76 results on '"Manoj P. Menezes"'
Search Results
2. CSF neopterin and quinolinic acid are biomarkers of neuroinflammation and neurotoxicity in FIRES and other infection‐triggered encephalopathy syndromes
- Author
-
Russell C. Dale, Terrence Thomas, Shrujna Patel, Velda X. Han, Kavitha Kothur, Christopher Troedson, Sachin Gupta, Deepak Gill, Stephen Malone, Michaela Waak, Sophie Calvert, Gopinath Subramanian, P. Ian Andrews, Tejaswi Kandula, Manoj P. Menezes, Simone Ardern‐Holmes, Shekeeb Mohammad, Sushil Bandodkar, and Jingya Yan
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective Infection‐triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI neuroimaging phenotypes, there are otherwise few biomarkers of disease. Early detection to enable immune modulatory treatments could improve outcomes. Methods We measured CSF neopterin, quinolinic acid, kynurenine and kynurenine/tryptophan ratio using a liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) system. The CSF of 18 children with ITES were compared with acute encephalitis (n = 20), and three control groups, namely epilepsy (n = 20), status epilepticus (n = 18) and neurogenetic controls (n = 20). Results The main ITES phenotypes in 18 patients were acute encephalopathy with biphasic seizures and late restricted diffusion (AESD, n = 4), febrile infection‐related epilepsy syndrome (FIRES n = 4) and other ITES phenotypes. Influenza A was the most common infectious trigger (n = 5), and 50% of patients had a preceding notable neurodevelopmental or family history. CSF neopterin, quinolinic acid and kynurenine were elevated in ITES group compared to the three control groups (all p
- Published
- 2023
- Full Text
- View/download PDF
3. CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context
- Author
-
Jingya Yan, Kavitha Kothur, Shekeeb Mohammad, Jason Chung, Shrujna Patel, Hannah F. Jones, Brooke A. Keating, Velda X. Han, Richard Webster, Simone Ardern-Holmes, Jayne Antony, Manoj P. Menezes, Esther Tantsis, Deepak Gill, Sachin Gupta, Tejaswi Kandula, Hugo Sampaio, Michelle A. Farrar, Christopher Troedson, P Ian Andrews, Sekhar C. Pillai, Benjamin Heng, Gilles J. Guillemin, Anna Guller, Sushil Bandodkar, and Russell C. Dale
- Subjects
Cerebrospinal fluid metabolomics ,Neopterin ,Kynurenine pathway ,Encephalitis ,Epilepsy ,Neurodevelopmental disorders ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. Methods: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1–17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). Findings: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p
- Published
- 2023
- Full Text
- View/download PDF
4. Decreased cerebrospinal fluid kynurenic acid in epileptic spasms: A biomarker of response to corticosteroids
- Author
-
Jingya Yan, Kavitha Kothur, Emily A. Innes, Velda X. Han, Hannah F. Jones, Shrujna Patel, Erica Tsang, Richard Webster, Sachin Gupta, Christopher Troedson, Manoj P. Menezes, Jayne Antony, Simone Ardern-Holmes, Esther Tantsis, Shekeeb Mohammad, Louise Wienholt, Ananda S. Pires, Benjamin Heng, Gilles J. Guillemin, Anna Guller, Deepak Gill, Sushil Bandodkar, and Russell C. Dale
- Subjects
Cerebrospinal fluid ,Tryptophan-kynurenine pathway ,Infantile spasms ,Epileptic spasms ,Metabolomics ,Ketogenic diet ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Epileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations. Methods: A panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3–3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3–3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1–2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8–2.5 yrs). Findings: There was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p
- Published
- 2022
- Full Text
- View/download PDF
5. Refining clinical trial inclusion criteria to optimize the standardized response mean of the CMTPedS
- Author
-
Kayla M. D. Cornett, Manoj P. Menezes, Paula Bray, Rosemary R. Shy, Isabella Moroni, Emanuela Pagliano, Davide Pareyson, Tim Estilow, Sabrina W. Yum, Trupti Bhandari, Francesco Muntoni, Matilde Laura, Mary M. Reilly, Richard S. Finkel, Katy J. Eichinger, David N. Herrmann, Michael E. Shy, Joshua Burns, and CMTPedS Study Group
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2‐year natural history data from 187 children aged 3–20 years with a range of CMT genetic subtypes. Subsets based on age (3–8 years), disability level (CMTPedS score 0–14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS.
- Published
- 2020
- Full Text
- View/download PDF
6. Feasibility of designing, manufacturing and delivering 3D printed ankle-foot orthoses: a systematic review
- Author
-
Elizabeth Wojciechowski, Angela Y. Chang, Daniel Balassone, Jacqueline Ford, Tegan L. Cheng, David Little, Manoj P. Menezes, Sean Hogan, and Joshua Burns
- Subjects
3D printing ,Additive manufacturing ,Ankle foot orthoses ,AFO ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Ankle-foot orthoses (AFO) are prescribed to manage difficulty walking due to foot drop, bony foot deformities and poor balance. Traditional AFOs are handmade using thermoplastic vacuum forming which provides limited design options, is labour-intensive and associated with long wait times. 3D printing has the potential to transform AFO production and health service delivery. The aim of this systematic review was to determine the feasibility of designing, manufacturing and delivering customised 3D printed AFOs by evaluating the biomechanical outcomes, mechanical properties and fit of 3D printed compared to traditionally manufactured AFOs. Method Electronic databases were searched from January 1985 to June 2018 according to terms related to 3D printing and AFOs. Studies of any design from healthy or pathological populations of any age were eligible for inclusion. Studies must have investigated the effect of customised 3D printed AFOs using any 3D printing technique on outcomes related to walking ability, biomechanical function, mechanical properties, patient comfort, pain and disability. Any other orthotic type or AFOs without a 3D printed calf and foot section were excluded. The quality of evidence was assessed using the GRADE process. Results Eleven studies met the eligibility criteria evaluating 3D printed AFOs in healthy adults, and adults and children with unilateral foot drop from a variety of conditions. 3D printing was used to replicate traditional AFOs and develop novel designs to optimise the stiffness properties or reduce the weight and improve the ease of use of the AFO. 3D printed custom AFOs were found to be comparable to traditional custom AFOs and prefabricated AFOs in terms of temporal-spatial parameters. The mechanical stiffness and energy dissipation of 3D printed AFOs were found to be similar to prefabricated carbon-fibre AFOs. However, the sample sizes were small (n = 1 to 8) and study quality was generally low. Conclusion The biomechanical effects and mechanical properties of 3D printed AFOs were comparable to traditionally manufactured AFOs. Developing novel AFO designs using 3D printing has many potential benefits including stiffness and weight optimisation to improve biomechanical function and comfort.
- Published
- 2019
- Full Text
- View/download PDF
7. A genetic basis is identified in 74% cases of paediatric hyperCKaemia without weakness presenting to a tertiary paediatric neuromuscular centre
- Author
-
Wui-Kwan Wong, Samantha J Bryen, Adam Bournazos, Joe Yasa, Frances Lemckert, Shobhana Bommireddipall, Leigh B Waddell, Manoj P Menezes, Richard Webster, Mark Davis, Christina Liang, Sandra T Cooper, and Kristi J Jones
- Subjects
Male ,Muscle Weakness ,Neuromuscular Diseases ,Muscular Diseases ,Neurology ,Pediatrics, Perinatology and Child Health ,Humans ,Female ,Genetic Testing ,Neurology (clinical) ,Child ,Creatine Kinase ,Genetics (clinical) ,Retrospective Studies - Abstract
Paediatric hyperCKaemia without weakness presents a clinical conundrum. Invasive investigations with low diagnostic yields, including muscle biopsy, may be considered unjustifiable. Improved access to genome-wide genetic testing has shifted first-line investigations towards genetic studies in neuromuscular disease. This research aims to provide an evidence-based diagnostic approach to paediatric hyperCKaemia without weakness, a current gap in the literature. We identified 47 individuals (10-months to 16-years-old; 34 males, 13 females) from 43 families presenting with hyperCKaemia on two or more occasions, without weakness, from The Children's Hospital at Westmead Neuromuscular Clinic Database. Clinical features, investigations and outcomes were analysed via retrospective chart review. Genetic testing has been performed in 34/43. Genetic variants explaining hyperCKaemia were identified in 25/34 (74%) using multiplex ligation-dependent probe amplification, massive parallel sequencing, single gene testing and exome sequencing. Pathogenic/likely pathogenic variants were identified in 19 neuromuscular disease genes and six metabolic myopathy genes. Individuals with metabolic diagnoses had higher peak creatine kinase levels that sometimes normalized. Conversely, creatine kinase levels remained persistently elevated those with neuromuscular diagnoses. In summary, a genetic cause is found in most paediatric patients with hyperCKaemia without weakness informing clinical management and counselling. Thus, we propose a diagnostic algorithm for this cohort.
- Published
- 2022
8. Steroid‐responsive aseptic meningitis with raised intracranial pressure syndrome associated with myelin oligodendrocyte glycoprotein autoantibodies
- Author
-
Wui‐Kwan Wong, Christopher Troedson, Ken Peacock, Fabienne Brilot‐Turville, Manoj P Menezes, Russell C Dale, and Richard Webster
- Subjects
Pediatrics, Perinatology and Child Health - Published
- 2022
9. Paediatric neurocysticercosis in high income countries
- Author
-
Indhumathi Babu, Annaleise R Howard-Jones, Robert Goetti, Manoj P Menezes, Susan Arbuckle, and Philip N Britton
- Subjects
Epilepsy ,Seizures ,Developed Countries ,Pediatrics, Perinatology and Child Health ,Humans ,Neuroimaging ,Neurology (clinical) ,General Medicine ,Child ,Neurocysticercosis - Abstract
Neurocysticercosis (NCC) is an unusual cause of seizures in high income settings. It typically presents as an afebrile seizure in a previously well child and can occur years after migration or travel.Children diagnosed with neurocysticercosis from 01 July 2005 to 30 June 2020 were identified from the electronic medical records of a tertiary children's hospital in Australia. Additionally, a 10-year compilation of case reports of paediatric NCC in high income settings was performed by medline search (publication years 2011-2021). Diagnosis and treatment of neurocysticercosis were reviewed with reference to diagnostic criteria of Del Brutto et al., and the 2017 Infectious Diseases Society of America treatment guidelines.Over a fifteen-year period, eight children were diagnosed with NCC at our hospital in Sydney, Australia. Seizures and history of travel to or migration from South Asia were the two most frequently occurring findings. Children diagnosed after 2016 all received antiparasitic therapy. Outcomes were generally favorable, though long-term epilepsy resulted in some cases. Compiled case reports from high income settings revealed migration and travel exposures commensurate with local demographic patterns, and treatment approaches conforming with 2017 Infectious Diseases Society of America guidelines.Clinicians should be aware of NCC as a differential diagnosis in children from endemic areas presenting with unprovoked seizures as misdiagnosis can occur. Expert review of neuroimaging facilitates diagnosis and can avert unnecessary neurosurgery. In Australia, India was a key exposure country for NCC, reflecting its endemic burden of disease and local travel and migration patterns.
