Publications by authors named "Paula Bray"

29 Publications

  • Page 1 of 1

L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial.

Am J Med Genet A 2021 Jun 21. Epub 2021 Jun 21.

Orthopaedic Research & Biotechnology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.
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http://dx.doi.org/10.1002/ajmg.a.62392DOI Listing
June 2021

Everyday Life Participation Using Powered Wheelchair Standing Devices by Boys With DMD.

OTJR (Thorofare N J) 2021 Jul 3;41(3):175-184. Epub 2021 May 3.

The University of Sydney School of Health Sciences, New South Wales, Australia.

Powered wheelchair standing devices (PWSDs) allow supported standing for activity; however, little is known about their use. To understand factors affecting use of supported standing for participation among boys with Duchenne muscular dystrophy (DMD) and characteristics of successful users, we gathered data over 7 days from boys who had used PWSDs for 24 months, using a smartphone application. We used descriptive statistics to identify factors that affected their participation. Physical/social engagement and independence were motivators for standing in PWSDs. Enablers included positive attitudinal/social environments. Barriers included pain during supported standing and lack of physical environment accessibility. The characteristics of successful users were identified. Supported standing via PWSDs has potential to improve participation for boys with DMD. The disease stage, individual personal factors and environmental supports impact on use. Therapists should carefully consider and manage factors that impact on uptake and sustainability of use.
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http://dx.doi.org/10.1177/15394492211004844DOI Listing
July 2021

Comparison of 3D scanning versus traditional methods of capturing foot and ankle morphology for the fabrication of orthoses: a systematic review.

J Foot Ankle Res 2021 Jan 7;14(1). Epub 2021 Jan 7.

Engineering Prototypes & Implants for Children (EPIC) Lab, The Children's Hospital at Westmead, Sydney, NSW, Australia.

Background: In the production of ankle-foot orthoses and in-shoe foot orthoses, lower leg morphology is traditionally captured using a plaster cast or foam impression box. Plaster-based processes are a time-consuming and labour-intensive fabrication method. 3D scanning is a promising alternative, however how these new technologies compare with traditional methods is unclear. The aim of this systematic review was to compare the speed, accuracy and reliability of 3D scanning with traditional methods of capturing foot and ankle morphology for fabricating orthoses.

Methods: PRISMA guidelines were followed and electronic databases were searched to March 2020 using keywords related to 3D scanning technologies and traditional foot and ankle morphology capture methods. Studies of any design from healthy or clinical populations of any age and gender were eligible for inclusion. Studies must have compared 3D scanning to another form of capturing morphology of the foot and/or ankle. Data relating to speed, accuracy and reliability as well as study design, 3D scanner specifications and comparative capture techniques were extracted by two authors (M.F. and Z.W.). Study quality was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN).

Results: Six articles met the inclusion criteria, whereby 3D scanning was compared to five traditional methods (plaster cast, foam impression box, ink footprint, digital footprint and clinical assessment). The quality of study outcomes was rated low to moderate (GRADE) and doubtful to adequate (COSMIN). Compared to traditional methods, 3D scanning appeared to be faster than casting (2 to 11 min vs 11 to 16 min). Inter-rater reliability (ICC 0.18-0.99) and intra-rater reliability (ICCs 0.25-0.99) were highly variable for both 3D scanning and traditional techniques, with higher agreement generally dependent on the foot parameter measured.

Conclusions: The quality and quantity of literature comparing the speed, accuracy and reliability of 3D scanning with traditional methods of capturing foot and ankle morphology is low. 3D scanning appears to be faster especially for experienced users, however accuracy and reliability between methods is variable.
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http://dx.doi.org/10.1186/s13047-020-00442-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792297PMC
January 2021

Impact of heritable disorders of connective tissue on daily life of children: Parent perspectives.

J Paediatr Child Health 2021 May 26;57(5):626-630. Epub 2020 Nov 26.

Faculty of Medicine and Health Sydney, The University of Sydney, Sydney, Australia.

Aim: The aim of this study was to investigate parent perspectives on how heritable disorders of connective tissue (HDCT) affect a child's everyday life. In addition, this study aimed to determine if parents seeking health professional services perceive their children with HDCT to have difficulties with activities reliant on hand function.

