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1. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Author

Alistair T. Pagnamenta, Carme Camps, Edoardo Giacopuzzi, John M. Taylor, Mona Hashim, Eduardo Calpena, Pamela J. Kaisaki, Akiko Hashimoto, Jing Yu, Edward Sanders, Ron Schwessinger, Jim R. Hughes, Gerton Lunter, Helene Dreau, Matteo Ferla, Lukas Lange, Yesim Kesim, Vassilis Ragoussis, Dimitrios V. Vavoulis, Holger Allroggen, Olaf Ansorge, Christian Babbs, Siddharth Banka, Benito Baños-Piñero, David Beeson, Tal Ben-Ami, David L. Bennett, Celeste Bento, Edward Blair, Charlotte Brasch-Andersen, Katherine R. Bull, Holger Cario, Deirdre Cilliers, Valerio Conti, E. Graham Davies, Fatima Dhalla, Beatriz Diez Dacal, Yin Dong, James E. Dunford, Renzo Guerrini, Adrian L. Harris, Jane Hartley, Georg Hollander, Kassim Javaid, Maureen Kane, Deirdre Kelly, Dominic Kelly, Samantha J. L. Knight, Alexandra Y. Kreins, Erika M. Kvikstad, Craig B. Langman, Tracy Lester, Kate E. Lines, Simon R. Lord, Xin Lu, Sahar Mansour, Adnan Manzur, Reza Maroofian, Brian Marsden, Joanne Mason, Simon J. McGowan, Davide Mei, Hana Mlcochova, Yoshiko Murakami, Andrea H. Németh, Steven Okoli, Elizabeth Ormondroyd, Lilian Bomme Ousager, Jacqueline Palace, Smita Y. Patel, Melissa M. Pentony, Chris Pugh, Aboulfazl Rad, Archana Ramesh, Simone G. Riva, Irene Roberts, Noémi Roy, Outi Salminen, Kyleen D. Schilling, Caroline Scott, Arjune Sen, Conrad Smith, Mark Stevenson, Rajesh V. Thakker, Stephen R. F. Twigg, Holm H. Uhlig, Richard van Wijk, Barbara Vona, Steven Wall, Jing Wang, Hugh Watkins, Jaroslav Zak, Anna H. Schuh, Usha Kini, Andrew O. M. Wilkie, Niko Popitsch, and Jenny C. Taylor

Subjects
Genome sequencing, Rare diseases, Structural variant, Splice site variant, Non-coding, Diagnostic yield, Medicine, Genetics, QH426-470
Abstract

Abstract Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. Methods We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. Results Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. Conclusions Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

Published
2023
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2. Meaningful changes in motor function in Duchenne muscular dystrophy (DMD): A multi-center study.

Author

Francesco Muntoni, James Signorovitch, Gautam Sajeev, Nicolae Done, Zhiwen Yao, Nathalie Goemans, Craig McDonald, Eugenio Mercuri, Erik H Niks, Brenda Wong, Krista Vandenborne, Volker Straub, Imelda J M de Groot, Cuixia Tian, Adnan Manzur, Ibrahima Dieye, Henry Lane, Susan J Ward, Laurent Servais, PRO-DMD-01 study investigators, Association Française contre les Myopathies, UK NorthStar Clinical Network, ImagingDMD investigators, and cTAP

Subjects
Medicine, Science
Abstract

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to 80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.

Published
2024
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3. Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

Author

Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O’Donovan, Maura Coughlin, Xaviere Lornage, Nicola Foulds, Simon R. Hammans, A. Reghan Foley, Charlotte M. Fare, Alice F. Ford, Masashi Ogasawara, Aki Sato, Aritoshi Iida, Pinki Munot, Gautam Ambegaonkar, Rahul Phadke, Dominic G. O’Donovan, Rebecca Buchert, Mona Grimmel, Ana Töpf, Irina T. Zaharieva, Lauren Brady, Ying Hu, Thomas E. Lloyd, Andrea Klein, Maja Steinlin, Alice Kuster, Sandra Mercier, Pascale Marcorelles, Yann Péréon, Emmanuelle Fleurence, Adnan Manzur, Sarah Ennis, Rosanna Upstill-Goddard, Luca Bello, Cinzia Bertolin, Elena Pegoraro, Leonardo Salviati, Courtney E. French, Andriy Shatillo, F. Lucy Raymond, Tobias B. Haack, Susana Quijano-Roy, Johann Böhm, Isabelle Nelson, Tanya Stojkovic, Teresinha Evangelista, Volker Straub, Norma B. Romero, Jocelyn Laporte, Francesco Muntoni, Ichizo Nishino, Mark A. Tarnopolsky, James Shorter, Carsten G. Bönnemann, and J. Paul Taylor

Subjects
Science
Abstract

Missense variants in RNA-binding proteins underlie many diseases. Here the authors report an oculopharyngeal muscular dystrophy caused by heterozygous frameshift mutations in HNRNPA2B1 that alter its nucleocytoplasmic transport dynamics and result in cytoplasmic accumulation of hnRNPA2 protein.