- Published
- 2022
10. Connective tissue presentation in two families expands the phenotypic spectrum of PYROXD1 disorders
- Author
-
Frances J Evesson, Gregory Dziaduch, Samantha J Bryen, Francesca Moore, Sara Pittman, Beena Devanapalli, Leigh B Waddell, Monique M Ryan, Manoj P Menezes, Conrad C Weihl, Adviye Ayper Tolun, Craig Zaidman, Helen Young, Lesley C Adès, and Sandra T Cooper
- Subjects
Genetics ,General Medicine ,Molecular Biology ,Genetics (clinical) - Abstract
Recessive variants in the oxidoreductase PYROXD1 are reported to cause a myopathy in 22 affected individuals from 15 families. Here, we describe two female probands from unrelated families presenting with features of a congenital connective tissue disorder including osteopenia, blue sclera, soft skin, joint hypermobility and neuromuscular junction dysfunction in addition to known features of PYROXD1 myopathy including respiratory difficulties, weakness, hypotonia and oromotor dysfunction. Proband AII:1 is compound heterozygous for the recurrent PYROXD1 variant Chr12(GRCh38):g.21452130A>G;NM_024854.5:c.464A>G;p.(N155S) and Chr12(GRCh38):g.21462019_21462022del;NM_024854.5:c.892_895del;p.(V298Mfs*4) and proband BII:1 is compound heterozygous for Chr12(GRCh38):g.21468739-21468741del;NM_024854.5:c.1488_1490del;p.(E496del) and Chr12(GRCh38):g.21467619del;NM_024854.5:c.1254+1del. RNA studies demonstrate c.892_895del;p.(V298Mfs*4) is targeted by nonsense mediated decay and c.1254+1delG elicits in-frame skipping of exon-11. Western blot from cultured fibroblasts shows reduced PYROXD1 protein levels in both probands. Testing urine from BII:1 and six individuals with PYROXD1 myopathy showed elevated levels of deoxypyridinoline, a mature collagen crosslink, correlating with PYROXD1-disorder severity. Urine and serum amino acid testing of the same individuals revealed no reportable changes. In contrast to PYROXD1 knock-out, we find no evidence for disrupted tRNA ligase activity, as measured via XBP1 splicing, in fibroblasts expressing PYROXD1 variants. In summary, we expand the clinical spectrum of PYROXD1-related disorders to include an overlapping connective tissue and myopathy presentation, identify three novel, pathogenic PYROXD1 variants, and provide preliminary evidence that elevated urine DPD crosslinks may provide a clinical biomarker for PYROXD1 disorders. Our results advocate consideration of PYROXD1 variants in the differential diagnosis for undiagnosed individuals presenting with a connective tissue disorder and myopathy.
- Published
- 2023
11. An Infant With Paroxysms of Screaming and Unilateral Lacrimation and Rhinorrhea
- Author
-
Manoj P. Menezes, Ryan Lucas, and Stephen Sze Shing Teo
- Subjects
book.periodical ,Conjunctival injection ,medicine.medical_specialty ,rhinorrhea ,Erythema ,business.industry ,Periorbital Edema ,Emergency department ,Screaming ,Dermatology ,humanities ,Cephalalgia ,medicine ,medicine.symptom ,Trigeminal autonomic cephalalgia ,business ,book - Abstract
We describe the case of a 5-month-old girl who presented to the emergency department with left-sided periorbital edema and erythema. During the assessment, she was observed to suffer repeated hyper-acute episodes of screaming associated with left-sided hemifacial flushing, lacrimation and rhinorrhea. This child was diagnosed with probable short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), one of the trigeminal autonomic cephalalgias. We believe that this is the youngest probable case of SUNCT for which there is photographic and video evidence. Int J Clin Pediatr. 2021;10(2-3):49-52 doi: https://doi.org/10.14740/ijcp433
- Published
- 2021
12. Reliability and sensitivity of radiographic measures of hip dysplasia in childhood Charcot-Marie-Tooth disease
- Author
-
Oliver Birke, Paul Gibbons, Leanne N Dwan, David G. Little, Kamal Jamil, Manoj P. Menezes, and Joshua Burns
- Subjects
musculoskeletal diseases ,Hip dysplasia ,Subluxation ,Orthodontics ,business.industry ,Radiography ,medicine.disease ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Femoral head ,Tooth disease ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,Orthopedics and Sports Medicine ,Surgery ,business ,030217 neurology & neurosurgery - Abstract
Background: Hip dysplasia is a lack of femoral head coverage and disruption of hip and acetabular alignment and congruency, with severity ranging from mild subluxation in nascent at-risk hips to complete dislocation. Presentation of hip dysplasia in neuromuscular conditions can be sub-clinical or associated with a limp with or without hip pain, abductor and flexor weakness and reduced hip range of motion. Untreated hip dysplasia leads to early onset osteoarthritis requiring hip arthroplasty in early adulthood. Hip dysplasia occurs in 6–20% of children with Charcot-Marie-Tooth disease, however little is known about the reliability and sensitivity of detection on plain film pelvic radiographs. Methods: 14 common measures of hip dysplasia on anteroposterior pelvis radiographs were independently assessed by 2 orthopaedic specialists in 30 ambulant children with Charcot-Marie-Tooth disease. Hip health was also categorised based on clinical impression to assess the sensitivity of radiographic measures to identify hip dysplasia status. Results: 8 measures (acetabular index, head width, lateral centre-edge angle, lateral uncoverage, medial joint width, migration percentage, neck shaft angle, triradiate status) exhibited ‘excellent’ reliability between clinical evaluators. 5 of the 30 patients (17%) were identified as having nascent hip dysplasia. Reliable radiographic measures that significantly distinguished between nascent hip dysplasia and healthy hips were acetabular index, lateral centre edge angle, medial joint width and migration percentage. Conclusions: We have identified a subset of reliable and sensitive radiographic hip measures in children with Charcot-Marie-Tooth disease to prioritise during hip screening to mitigate the deleterious effects of hip dysplasia, pain and disability in adulthood.
- Published
- 2021
13. Clinical, Genetic, and Disability Profile of Pediatric Distal Hereditary Motor Neuropathy
- Author
-
Manoj P. Menezes, Marina Frasquet, Kayla M.D. Cornett, Joshua Burns, Teresa Sevilla, Gabrielle Donlevy, and Herminia Argente-Escrig
- Subjects
Cytoplasmic Dyneins ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Neural Conduction ,Disease ,GTP Phosphohydrolases ,Mitochondrial Proteins ,Muscular Atrophy, Spinal ,Disability Evaluation ,03 medical and health sciences ,Grip strength ,0302 clinical medicine ,Sensation ,Intellectual disability ,medicine ,Clinical genetic ,Humans ,Child ,Muscle, Skeletal ,Retrospective Studies ,business.industry ,Retrospective cohort study ,medicine.disease ,Magnetic Resonance Imaging ,Phenotype ,030104 developmental biology ,Child, Preschool ,Mutation ,Cohort ,Female ,Neurology (clinical) ,business ,Microtubule-Associated Proteins ,Motor neuropathy ,030217 neurology & neurosurgery - Abstract
ObjectiveTo describe the clinical, genetic, and disability profile of pediatric distal hereditary motor neuropathy (dHMN) and to determine the utility of an outcome measure validated for children with Charcot-Marie-Tooth disease (CMT) in assessing disability in this cohort.MethodsWe reviewed the clinical, neurophysiologic, and disability data on individuals with dHMN, evaluated before the age of 20 years, at 2 tertiary neuromuscular clinics in Australia and Spain. Disability was assessed annually with the CMT Pediatric Scale (CMTPedS) in a subset of individuals.ResultsTwenty-two children (13 female) from 19 families were included. Fourteen individuals were symptomatic in the first year of life. Intellectual disability was present in 6 individuals; upper motor neuron signs were seen in 8. Pathogenic variants were found in 9 families, more frequently inBICD2(BICD2-4,DYNC1H1-2,MFN2-2,GARS-1). A novel pathogenic variant in theGARSgene was detected and characterized phenotypically. Disability was moderate on the CMTPedS (mean [SD] 18.2 [6.3], n = 16), with balance and long jump being the most affected and sensation items and grip strength the least affected. Over 1 year, the CMTPedS total score deteriorated, on average 1.5 points (SD 3.7) or 9% (n = 12), with significant variability in the rate of progression within the cohort.ConclusionsThe genetic profile of pediatric dHMN is different from that identified in adult cohorts. This study has identified distinct functional limitations for the CMTPedS in children and adolescents with dHMN.
- Published
- 2020
14. Advances in the management of <scp>Charcot–Marie–Tooth</scp> disease in childhood
- Author
-
Manoj P. Menezes
- Subjects
Developmental Neuroscience ,Charcot-Marie-Tooth Disease ,Pediatrics, Perinatology and Child Health ,Humans ,Neurology (clinical) - Published
- 2022
15. Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants
- Author
-
Adam M. Bournazos, Lisa G. Riley, Shobhana Bommireddipalli, Lesley Ades, Lauren S. Akesson, Mohammad Al-Shinnag, Stephen I. Alexander, Alison D. Archibald, Shanti Balasubramaniam, Yemima Berman, Victoria Beshay, Kirsten Boggs, Jasmina Bojadzieva, Natasha J. Brown, Samantha J. Bryen, Michael F. Buckley, Belinda Chong, Mark R. Davis, Ruebena Dawes, Martin Delatycki, Liz Donaldson, Lilian Downie, Caitlin Edwards, Matthew Edwards, Amanda Engel, Lisa J. Ewans, Fathimath Faiz, Andrew Fennell, Michael Field, Mary-Louise Freckmann, Lyndon Gallacher, Russell Gear, Himanshu Goel, Shuxiang Goh, Linda Goodwin, Bernadette Hanna, James Harraway, Megan Higgins, Gladys Ho, Bruce K. Hopper, Ari E. Horton, Matthew F. Hunter, Aamira J. Huq, Sarah Josephi-Taylor, Himanshu Joshi, Edwin Kirk, Emma Krzesinski, Kishore R. Kumar, Frances Lemckert, Richard J. Leventer, Suzanna E. Lindsey-Temple, Sebastian Lunke, Alan Ma, Steven Macaskill, Amali Mallawaarachchi, Melanie Marty, Justine E. Marum, Hugh J. McCarthy, Manoj P. Menezes, Alison McLean, Di Milnes, Shekeeb Mohammad, David Mowat, Aram Niaz, Elizabeth E. Palmer, Chirag Patel, Shilpan G. Patel, Dean Phelan, Jason R. Pinner, Sulekha Rajagopalan, Matthew Regan, Jonathan Rodgers, Miriam Rodrigues, Richard H. Roxburgh, Rani Sachdev, Tony Roscioli, Ruvishani Samarasekera, Sarah A. Sandaradura, Elena Savva, Tim Schindler, Margit Shah, Ingrid B. Sinnerbrink, Janine M. Smith, Richard J. Smith, Amanda Springer, Zornitza Stark, Samuel P. Strom, Carolyn M. Sue, Kenneth Tan, Tiong Y. Tan, Esther Tantsis, Michel C. Tchan, Bryony A. Thompson, Alison H. Trainer, Karin van Spaendonck-Zwarts, Rebecca Walsh, Linda Warwick, Stephanie White, Susan M. White, Mark G. Williams, Meredith J. Wilson, Wui Kwan Wong, Dale C. Wright, Patrick Yap, Alison Yeung, Helen Young, Kristi J. Jones, Bruce Bennetts, Sandra T. Cooper, Ghusoon Abdulrasool, Ghamdan Al Eryani, Peer Arts, Richard Bagnall, Naomi L. Baker, Christopher Barnett, Sarah Beecroft, Marina Berbic, Michael Black, Jim Blackburn, Piers Blombery, Susan Branford, Jimmy Breen, Leslie Burnett, Daffodil Canson, Pak Cheong, Edward Chew, John Christodoulou, Seo-Kyung Chung, Mike Clark, Corrina Cliffe, Melissa Cole, Felicity Collins, Alison Compton, Antony Cooper, Mark Corbett, Mark Cowley, Tracy Dudding, Stefanie Eggers, Eduardo Eyras, Miriam Fanjul Fernandez, Andrew Fellowes, Ron Fleischer, Chiara Folland, Lucy Fox, Clara Gaff, Melanie Galea, Roula Ghaoui, Ilias Gornanitis, Thuong Ha, Rippei Hayashi, Ian Hayes, Alex Henderson, Luke Hesson, Erin Heyer, Michael Hildebrand, Michael Hipwell, Cass Hoskins, Matilda Jackson, Paul James, Justin Jong-Leong Wong, Karin Kassahn, Peter Kaub, Lucy Kevin, Smitha Kumble, Sarah Kummerfeld, Nigel Laing, Chiyan Lau, Eric Lee, Sarah Leighton, Ben Lundie, Chelsea Mayoh, Julie McGaughran, Mary McPhillips, Cliff Meldrum, Edwina Middleton, Kym Mina, Amy Nisselle, Emily Oates, Alicia Oshlack, Gayathri Parasivam, Michael Parsons, Michael Quinn, John Rasko, Gina Ravenscroft, Anja Ravine, Krista Recsei, Jacqueline Rehn, Stephen Robertson, Anne Ronan, Georgina Ryland, Simon Sadedin, Andreas Schreiber, Hamish Scott, Rodney Scott, Christopher Semsarian, Cas Simons, Emma Singer, Renee Smyth, Amanda Spurdle, Patricia Sullivan, Samantha Sundercombe, David Thorburn, John Toubia, Ronald Trent, Emma Tudini, Irina Voneague, Leigh Waddell, Logan Walker, Mathew Wallis, Nick Warnock, Robert Weatheritt, Deborah White, Ingrid Winship, Lisa Worgan, Kathy Wu, Andrew Ziolowski, Bournazos, Adam M, Riley, Lisa G, Bommireddipalli, Shobhana, Ades, Lesley, Cooper, Sandra T, Toubia, John, and Australasian Consortium for RNA Diagnostics
- Subjects
Adult ,Adolescent ,RNA Splicing ,Genetic counseling ,putative splice variant ,Biology ,law.invention ,genetic diagnosis ,law ,Exome Sequencing ,Biopsy ,medicine ,Humans ,variant classification ,Gene ,Genetics (clinical) ,Polymerase chain reaction ,Genetics ,medicine.diagnostic_test ,Sequence Analysis, RNA ,noncoding variant ,RNA ,Heterozygote advantage ,Amplicon ,Child, Preschool ,Mutation ,RNA splicing ,pre-mRNA splicing - Abstract
usc Refereed/Peer-reviewed Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.