Methods: This cross-sectional study used a questionnaire for parents to explore the impact of an HDCT on a child's ability to carry out everyday activities. Parents of children (8-18 years) attending a tertiary connective tissue dysplasia clinic, over a 12-month period, were invited to participate.

Results: We analysed 100 surveys completed by parents. Children with Ehlers-Danlos syndrome-hypermobile type, joint hypermobility syndrome (48%) and osteogenesis imperfecta (42%) were the largest diagnostic groups represented. Pain (73%) and fatigue (68%) were the most common symptoms parents perceived to affect day-to-day activities. More parents were satisfied with their child's self-care (61%) than school participation (33%). Keeping up with handwriting (71%) and gross motor activities (70%) were the most frequently reported difficulties at school. Most parents (65%) reported leisure activity difficulties, with pain (64%) and fatigue (60%) as the main contributing factors.

Conclusions: This study has provided new knowledge about the concerns of parents with their child's engagement in everyday life including the impact of HDCT on hand function. Further research is needed on effective management strategies to reduce symptoms and improve hand function for these children.
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http://dx.doi.org/10.1111/jpc.15284DOI Listing
May 2021

Multidisciplinary perspectives and practices of wheelchair prescription for children with neuromuscular conditions.

Disabil Rehabil Assist Technol 2020 Nov 4:1-9. Epub 2020 Nov 4.

Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, Australia.

Purpose: Clinical practice guidelines for paediatric neuromuscular disorders (NMDs) recommend timely provision of wheelchair equipment. The aim of this qualitative study was to understand healthcare professionals' clinical perspectives and practices when recommending wheelchair equipment for the first time, as well as perceived barriers and enablers to timely wheelchair provision.

Methods: Twenty-one healthcare professionals (HCPs) from Australia and the United States participated in an interview (response rate: 88%, 16/21 women). Participants were from diverse disciplines, based in hospital or community health settings, and had at least one year of experience working in paediatric neuromuscular care.

Results: Child fatigue, falls and engagement in age-appropriate activity were common reasons for HCP's wheelchair recommendation. HCPs were acutely aware of parents' experiences of grief and loss throughout the wheelchair prescription process, and over half acknowledged the lack of psychological care available to families affected by NMDs. Multi-disciplinary collaboration, psychologically-informed care, and shared decision-making with stakeholders were perceived enablers of wheelchair transition. Barriers included limited access to equipment, lengthy funding processes and lack of funding for home and vehicle modifications.

Conclusions: Integrated psychosocial care is needed to support families throughout their child's disease progression, including wheelchair transition. Implementation of readiness for change tools, and development of tailored informational resources is recommended. Improved access to equipment options and trials, and more efficient funding processes are highly likely to improve parental engagement throughout the wheelchair prescription process.Implications for rehabilitationHealthcare professionals express a strong demand for integrated psychosocial care within paediatric neuromuscular clinics to support families throughout transitions, including wheelchair introduction.Identifying parents' readiness for change can inform their information and support needs, strengthen their decision-making capacity and facilitate timely wheelchair introduction.Stronger collaboration between hospital- and community-based health professionals working in paediatric neuromuscular care is recommended to facilitate knowledge exchange and support families' transition to wheelchair use.Access to equipment options for extended loan or trial in the community can support timely wheelchair introduction.
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http://dx.doi.org/10.1080/17483107.2020.1839793DOI Listing
November 2020

Reliability of the Charcot-Marie-Tooth functional outcome measure.

J Peripher Nerv Syst 2020 09 26;25(3):288-291. Epub 2020 Aug 26.

Department of Neurology, University of Rochester, Rochester, New York, USA.

The CMT-FOM is a 13-item clinical outcome assessment (COA) that measures physical ability in adults with Charcot-Marie-Tooth disease (CMT). Test-retest reliability, internal consistency and convergent validity have been established for the CMT-FOM. This current study sought to establish inter-rater reliability. Following an in-person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18-74 years, 6 female). Participants were evaluated using the CMT-FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. Following the provision of training by master trainers, all 13 items of the CMT-FOM exhibited excellent inter-rater reliability for raw scores (ICC 0.825-0.989) and z-scores (ICC 0.762-0.969). Reliability of the CMT-FOM total score was excellent (ICC 0.983, 95% CI 0.958-0.995). The CMT-FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT-FOM in the Accelerate Clinical Trials in CMT (ACT-CMT) study.
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http://dx.doi.org/10.1111/jns.12406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520097PMC
September 2020

Refining clinical trial inclusion criteria to optimize the standardized response mean of the CMTPedS.