Published
2022
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4. Investigating the role of dystrophin isoform deficiency in motor function in Duchenne muscular dystrophy

Author

Mary Chesshyre, Deborah Ridout, Yasumasa Hashimoto, Yoko Ookubo, Silvia Torelli, Kate Maresh, Valeria Ricotti, Lianne Abbott, Vandana Ayyar Gupta, Marion Main, Giulia Ferrari, Anna Kowala, Yung‐Yao Lin, Francesco Saverio Tedesco, Mariacristina Scoto, Giovanni Baranello, Adnan Manzur, Yoshitsugu Aoki, and Francesco Muntoni

Subjects
Duchenne muscular dystrophy, Isoform, Motor function, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract

Abstract Background Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full‐length Dp427 is the primary dystrophin isoform expressed in muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS comorbidities is well known, relationships between mutations expected to disrupt Dp140 and Dp71 and motor outcomes are not. Methods Functional outcome data from 387 DMD boys aged 4–15 years were subdivided by DMD mutation expected effects on dystrophin isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n = 201); Group 2 (Dp427/Dp140 absent, Dp71 present, n = 152); and Group 3 (Dp427/Dp140/Dp71 absent, n = 34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10 m walk/run velocities and rise time velocities were explored using regression analysis. Western blot analysis was used to study Dp427, Dp140 and Dp71 production in myogenic cells (control and DMD human), control skeletal muscle, DMD skeletal muscle from the three isoform groups and cerebral cortex from mice (wild‐type and DMD models). Grip strength and rotarod running test were studied in wild‐type mice and DMD mouse models. DMD mouse models were mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD‐null (lacking all isoforms). Results In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in Group 3 than Group 1 (P

Published
2022
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5. Growth pattern trajectories in boys with Duchenne muscular dystrophy

Author

Georgia Stimpson, Sarah Raquq, Mary Chesshyre, Mary Fewtrell, Deborah Ridout, Anna Sarkozy, Adnan Manzur, Vandana Ayyar Gupta, Ramona De Amicis, Francesco Muntoni, Giovanni Baranello, and the NorthStar Network

Subjects
Duchenne muscular dystrophy, Growth, Isoforms, Glucocorticoids, Prednisolone, Deflazacort, Medicine
Abstract

Abstract Objectives The objective of this study is to analyse retrospective, observational, longitudinal growth (weight, height and BMI) data in ambulatory boys aged 5–12 years with Duchenne muscular dystrophy (DMD). Background We considered glucocorticoids (GC) use, dystrophin isoforms and amenability to exon 8, 44, 45, 51 and 53 skipping drug subgroups, and the impact of growth on loss of ambulation. We analysed 598 boys, with 2604 observations. This analysis considered patients from the UK NorthStar database (2003–2020) on one of five regimes: “GC naïve”, “deflazacort daily” (DD), “deflazacort intermittent” (DI), “prednisolone daily” (PD) and “prednisolone intermittent” (PI). A random slope model was used to model the weight, height and BMI SD scores (using the UK90). Results The daily regime subgroups had significant yearly height stunting compared to the GC naïve subgroup. Notably, the average height change for the DD subgroup was 0.25 SD (95% CI − 0.30, − 0.21) less than reference values. Those with affected expression of Dp427, Dp140 and Dp71 isoforms were 0.77 (95% CI 0.3, 1.24) and 0.82 (95% CI 1.28, 0.36) SD shorter than those with Dp427 and/or Dp140 expression affected respectively. Increased weight was not associated with earlier loss of ambulation, but taller boys still ambulant between the age of 10 and 11 years were more at risk of losing ambulation. Conclusion These findings may provide further guidance to clinicians when counselling and discussing GCs commencement with patients and their carers and may represent a benchmark set of data to evaluate the effects of new generations of GC.