- Published
- 2022
16. Clinical practice guideline for the management of paediatric Charcot-Marie-Tooth disease
- Author
-
Eppie M Yiu, Paula Bray, Jonathan Baets, Steven K Baker, Nina Barisic, Katy de Valle, Timothy Estilow, Michelle A Farrar, Richard S Finkel, Jana Haberlová, Rachel A Kennedy, Isabella Moroni, Garth A Nicholson, Sindhu Ramchandren, Mary M Reilly, Kristy Rose, Michael E Shy, Carly E Siskind, Sabrina W Yum, Manoj P Menezes, Monique M Ryan, and Joshua Burns
- Subjects
Adult ,Consensus ,Muscle Weakness ,Adolescent ,Psychiatry and Mental health ,Chemistry ,Charcot-Marie-Tooth Disease ,Practice Guidelines as Topic ,Humans ,Surgery ,Neurology (clinical) ,Human medicine ,Child ,Biology ,Muscle Cramp ,Systematic Reviews as Topic - Abstract
Background and objectivesCharcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally.MethodsDevelopment of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations.ResultsThe final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research.ConclusionsThis clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings.
- Published
- 2022
- Full Text
- View/download PDF
17. Association Between Body Mass Index and Disability in Children With Charcot-Marie-Tooth Disease
- Author
-
Francesco Muntoni, Gabrielle A. Donlevy, Kayla M.D. Cornett, Davide Pareyson, Isabella Moroni, Sabrina W. Yum, Michael E. Shy, Sarah P. Garnett, Joshua Burns, Trupti Bhandari, Richard S. Finkel, Matilde Laura, Jennifer N. Baldwin, Janet E. Sowden, Manoj P. Menezes, David N. Herrmann, Emanuela Pagliano, Maria Foscan, Katy Eichinger, Mary M. Reilly, R Shy, T Estilow, and Marnee J. McKay
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Disease ,Body Mass Index ,Tooth disease ,Disability Evaluation ,Young Adult ,Thinness ,Charcot-Marie-Tooth Disease ,medicine ,Humans ,Obesity ,Association (psychology) ,Child ,Inherited neuropathy ,Task force ,business.industry ,nutritional and metabolic diseases ,medicine.disease ,Cross-Sectional Studies ,Child, Preschool ,Female ,Neurology (clinical) ,Underweight ,medicine.symptom ,business ,Body mass index ,Research Article - Abstract
Background and ObjectivesThis study examined the association between body mass index (BMI) and disability in children with Charcot-Marie-Tooth disease (CMT).MethodsWe conducted a cross-sectional analysis of 477 patients with CMT who were 3 to 20 years of age from the Inherited Neuropathy Consortium and 316 age- and sex-matched healthy children from the 1,000 Norms Project. BMI was categorized according to the International Obesity Task Force (IOTF) criteria, and BMI categorization was compared with healthy children. IOTF categories (adult equivalent BMI cut points) were severely underweight (BMI 2), underweight (BMI ≥17–2), healthy weight (BMI ≥18.5–2), overweight (BMI ≥25–2), and obese (BMI ≥30 kg/m2). Scores on the 0 to 44–point CMT Pediatric Scale (CMTPedS), a well-validated measure of disability, were examined in relation to BMI.ResultsThere was a higher proportion of children with CMT categorized as severely underweight (5.7% vs 0.3%), underweight (10.3% vs 5.1%), and obese (7.3% vs 3.8%) (p< 0.05). Fewer children with CMT were categorized as healthy weight (61.8% vs 74.4%) (p< 0.05), and the proportion of overweight (14.9% vs 16.5%) between groups was similar. CMTPedS scores (mean ± SD) for weight categories were as follows: severely underweight 27 ± 9, underweight 20 ± 8, healthy weight 17 ± 9, overweight 17 ± 9, and obese 22 ± 10. Compared to children with a healthy weight with CMT, being severely underweight was associated with being more disabled (p< 0.001), as was being obese (p= 0.015).DiscussionThe proportion of children with CMT who are underweight or obese is higher compared to age- and sex-matched healthy children. In children with CMT, being underweight or obese is associated with greater disability, when compared to children with CMT of healthy weight.
- Published
- 2021
18. Replicating and redesigning ankle-foot orthoses with 3D printing for children with Charcot-Marie-Tooth disease
- Author
-
Elizabeth A. Wojciechowski, Tegan L. Cheng, Sean M. Hogan, Anita J. Mudge, Daniel Balassone, Manoj P. Menezes, David G. Little, Leanne N. Dwan, and Joshua Burns
- Subjects
Charcot-Marie-Tooth Disease ,Rehabilitation ,Printing, Three-Dimensional ,Biophysics ,Foot Orthoses ,Humans ,Orthopedics and Sports Medicine ,Ankle ,Child ,Peroneal Neuropathies ,Gait ,Biomechanical Phenomena - Abstract
Children with the most common inherited neuropathy, Charcot-Marie-Tooth disease (CMT), are often prescribed ankle-foot orthoses (AFOs) to improve walking ability and prevent falls by reducing foot drop, postural instability, and other gait impairments. These externally worn assistive devices are traditionally custom-made using thermoplastic vacuum forming. This labour-intensive manufacturing process often results in AFOs which are cumbersome due to limited design options, and are associated with low acceptability, discomfort, and suboptimal impact on gait. The aim of this study was to determine how 3D printing can be used to replicate and redesign AFOs in children with CMT.Traditional AFOs, 3D printed replica AFOs (same design as traditional AFOs), 3D printed redesigned AFOs and a shoes only control condition were compared in 12 children with CMT. 3D printed AFOs were manufactured using material extrusion in Nylon-12. 3D gait analysis (temporal-spatial, kinematic, kinetic), in-shoe pedobarography and self-reported satisfaction were used to compare conditions. The primary kinematic and kinetic outcome measures were maximum ankle dorsiflexion in swing and maximum ankle dorsiflexor moment in loading response, to capture foot drop and an absent of heel rocker.The 3D printed replica AFOs were comparable to traditional AFOs for all outcomes. The 3D printed replica AFOs improved foot position at initial contact and during loading response and significantly reduced pressure beneath the whole foot, rearfoot and forefoot compared to the shoes only. The 3D printed redesigned AFOs produced a device that was significantly lighter (mean -35.2, SD 13.3%), and normalised maximum ankle dorsiflexor moment in loading response compared to shoes only and traditional AFOs.3D printing can be used to replicate traditional handmade AFOs and to redesign AFOs to produce a lighter device with improved biomechanics by incorporating novel design features.
- Published
- 2021
19. Refining clinical trial inclusion criteria to optimize the standardized response mean of the CMTPedS
- Author
-
Joshua Burns, Paula Bray, Davide Pareyson, Emanuela Pagliano, David N. Herrmann, Kayla M.D. Cornett, Isabella Moroni, Manoj P. Menezes, Michael E. Shy, Francesco Muntoni, Mary M. Reilly, Katy Eichinger, R Shy, T Estilow, T Bhandari, Matilde Laura, Richard S. Finkel, and Sabrina W. Yum
- Subjects
0301 basic medicine ,Adult ,Pediatrics ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Inclusion (disability rights) ,Adolescent ,MEDLINE ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Brief Communication ,Severity of Illness Index ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Primary outcome ,Charcot-Marie-Tooth Disease ,Outcome Assessment, Health Care ,Medicine ,Humans ,Child ,RC346-429 ,Clinical Trials as Topic ,business.industry ,General Neuroscience ,Patient Selection ,Outcome measures ,Reference Standards ,Disabled Children ,Clinical trial ,030104 developmental biology ,Child, Preschool ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,business ,Brief Communications ,030217 neurology & neurosurgery ,RC321-571 - Abstract
The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2‐year natural history data from 187 children aged 3–20 years with a range of CMT genetic subtypes. Subsets based on age (3–8 years), disability level (CMTPedS score 0–14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS.
- Published
- 2020
20. Surgical outcomes of cavovarus foot deformity in children with Charcot-Marie-Tooth disease
- Author
-
Anita J. Mudge, Kayla M.D. Cornett, Joshua Burns, Paul Gibbons, Ting Lin, and Manoj P. Menezes
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Child health ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Charcot-Marie-Tooth Disease ,medicine ,Humans ,Child ,Genetics (clinical) ,Balance (ability) ,business.industry ,Gait ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Talipes Cavus ,Pediatrics, Perinatology and Child Health ,Orthopedic surgery ,Quality of Life ,Physical therapy ,Female ,Neurology (clinical) ,Ankle ,business ,030217 neurology & neurosurgery ,Cavovarus Foot Deformity ,Foot (unit) - Abstract
Charcot-Marie-Tooth disease (CMT) causes disabling cavovarus foot deformity. Orthopaedic surgery is performed in severe cases; however few studies have investigated whether surgery improves health outcomes during childhood. This study investigated the impact of cavovarus surgery on validated physical, functional, parent/self-reported and biomechanical measures in 21 consecutive patients (mean age at surgery 12.5 years, SD 2.7) evaluated before and after surgery (mean duration 15.7 months, SD 5.9), and compared to natural history data from 206 children with CMT. Measures from the CMT Pediatric Scale evaluated foot alignment (Foot Posture Index), ankle flexibility (lunge test), strength (foot dorsiflexion/plantarflexion by hand-held dynamometry), function (balance, long jump, 6-minute walk test) and self-reported symptoms. Quality of life (Child Health Questionnaire) and gait (pressure loading) were also assessed. Foot Posture Index and lunge improved with surgery by 6.0 points (SD 3.2) and 6.1° (SD 7.3) respectively (p 0.01), and differed to the natural course of the disease (p 0.005). Self-reported daily trips/falls reduced from 60% to 13% (p = 0.016). Pressure improved beneath the rearfoot and midfoot (p = 0.043). Surgery had no effect on strength, function or quality of life, which generally mirrored the natural course. Cavovarus surgery improved foot alignment, ankle flexibility and self-reported trips/falls in children with CMT.