Ann Clin Transl Neurol 2020 09 6;7(9):1713-1715. Epub 2020 Aug 6.

School of Health Sciences, University of Sydney, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1002/acn3.51145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480902PMC
September 2020

The Development of Clinical Genomics and Genetics Within Healthcare: How Should the Allied Health Professions Respond?

J Allied Health 2019 ;48(4):e101-e105

Northern Sydney Local Health District, The Kolling Research Institute and Faculty of Health Sciences, The University of Sydney, St. Leonards, NSW 2065, Australia. Tel +61 2 9351 9385.

Clinical genomics is becoming mainstream, providing personalized information that is relevant to clinical assessment, management, and decision-making on a patient-by-patient basis. This emphasis on personalized medicine has been featured in medical and nursing/midwifery entry-level curricula for some time. These curricula frameworks enable work-ready professionals to embrace genomics as part of standard care. The uptake of genomics across healthcare should also feature across the allied health professions worldwide. While some allied health professions are active in the research and clinical domains, there is, to our knowledge, scant evidence of a collective effort to bring genomics into mainstream allied health practice. It is suggested that the allied health professions need to recognize and embrace opportunities to collaborate with our colleagues in medicine, nursing/midwifery, and healthcare consumers to integrate genomics into and across allied health clinical practice. This includes: understanding what "genomics" is; recognizing who may benefit from genetic testing; the cultural, ethical, and legal implications of genomics in practice; and the potential to inform treatment decisions and/or justify referral. Discussion surrounding the integration of genomics competencies within the allied health professions is required to both enlighten and determine professional practice roles in response to this increasingly relevant element of healthcare delivery worldwide.
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May 2020

Sensory dysregulation in tic disorders is associated with executive dysfunction and comorbidities.

Mov Disord 2019 12 10;34(12):1901-1909. Epub 2019 Sep 10.

Department of Pediatric Neurology, The Children's Hospital at Westmead, Sydney, Australia.

Background: Tics are conceptualized as a sensorimotor phenomenon with a premonitory urge typically described by patients. As observed in other neurodevelopmental disorders, we have observed sensory dysregulation symptoms, such as tactile hypersensitivity to clothing, in children with tic disorders; however, formal clinical research in this area is limited.

Objective: To define the presence of sensory dysregulation symptoms in tic disorders, and their clinical associations.

Methods: Prevalence of sensory dysregulation in 102 children with tic disorders was compared to 61 age- and sex-matched healthy controls. Sensory dysregulation, executive function, and quality of life data were obtained through the Short Sensory Profile-2, Sensory Profile-2, Sensory Processing Measure, Behaviour Rating Inventory of Executive Function-2, and Strength and Difficulties Questionnaire and Pediatric Quality of Life Inventory. Tics were assessed with the Yale Global Tic Severity Scale.

Results: Children with tics, in the presence of comorbidity, had elevated sensory dysregulation compared to healthy controls (P < 0.001). There was a positive correlation between sensory dysregulation and global executive difficulties in children with tics and comorbidity (n = 87; rho = 0.716; P < 0.001) and a negative correlation of sensory dysregulation with quality of life (n = 87; rho = -0.595; P < 0.001). In children with tics, there was an association between sensory dysregulation and number of comorbidities (P < 0.001).

Conclusion: In the presence of comorbidity, children with tic disorders have broad sensory dysregulation symptoms beyond the premonitory urge. There was a statistically significant association between sensory dysregulation and executive function difficulties and the presence of neurodevelopmental and psychiatric comorbidity. Sensory dysregulation can be considered neurodevelopmental symptoms, providing insight into the neurobiology of tics and opportunities for therapeutic intervention. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27817DOI Listing
December 2019

Balance impairment in pediatric charcot-marie-tooth disease.