Published
2022
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6. Cardiac Manifestations of Myotonic Dystrophy in a Pediatric Cohort

Author

Laia Brunet Garcia, Ankita Hajra, Ella Field, Joseph Wacher, Helen Walsh, Gabrielle Norrish, Adnan Manzur, Francesco Muntoni, Pinki Munot, Stephanie Robb, Rosaline Quinlivan, Mariacristina Scoto, Giovanni Baranello, Anna Sarkozy, Luke Starling, Juan Pablo Kaski, and Elena Cervi

Subjects
myotonic dystrophy (DM1), congenital myotonic dystrophy, pediatric population, neuromuscular disorder, cardiac conduction disease, electrocardiographic abnormalities, Pediatrics, RJ1-570
Abstract

Myotonic dystrophy type 1 (DM1) is the most prevalent inherited neuromuscular dystrophy in adults. It is a multisystem disease with cardiac manifestations. Whilst these are well-defined in adults, there are scarce published data in the pediatric population. This study aimed to investigate the yield and progression of cardiac disease in pediatric DM1 patients, focusing on congenital DM1 (cDM1).MethodsA retrospective observational study of all pediatric DM1 patients referred to our center (December 2000-November 2020) was conducted. Patients were classified into DM1 forms according to age of symptom onset and disease severity. Patients underwent clinical and cardiac evaluation with 12-lead ECG, transthoracic echocardiography and 24-h ECG Holter monitoring.Results67 DM1 pediatric patients were included: 56 (83.6%) cDM1 and 11 (16.4%) non-cDM1. Median follow-up time of cDM1 patients was 8.0 [3.25–11.0] years. 49 (87.5%) cDM1 patients had baseline 12-lead ECG and 44 (78.6%) had a follow-up 12-lead-ECG, with a median follow-up time from diagnosis to baseline ECG of 2.8 [1.0–8.5] years and to follow-up ECG of 10.9 [5.7–14.2] years. Overall, 43 (87.8%) presented ECG abnormalities, most commonly in the form of asymptomatic conduction disease (n = 23, 46.9%), of which 21 (42.9%) had first degree atrioventricular block (1st AVB). There was an increase of prevalence from baseline to follow-up ECG in low QRS voltage (16.7%), poor R wave progression (13.9%), abnormal repolarisation (11.9%) and 1st AVB (7.6%). one patient (1.8%) underwent pacemaker implantation for syncope in the context of progressive conduction disease. No patients developed left ventricular systolic dysfunction. 4 (7.1%) cDM1 patients died during follow up, including three who died suddenly with no clear cause of death.ConclusionsThis study is the first to analyse the prevalence and progression of ECG abnormalities in cDM1 pediatric patients. The high prevalence of abnormal findings, progressive changes and number of potentially associated events (1 pacemaker implantation and 3 unexplained sudden deaths) stresses the importance of systematic and continued cardiac evaluation of these patients.

Published
2022
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7. POMK regulates dystroglycan function via LARGE1-mediated elongation of matriglycan

Author

Ameya S Walimbe, Hidehiko Okuma, Soumya Joseph, Tiandi Yang, Takahiro Yonekawa, Jeffrey M Hord, David Venzke, Mary E Anderson, Silvia Torelli, Adnan Manzur, Megan Devereaux, Marco Cuellar, Sally Prouty, Saul Ocampo Landa, Liping Yu, Junyu Xiao, Jack E Dixon, Francesco Muntoni, and Kevin P Campbell

Subjects
dystroglycan, matriglycan, LARGE, POMK, laminin, muscular dystrophy, Medicine, Science, Biology (General), QH301-705.5
Abstract

Matriglycan [-GlcA-β1,3-Xyl-α1,3-]n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetyl-glucosaminyltransferase 1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNAc-β1,3-GlcNAc-β1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on α-DG (~150 kDa). In the absence of Pomk gene expression in mouse skeletal muscle, LARGE1 synthesizes a very short matriglycan resulting in a ~ 90 kDa α-DG which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Solution NMR spectroscopy studies demonstrate that LARGE1 directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE1 to elongate matriglycan on α-DG, thereby preventing muscular dystrophy.

Published
2020
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8. A novel phenotype of AChR-deficiency syndrome with predominant facial and distal weakness resulting from the inclusion of an evolutionary alternatively-spliced exon in CHRNA1

Author

Pedro M Rodríguez Cruz, Gianina Ravenscroft, Daniel Natera, Aisling Carr, Adnan Manzur, Wei Wei Liu, Norbert R Vella, Ivonne Jericó, Lidia Gonzalez-Quereda, Pia Gallano, Simon Attard Montalto, Mark R Davis, Phillipa J Lamont, Nigel G Laing, Pierre Bourque, Andres Nascimento, Francesco Muntoni, Kiran Polavarapu, Hanns Lochmüller, Jacqueline Palace, and David Beeson

Subjects
Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)
Published
2023
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9. Troponin-T type 1 (TNNT1)-related nemaline myopathy: unique respiratory phenotype and muscle pathology findings

Author

Alberto A. Zambon, François Abel, Barry Linnane, Declan O'Rourke, Rahul Phadke, Caroline A Sewry, Anna Sarkozy, Adnan Manzur, and Francesco Muntoni

