Publications by authors named "Miriam Rodrigues"

30 Publications

  • Page 1 of 1

Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants.

Genet Med 2022 Jan 30;24(1):130-145. Epub 2021 Nov 30.

Department of Clinical Genetics, The Canberra Hospital, Garran, ACT, Australia.

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.
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http://dx.doi.org/10.1016/j.gim.2021.09.001DOI Listing
January 2022

Impact and predictors of quality of life in adults diagnosed with a genetic muscle disorder: a nationwide population-based study.

Qual Life Res 2021 Nov 27. Epub 2021 Nov 27.

Neurology Department, Auckland City Hospital, Auckland, New Zealand.

Objectives: To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, and symptom factors influencing quality of life.

Methods: Adults (aged 16-90 years) with a confirmed clinical or molecular diagnosis of a genetic muscle disorder identified as part of a nationwide prevalence study were invited to complete an assessment of the impact of their condition. Quality of life was measured using the World Health Organization Quality of Life questionnaire. Impact was measured via the prevalence of symptoms and comparisons of quality of life against New Zealand norms. Multivariate regression models were used to identify the most significant predictors of quality of life domains.

Results: 490/596 participants completed the assessment (82.2% consent rate). Quality of life was lower than the general population on physical (t = 9.37 p < 0.0001, d = 0.54) social (t = 2.27 p = 0.02, d = 0.13) and environmental domains (t = 2.28 p = 0.02, d = 0.13), although effect sizes were small. No difference was found on the psychological domain (t = - 1.17 p = 0.24, d = 0.07). Multivariate regression models (predicting 42%-64% of the variance) revealed personal factors (younger age, being in employment and in a relationship), symptoms (lower pain, fatigue, and sleep difficulties), physical health (no need for ventilation support, fewer activity limitations and no comorbidities), and psychosocial factors (lower depression, anxiety, behavioural dyscontrol and higher self-efficacy, satisfaction with health care and social support) contributed to improved quality of life.

Conclusions: A range of factors influence the quality of life in adults diagnosed with a genetic muscle disorder and some may serve as targets for multi-faceted intervention.
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http://dx.doi.org/10.1007/s11136-021-03046-2DOI Listing
November 2021

Coping in Children and Adolescents with a Genetic Muscle Disorder -Findings from a Population-Based Study.

J Neuromuscul Dis 2021 ;8(6):1069-1078

National Institute for Stroke and Applied Neurosciences, School of Clinical Sciences, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand.

Background: The impacts of genetic muscle disorders on quality of life in affected children are well-documented. However, few studies have investigated children's coping strategies and relationships between coping and quality of life.

Objectives: To determine coping strategy use, efficacy, and associations with quality of life in children with a genetic muscle disorder.

Methods: Forty-eight children (6-15 years, 58% male) with a genetic muscle disorder were identified as part of a national prevalence study. Children completed the Kidcope in response to a specific stressor (doctors visits) and the Pediatric Quality of Life Inventory Neuromuscular Module.

Results: 'Wishful thinking' (75%, 36/48) and 'cognitive restructuring' (71%, 34/48) were the most frequently used coping strategies. 'Self-criticism' (12%, 6/48), and 'blaming others' and 'resignation' (both 19%, 9/48) were the least used strategies. Coping strategy use did not differ across age and sex groups (p's from 0.08 to 1.00). Positive coping strategies tended to be more effective (medians ranged from 2.00 to 2.75) than negative strategies (medians ranged from 1.38 to 2.50). Using a greater number of different types of positive (F(4, 46) = 5.79, p = 0.001) and/or negative (F(4, 44) = 5.64, p 0.001) coping strategies was linked to poorer health-related quality of life.

Conclusion: We conclude that children with genetic muscle disorders use a wide range of positive and/or negative coping strategies in response to stressors associated with a doctor visit and may benefit from greater support to improve health-related quality of life. Findings support the value of routine screening of children's coping to identify those who would benefit from support.
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http://dx.doi.org/10.3233/JND-200564DOI Listing
January 2021

Strategies for identifying pollution sources in a headwater catchment based on multi-scale water quality monitoring.

Environ Monit Assess 2021 Mar 8;193(4):169. Epub 2021 Mar 8.

Soils Department, Universidade Federal de Santa Maria, Av. Roraima 1000, Santa Maria, RS, 97105-900, Brazil.

Rural headwater catchments are important to describe the connectivity of pollution sources to water bodies. Strategies to optimize water quality monitoring networks, as parameter definition, sampling, and statistical approach, have been widely discussed. The objectives of this study were to describe the spatial and temporal dynamics (intra- and inter-events) of water quality and to establish its implications for environmental monitoring programs. The monitoring was carried out in a rural headwater catchment (1.2 km) with shallow soils, high slopes, and intense agricultural activity in Southern Brazil. To better describe the impact of agriculture on water resources, the monitoring strategy was based on definition of the best set of parameters and different sampling frequency to incorporate intra- and inter-event variability and statistical analysis approach. We also analyzed parameters in different sub-basins with physiographic traits. Three hydrological compartments were analyzed: surface flow, groundwater, and base flow. Physico-chemical parameters, the concentration of elements associated with agricultural activity, and biological parameters were evaluated. Total phosphorus and turbidity were the parameters most affected by agricultural activity. They reflected on the inter- and intra-events, the impacts of soil and water degradation by agricultural activity, and the precarious rural sanitation conditions. Spatiotemporal variability of the parameters characterizes the different mechanisms for transferring pollutants from diffuse sources to water bodies. Spatial and temporal patterns in water quality changes were used to discuss environmental monitoring strategies, such as parameter and sampling frequency definition, to improve soil and water conservation programs at the catchment scale.
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http://dx.doi.org/10.1007/s10661-021-08930-5DOI Listing
March 2021

Heterogeneity of nerve ultrasound findings in mitochondrial disorders.