Muscle Nerve 2019 09 15;60(3):242-249. Epub 2019 May 15.

Children's Hospital of Philadelphia, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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 R = 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.
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http://dx.doi.org/10.1002/mus.26500DOI Listing
September 2019

"It's not just the wheelchair, it's everything else": Australian parents' perspectives of wheelchair prescription for children with neuromuscular disorders.

Disabil Rehabil 2020 12 21;42(24):3457-3466. Epub 2019 Apr 21.

Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, NSW, Australia.

Standards of care for neuromuscular disorders recommend timely provision of wheelchair equipment to support independent and spontaneous movement, age-appropriate participation, and psychological, social, cognitive and communication skills. Parental engagement is crucial to initiating wheelchair prescription. No studies have investigated parents' perceptions of this process or their experiences of their child's transition to wheelchair equipment. Seventeen families of children with a neuromuscular disorder who were recommended wheelchair equipment participated in an interview (response rate: 53%). Diagnoses included muscular dystrophies, spinal muscular atrophy, and congenital myopathy. Findings showed that wheelchair prescription represented a milestone for parents in their child's disease progression. Parents described experiencing strong emotional responses, with the potential to eclipse pragmatic factors. Perceiving wheelchair equipment as an adjunct to their child's functioning and participation positively influenced parents' receptivity to wheelchair recommendation. Parents' receptivity to wheelchair recommendation was also influenced by their emotional experience, their child's weight-bearing ability and participation in age appropriate activities. Enablers to parental engagement in the wheelchair prescription process included timely psychological care and social support, a child- and family-centered approach to care, and ease of access to credible information. This study shows wheelchair prescription is a complex and multi-faceted process that represents more than just a piece of equipment to parents.Implications for rehabilitationParents experience a range of emotions and challenges as their child's neuromuscular condition progresses, including the introduction of a wheelchair.Anticipatory care and education from health professionals is required to support families' transition to wheelchair equipment.Facilitators to parents' engagement in wheelchair prescription include a family-centered approach, collaborative decision-making between families and health professionals, and access to information and psychosocial support.
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http://dx.doi.org/10.1080/09638288.2019.1595749DOI Listing
December 2020

An exploratory study into an adapted use of the Alert Program for tic disorder in children.

Australas Psychiatry 2019 04 3;27(2):144-151. Epub 2018 Dec 3.

Paediatric Neurologist, Department of Paediatric Neurology, The Children's Hospital at Westmead, Sydney, NSW, and; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.

Objectives: This preliminary study explored whether an adapted approach to the Alert Program, that uses sensorimotor strategies, might assist with management of tic disorders in children. The Alert Program, a program that uses sensorimotor strategies for self-regulation in children with neurodevelopmental disorders, had not been trialled with children with tic disorders.

Methods: Ten children with tic disorder were assessed using the Dunn Sensory Profile 2 (SP2), the Yale Global Tic Severity Scale (YGTSS) and the Parent Tic Questionnaire (PTQ). Participants attended three 60-90-minute appointments with an occupational therapist and clinical psychologist for implementation of the adapted Alert Program.

Results: The YGTSS showed tic reduction in all participants. The total YGTSS pre-intervention mean score of 46.5 improved to 17.7 post-therapy. Five participants reported no impairment post-therapy. PTQ scores reduced in nine participants. On the SP2, 30% of participants scored as having sensory sensitivities that impaired daily function.

Conclusions: This exploratory study found trialling an adapted approach to the Alert Program that uses sensorimotor-based approach decreased tic severity in children with tic disorders. A randomised controlled trial is needed to establish the effectiveness and feasibility of this approach.
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http://dx.doi.org/10.1177/1039856218815750DOI Listing
April 2019

Development and validation of the Charcot-Marie-Tooth Disease Infant Scale.

Brain 2018 12;141(12):3319-3330

Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

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.
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http://dx.doi.org/10.1093/brain/awy280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312041PMC
December 2018

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.

Muscle Nerve 2019 02 19;59(2):213-217. Epub 2018 Dec 19.

Sydney Children's Hospitals Network (Randwick and Westmead), The University of Sydney, Locked Bag 4001, Westmead, Sydney, New South Wales, 2145, Australia.