Subjects
Phenotype, Troponin T, Neurology, Muscles, Mutation, Pediatrics, Perinatology and Child Health, Humans, Neurology (clinical), Muscle, Skeletal, Myopathies, Nemaline, Genetics (clinical)
Abstract

Biallelic pathogenic variants in the troponin T type 1 (TNNT1) gene cause a severe form of congenital nemaline myopathy. Typical features include severe motor delay, proximal contractures and weakness, pectus carinatum, chest wall rigidity and tremor. If left untreated, respiratory failure leads to early death at a median age of 18 months. Here we report on three non-Amish, unrelated patients harbouring novel TNNT1 variants. The peculiar combination of respiratory muscle weakness and chest wall stiffness caused early severe hypoventilation warranting the use of high pressures on BiPAP ventilator, with subsequent rapid escalation of pressures delivered with limited efficacy secondary to the extreme rib cage stiffness. Severe respiratory impairment occurred despite a relatively milder motor involvement in one patient. Muscle biopsies from two individuals showed predominant involvement of type 1 fibres, abundant nemaline bodies, marked fibrosis and loss of TNNT1 protein. We aim to increase the awareness of the challenges of managing respiratory support in patients with this unique respiratory phenotype.

Published
2022
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12. Recessive variants in COL25A1 gene as novel cause of arthrogryposis multiplex congenita with ocular congenital cranial dysinnervation disorder

Author

Daniel Natera‐de Benito, Julie A. Jurgens, Alison Yeung, Irina T. Zaharieva, Adnan Manzur, Stephanie P. DiTroia, Silvio Alessandro Di Gioia, Lynn Pais, Veronica Pini, Brenda J. Barry, Wai‐Man Chan, James E. Elder, John Christodoulou, Eleanor Hay, Eleina M. England, Pinki Munot, David G. Hunter, Lucy Feng, Danielle Ledoux, Anne O'Donnell‐Luria, Rahul Phadke, Elizabeth C. Engle, Anna Sarkozy, and Francesco Muntoni

Subjects
Arthrogryposis, Phenotype, axon guidance, Face, Mutation, Genetics, Humans, distal arthrogryposis, Muscle, Skeletal, congenital cranial dysinnervation disorders, Genetics (clinical), Article, arthrogryposis
Abstract

A proper interaction between muscle-derived collagen XXV and its motor neuron-derived receptors protein tyrosine phosphatases sigma and delta (PTP sigma/delta) is indispensable for intramuscular motor innervation. Despite this, thus far, pathogenic recessive variants in the COL25A1 gene had only been detected in a few patients with isolated ocular congenital cranial dysinnervation disorders. Here we describe five patients from three unrelated families with recessive missense and splice site COL25A1 variants presenting with a recognizable phenotype characterized by arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder phenotype. The clinical features of the older patients remained stable over time, without central nervous system involvement. This study extends the phenotypic and genotypic spectrum of COL25A1 related conditions, and further adds to our knowledge of the complex process of intramuscular motor innervation. Our observations indicate a role for collagen XXV in regulating the appropriate innervation not only of extraocular muscles, but also of bulbar, axial, and limb muscles in the human.

Published
2022

15. Digenic Inheritance Involving a Muscle Specific Protein Kinase and the Giant Titin Protein Causes a Skeletal Muscle Myopathy

Author

Ana Topf, Irina Zaharieva, Valeria Di Leo, Anna Vihola, Neha Wali, Marco Savarese, Kristen Laricchia, Cristina Venturini, Bas Vroling, Beryl Cummings, Rita Barresi, Elizabeth Harris, Chiara Marini Bettolo, Dan Cox, Jennifer Duff, Eleina England, Jane Patrick, Valerie Biancalana, Shobhana Bommireddipalli, Carsten Bonnemann, Anita Cairns, Mei Chiew, Kristl G. Claeys, Sandra Cooper, Mark R. Davis, Sandra Donkervoort, Corrie E. Erasmus, Carla Grosmann, Heinz Jungbluth, Erik-Jan Kamsteeg, Xaviere Lornage, Wolfgang Löscher, Edoardo Malfatti, Adnan Manzur, Pilar Marti, Tiziana Mongini, Nuria Muelas, Atsuko Nishikawa, Narumi Ogonuki, Gina O'Grady, Stephanie Paquay, Rahul Phadke, Beth Pletcher, Norma Romero, Meyke Schouten, Snehal Shah, Yves Sznajer, Giorgio Tasca, Allysa Tuite, Peter van den Bergh, Nicol Voermans, Julia Wanschitz, Elizabeth Wraige, Kimihiko Yoshimura, Emily Oates, Osamu Nakagawa, Ichizo Nishino, Jocelyn Laporte, Juan Vilchez, Daniel Macarthur, Anna Sarkozy, Bjarne Udd, Elisabeth Busch-Nentwich, Francesco Muntoni, and Volker Straub

