. Electronic address:

Mutations in calpain-3 cause limb girdle muscular dystrophy 2A. Biopsy pathology is typically dystrophic, sometimes characterized by frequent lobulated fibres. More recently calpain mutations have been shown in association with eosinophilic myositis, suggesting that calpain mutations may render muscle susceptible to inflammatory change. We present the case of a 33-year old female with mild proximal muscle weakness and high CK levels (6698 IU/L at presentation). Muscle biopsy showed clusters of fibre necrosis associated with very dense macrophage infiltrates and small numbers of lymphocytes, raising the possibility of an inflammatory myopathy. No eosinophils were observed. Immunosuppressive treatment was started without clinical improvement. MRI demonstrated bilateral fatty replacement in posterior thigh and calf muscles. Western blot results prompted Sanger sequencing of the calpain-3 gene revealing compound heterozygous mutations c.643_663del and c.1746-20C>G. Our case widens the myopathological spectrum of calpainopathies to include focal macrophage rich inflammatory change.
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http://dx.doi.org/10.1016/j.nmd.2017.04.012DOI Listing
August 2017

Exertional rhabdomyolysis: physiological response or manifestation of an underlying myopathy?

BMJ Open Sport Exerc Med 2016 7;2(1):e000151. Epub 2016 Sep 7.

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

Exertional rhabdomyolysis is characterised by muscle breakdown associated with strenuous exercise or normal exercise under extreme circumstances. Key features are severe muscle pain and sudden transient elevation of serum creatine kinase (CK) levels with or without associated myoglobinuria. Mild cases may remain unnoticed or undiagnosed. Exertional rhabdomyolysis is well described among athletes and military personnel, but may occur in anybody exposed to unaccustomed exercise. In contrast, exertional rhabdomyolysis may be the first manifestation of a genetic muscle disease that lowers the exercise threshold for developing muscle breakdown. Repeated episodes of exertional rhabdomyolysis should raise the suspicion of such an underlying disorder, in particular in individuals in whom the severity of the rhabdomyolysis episodes exceeds the expected response to the exercise performed. The present review aims to provide a practical guideline for the acute management and postepisode counselling of patients with exertional rhabdomyolysis, with a particular emphasis on when to suspect an underlying genetic disorder. The pathophysiology and its clinical features are reviewed, emphasising four main stepwise approaches: (1) the clinical significance of an acute episode, (2) risks of renal impairment, (3) clinical indicators of an underlying genetic disorders and (4) when and how to recommence sport activity following an acute episode of rhabdomyolysis. Genetic backgrounds that appear to be associated with both enhanced athletic performance and increased rhabdomyolysis risk are briefly reviewed.
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http://dx.doi.org/10.1136/bmjsem-2016-000151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117086PMC
September 2016

Report on the EUROMAC McArdle Exercise Testing Workshop, Madrid, Spain, 11-12 July 2014.

Neuromuscul Disord 2015 Sep 27;25(9):739-45. Epub 2015 May 27.

Vall D'Hebron Research Institute and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Catalonia, Spain.

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http://dx.doi.org/10.1016/j.nmd.2015.05.009DOI Listing
September 2015

Emotionally-intense situations can result in rhabdomyolysis in McArdle disease.

BMJ Case Rep 2014 Oct 7;2014. Epub 2014 Oct 7.

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

Despite the majority of patients with McArdle disease reporting symptoms including fatigue, cramps and episodes of myoglobinuria from early childhood, diagnosis is often delayed by several decades. Additionally, many individuals with rhabdomyolysis remain undiagnosed. The occurrence of symptoms during exercise, particularly isometric muscle contraction such as heavy lifting, is well known in McArdle disease. However, isometric muscle contraction that occurs with emotion is not recognised as exercise and may be missed as a trigger for rhabdomyolysis, potentially leading to a delay in diagnosis. Three patients are presented here, all with symptoms from childhood including episodes of rhabdomyolysis induced by tense emotional situations without physical exertion; two patients reported recurrent episodes while watching rather than playing football. The remaining patient developed rhabdomyolysis during a heated argument. These patients' histories emphasise the risk from sustained isometric muscle contraction that occurs in emotive situations for patients with McArdle disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187416PMC
http://dx.doi.org/10.1136/bcr-2013-203272DOI Listing
October 2014

Fatal cardiac involvement complicating antisynthetase syndrome.

BMJ Case Rep 2014 Aug 25;2014. Epub 2014 Aug 25.

Department of Rheumatology, Northwick Park Hospital, London, UK.

A 35-year-old Afro-Caribbean woman presented with dyspnoea, urticarial rash and myalgia 1 month after treatment for a community-acquired respiratory tract infection. Investigations revealed raised antisynthetase antibodies, lung fibrosis and an inflammatory myopathy. The patient was diagnosed with antisynthetase syndrome (ASS) and started on immunosuppressive medication. Despite treatment she died 4 weeks after presentation from a fulminant cardiomyopathy. ASS is a rare condition and is not typically associated with a cardiomyopathy. This case report intends to raise awareness that cardiomyopathy is a potentially fatal complication of ASS.
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http://dx.doi.org/10.1136/bcr-2014-204409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154036PMC
August 2014
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