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.
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http://dx.doi.org/10.1002/mus.26352DOI Listing
February 2019

Safety and efficacy of progressive resistance exercise for Charcot-Marie-Tooth disease in children: a randomised, double-blind, sham-controlled trial.

Lancet Child Adolesc Health 2017 Oct 10;1(2):106-113. Epub 2017 Jul 10.

Faculty of Health Sciences, The University of Sydney, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1016/S2352-4642(17)30013-5DOI Listing
October 2017

Parents' perceptions of power wheelchair prescription for children with a neuromuscular disorder: a scoping review.

Disabil Rehabil 2019 11 18;41(23):2750-2757. Epub 2018 Jun 18.

Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, Australia.

To conduct a scoping review of the published evidence on parents' perceptions of power wheelchair prescription for children with a neuromuscular disorder and clinicians' influence on timely wheelchair implementation. Nine electronic databases and reference lists of all retrieved full-text articles were searched up to March 2017. Eligibility criteria included (1) at least one child participant with a neuromuscular disorder, (2) power wheelchair as an intervention, and (3) qualitative, quantitative or mixed methods parent-reported outcomes related to power wheelchair equipment. None of the 67 eligible studies examined parental perceptions of wheelchair prescription as a primary aim, and only 10 studies included children with a neuromuscular disorder. Parents reported their own emotional responses including grief and loss, emphasis on their child's walking and lack of accessibility as key barriers to power wheelchair prescription. Clinicians' perspectives on walking and powered mobility influenced parental decision-making regarding power wheelchair use for their child. Parents' experiences of initial wheelchair prescription have not been explored in existing literature. Clinicians' understanding of the benefits of power wheelchair equipment, particularly in the context of progression of neuromuscular disorders, is critical to facilitating timely wheelchair prescription with children. Condition-specific evidence is urgently needed to inform and support multidisciplinary management of children and their families.Implications for RehabilitationIt is important that rehabilitation professionals recognize parental barriers to initial power wheelchair prescription, such as strong emotional responses, an emphasis on their child's walking and lack of access.Clinicians' perspectives on walking and powered mobility may influence parental decision-making regarding engagement in power wheelchair prescription and rehabilitation.It is critical that clinicians are aware of and actively educate families regarding the benefits of powered mobility to facilitate timely prescription and support physical and psychological adjustment.
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http://dx.doi.org/10.1080/09638288.2018.1474496DOI Listing
November 2019

Established and novel measures of upper limb impairment in children with Charcot-Marie-tooth disease type 1A and riboflavin transporter deficiency type 2.

J Peripher Nerv Syst 2018 Mar 11;23(1):29-35. Epub 2017 Dec 11.

Sydney Children's Hospitals Network (Randwick and Westmead), Sydney, New South Wales, Australia.

Hand function is a problem in patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and Riboflavin Transporter Deficiency type 2 (RTD2). However, a detailed understanding of upper limb involvement in these conditions is lacking. The aim of this pilot study was to compare hand and upper limb function between children with CMT1A, RTD2 and healthy controls using established and novel outcome measures. Three age-and sex-matched groups of four children (5-15 years, 1 male/group) with CMT1A, RTD2, and healthy controls were assessed for function, strength, and sensation. Fatigue and muscle activity of the FDI was also assessed using a submaximal contraction at 40% of the participants' maximal voluntary contraction. Functional measures were most affected in children with RTD2 followed by children with CMT1A, compared to healthy controls. Strength was similarly impaired in CMT1A and RTD2 compared to controls (p < 0.05). Sensation was significantly impaired in RTD2 compared to CMT1A and controls (p = 0.008). While time to fatigue did not differ between groups, a decline in muscle activity while force remained constant showed that controls compensated with other muscles during the fatigue task while children with CMT1A and RTD2 did not have this compensatory ability. Children with CMT1A and RTD2 exhibited marked hand/upper limb impairment. These results suggest the upper limb should be a focus of rehabilitative therapy in affected children using sensitive outcome measures of strength and sensation, as well as functional activities of daily living, which are most relevant to the patient.
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http://dx.doi.org/10.1111/jns.12245DOI Listing
March 2018

Natural history of Charcot-Marie-Tooth disease during childhood.