Published
2021
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16. 100 All that glitters is not GARS

Author

Carolynne M Doherty, Menelaos Pipis, Mariola Skorupinska, Adnan Manzur, Francesco Muntoni, Sachit Shah, Jasper Morrow, Alexander M Rossor, and Mary M Reilly

Subjects
Psychiatry and Mental health, Surgery, Neurology (clinical)
Abstract

BackgroundA 22-year-old woman was initially assessed in the context of a family history of distal wasting and weakness, typically with upper limb onset, then lower limb involvement. When assessed as a child her phenotype was recognised to be atypical compared to her sister, but she was thought to be affected. Ultimately the family was diagnosed with distal hereditary motor neuropathy due to a GARS mutation. However, this patient did not carry the mutation, prompting further evaluation.CaseAt age 11 the left foot was smaller with some toe clawing and cavus deformity. Left sided wasting of tibialis anterior and the posterior compartment was seen, ankle dorsiflexors were grade 3.ResultsNerve conduction studies and EMG were normal in the right leg and arms. Chronic denervation was identified in L4, L5 and S1. MRI of lumbar spine was normal. However, 2 areas of marked thickening and enhancement were seen in the left sciatic nerve in the upper thigh and a further lesion in the mid- thigh. Fascicular preservation of the nerve was felt to be strongly suggestive of a perineurioma.DiscussionThis case highlights the importance of careful phenotyping when validating novel variants in potentially causative genes.c.doherty@ucl.ac.uk

Published
2022
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17. 127 ACTA1 associated myopathy with neurogenic EMG changes

Author

Carolynne Doherty, Julian Blake, Adnan Manzur, Emma Wakeling, Sachit Shah, Francesco Muntoni, and Mary Reilly

Subjects
Psychiatry and Mental health, Surgery, Neurology (clinical)
Abstract

BackgroundWe describe a proband and her son who have proximal limb and facial weakness and marked hand involvement. A congenital myopathy panel demonstrated two RYR1 variants and the p.Ile289Phe novel variant in ACTA1.Cases: The proband had initially been diagnosed with SMA following premature birth, late milestones, scoliosis and proximal and distal weakness which was relatively static until age 40. EMG as a child was neurogenic. Her son had poor feeding after birth, delayed motor milestones, intellectual delay, and by his teens, severe facial weakness and distal upper limb wasting particularly the finger flexors and extensors, with hip flexion of grade 3. Repeat neurophysiological evaluation of the proband at age 60, demonstrated a neurogenic pattern but also brief polyphasic motor units, raising suspicion of an addi- tional myopathic process.DiscussionZukosky and colleagues1also described a family with a different missense mutation in the ACTA1 gene who had been diagnosed with SMA on the basis of neurogenic EMG findings. Our additional family confirms that myopathy can be accompanied by neurogenic EMG changes in ACTA1 associated myopathy.Reference1. Zukosky K, Meilleur K, Traynor BJ, Dastgir J, Medne L, Devoto M, et al. Association of a Novel ACTA1 Mutation With a Dominant Progressive Scapuloperoneal Myopathy in an Extended Family. JAMA Neurol. 2015 Jun 1;72(6):689–98.carolynnedoherty@doctors.org.uk|NIHR Bursary

Published
2022
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18. POMK regulates dystroglycan function via LARGE-mediated elongation of matriglycan

Author

Ameya S. Walimbe, Hidehiko Okuma, Soumya Joseph, Tiandi Yang, Takahiro Yonekawa, Jeffrey M. Hord, David Venzke, Mary E. Anderson, Silvia Torelli, Adnan Manzur, Megan Devereaux, Marco Cuellar, Sally Prouty, Saul Ocampo Landa, Liping Yu, Junyu Xiao, Jack E. Dixon, Francesco Muntoni, and Kevin P. Campbell

Subjects
0303 health sciences, biology, Kinase, Chemistry, Skeletal muscle, medicine.disease, Cell biology, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, Dystroglycan, biology.protein, Phosphorylation, Muscular dystrophy, Receptor, 030217 neurology & neurosurgery, Function (biology), 030304 developmental biology
Abstract

Matriglycan [-GlcA-β1,3-Xyl-α1,3-]n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetylglucosaminyltransferase-1 (LARGE) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNac-β1,3-GlcNac-β1,4-Man) preceding matriglycan synthesis, is required for LARGE-mediated generation of full-length matriglycan on α-DG (∼150 kDa). In the absence of POMK, LARGE synthesizes a very short matriglycan resulting in a ∼90 kDa α-DG in mouse skeletal muscle which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Solution NMR spectroscopy studies demonstrate that LARGE directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE to elongate matriglycan on α-DG, thereby preventing muscular dystrophy.