- Published
- 2019
21. Magnetic resonance imaging of the anterior compartment of the lower leg is a biomarker for weakness, disability, and impaired gait in childhood Charcot-Marie-Tooth disease
- Author
-
Manoj P. Menezes, Paula Bray, Kayla M.D. Cornett, Mark Halaki, Joshua Burns, Amy D. Sman, Terri Walker, and Elizabeth Wojciechowski
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Weakness ,Foot drop ,medicine.diagnostic_test ,Physiology ,business.industry ,Compartment (ship) ,Magnetic resonance imaging ,Impaired gait ,030105 genetics & heredity ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Physical medicine and rehabilitation ,Physiology (medical) ,Gait analysis ,medicine ,Biomarker (medicine) ,Neurology (clinical) ,Intramuscular fat ,medicine.symptom ,business ,human activities ,030217 neurology & neurosurgery - Abstract
INTRODUCTION: Biomarkers of disease severity in Charcot-Marie-Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents. METHODS: Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system. RESULTS: Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score. DISCUSSION: The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59:213-217, 2019.
- Published
- 2018
22. Psychiatric comorbidity is common in dystonia and other movement disorders
- Author
-
Manju A. Kurian, Mary-Clare Waugh, Robert Goodman, Belinda H A Crowe, Michelle S Lorentzos, Padraig Grattan-Smith, David Dossetor, Manoj P. Menezes, Joshua Burns, Kathleen M. Gorman, Shekeeb S. Mohammad, Josie Hollywood, Russell C. Dale, Ruth Evans, Isobel Heyman, Anna E. Coughtrey, Benjamin J Baig, and Andrew McWilliams
- Subjects
Male ,medicine.medical_specialty ,Pediatrics ,Neurology ,Movement disorders ,Psychometrics ,Psychological intervention ,Comorbidity ,Cohort Studies ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,mental disorders ,medicine ,Humans ,0501 psychology and cognitive sciences ,Child ,Dystonia ,Depressive Disorder ,Movement Disorders ,business.industry ,05 social sciences ,Australia ,Emergency department ,medicine.disease ,Diagnostic and Statistical Manual of Mental Disorders ,England ,Case-Control Studies ,Pediatrics, Perinatology and Child Health ,Cohort ,Female ,medicine.symptom ,business ,Emergency Service, Hospital ,030217 neurology & neurosurgery ,050104 developmental & child psychology ,Cohort study - Abstract
ObjectiveTo determine rates of psychiatric comorbidity in a clinical sample of childhood movement disorders (MDs).DesignCohort study.SettingTertiary children’s hospital MD clinics in Sydney, Australia and London, UK.PatientsCases were children with tic MDs (n=158) and non-tic MDs (n=102), including 66 children with dystonia. Comparison was made with emergency department controls (n=100), neurology controls with peripheral neuropathy or epilepsy (n=37), and community controls (n=10 438).InterventionsOn-line development and well-being assessment which was additionally clinically rated by experienced child psychiatrists.Main outcome measuresDiagnostic schedule and manual of mental disorders-5 criteria for psychiatric diagnoses.ResultsPsychiatric comorbidity in the non-tic MD cohort (39.2%) was comparable to the tic cohort (41.8%) (not significant). Psychiatric comorbidity in the non-tic MD cohort was greater than the emergency control group (18%, pConclusionsPsychiatric comorbidity is common in non-tic MDs such as dystonia. These psychiatric comorbidities appear to be under-recognised and undertreated.
- Published
- 2020
23. Genetic, Radiologic, and Clinical Variability in Brown-Vialetto-van Laere Syndrome
- Author
-
Susan M. White, Dean Phelan, Ian R. Woodcock, Manoj P. Menezes, Heidi Peters, Lee Coleman, Joy Yaplito-Lee, Eppie M. Yiu, Rachel Stapleton, Monique M. Ryan, Sebastian Lunke, Belinda Chong, Zornitza Stark, James Pitt, and Colin F. Robertson
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Hearing loss ,Hearing Loss, Sensorineural ,Bulbar Palsy, Progressive ,Receptors, G-Protein-Coupled ,Consanguinity ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Brown–Vialetto–Van Laere syndrome ,medicine ,Humans ,Bulbar palsy ,business.industry ,Brain ,Infant ,Membrane Transport Proteins ,Cauda equina ,Fazio–Londe disease ,medicine.disease ,Spinal cord ,030104 developmental biology ,medicine.anatomical_structure ,Spinal Cord ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,Sensorineural hearing loss ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Brown-Vialetto-van Laere syndrome is characterized by a progressive sensorimotor neuropathy, optic atrophy, hearing loss, bulbar dysfunction, and respiratory insufficiency. Mutations in SLC52A2 and SLC52A3, encoding riboflavin transporters RFVT2 and RFVT3, respectively, are the genetic basis of this disorder, often referred to as riboflavin transporter deficiency types 2 and 3, respectively. We present cases of both types of riboflavin transporter deficiency, highlighting the distinguishing clinical features of a rapidly progressive motor or sensorimotor axonal neuropathy, optic atrophy, sensorineural hearing loss, and bulbar dysfunction. One child presented with isolated central apnea and hypoventilation, not previously described in genetically confirmed Brown-Vialetto-van Laere, later complicated by diaphragmatic paralysis secondary to phrenic nerve palsy. Magnetic resonance imaging showed T2 hyperintensity in the dorsal spinal cord in 2 children, as well as previously unreported cervical nerve root enlargement and cauda equina ventral nerve root enhancement in 1 child. Novel homozygous mutations were identified in each gene-a NM_024531.4(SLC52A2):c.505C > T, NP_078807.1(SLC52A2):p.(Arg169Cys) variant in SLC52A2 and NM_033409.3(SLC52A3):c.1316G > A, NP_212134.3(SLC52A3):p.(Gly439Asp) variant in SLC52A3. Both treated children showed improvement on high-dose riboflavin supplementation, highlighting the importance of early recognition of this treatable clinical entity.
- Published
- 2018
24. Functional outcome measures for infantile Charcot‐Marie‐Tooth disease: a systematic review
- Author
-
Kristy Rose, Oranee Sanmaneechai, Melissa R Mandarakas, Joshua Burns, Kathryn M. Refshauge, and Manoj P. Menezes
- Subjects
medicine.medical_specialty ,Gross motor skill ,Concurrent validity ,Population ,Psychological intervention ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,Charcot-Marie-Tooth Disease ,Rating scale ,Outcome Assessment, Health Care ,Item response theory ,Humans ,Medicine ,030212 general & internal medicine ,education ,education.field_of_study ,business.industry ,General Neuroscience ,Infant ,Spinal muscular atrophy ,medicine.disease ,Clinical trial ,Child, Preschool ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
A functional outcome measure for infants (aged 0-3 years) with Charcot-Marie-Tooth (CMT) disease is needed for upcoming disease-modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for spinal muscular atrophy (SMA). There were no CMT-specific outcome measures identified; however, one (motor function measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT. The included studies exhibited "good" face, discriminant, convergent and concurrent validity, and reported excellent intra- and inter-rater reliability. No outcome measure was subjected to item response theory. Studies reported outcome measures comprising of 51 different items assessing six domains of function: reflexive movement, axial movement, limb movement, positioning, gross motor, and fine-motor skills. Scoring of items ranged from 2- to 7-point rating scales; and none were scaled to normative reference values to account for changes in growth and development. The SMA focus of most items is likely to produce ceiling effects and lack sensitivity and responsiveness for within and between types of CMT in infants. Nevertheless, several items across scales assessing distal strength, gross- and fine-motor function, could be included in the development of a composite functional outcome measure for infants with CMT to assess disease-modifying interventions.
- Published
- 2018
25. Natural history of Charcot-Marie-Tooth disease during childhood
- Author
-
Manoj P. Menezes, Mary M. Reilly, Michael E. Shy, Matilde Laura, David N. Herrmann, R Shy, Francesco Muntoni, Emanuela Pagliano, Isabella Moroni, Paula Bray, T Estilow, T Bhandari, Kate Eichinger, Richard S. Finkel, Joshua Burns, Kayla M.D. Cornett, Mark Halaki, Davide Pareyson, and Sabrina W. Yum
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Disease progression ,Disease ,Anthropometry ,Confidence interval ,Developmental psychology ,Natural history ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Neurology ,Internal medicine ,medicine ,Neurology (clinical) ,Early childhood ,Young adult ,Psychology ,030217 neurology & neurosurgery ,Natural history study - Abstract
Objective To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease. Methods Two hundred six (103 female) participants aged 3 to 20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2 years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance. Results On average, CMTPedS Total scores progressed at a rate of 2.4 ± 4.9 over 2 years (14% change from baseline; p
- Published
- 2017
26. Gait patterns of children and adolescents with Charcot-Marie-Tooth disease
- Author
-
Manoj P. Menezes, Elizabeth Wojciechowski, Joshua Burns, Kathryn M. Refshauge, Jacqueline Raymond, Amy D. Sman, and Kayla M.D. Cornett
- Subjects
Male ,musculoskeletal diseases ,030506 rehabilitation ,Weakness ,medicine.medical_specialty ,Heel ,Adolescent ,Knee Joint ,Population ,Biophysics ,Walking ,03 medical and health sciences ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,medicine ,Humans ,Orthopedics and Sports Medicine ,Range of Motion, Articular ,Child ,education ,Gait Disorders, Neurologic ,education.field_of_study ,Foot ,business.industry ,Rehabilitation ,Steppage gait ,Functional weakness ,medicine.disease ,Gait ,Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10] ,body regions ,medicine.anatomical_structure ,Case-Control Studies ,Gait analysis ,Physical therapy ,Female ,medicine.symptom ,Ankle ,0305 other medical science ,business ,human activities ,Ankle Joint ,030217 neurology & neurosurgery - Abstract
Item does not contain fulltext Gait abnormalities reported in childhood Charcot-Marie-Tooth disease (CMT) include foot-drop, reduced ankle power at push-off and increased knee and hip flexion for swing clearance ('steppage-gait'). The purpose of this study was to describe the gait patterns of 60 children aged 6-17 years with CMT (CMTall) and distinguish differences based on functional weakness using the CMT Pediatric Scale (CMTPedS). Data were captured using Vicon Nexus system and compared to 50 healthy norms. Data were subdivided into three groups denoting increasing severity of dorsiflexion and plantarflexion weakness from the CMTPedS: no difficulty heel or toe walking (CMTND), difficulty heel walking (CMTDH), difficulty toe and heel walking (CMTDTH). Compared to healthy norms, CMTall demonstrated significantly worse gait profile score, reduced ankle dorsiflexion during swing (foot-drop), reduced ankle dorsiflexor moment in loading response and reduced external thigh-foot angle. Contrary to previous studies there were no signs of reduced ankle power or compensation through 'steppage gait' in this mild-moderately affected population. Instead, CMTall demonstrated reduced internal hip rotation and reduced hip abductor moment. When data were sub-grouped and compared to healthy norms, three different gait patterns at the ankle emerged: CMTND had a near-normal gait pattern, CMTDH presented with foot-drop, and CMTDTH had increased peak dorsiflexion and reduced ankle power generation. Several distinct and abnormal gait patterns were identified in children with CMT, with increasing gait abnormalities in more functionally severe cases. Classifying gait patterns based on disease severity might be a valuable tool in clinical decision making, assessing disease progression and phenotype-genotype correlation studies. 01 juli 2017
- Published
- 2017
27. Prenusinersen economic and health-related quality of life burden of spinal muscular atrophy
- Author
-
Stella Nalukwago Settumba, Anita Cairns, Monique M. Ryan, Kate A. Carey, Georgina M. Chambers, Manoj P. Menezes, and Michelle A. Farrar
- Subjects
Adult ,Male ,Adolescent ,Total cost ,Spinal Muscular Atrophies of Childhood ,03 medical and health sciences ,Indirect costs ,Young Adult ,0302 clinical medicine ,Quality of life (healthcare) ,Cost of Illness ,Health care ,Medicine ,Humans ,030212 general & internal medicine ,Young adult ,Activity-based costing ,Child ,health care economics and organizations ,business.industry ,Australia ,Infant ,Health Care Costs ,SMA ,Purchasing power parity ,Caregivers ,Child, Preschool ,Quality of Life ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Demography - Abstract
ObjectiveTo quantify the economic and health-related quality of life (HRQoL) burden incurred by households with a child affected by spinal muscular atrophy (SMA).MethodsHospital records, insurance claims, and detailed resource use questionnaires completed by caregivers were used to capture the direct and indirect costs to households of 40 children affected by SMA I, II, and III in Australia between 2016 and 2017. Prevalence costing methods were used and reported in 2017 US dollar (USD) purchasing power parity (PPP). The HRQoL for patients and primary caregivers was quantified with the youth version of the EQ-5D and CareQoL multiattribute utility instruments and Australian utility weights.ResultsThe average total annual cost of SMA per household was $143,705 USD PPP for all SMA types (SMA I $229,346, SMA II $150,909, SMA III $94,948). Direct costs accounted for 56% of total costs. The average total indirect health care costs for all SMA types were $63,145 per annum and were highest in families affected by SMA II. Loss of income and unpaid informal care made up 24.2% and 19.8% respectively, of annual SMA costs. Three of 4 (78%) caregivers stated that they experienced financial problems because of care tasks. The loss in HRQoL of children affected by SMA and caregivers was substantial, with average caregiver and patient scores of 0.708 and 0.115, respectively (reference range 0 = death and 1 = full health).ConclusionOur results demonstrate the substantial and far-ranging economic and quality of life burden on households and society of SMA and are essential to fully understanding the health benefits and cost-effectiveness associated with emerging disease-modifying therapies for SMA.