Ann Neurol 2017 Sep;82(3):353-359

The University of Sydney, Sydney Children's Hospitals Network (Randwick and Westmead, Sydney, New South Wales, Australia.

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 < 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).

Interpretation: 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.
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http://dx.doi.org/10.1002/ana.25009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294172PMC
September 2017

Handwriting difficulties of children with Charcot-Marie-Tooth disease type 1A.

J Peripher Nerv Syst 2017 03;22(1):34-38

Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia.

Hand weakness and impaired manual dexterity have been reported in children with Charcot-Marie-Tooth disease type 1A (CMT1A). This early onset of upper limb involvement might explain frequent clinical referrals for assessment and treatment of impaired handwriting performance. The aim of this study was to examine the impact of CMT1A on handwriting speed and legibility, and identify demographic, anthropometric, and physical measures that might relate to handwriting performance. Handwriting speed (Handwriting Speed Test), handwriting legibility (Evaluation Tool of Children's Handwriting-Cursive), and hand strength (hand-held dynamometry of tip pinch, lateral pinch and grip) were assessed in 30 children with CMT1A (aged 8-17 years) and 30 age- and sex-matched controls. Children with CMT1A exhibited 34% slower handwriting speed (p < 0.0001) with 4% reduced legibility (p = 0.001) and 37-48% lower hand strength (p < 0.0001). All measures of strength, age, height, and weight were positively associated with handwriting speed (r = 0.39-0.79, p < 0.01). None of these factors related to handwriting legibility (p > 0.05). Regression modelling identified a diagnosis of CMT1A, lateral pinch weakness and younger age as significant independent predictors of slower handwriting speed, explaining 78% of the variance. Children with CMT1A have considerable handwriting difficulties, primarily with speed, and substantial associated hand and finger weakness. Understanding the cause-effect relationship between strength and function might provide modifiable targets for upper limb intervention.
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http://dx.doi.org/10.1111/jns.12198DOI Listing
March 2017

Can in-the-moment diary methods measure health-related quality of life in Duchenne muscular dystrophy?

Qual Life Res 2017 05 3;26(5):1145-1152. Epub 2016 Nov 3.

Murdoch Children's Research Institute, Melbourne, VIC, Australia.

Aim: To investigate whether in-the-moment diary reports of daily experience, taken collectively, are a valid representation of health-related quality of life (HRQL).

Methods: A total of 35 boys with Duchenne muscular dystrophy (DMD) were recruited through four neuromuscular care providers across Australia. Participants completed the PedsQL™ Generic Core scales and one week of experience-sampling diary reporting on a personal digital assistant. Rasch analysis was undertaken on the diary data to derive a single valid measure score. The resulting measure score for each participant was correlated with the summary score from the PedsQL™ Generic Core scales to examine whether daily experience was representative of HRQL.

Results: The daily diary method showed good metric properties, with adequate goodness of fit for data from items and participants suggesting unidimensionality of the construct: quality of everyday experience. The correlation of the daily diary measure score with overall PedsQL™ summary score showed moderate agreement (r = .60, p = 0.001).

Conclusions: The benefits of measuring daily quality of life include detailed descriptions of day-to-day experiences of children without the need for retrospective recall. Diary methods on an electronic platform or software application for personal devices may be a useful tool to understand HRQL as the repeated measures data provide a detailed experience directly from the child and the platform makes data completion highly motivating.
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http://dx.doi.org/10.1007/s11136-016-1442-zDOI Listing
May 2017

Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease.

JAMA Neurol 2016 Jun;73(6):645-51

University of Sydney & Children's Hospital at Westmead, Sydney Australia.

Importance: Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date.

Objective: To assess the variability of disease severity in a large cohort of children and adolescents with CMT.

Design, Setting, And Participants: A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015.

Main Outcomes And Measures: Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected).

Results: Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P < .001) as independent predictors of disease severity.

Conclusions And Relevance: These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials.
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http://dx.doi.org/10.1001/jamaneurol.2016.0171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916861PMC
June 2016

Health status of boys with Duchenne muscular dystrophy: a parent's perspective.

J Paediatr Child Health 2011 Aug 10;47(8):557-62. Epub 2011 Mar 10.

Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Westmead, Sydney, NSW, Australia.

Aim: To investigate parent-reported health status of boys with Duchenne muscular dystrophy (DMD) compared with a large Australian normative population and a cohort of children with Charcot-Marie-Tooth disease type 1A (CMT1A).

Methods: The Child Health Questionnaire parent form (CHQ-PF50) was completed by parents of 34 boys with confirmed DMD. Seventeen parents were followed up at 6 months. CHQ-PF50 data were compared with 2620 age-matched norms and 90 children with CMT1A.

Results: All domains of the CHQ-PF50 for the DMD cohort were significantly lower than the general paediatric population, particularly for physical functioning (t = -17.2, P < 0.001) and the child's ability to fulfil school and social roles because of physical limitations (t = -9.4, P < 0.001). Parents experienced greatest emotional impact of their child's DMD around the time of loss of ambulation. Children with DMD had lower health status compared with children with CMT1A with the exception of the behaviour and pain domains. Physical functioning worsened during 6 months (P = 0.04); no other changes in health status were observed at follow-up.

Conclusions: Parents report the impact of DMD on health status to be considerably worse when compared with CMT1A. Interventions should target minimising the impact of physical limitations on role functioning.
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http://dx.doi.org/10.1111/j.1440-1754.2011.02022.xDOI Listing
August 2011

Health-related quality of life in boys with Duchenne muscular dystrophy: agreement between parents and their sons.

J Child Neurol 2010 Oct 12;25(10):1188-94. Epub 2010 Oct 12.

Discipline of Occupational Therapy, Faculty of Health Sciences, The University of Sydney, Sydney, Australia, Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia.

This study investigated agreement between boys and their parents when reporting on health-related quality of life and the effects of steroid use, age, and physical functioning on self-reported health-related quality of life in boys with Duchenne muscular dystrophy. The Pediatric Quality of Life Inventory™ and brief functional measures were administered to 35 parent-son dyads. We found that agreement between parents and their sons was moderate (intraclass correlation coefficient [ICC](2,1) = 0.66; 95% confidence interval [CI], 0.40-0.80) to poor (ICC(2,1) = 0.64; 95% CI, 0.43-0.64). The boys' self-reports revealed a relationship between disease progression and physical functioning (r = -.75; P = .01); however, disease stage was not related to psychosocial functioning (r = -.27; NS). Parents and boys affected by Duchenne muscular dystrophy have a moderate to poor agreement on health-related quality of life measures, with parents reporting lower overall health-related quality of life when compared with their sons.
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http://dx.doi.org/10.1177/0883073809357624DOI Listing
October 2010

Feasibility of a computerized method to measure quality of "everyday" life in children with neuromuscular disorders.

Phys Occup Ther Pediatr 2010 Feb;30(1):43-53

Faculty of Health Sciences, The University of Sydney, Lidcombe, NSW, Australia.

Measurement of quality of life is becoming increasingly important in health care. Self-reported quality of life is the preferred method of gathering this information, but children are often excluded from this process, their input being replaced by parent-proxy report. This feasibility study tested assessment of "daily" quality-of-life by a self-reported computerized method in boys with neuromuscular disorders. To establish feasibility, the method was required to be engaging, consistent, and convenient. Ten boys, aged 9-16 years, were given a personal digital assistant (PDA) and prompted randomly, eight times/day for 1 week, to answer 19 questions about their daily experiences (including happiness, mood, self-esteem, location, and activity). Subjects completed sampling with an acceptable response rate (79%). Split-week reliability analysis for participant variability (r = 0.45-0.88) indicated acceptable consistency. Participants reported that the method was easy and convenient, and analysis of standardized mean scores supported internal validity. The computerized method to assess "daily" quality of life, from the child's perspective, was feasible and may be useful to understand the impact of disease progression and interventions on day-to-day function.
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http://dx.doi.org/10.3109/01942630903294687DOI Listing
February 2010

Hand involvement in children with Charcot-Marie-Tooth disease type 1A.

Neuromuscul Disord 2008 Dec 6;18(12):970-3. Epub 2008 Nov 6.

Discipline of Paediatrics and Child Health, Faculty of Medicine, The University of Sydney, New South Wales, Australia.