Published
2020
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19. 221st ENMC International Workshop

Author

Mary M. Reilly, Davide Pareyson, Joshua Burns, Matilde Laurá, Michael E. Shy, Dishan Singh, Per Henrik Agren, Viola Altmann, Jonathan Baets, Peter Briggs, Karen Butcher, Luca Gaiani, Filippo Genovese, Paul Gibbons, Jan Willem Louwerens, Adnan Manzur, Isabella Moroni, Nicolò Martinelli, Glenn Pfeffer, Gita Ramdharry, Michael Shy, Marco van der Linden, and Wolfram Wenz

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, 030222 orthopedics, medicine.medical_specialty, Surgical approach, business.industry, Extramural, MEDLINE, Health services research, Disease, nervous system diseases, 03 medical and health sciences, Tooth disease, 0302 clinical medicine, stomatognathic system, Neurology, Pediatrics, Perinatology and Child Health, Physical therapy, Medicine, Neurology (clinical), Foot surgery, business, 030217 neurology & neurosurgery, Genetics (clinical), Foot (unit)
Abstract

•Foot deformities are frequently observed in Charcot-Marie-Tooth disease patients.•Surgical management is variable among centres.•During the workshop current surgical approaches were reviewed.•Recommendations for foot surgery in CMT patients were agreed by the participants.

Published
2017
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21. Bi-allelic mutations in MYL1 cause a severe congenital myopathy

Author

Gianina, Ravenscroft, Irina T, Zaharieva, Carlo A, Bortolotti, Matteo, Lambrughi, Marcello, Pignataro, Marco, Borsari, Caroline A, Sewry, Rahul, Phadke, Goknur, Haliloglu, Royston, Ong, Hayley, Goullée, Tamieka, Whyte, Uk K, Consortium, Adnan, Manzur, Beril, Talim, Ulkuhan, Kaya, Daniel P S, Osborn, Alistair R R, Forrest, Nigel G, Laing, and Francesco, Muntoni

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Myosin Light Chains, Muscle Hypotonia, Myosin light-chain kinase, Myotonia Congenita, Biology, Alleles, Animals, Consanguinity, Disease Models, Animal, Exome, Homozygote, Humans, Muscle, Skeletal, Mutation, Myosin Heavy Chains, Pedigree, Zebrafish, 03 medical and health sciences, Internal medicine, Myosin, Genetics, medicine, Molecular Biology, Genetics (clinical), Muscle biopsy, medicine.diagnostic_test, Animal, Myotonia congenita, Skeletal muscle, Skeletal, General Medicine, medicine.disease, Congenital myopathy, Hypotonia, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Disease Models, Muscle, General Article, medicine.symptom
Abstract

OBJECTIVE: Congenital myopathies are typically characterised by early onset hypotonia, weakness and hallmark features on biopsy. Despite the rapid pace of gene discovery, approximately 50% of patients with a congenital myopathy remain without a genetic diagnosis following screening of known disease genes. METHODS: We performed exome sequencing on two consanguineous probands diagnosed with a congenital myopathy and muscle biopsy showing selective atrophy/hypotrophy or absence of type II myofibres. RESULTS: We identified variants in the gene (MYL1) encoding the skeletal muscle fast-twitch specific myosin essential light chain in both probands. A homozygous essential splice acceptor variant (c.479-2A>G, predicted to result in skipping of exon 5 was identified in Proband 1, and a homozygous missense substitution (c.488T>G, p.(Met163Arg)) was identified in Proband 2. Protein modeling of the p.(Met163Arg) substitution predicted it might impede intermolecular interactions that facilitate binding to the IQ domain of myosin heavy chain, thus likely impacting on the structure and functioning of the myosin motor. MYL1 was markedly reduced in skeletal muscle from both probands, suggesting that the missense substitution likely results in an unstable protein. Knock down of myl1 in zebrafish resulted in abnormal morphology, disrupted muscle structure and impaired touch-evoked escape responses, thus confirming that skeletal muscle fast-twitch specific myosin essential light chain is critical for myofibre development and function. INTERPRETATION: Our data implicate MYL1 as a crucial protein for adequate skeletal muscle function and that MYL1 deficiency is associated with a severe congenital myopathy.