- Published
- 2019
28. Erratum to: Development and validation of the Charcot-Marie-Tooth Disease Infant Scale
- Author
-
Davide Pareyson, Joshua Burns, Emanuela Pagliano, Isabella Moroni, Michael E. Shy, Maria Foscan, Kathryn M. Refshauge, Oranee Sanmaneechai, Hugo Sampaio, Rachel A. Kennedy, Gyula Acsadi, Karen Herbert, Sabrina W. Yum, David N. Herrmann, Paula Bray, Kristy Rose, Eppie M. Yiu, Michelle A. Farrar, Manoj P. Menezes, T Estilow, Kate Eichinger, Monique M. Ryan, R Shy, and Melissa R Mandarakas
- Subjects
Tooth disease ,business.industry ,Infant scale ,Dentistry ,Medicine ,Neurology (clinical) ,Original Articles ,business - Abstract
Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0–4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven ‘at risk’ cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3–4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)(3,1) 0.999, 95% confidence interval 0.996–1.000) and inter-rater reliability (ICC(2,1) 0.997, 95% confidence interval 0.992–0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.
- Published
- 2019
29. Feasibility of designing, manufacturing and delivering 3D printed ankle-foot orthoses: a systematic review
- Author
-
Joshua Burns, David G. Little, Angela Y. Chang, Sean Hogan, Jacqueline Ford, Daniel Balassone, Tegan L. Cheng, Elizabeth Wojciechowski, and Manoj P. Menezes
- Subjects
Patient-Specific Modeling ,3d printed ,medicine.medical_specialty ,Foot drop ,lcsh:Diseases of the musculoskeletal system ,Additive manufacturing ,AFO ,education ,Foot Orthoses ,Review ,03 medical and health sciences ,Health services ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine ,Humans ,Orthopedics and Sports Medicine ,Gait ,Patient comfort ,030203 arthritis & rheumatology ,Ankle foot orthoses ,Study quality ,Poor balance ,business.industry ,3D printing ,030229 sport sciences ,Equipment Design ,Biomechanical Phenomena ,Quality of evidence ,Printing, Three-Dimensional ,Feasibility Studies ,lcsh:RC925-935 ,medicine.symptom ,business ,Ankle Joint - Abstract
Background Ankle-foot orthoses (AFO) are prescribed to manage difficulty walking due to foot drop, bony foot deformities and poor balance. Traditional AFOs are handmade using thermoplastic vacuum forming which provides limited design options, is labour-intensive and associated with long wait times. 3D printing has the potential to transform AFO production and health service delivery. The aim of this systematic review was to determine the feasibility of designing, manufacturing and delivering customised 3D printed AFOs by evaluating the biomechanical outcomes, mechanical properties and fit of 3D printed compared to traditionally manufactured AFOs. Method Electronic databases were searched from January 1985 to June 2018 according to terms related to 3D printing and AFOs. Studies of any design from healthy or pathological populations of any age were eligible for inclusion. Studies must have investigated the effect of customised 3D printed AFOs using any 3D printing technique on outcomes related to walking ability, biomechanical function, mechanical properties, patient comfort, pain and disability. Any other orthotic type or AFOs without a 3D printed calf and foot section were excluded. The quality of evidence was assessed using the GRADE process. Results Eleven studies met the eligibility criteria evaluating 3D printed AFOs in healthy adults, and adults and children with unilateral foot drop from a variety of conditions. 3D printing was used to replicate traditional AFOs and develop novel designs to optimise the stiffness properties or reduce the weight and improve the ease of use of the AFO. 3D printed custom AFOs were found to be comparable to traditional custom AFOs and prefabricated AFOs in terms of temporal-spatial parameters. The mechanical stiffness and energy dissipation of 3D printed AFOs were found to be similar to prefabricated carbon-fibre AFOs. However, the sample sizes were small (n = 1 to 8) and study quality was generally low. Conclusion The biomechanical effects and mechanical properties of 3D printed AFOs were comparable to traditionally manufactured AFOs. Developing novel AFO designs using 3D printing has many potential benefits including stiffness and weight optimisation to improve biomechanical function and comfort. Electronic supplementary material The online version of this article (10.1186/s13047-019-0321-6) contains supplementary material, which is available to authorized users.
- Published
- 2018
30. MITOCHONDRIAL DISEASES & METABOLIC MYOPATHIES
- Author
-
Sandra T. Cooper, Kristi J. Jones, Mark M. Davis, Richard D. Webster, Adam Bournazos, Samantha J. Bryen, Christina Liang, W. Wong, Manoj P. Menezes, S. Bommireddipall, and Leigh B. Waddell
- Subjects
Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Genetics (clinical) - Published
- 2020
31. Prominent scapulae mimicking an inherited myopathy expands the phenotype of CHD7-related disease
- Author
-
Helen Young, Kathryn N. North, Nigel F. Clarke, Deborah A Sival, Manoj P. Menezes, Monica T. Y. Wong, Gina L. O'Grady, Tony Peduto, Conny M. A. van Ravenswaaij-Arts, Roula Ghaoui, Daniel G. MacArthur, Alan Ma, Monkol Lek, Merrilee Needham, Leigh B. Waddell, Movement Disorder (MD), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
- Subjects
Adult ,Male ,0301 basic medicine ,Proband ,medicine.medical_specialty ,Short Report ,Mutation, Missense ,VARIANTS ,030105 genetics & heredity ,Bioinformatics ,Diagnosis, Differential ,03 medical and health sciences ,CHARGE syndrome ,Neck Muscles ,Intellectual disability ,Genetics ,Humans ,Medicine ,Missense mutation ,Myopathy ,Genetics (clinical) ,CHD7 GENE ,MUTATIONS ,business.industry ,DNA Helicases ,Infant ,medicine.disease ,Dermatology ,Hypoplasia ,Musculoskeletal Abnormalities ,Pedigree ,FAMILY ,DNA-Binding Proteins ,Scapula ,Phenotype ,030104 developmental biology ,NEURAL CREST CELLS ,CHARGE-SYNDROME ,UPDATE ,Medical genetics ,Female ,CHARGE Syndrome ,Differential diagnosis ,medicine.symptom ,business - Abstract
CHD7 variants are a well-established cause of CHARGE syndrome, a disabling multi-system malformation disorder that is often associated with deafness, visual impairment and intellectual disability. Less severe forms of CHD7-related disease are known to exist, but the full spectrum of phenotypes remains uncertain. We identified a de novo missense variant in CHD7 in a family presenting with musculoskeletal abnormalities as the main manifestation of CHD7-related disease, representing a new phenotype. The proband presented with prominent scapulae, mild shoulder girdle weakness and only subtle dysmorphic features. Investigation revealed hypoplasia of the trapezius and sternocleidomastoid muscles and semicircular canal defects, but he did not fulfill diagnostic criteria for CHARGE syndrome. Although the shoulders are often sloping and anteverted in CHARGE syndrome, the underlying neuromuscular cause has never been investigated. This report expands the phenotypes associated with CHD7 mutations to include a musculoskeletal presentation, with hypoplasia of the shoulder and neck muscles. CHD7 should be considered in patients presenting in childhood with stable scapular winging, particularly if accompanied by dysmorphic features and balance difficulties.
- Published
- 2016
32. Eye movement disorders are an early manifestation ofCACNA1Amutations in children
- Author
-
Manoj P. Menezes, Esther M Tantsis, John A. Lawson, Robert A. Smith, Florence Riant, Deepak Gill, Robert A. Ouvrier, Christopher Troedson, Richard Webster, Sachin Gupta, Neven Maksemous, and Lyn R. Griffiths
- Subjects
0301 basic medicine ,Episodic ataxia ,Pediatrics ,medicine.medical_specialty ,business.industry ,Calcium channel ,Eye movement ,medicine.disease ,03 medical and health sciences ,Tonic upgaze ,030104 developmental biology ,0302 clinical medicine ,Developmental Neuroscience ,Pediatrics, Perinatology and Child Health ,Abnormal saccades ,medicine ,Hemiplegic migraine ,Spinocerebellar ataxia type 6 ,Neurology (clinical) ,Presentation (obstetrics) ,business ,030217 neurology & neurosurgery - Abstract
Free to read at publisher Aim The alpha-1 isoform of the calcium channel gene is expressed abundantly in neuronal tissue, especially within the cerebellum. Mutations in this gene may manifest with hemiplegic migraine, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) in adults. There are reports of children with CACAN1A mutations presenting with paroxysmal tonic upgaze, abnormal saccades and congenital nystagmus as well as severe forms of hemiplegic migraine. The aim of this study was to review the clinical presentation and subsequent course of all children with a CACNA1A mutation who presented to a tertiary children's hospital. Method We reviewed retrospectively nine children with a proven CACNA1A mutation who presented to the Children's Hospital at Westmead between 2005–2015. The initial and subsequent clinical presentation, radiological features and molecular genetic profile of each child was reviewed. Results Nine children presented to out institute over a 10 year period; six were female and three male. The median age of presentation was 1.2 years. Eye movement disorders were the presenting feature in eight children. Three of these children later presented with severe hemiplegic migraine episodes often requiring ICU care. Affected children also had developmental delay and developed classical hemiplegic migraine, episodic ataxia and seizures. Calcium channel blockers were used with some efficacy in preventing severe HM episodes. Interpretation Eye movement disorders are an early manifestation of CACNA1A mutations in children. Improved recognition of the CACNA1A phenotype in childhood is important for early diagnosis, counselling and appropriate emergency management. There is some early evidence that calcium channel blockers may be an effective prophylactic agent for the severe hemiplegic migraine episodes.