Charcot-Marie-Tooth disease type 1A (CMT1A), a demyelinating neuropathy characterised by progressive length-dependent muscle weakness and atrophy, is thought to affect the foot and leg first followed some time later by hand weakness and dysfunction. We aimed to characterise hand strength, function and disease-related symptoms in children with CMT1A. Intrinsic and extrinsic hand strength was measured by hand-held dynamometry, function by nine-hole peg test, and disease-related symptoms by interview and examination in 84 affected children aged 2-16 years. Hand weakness and dysfunction was present from the earliest stages of the disease. While hand strength and function measures tended to increase with age throughout childhood, at no point did they reach normal values. Day-to-day hand problems such as poor handwriting, weakness, pain and sensory symptoms also worsened with age. The hand is affected at all ages in children with CMT1A, but may be under-recognised in its early stages, potentially delaying therapy.
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http://dx.doi.org/10.1016/j.nmd.2008.08.004DOI Listing
December 2008

Toll-like receptors in the brain and their potential roles in neuropathology.

Immunol Cell Biol 2007 Aug-Sep;85(6):476-80. Epub 2007 Jul 31.

Department of Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia.

The explosion of the toll-like receptors (TLRs) over the past decade has touched almost every field of mammalian biology and neuroscience is not an exception. The current advent of research papers examining the TLRs in the central nervous system (CNS) signifies that these receptors are not only involved in peripheral innate immunity but may also play a role in the development and regulation of CNS inflammation, neurodegeneration and brain trauma. This review addresses the potential role of TLRs in the brain and how they may be involved in various neuropathologies.
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http://dx.doi.org/10.1038/sj.icb.7100103DOI Listing
November 2007

Scanning the ocular albinism 1 (OA1) gene for polymorphisms in congenital nystagmus by DHPLC.

Ophthalmic Genet 2006 Jun;27(2):43-9

Genomic Disorders Research Centre, St. Vincent's Hospital, Victoria, Australia.

Background: Nystagmus is common to all types of albinism. Some subjects with nystagmus lack convincing signs of albinism, have no other visual pathway disease, and are classified as possessing congenital idiopathic nystagmus (CN). It has been postulated that CN may be a form of ocular albinism.

Methods: The presence of nystagmus, iris transillumination, and visual acuity were recorded in 39 CN and albino patients and their families. Physical characteristics were also noted. DNA from buccal swabs was obtained for use in denaturing high performance liquid chromatography (DHPLC) and chemical cleavage of mismatch (CCM) to scan several hotspots for X-linked ocular albinism (OA1) mutations.

Results: Two previously reported polymorphisms were confirmed: neither was found to be a causative mutation.

Conclusion: No correlation was identified between nystagmus and OA1.
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http://dx.doi.org/10.1080/13816810600677834DOI Listing
June 2006

Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms.

Hum Mutat 2003 Jun;21(6):557-68

Genomic Disorders Research Centre, St. Vincent's Hospital, Fitzroy, Victoria, Australia.

Glucocorticoid (GC) resistance can occur in a number of diseases. It can be either generalized (i.e., familial glucocorticoid resistance) or localized (i.e., asthma). In many cases, a reason for this resistance to steroids lies with mutations or polymorphisms present in the glucocorticoid receptor gene (GR/NR3C1) that belongs to a large family of nuclear receptors. A number of GC-resistant cell lines have been isolated in vitro, some of which arose or may have arisen in vivo. These and the mutations defined in them are included in this review as well as mutations engineered in plasmids and expressed in vitro. It also lists polymorphisms and the individual studies where association-related studies have been performed. NR3C1 is located on chromosome 5q31 and contains 10 exons that code for a 777 amino acid protein. There are two naturally occurring isoforms of the NR3C1, GRalpha (functional) and GRbeta (no hormone-binding ability). A total of 15 missense, three nonsense, three frameshift, one splice site, and two alternative spliced mutations have been reported in the NR3C1 gene associated with glucocorticoid resistance as well as 16 polymorphisms. Mutation and polymorphism data for NR3C1 will soon be found on the newly created locus-specific database.
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http://dx.doi.org/10.1002/humu.10213DOI Listing
June 2003
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