Published
2018
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22. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author

Yoko Ito, Keren J. Carss, Sofia T. Duarte, Taila Hartley, Boris Keren, Manju A. Kurian, Isabelle Marey, Perinne Charles, Carla Mendonça, Caroline Nava, Rolph Pfundt, Alba Sanchis-Juan, Hans van Bokhoven, Anthony van Essen, Conny van Ravenswaaij-Arts, Kym M. Boycott, Kristin D. Kernohan, Sarah Dyack, F. Lucy Raymond, Timothy Aitman, David Bennett, Mark Caulfield, Patrick Chinnery, Daniel Gale, Ania Koziell, Taco W. Kuijpers, Michael A. Laffan, Eamonn Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry, Irene Roberts, Kenneth G.C. Smith, Adrian Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnstrom, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton-Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Remi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele, Daniel Hart, Johan W.M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne, Ri Liesner, Mike Makris, Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel-Vilk, Michael Richards, Matthew Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng-Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry Watson, Sarah Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher Watt, Deborah Whitehorn, Antony Attwood, Louise Daugherty, Sri V.V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Megy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William Astle, Marta Bleda, Stefan Gräf, Matthias Haimel, Hana Lango-Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner-Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Doffinger, Helen Firth, Frances Flinter, Courtney French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane Hurst, Dragana Josifova, Deepa Krishnakumar, Melissa Lees, Robert MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides, Anthony Moore, Elaine Murphy, Soo-Mi Park, Alasdair Parker, Chris Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser, Richard Sandford, Saikat Santra, Richard Scott, Aman Sohal, Penelope Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew Webster, Sonia Ali, Souad Ali, Harm J. Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep K. Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gabor Kovacs, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke-Zaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kevin Rue-Albrecht, Gwen Schotte, Debbie Shipley, Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen M. Treacy, Richard Trembath, Anton Vonk Noordegraaf, Sara Walker, Ivy Wanjiku, John Wharton, Martin Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael Browning, Siobhan Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewell, Emily Staples, Hans Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon McGowan, Adam Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns-Ulrich Marschall, Michael Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Rob Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary Reilly, Tara Renton, Andrew Rice, Andreas Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen Walker, Liz Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James Whitworth, Maryam Afzal, Elizabeth Colby, Moin Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin K.S. Wong, Rhea Tan, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis Bulman, David Dyment, Freson, Kathleen, Peerlinck, Kathelijne, Van Geet, Christel, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Medical Research Council (MRC), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Aging & Later Life, Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, and Molecular cell biology and Immunology

Subjects
0301 basic medicine, Male, Care4Rare Canada Consortium, WAVE FAMILY PROTEINS, actin cytoskeleton, PROTEIN, HDE NEU PED, medicine.disease_cause, Whole Exome Sequencing, 0302 clinical medicine, Neurodevelopmental disorder, SYNAPTIC PLASTICITY, Intellectual disability, WAVE1 complex, PLASTICITY, EXCHANGE, 11 Medical and Health Sciences, Exome sequencing, Genetics (clinical), seizures, Genetics & Heredity, Genetics, Mutation, WASF1, DENDRITIC SPINES, developmental delay, Female, DISEASE GENE-DISCOVERY, Adult, Heterozygote, GENES, DISORDERS, autism, Biology, ACTIN, 03 medical and health sciences, Young Adult, Seizures, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, PROTRUSIONS, recurrent de novo truncating mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, lamellipodia, neurodevelopmental disorder, Actin remodeling, Heterozygote advantage, NIHR BioResource, 06 Biological Sciences, medicine.disease, Actin cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, WAVE, RETARDATION, 030217 neurology & neurosurgery
Abstract

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published

Published
2018
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23. Mobility shift of beta-dystroglycan as a marker of

Author

Anna, Sarkozy, Silvia, Torelli, Rachael, Mein, Matt, Henderson, Rahul, Phadke, Lucy, Feng, Caroline, Sewry, Pierpaolo, Ala, Michael, Yau, Marta, Bertoli, Tracey, Willis, Simon, Hammans, Adnan, Manzur, Maria, Sframeli, Fiona, Norwood, Wojtek, Rakowicz, Aleksandar, Radunovic, Sujit S, Vaidya, Matt, Parton, Mark, Walker, Silvia, Marino, Curtis, Offiah, Maria Elena, Farrugia, Godwin, Mamutse, Chiara, Marini-Bettolo, Elizabeth, Wraige, David, Beeson, Hanns, Lochmüller, Volker, Straub, Kate, Bushby, Rita, Barresi, and Francesco, Muntoni

Subjects
Guanosine Diphosphate Mannose, Male, Adolescent, Middle Aged, Nucleotidyltransferases, Muscular Dystrophies, Cohort Studies, Child, Preschool, Mutation, Humans, Female, Child, Dystroglycans, Biomarkers, Aged
Abstract