- Published
- 2016
33. Pathophysiology of motor dysfunction in a childhood motor neuron disease caused by mutations in the riboflavin transporter
- Author
-
Steve Vucic, Jayne Antony, Joshua Burns, Richard Webster, Matthew C. Kiernan, Michelle A. Farrar, Robert A. Ouvrier, Manoj P. Menezes, and Katherine O'Brien
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Refractory period ,Hearing Loss, Sensorineural ,Bulbar Palsy, Progressive ,Motor nerve ,Riboflavin ,Receptors, G-Protein-Coupled ,Young Adult ,03 medical and health sciences ,Myelin ,0302 clinical medicine ,Sensory ataxia ,Atrophy ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Motor Neuron Disease ,Child ,Membrane Transport Proteins ,Motor neuron ,medicine.disease ,Sensory Systems ,Pathophysiology ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Neurology ,Mutation ,Female ,Neurology (clinical) ,medicine.symptom ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Objective Brown–Vialetto–Van Laere (BVVL) syndrome is a progressive motor and sensory neuronopathy secondary to mutations in SLC52A2 encoding the riboflavin transporter type 2 (RFVT2). The phenotype is characterized by early childhood onset hearing loss and sensory ataxia followed by progressive upper limb weakness, optic atrophy, bulbar weakness and respiratory failure. To gain further insight into disease pathophysiology and response to riboflavin supplementation, the present study investigated whether axonal ion channel or membrane abnormalities were a feature of BVVL. Methods Axonal excitability studies and clinical assessments were prospectively undertaken on six patients with BVVL secondary to riboflavin transporter deficiency type 2 (age range 10–21years) at baseline and after 12months of riboflavin (1000mg daily) therapy. Results At baseline, depolarizing and hyperpolarizing threshold electrotonus was ‘fanned out' and superexcitability was increased, while the resting current–threshold gradient and refractoriness were significantly reduced in BVVL patients when compared to controls. Mathematical modeling suggested that functional alterations of myelin underlay these findings with an increase in myelin permeability. Riboflavin therapy resulted in partial normalization of the axonal excitability findings, paralleled by maintenance of muscle strength. Conclusions The present study established that abnormalities in myelin permeability at the paranode was a feature of BVVL and were partially normalized with riboflavin therapy. Significance This study reveals a novel pathophysiological process for motor nerve dysfunction in BVVL. It also indicates that nerve excitability studies may be further developed in larger cohorts as a potential biomarker to identify treatment response for BVVL patients.
- Published
- 2016
34. Systematic review of exercise for Charcot-Marie-Tooth disease
- Author
-
Ché Fornusek, Joshua Burns, Daniel A. Hackett, Manoj P. Menezes, Maria A. Fiatarone Singh, and Amy D. Sman
- Subjects
medicine.medical_specialty ,Modalities ,business.industry ,General Neuroscience ,Psychological intervention ,Alternative medicine ,Disease ,medicine.disease ,Tooth disease ,Degenerative disease ,Physical medicine and rehabilitation ,Sample size determination ,Physical therapy ,medicine ,Neurology (clinical) ,Hereditary motor and sensory neuropathy ,business - Abstract
Charcot-Marie-Tooth disease (CMT) is a slowly progressive hereditary degenerative disease and one of the most common neuromuscular disorders. Exercise may be beneficial to maintain strength and function for people with CMT, however, no comprehensive evaluation of the benefits and risks of exercise have been conducted. A systematic review was completed searching numerous electronic databases from earliest records to February 2015. Studies of any design including participants of any age with confirmed diagnosis of CMT that investigated the effects of exercise were eligible for inclusion. Of 13,301 articles identified following removal of duplicates, 11 articles including 9 unique studies met the criteria. Methodological quality of studies was moderate, sample sizes were small, and interventions and outcome measures used varied widely. Although the majority of the studies identified changes in one or more outcome measurements across exercise modalities, the majority were non-significant, possibly due to Type II errors. Significant effects described included improvements in strength, functional activities, and physiological adaptations following exercise. Despite many studies showing changes in strength and function following exercise, findings of this review should be met with caution due to the few studies available and moderate quality of evidence. Well-powered studies, harmonisation of outcome measures, and clearly described interventions across studies would improve the quality and comparability of the evidence base. The optimal exercise modality and intensity for people with CMT as well as the long-term safety of exercise remain unclear.
- Published
- 2015
35. Balance impairment in pediatric charcot-marie-tooth disease
- Author
-
Kate Eichinger, Mark Halaki, Joshua Burns, Davide Pareyson, Richard S. Finkel, T Estilow, Paula Bray, T Bhandari, Sabrina W. Yum, Kayla M.D. Cornett, Emanuela Pagliano, Gregory S. Troutman, Allan M. Glanzman, Michael E. Shy, David N. Herrmann, Isabella Moroni, Mary M. Reilly, Manoj P. Menezes, Francesco Muntoni, Matilde Laura, Ann T. Harrington, and R Shy
- Subjects
0301 basic medicine ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,Physiology ,030105 genetics & heredity ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Tooth disease ,Young Adult ,0302 clinical medicine ,Physical medicine and rehabilitation ,Quality of life ,Charcot-Marie-Tooth Disease ,Physiology (medical) ,Ankle dorsiflexion ,Medicine ,Humans ,Muscle Strength ,Child ,Gait ,Gait Disorders, Neurologic ,Physical Therapy Modalities ,Balance (ability) ,Movement Disorders ,business.industry ,Age Factors ,Intervention studies ,nervous system diseases ,Young age ,Child, Preschool ,Quality of Life ,Female ,Neurology (clinical) ,business ,Balance impairment ,030217 neurology & neurosurgery - Abstract
INTRODUCTION Balance impairment contributes to gait dysfunction, falls, and reduced quality of life in adults with Charcot-Marie-Tooth disease (CMT) but has been minimally examined in pediatric CMT. METHODS The CMT Pediatric Scale (CMTPedS) was administered to 520 children with CMT. Associations between balance function (Bruininks-Oseretsky Test of Motor Proficiency [BOT-2]) and sensorimotor and gait impairments were investigated. RESULTS Daily trips/falls were reported by 42.3% of participants. Balance (BOT-2) varied by CMT subtype, was impaired in 42% of 4-year-olds, and declined with age (P < 0.001). Vibration (P < 0.001), pinprick (P < 0.004), ankle dorsiflexion strength (P < 0.001), and foot alignment (P < 0.004) were associated with BOT-2 balance (adjusted R2 = 0.28). The visual dependence of balance increased with age. DISCUSSION Balance impairment occurs from a young age in children with CMT. Balance intervention studies are required in pediatric CMT and should consider the degree of sensorimotor impairment, foot malalignment, and visual dependence. Muscle Nerve, 2019.
- Published
- 2018
36. The First Case of Riboflavin Transporter Deficiency in sub-Saharan Africa
- Author
-
Jody A Rusch, Manoj P. Menezes, Gillian Riordan, Marco Zampoli, Alvin Ndondo, Jane Booth, Karen Fieggen, Diane Gray, Komala Pillay, Francois H. van der Westhuizen, Shaakira Chaya, George van der Watt, and Jo M. Wilmshurst
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Hearing loss ,Stridor ,Hearing Loss, Sensorineural ,Riboflavin ,Auditory neuropathy ,Bulbar Palsy, Progressive ,Physiology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Vocal cord paralysis ,Respiratory system ,Africa South of the Sahara ,Bulbar palsy ,Muscle weakness ,Infant ,Membrane Transport Proteins ,medicine.disease ,Surgery ,030104 developmental biology ,Phenotype ,Pediatrics, Perinatology and Child Health ,Dietary Supplements ,Neurology (clinical) ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
This report describes the first case of a child with genetically confirmed Brown-Vialetto-van Laere syndrome in sub-Saharan Africa. This is an extremely rare clinical condition that presents with an auditory neuropathy, bulbar palsy, stridor, muscle weakness, and respiratory compromise that manifests with diaphragmatic and vocal cord paralysis. It is an autosomal recessive condition for which the genetic mutation has only recently been linked to a riboflavin transporter deficiency. We describe an 11-month-old affected male infant. He has required long-term respiratory support and a gastrostomy tube to support feeding. With high-dose riboflavin supplementation, he had limited recovery of motor function. His respiratory chain enzyme studies were abnormal suggestive of mitochondrial (mt) dysfunction. In the setting of limited resources, recognition of this striking clinical phenotype is important to highlight, specifically regarding the genetic implications of the condition and the potentially remedial response to vitamin supplementation.
- Published
- 2018
37. Development and validation of the Charcot-Marie-Tooth Disease Infant Scale
- Author
-
Sabrina W. Yum, Michelle A. Farrar, Gyula Acsadi, Karen Herbert, T Estilow, Michael E. Shy, Manoj P. Menezes, Paula Bray, Joshua Burns, Kristy Rose, Emanuela Pagliano, Melissa R Mandarakas, Kate Eichinger, Oranee Sanmaneechai, Rachel A. Kennedy, R Shy, Eppie M. Yiu, Hugo Sampaio, Kathryn M. Refshauge, David N. Herrmann, Isabella Moroni, Monique M. Ryan, Maria Foscan, and Davide Pareyson
- Subjects
0301 basic medicine ,Male ,Pediatrics ,medicine.medical_specialty ,Psychometrics ,Intraclass correlation ,Disease ,Severity of Illness Index ,03 medical and health sciences ,Disability Evaluation ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Severity of illness ,Medicine ,Humans ,Observer Variation ,Rasch model ,business.industry ,Infant, Newborn ,Infant ,Reproducibility of Results ,Confidence interval ,Inter-rater reliability ,030104 developmental biology ,Convergent validity ,Child, Preschool ,Disease Progression ,Female ,Neurology (clinical) ,Erratum ,business ,030217 neurology & neurosurgery - Abstract
Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001.
- Published
- 2018
38. Magnetic resonance imaging of the anterior compartment of the lower leg is a biomarker for weakness, disability, and impaired gait in childhood Charcot-Marie-Tooth disease
- Author
-
Kayla M D, Cornett, Elizabeth, Wojciechowski, Amy D, Sman, Terri, Walker, Manoj P, Menezes, Paula, Bray, Mark, Halaki, Joshua, Burns, and Amy, Sman
- Subjects
Male ,Leg ,Muscle Weakness ,Adolescent ,Magnetic Resonance Imaging ,Charcot-Marie-Tooth Disease ,Image Processing, Computer-Assisted ,Humans ,Disabled Persons ,Female ,Muscle Strength ,Child ,Muscle, Skeletal ,Gait Disorders, Neurologic - Abstract
Biomarkers of disease severity in Charcot-Marie-Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents.Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system.Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score.The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59:213-217, 2019.
- Published
- 2018
39. Unique clinical and neurophysiologic profile of a cohort of children with CMTX3
- Author
-
Manoj Kanhangad, Helen Young, Robert L. Smith, Joshua Burns, Gopinath M. Subramanian, Kayla M.D. Cornett, Monique M. Ryan, Marina L. Kennerson, Manoj P. Menezes, Garth A. Nicholson, Megan H. Brewer, and Stephan Züchner
- Subjects
0301 basic medicine ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Neural Conduction ,Nerve conduction velocity ,Connexins ,Cohort Studies ,03 medical and health sciences ,Grip strength ,Young Adult ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Hand strength ,medicine ,Humans ,Genetic Testing ,Child ,Foot deformity ,Genetic testing ,Family Health ,Rehabilitation ,medicine.diagnostic_test ,Hand Strength ,business.industry ,Australia ,Infant ,medicine.disease ,030104 developmental biology ,Case-Control Studies ,Child, Preschool ,Cohort ,Mutation ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
ObjectiveTo describe in detail the clinical profile of Charcot-Marie-Tooth disease subtype 3 (CMTX3) to aid appropriate genetic testing and rehabilitative therapy.MethodsWe reviewed the clinical and neurophysiologic profile and CMT Pediatric Scale (CMTPedS) assessments of 11 children with CMTX3.ResultsCompared with the more common forms of CMT, CMT1A and CMTX, CMTX3 was characterized by early onset with early and progressive hand weakness. Most affected children were symptomatic within the first 2 years of life. The most common presentation was foot deformity in the first year of life. CMTPedS analysis in these children revealed that CMTX3 progressed more rapidly (4.3 ± 4.1 points over 2 years, n = 7) than CMT1A and CMTX1. Grip strength in affected boys was 2 SDs below age- and sex-matched normative reference values (z score −2.05 ± 1.32) in the second decade of life. The most severely affected individual was wheelchair bound at 14 years of age, and 2 individuals had no movement in the small muscles of the hand in the second decade of life. Nerve conduction studies showed a demyelinating sensorimotor neuropathy with motor conduction velocity ≤23 m/s.ConclusionsCMTX3 had an earlier onset, severe hand weakness, and more rapidly progressive disability compared to the more common forms of CMT. Understanding the unique phenotype of CMTX3 is essential for directing genetic testing because the CMTX3 insertion will not be seen on a routine microarray or neuromuscular gene panel. Early diagnosis will enable rehabilitation to be started early in this rapidly progressive neuropathy.
- Published
- 2017
40. Nusinersen for SMA: expanded access programme
- Author
-
Sandra Holland, Margot Morrison, Manoj P. Menezes, Michelle A. Farrar, Eppie M. Yiu, Daniella Villano, Ian R. Woodcock, Kate A. Carey, Hugo Sampaio, Anita Cairns, Hooi Ling Teoh, Monique M. Ryan, Richard D. Webster, Robin Forbes, Kristi J. Jones, Karen Herbert, and Kate Munro
- Subjects
Male ,medicine.medical_specialty ,Oligonucleotides ,Spinal Muscular Atrophies of Childhood ,Intrathecal ,Health Services Accessibility ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,business.industry ,Age Factors ,Australia ,Infant ,Spinal muscular atrophy ,Progressive muscle weakness ,SMA ,medicine.disease ,Psychiatry and Mental health ,Treatment Outcome ,Expanded access ,Child, Preschool ,Physical therapy ,Surgery ,Nusinersen ,Female ,Neurology (clinical) ,Age of onset ,business ,030217 neurology & neurosurgery - Abstract
BackgroundSpinal muscular atrophy (SMA) is a devastating motor neuron disorder causing progressive muscle weakness and respiratory insufficiency. We present the initial Australian experiences implementing the expanded access programme (EAP) to enable preapproval access to nusinersen, the first disease-modifying therapy, for SMA type 1.MethodsAn Australian multicentre, open-label EAP for nusinersen enrolled patients with infantile-onset SMA type 1 from November 2016 to September 2017. Standard-of-care medical therapy and treatment with intrathecal nusinersen were provided to all patients. Clinical and diagnostic characteristics, molecular genetics, treatment administered, and functional motor outcomes were assessed.ResultsA total of 20 patients with SMA type 1 met the inclusion criteria, of whom 16 consented and received nusinersen treatment. Median time to diagnosis from symptom onset was 5.0 months and was correlated with age of onset (r=0.54, PSMN2 copies.ConclusionsThe nusinersen EAP highlights difficulties in achieving early diagnosis and/or prevention, the evolution of optimal clinical care in a time of uncertain prognostication, resource implications and ethical issues in clinical practice for SMA type 1. These challenges are broadly relevant to the realisation of all novel therapeutics in neurological disorders.
- Published
- 2017
41. Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome
- Author
-
Richard D. Webster, Alison M. Kesson, Robert A. Ouvrier, Sekhar Pillai, Jayne Antony, Yael Hacohen, Christopher Troedson, Fabienne Brilot, Russell C. Dale, Esther M Tantsis, Ming K. Lim, Manoj P. Menezes, Sachin Gupta, Elizabeth H Barnes, Simone L. Ardern-Holmes, Angela Vincent, Vera Merheb, Kristina Prelog, Deepak Gill, Bethan Lang, Patrick Waters, Yann Polfrit, Nicholas W S Davies, and Peter Procopis
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Encephalopathy ,Nerve Tissue Proteins ,Autoantigens ,Receptors, N-Methyl-D-Aspartate ,Autoimmune Diseases ,Disability Evaluation ,Internal medicine ,Outcome Assessment, Health Care ,Infectious encephalitis ,Humans ,Medicine ,Child ,Autoantibodies ,Retrospective Studies ,business.industry ,Limbic encephalitis ,Autoantibody ,Brain ,Infant ,medicine.disease ,Magnetic Resonance Imaging ,Potassium channel complex ,Cross-Sectional Studies ,Potassium Channels, Voltage-Gated ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Acute disseminated encephalomyelitis ,Immunology ,Etiology ,Encephalitis ,Female ,business ,Follow-Up Studies - Abstract
BACKGROUND AND OBJECTIVES: Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immune-mediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome. METHODS: By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis). RESULTS: An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. CONCLUSIONS: We have defined clinical and radiologic phenotypes of infectious and immune-mediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/autoantibody-associated etiologies are common, and the recognition and treatment of these entities should be a clinical priority.
- Published
- 2015
42. Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy
- Author
-
Deepak Gill, Bruce Bennetts, Michelle S Lorentzos, Christopher Troedson, Peter Procopis, Jayne Antony, Manoj P. Menezes, Gladys Ho, Richard Webster, Elizabeth Farnsworth, Russell C. Dale, John Christodoulou, Simone L. Ardern-Holmes, Kavitha Kothur, Sachin Gupta, and Katherine Holman
- Subjects
0301 basic medicine ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Cost-Benefit Analysis ,CDKL5 ,SYNGAP1 ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,UBE3A ,Medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Child ,Retrospective Studies ,Massive parallel sequencing ,business.industry ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Infant ,Retrospective cohort study ,General Medicine ,medicine.disease ,030104 developmental biology ,Phenotype ,Neurology ,Child, Preschool ,Etiology ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,PRRT2 - Abstract
To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy.We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants.The yield of pathogenic variants was 28.5% (n = 30/105), highest in early onset EE3 months including Ohtahara syndrome (52%, n = 10/19) and lowest in generalized epilepsy (0/17). Patients identified with pathogenic variants had earlier onset of seizures (median 3.6 m vs 1.1y, p 0.001, OR 0.6/year, P 0.02) compared to those without pathogenic variants. Pathogenic/likely pathogenic variants were found in ALDH7A1 (2), CACNA1A (1), CDKL5 (3), FOXG1 (2), GABRB3 (1), GRIN2A (1), KCNQ2 (4), KCNQ3 (1), PRRT2 (1), SCN1A (6), SCN2A (2), SCN8A (2), SYNGAP1 (1), UBE3A (2) and WWOX (1) genes. This study expands the inheritance pattern caused by KCNQ3 mutations to include an autosomal recessive severe phenotype with neonatal seizures and severe developmental delay. The average cost of etiological evaluation was less with early use of EE panel compared to the traditional investigation approach ($5990 Australian dollars (AUD) vs $13069 AUD ; p = 0.02) among the patients with identified pathogenic variants.Targeted MPS testing is a comprehensive and economical investigation that enables early genetic diagnosis in children with EE. Careful clinical triage and selection of patients with young onset EE may maximize the yield of EE panel testing.
- Published
- 2017
43. Safety and efficacy of progressive resistance exercise for Charcot-Marie-Tooth disease in children: a randomised, double-blind, sham-controlled trial
- Author
-
Joshua Burns, Amy D Sman, Kayla M D Cornett, Elizabeth Wojciechowski, Terri Walker, Manoj P Menezes, Melissa R Mandarakas, Kristy J Rose, Paula Bray, Hugo Sampaio, Michelle Farrar, Kathryn M Refshauge, Jacqueline Raymond, Jennifer Baldwin, Marnee J McKay, Anita Mudge, Leanne Purcell, Clare Miller, Kelly Gray, Meghan Harman, Natalie Gabrael, and Robert A Ouvrier
- Subjects
Weakness ,medicine.medical_specialty ,Intention-to-treat analysis ,business.industry ,030229 sport sciences ,Standard score ,law.invention ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,One-repetition maximum ,Pediatrics, Perinatology and Child Health ,Developmental and Educational Psychology ,Physical therapy ,Medicine ,medicine.symptom ,business ,Adverse effect ,030217 neurology & neurosurgery ,Foot (unit) - Abstract
Summary Background Exercise is potentially therapeutic for neuromuscular disorders, but a risk of harm exists due to overwork weakness. We aimed to assess the safety and efficacy of progressive resistance exercise for foot dorsiflexion weakness in children with Charcot-Marie-Tooth disease. Methods We did this randomised, double-blind, sham-controlled trial across the Sydney Children's Hospitals Network (NSW, Australia). Children aged 6–17 years with Charcot-Marie-Tooth disease were eligible if they had foot dorsiflexion weakness (negative Z score based on age-matched and sex-matched normative reference values). We randomly allocated (1:1) children, with random block sizes of 4, 6, and 8 and stratification by age, to receive 6 months (three times per week on non-consecutive days; 72 sessions in total) of progressive resistance training (from 50% to 70% of the most recent one repetition maximum) or sham training (negligible non-progressed intensity), using an adjustable exercise cuff to exercise the dorsiflexors of each foot. The primary efficacy outcome was the between-group difference in dorsiflexion strength assessed by hand-held dynamometry (expressed as a Z score) from baseline to months 6, 12, and 24. The primary safety outcome was the between-group difference in muscle and intramuscular fat volume of the anterior compartment of the lower leg assessed by MRI (expressed as a scaled volume) from baseline to 6 months and 24 months. Participants, parents, outcome evaluators, and investigators other than the treatment team were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000552785. Findings From Sept 2, 2013, to Dec 11, 2014, we randomly assigned 60 children to receive progressive resistance exercise (n=30) or sham training (n=30), and 55 (92%) children completed the trial. ANCOVA-adjusted Z score differences in dorsiflexion strength between groups were 0 (95% CI −0·37 to 0·42; p=0·91) at 6 months, 0·3 (−0·23 to 0·81; p=0·27) at 12 months, and 0·6 (95% CI 0·03 to 1·12; p=0·041) at 24 months. Scaled muscle and fat volume was comparable between groups at 6 months (ANCOVA-adjusted muscle volume difference 0, 95% CI −0·03 to 0·10, p=0·24; and fat volume difference 0, 95% CI −0·01 to 0·05, p=0·25) and 24 months (0, −0·08 to 0·12, p=0·67; and 0, −0·05 to 0·03, p=0·58). No serious adverse events were reported. Interpretation 6 months of targeted progressive resistance exercise attenuated long-term progression of dorsiflexion weakness without detrimental effect on muscle morphology or other signs of overwork weakness in paediatric patients with Charcot-Marie-Tooth disease. Funding Muscular Dystrophy Association and Australian National Health and Medical Research Council.
- Published
- 2017
44. Natural history of Charcot-Marie-Tooth disease during childhood
- Author
-
Kayla M D, Cornett, Manoj P, Menezes, Rosemary R, Shy, Isabella, Moroni, Emanuela, Pagliano, Davide, Pareyson, Timothy, Estilow, Sabrina W, Yum, Trupti, Bhandari, Francesco, Muntoni, Matilde, Laura, Mary M, Reilly, Richard S, Finkel, Kate J, Eichinger, David N, Herrmann, Paula, Bray, Mark, Halaki, Michael E, Shy, and Joshua, Burns
- Subjects
Male ,Young Adult ,Adolescent ,Charcot-Marie-Tooth Disease ,Child, Preschool ,Mutation ,Disease Progression ,Humans ,Female ,Longitudinal Studies ,Child ,Myelin Proteins ,Article - Abstract
To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease.Two hundred six (103 female) participants aged 3 to 20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2 years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance.On average, CMTPedS Total scores progressed at a rate of 2.4 ± 4.9 over 2 years (14% change from baseline; p 0.001). There was no difference between males and females (mean difference, 0.5; 95% confidence interval [CI], -0.9 to 1.9; p = 0.49). The most responsive CMTPedS items were dorsiflexion strength (z-score change, -0.3; 95% CI, -0.6 to -0.05; p = 0.02), balance (z-score change, -1.0; 95% CI, -1.9 to -0.09; p = 0.03), and long jump (z-score change, -0.4; 95% CI, -0.7 to -0.02; p = 0.04). Of the most common genetic subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8 ± 4.2 (12% change from baseline; p 0.001), 9 participants with CMT1B/MPZ mutation progressed by 2.2 ± 5.1 (11% change), 6 participants with CMT2A/MFN2 mutation progressed by 6.2 ± 7.9 (23% change), and 7 participants with CMT4C/SH3TC2 mutations progressed by 3.0 ± 4.5 (12% change). Participants with CMT2A progressed faster than CMT1A (mean difference, -4.4; 95% CI, -8.1 to -0.8; p = 0.02). Children with CMT1A progressed consistently through early childhood (3-10 years) and adolescence (11-20 years; mean difference, 1.1; 95% CI, -0.6 to 2.7; p = 0.19), whereas CMT2A appeared to progress faster during early childhood than adolescence (mean difference, 10.0; 95% CI, -2.2 to 22.2; p = 0.08).Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2 years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions. Ann Neurol 2017;82:353-359.