Defects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (We describe clinical, genetic and biochemical findings of 21 patients withWe report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (β-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormalOur data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in

Published
2017

24. Contributors

Author

Neil Aiton, Nick Archer, Ruth M Ayling, Imelda Balchin, Peter G Barth, Alison Bedford Russell, Nick Bishop, Maggie Blott, Ann Bowron, Geraldine Boylan, Pamela Cairns, Oana Caluseriu, Andrew J Cant, Patrick H T Cartlidge, Tim Cheetham, Malcolm Chiswick, Sirinuch Chomtho, Imti Choonara, N M P Clarke, Tim Cole, Sharon Conroy, Christopher J Dare, Mark Davenport, Mark Denbow, Leigh Dyet, D Keith Edmonds, Kate Farrer, Mary Fewtrell, Brian Fleck, Grenville F Fox, Andrew R Gennery, Andrew Green, Anne Greenough, Floris Groenendaal, Nedim Hadžić, Cornelia Hagmann, Simon Hannam, Sian Harding, Jane Hawdon, Angela Huertas-Ceballos, Paul Humphries, David Isaacs, N Kevin Ives, Anoo Jain, Samantha Johnson, Simon A Jones, Steve Kempley, Gillian Kennedy, Pippa Kyle, Ian A Laing, Cassie Lawn, Bertie Leigh, Alan Lucas, Andrew Lyon, Alison Macfarlane, Adnan Manzur, Neil Marlow, Lila Mayahi, Hazel E Mchaffie, John Mcintyre, Judith Helen Meek, Giorgina Mieli-Vergani, Anthony D Milner, Neena Modi, Colin J Morley, Gavin Morrison, Miranda Mugford, Francesco Muntoni, Edile Murdoch, Neil A Murray, Simon Newell, Colm O'Donnell, Roger D Palmer, Dharmintra Pasupathy, Donald Peebles, Chinthika Piyasena, Nandiran Ratnavel, William Reardon, Janet M Rennie, Stephanie Robb, Irene Roberts, Nicola J Robertson, Maureen Rogers, Steven M Sale, Daniel J Schenk, Neil Sebire, Divyen K Shah, Naima Smeulders, Gordon C S Smith, Alistair G Smyth, Mark D Stringer, Ian Sugarman, Sudhin Thayyil, Carmen Turowski, Sukrutha Veerareddy, Martin A Weber, Duncan T Wilcox, David Williams, Denise M Williams, James E Wraith, John Wyatt, and Robert W M Yates

Published
2012
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25. Development of a functional assessment scale for ambulatory boys with Duchenne muscular dystrophy

Author

Elaine, Scott, Michelle, Eagle, Anna, Mayhew, Jenny, Freeman, Marion, Main, Jennie, Sheehan, Adnan, Manzur, Francesco, Muntoni, and C, Longman

Subjects
Male, Muscular Dystrophy, Duchenne, Observer Variation, Physical Therapists, Disability Evaluation, Humans, Reproducibility of Results, Walking, Focus Groups, Child, United Kingdom
Abstract

The aims of this study were to develop a clinical assessment scale to measure functional ability in ambulant boys with Duchenne muscular dystrophy and to determine the reliability of the scale in multiple centres in the UK.Focus groups and workshops were held with experienced paediatric neuromuscular physiotherapists to determine scale content. A manual was prepared with accompanying videos, and training sessions were conducted. A total of 17 physiotherapists from participating centres used the videos to determine inter-rater reliability. Five determined the intra-rater reliability.Strength of agreement for these groups based on total subject scores was very good (0.95 and ≥ 0.93 for consistency and absolute agreement, respectively). Test-retest ability was high, with perfect agreement between occasions for all but two items of the scale.Our study indicates that the North Star Ambulatory Assessment is practical and reliable. It takes only 10 minutes to perform and incorporates both universally used timed tests as well as levels of activities, which allow assessment of high-functioning boys with Duchenne muscular dystrophy.

Published
2011

26. Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies.

Author

Haiyan Zhou, Heinz Jungbluth, Caroline A. Sewry, Lucy Feng, Enrico Bertini, Kate Bushby, Volker Straub, Helen Roper, Michael R. Rose, Martin Brockington, Maria Kinali, Adnan Manzur, Stephanie Robb, Richard Appleton, Sonia Messina, Adele DAmico, Ros Quinlivan, Michael Swash, Clemens R. Müller, and Susan Brown

Subjects
PHENOTYPES, MUSCLE diseases, MALIGNANT hyperthermia, RYANODINE receptors
Abstract

Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channel. [ABSTRACT FROM AUTHOR]

Published
2007
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