- Published
- 2017
45. Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia
- Author
-
Francesco Muntoni, Thomas R. Pieber, Michael A. Gonzalez, Mariacristina Scoto, Michaela Auer-Grumbach, Kathryn N. North, Majid Hafezparast, Fiorella Speziani, Monkol Lek, Daniel G. MacArthur, Linda Greensmith, Alexander M. Rossor, Janet E. Sowden, A. Reghan Foley, Rebecca Schüle, E. Cottenie, Manoj P. Menezes, Tim M. Strom, David N. Herrmann, Henry Houlden, Nigel F. Clarke, Emily C. Oates, Mary M. Reilly, Matthew E. Hurles, Stephan Züchner, and Gyula Acsadi
- Subjects
Adult ,Cytoplasmic Dyneins ,Male ,Neurite ,Genetic Linkage ,Hereditary spastic paraplegia ,Mutation, Missense ,macromolecular substances ,Biology ,Polymorphism, Single Nucleotide ,Muscular Atrophy, Spinal ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Anterior Horn Cell ,Report ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Child ,Genetics (clinical) ,Aged ,Genes, Dominant ,030304 developmental biology ,Paraplegia ,0303 health sciences ,Upper motor neuron ,Spinal muscular atrophy ,Middle Aged ,Motor neuron ,medicine.disease ,BICD2 ,Pedigree ,HEK293 Cells ,medicine.anatomical_structure ,Haplotypes ,Child, Preschool ,Female ,Carrier Proteins ,Microtubule-Associated Proteins ,Neuroscience ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Protein Binding - Abstract
Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.
- Published
- 2013
46. Transitioning outcome measures: relationship between the CMTPedS and CMTNSv2 in children, adolescents, and young adults with Charcot-Marie-Tooth disease
- Author
-
Mary M. Reilly, Michael E. Shy, Francesco Muntoni, Matilde Laura, Davide Pareyson, T Estilow, Joshua Burns, R Shy, Kate Eichinger, Richard S. Finkel, Manoj P. Menezes, David N. Herrmann, Isabella Moroni, and Emanuela Pagliano
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Disease ,Severity of Illness Index ,Article ,Disability Evaluation ,Young Adult ,Charcot-Marie-Tooth Disease ,Floor effect ,Severity of illness ,Humans ,Medicine ,Young adult ,Child ,Univariate analysis ,business.industry ,General Neuroscience ,nervous system diseases ,Patient Outcome Assessment ,Natural history ,Clinical trial ,Child, Preschool ,Physical therapy ,Early adolescents ,Female ,Neurology (clinical) ,business - Abstract
Long-term studies of Charcot-Marie-Tooth (CMT) disease across the entire lifespan require stable endpoints that measure the same underlying construct (e.g., disability). The aim of this study was to assess the relationship between the CMT Pediatric Scale (CMTPedS) and the adult CMT Neuropathy Score (CMTNSv2) in 203 children, adolescents, and young adults with CMT. There was a moderate curvilinear correlation between the CMTPedS and the CMTNSv2 (Spearman's rho ρ = 0.716, p < 0.0001), although there appears to be a floor effect of the CMTNSv2 in patients with a milder CMT phenotype. Univariate analyses indicate that the relationship between the CMTPedS and CMTNSv2 scores improves with worsening disease severity and advancing age. Although one universal scale throughout life would be ideal, our data supports the transition from the CMTPedS in childhood to the CMTNSv2 in adulthood as a continuum of measuring lifelong disability in patients with CMT.
- Published
- 2013
47. Neurophysiological profile of peripheral neuropathy associated with childhood mitochondrial disease
- Author
-
Shamima Rahman, Kaustuv Bhattacharya, David R. Thorburn, Matthew Pitt, John Christodoulou, Monique M. Ryan, Yehani Wedatilake, Tyson L Ware, Manoj P. Menezes, Robert A. Ouvrier, Damian Clark, Michelle A. Farrar, Hugo Sampaio, and Carolyn Ellaway
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Mitochondrial DNA ,Mitochondrial Diseases ,Adolescent ,Mitochondrial disease ,Neural Conduction ,Tertiary Care Centers ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,medicine ,Humans ,SURF1 ,Prospective Studies ,Child ,Molecular Biology ,Genetic testing ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Chronic pain ,Infant, Newborn ,Infant ,Peripheral Nervous System Diseases ,Cell Biology ,medicine.disease ,Pyruvate dehydrogenase deficiency ,030104 developmental biology ,Peripheral neuropathy ,Lactic acidosis ,Child, Preschool ,Molecular Medicine ,business ,030217 neurology & neurosurgery - Abstract
Introduction Peripheral nerve involvement is common in mitochondrial disease but often unrecognised due to the prominent central nervous system features. Identification of the underlying neuropathy may assist syndrome classification, targeted genetic testing and rehabilitative interventions. Methods Clinical data and the results of nerve conduction studies were obtained retrospectively from the records of four tertiary children's hospital metabolic disease, neuromuscular or neurophysiology services. Nerve conductions studies were also performed prospectively on children attending a tertiary metabolic disease service. Results were classified and analysed according to the underlying genetic cause. Results Nerve conduction studies from 27 children with mitochondrial disease were included in the study (mitochondrial DNA (mtDNA) – 7, POLG – 7, SURF1 – 10, PDHc deficiency – 3). Four children with mtDNA mutations had a normal study while three had mild abnormalities in the form of an axonal sensorimotor neuropathy when not acutely unwell. One child with MELAS had a severe acute axonal motor neuropathy during an acute stroke-like episode that resolved over 12 months. Five children with POLG mutations and disease onset beyond infancy had a sensory ataxic neuropathy with an onset in the second decade of life, while the two infants with POLG mutations had a demyelinating neuropathy. Seven of the 10 children with SURF1 mutations had a demyelinating neuropathy. All three children with PDHc deficiency had an axonal sensorimotor neuropathy. Unlike CMT, the neuropathy associated with mitochondrial disease was not length-dependent. Conclusions This is the largest study to date of peripheral neuropathy in genetically- classified childhood mitochondrial disease. Characterising the underlying neuropathy may assist with the diagnosis of the mitochondrial syndrome and should be an integral part of the assessment of children with suspected mitochondrial disease.
- Published
- 2016
48. Peripheral neuropathy associated with mitochondrial disease in children
- Author
-
Manoj P. Menezes and Robert A. Ouvrier
- Subjects
Mitochondrial DNA ,Pathology ,medicine.medical_specialty ,Mitochondrial Diseases ,Ataxia ,Mitochondrial disease ,DNA Mutational Analysis ,DNA-Directed DNA Polymerase ,Mitochondrial Proteins ,Developmental Neuroscience ,Optic Nerve Diseases ,Secondary Prevention ,medicine ,Humans ,SURF1 ,Genetic Testing ,Child ,Subclinical infection ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Membrane Proteins ,Peripheral Nervous System Diseases ,Mitochondrial Proton-Translocating ATPases ,medicine.disease ,DNA Polymerase gamma ,Early Diagnosis ,Phenotype ,Peripheral neuropathy ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Leigh Disease ,Mitochondrial optic neuropathies ,medicine.symptom ,business - Abstract
Mitochondrial diseases in children are often associated with a peripheral neuropathy but the presence of the neuropathy is under-recognized because of the overwhelming involvement of the central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their clinical, neurophysiological, and histopathological characteristics. In this article, we provide a comprehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may help with the identification of the mitochondrial syndrome. While it is not definite that the characteristics of the neuropathy would help in directing genetic testing without the requirement for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially when associated with late-onset phenotypes, appear to cause a predominantly sensory neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative therapy. We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease.
- Published
- 2012
49. Auditory neuropathy in Brown-Vialetto-Van Laere syndrome due to riboflavin transporter RFVT2 deficiency
- Author
-
Manoj P. Menezes, Jayne Antony, Robert A. Ouvrier, Richard Webster, Katherine O'Brien, Mandy Hill, Catherine S. Birman, and Kirsty Gardner-Berry
- Subjects
Male ,medicine.medical_specialty ,Hearing loss ,Hearing Loss, Sensorineural ,Riboflavin ,Auditory neuropathy ,Bulbar Palsy, Progressive ,Otoacoustic Emissions, Spontaneous ,Audiology ,03 medical and health sciences ,0302 clinical medicine ,Riboflavin Deficiency ,Developmental Neuroscience ,Auditory neuropathy spectrum disorder ,Brown–Vialetto–Van Laere syndrome ,Audiometry ,otorhinolaryngologic diseases ,Evoked Potentials, Auditory, Brain Stem ,Medicine ,Humans ,Hearing Loss, Central ,Age of Onset ,030223 otorhinolaryngology ,Child ,Bulbar palsy ,medicine.diagnostic_test ,business.industry ,Membrane Transport Proteins ,Electroencephalography ,medicine.disease ,Cochlear Implantation ,Acoustic Stimulation ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation ,Speech Perception ,Female ,Neurology (clinical) ,medicine.symptom ,Age of onset ,business ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Aim Mutations in the genes encoding the riboflavin transporters RFVT2 and RFVT3 have been identified in Brown–Vialetto–Van Laere syndrome, a neurodegenerative disorder characterized by hearing loss and pontobulbar palsy. Treatment with riboflavin has been shown to benefit individuals with the phenotype of RFVT2 deficiency. Understanding the characteristics of hearing loss in riboflavin transporter deficiency would enable early diagnosis and therapy. Method We performed hearing assessments in seven children (from four families) with RFVT2 deficiency and reviewed results from previous assessments. Assessments were repeated after 12 months and 24 months of riboflavin therapy and after cochlear implantation in one individual. Results Hearing loss in these individuals was due to auditory neuropathy spectrum disorder (ANSD). Hearing loss was identified between 3 years and 8 years of age and progressed rapidly. Hearing aids were not beneficial. Riboflavin therapy resulted in improvement of hearing thresholds during the first year of treatment in those with recent-onset hearing loss. Cochlear implantation resulted in a significant improvement in speech perception in one individual. Interpretation Riboflavin transporter deficiency should be considered in all children presenting with an auditory neuropathy. Speech perception in children with ANSD due to RFVT2 deficiency may be significantly improved by cochlear implantation.
- Published
- 2015
50. Inherited neuromuscular disorders: Pathway to diagnosis
- Author
-
Kathryn N. North and Manoj P. Menezes
- Subjects
Weakness ,Pathology ,medicine.medical_specialty ,Muscle biopsy ,Neuromuscular disease ,medicine.diagnostic_test ,business.industry ,Duchenne muscular dystrophy ,Muscle weakness ,Spinal muscular atrophy ,Anatomy ,medicine.disease ,Myotonic dystrophy ,Pediatrics, Perinatology and Child Health ,medicine ,medicine.symptom ,Muscular dystrophy ,business - Abstract
Muscle weakness in childhood can be caused by a lesion at any point extending from the motor cortex, brainstem and spinal cord to the anterior horn cell, peripheral nerve, neuromuscular junction and muscle. A comprehensive history and physical examination is essential to aid classification of the neuromuscular disorder and direct gene testing. The more common disorders such as spinal muscular atrophy, Duchenne muscular dystrophy, myotonic dystrophy and facioscapulohumeral dystrophy may be diagnosed on direct gene testing based on the history and clinical examination. The congenital myopathies are classified based on structural abnormalities on muscle biopsy, while protein abnormalities on immunohistochemistry and immunoblotting aid classification of the muscular dystrophies. In this review, we provide an approach to diagnosis of a child with weakness, with a focus on the inherited neuromuscular disorders, and the features on history, examination and investigation that help to distinguish between them.
- Published
- 2011
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.