Clin Neurophysiol 2021 02 31;132(2):507-509. Epub 2020 Dec 31.

Department of Neurology and Clinical Neurophysiology, Bay of Plenty District Health Board, Tauranga, New Zealand. Electronic address:

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http://dx.doi.org/10.1016/j.clinph.2020.12.010DOI Listing
February 2021

A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.

Brain 2020 10;143(10):2904-2910

Neurogenetic Diseases Group, Centre for Medical Research, QEII Medical Centre, University of Western Australia, Nedlands, WA 6009, Australia.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.
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http://dx.doi.org/10.1093/brain/awaa263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780484PMC
October 2020

A Māori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.

Brain 2020 09;143(9):2673-2680

Neurology Department, Auckland City Hospital, Auckland, New Zealand.

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative disease with onset in mid- to late adulthood. The genetic basis for a large proportion of Caucasian patients was recently shown to be the biallelic expansion of a pentanucleotide (AAGGG)n repeat in RFC1. Here, we describe the first instance of CANVAS genetic testing in New Zealand Māori and Cook Island Māori individuals. We show a novel, possibly population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp, which was the cause of CANVAS in all patients. There were no apparent phenotypic differences compared with European CANVAS patients. Presence of a common disease haplotype among this cohort suggests this novel repeat expansion configuration is a founder effect in this population, which may indicate that CANVAS will be especially prevalent in this group. Haplotype dating estimated the most recent common ancestor at ∼1430 ce. We also show the same core haplotype as previously described, supporting a single origin of the CANVAS mutation.
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http://dx.doi.org/10.1093/brain/awaa203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526724PMC
September 2020

Correction to: Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease.

Orphanet J Rare Dis 2019 Aug 15;14(1):199. Epub 2019 Aug 15.

Neurology, Auckland City Hospital, Private Bag 92024, Auckland, 1142, New Zealand.

The original version of this article [1] unfortunately included an error to an author's name. Author Jordi Díaz-Manera was erroneously presented as Jorge Alberto Diaz Manera. The correct author name has been included in the author list of this Correction article.
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http://dx.doi.org/10.1186/s13023-019-1157-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696685PMC
August 2019

Family communication following a diagnosis of myotonic dystrophy: To tell or not to tell?

J Genet Couns 2019 10 5;28(5):1029-1041. Epub 2019 Aug 5.

University of Technology Sydney, Sydney, Australia.

Family communication about genetic information enables informed medical and reproductive decision-making. The literature suggests that a significant proportion of genetically at-risk family members remain uninformed about genetic risk information as a result of non-disclosure. This study explored the experiences of New Zealand families communicating about a diagnosis of type 1 myotonic dystrophy (DM1). Eligible individuals were identified and recruited from the New Zealand (NZ) MD Prev study, a nationwide study which aimed to determine the prevalence, impact, and costs of genetic muscle disorders across the lifespan. Twelve qualitative semi-structured interviews were conducted with 17 participants. The findings demonstrate diversity among and within families, with several distinct family narratives described. Most participants reported a motivation to tell relatives about their diagnosis to promote autonomy. Women were pivotal throughout communication processes and this was often tied to the concept of maternal responsibility and a desire to promote relatives' reproductive autonomy. The diagnosis of DM1 and the subsequent family communication decisions altered relationships for many, with both positive and negative impacts described. The findings demonstrate that individuals require time to explore the impact of a diagnosis of DM1 on self, family and intimate partner relationships to anticipate unique communication challenges. Genetic counselors can use these findings to inform their approach to counseling families with DM1. Longitudinal genetic counseling may be beneficial as a way to provide individuals with life stage specific support as they communicate with their relatives about a diagnosis of DM1.
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http://dx.doi.org/10.1002/jgc4.1156DOI Listing
October 2019

Spinocerebellar ataxia type 2-neuronopathy or neuropathy?

Muscle Nerve 2019 09 5;60(3):271-278. Epub 2019 Jul 5.

Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II, Naples, Italy.

Introduction: Use of peripheral nerve ultrasound alongside standard electrodiagnostic tests may help to gain insight into the pathophysiology of peripheral nerve involvement in type 2 spinocerebellar ataxia (SCA2).

Methods: Twenty-seven patients with SCA2 underwent ultrasound cross-sectional area (CSA) measurement of median, ulnar, sural and tibial nerves, and motor (median, ulnar, tibial) and sensory (median, ulnar, radial, sural) nerve conduction studies.

Results: Twenty patients had pathologically small-nerve CSAs, suggestive of sensory neuronopathy. In these patients, electrophysiology showed non-length-dependent sensory neuropathy (14 of 20), "possible sensory neuropathy" (1 of 20), or normal findings (5 of 20). Four different patients had length-dependent sensory neuropathy on electrophysiology, and 1 had enlarged nerve CSAs. Regression analysis showed an inverse relationship between ataxia scores and upper limb nerve CSA (P < 0.03).

Discussion: Our findings suggest that a majority of patients with SCA2 (74%) have a sensory neuronopathy and this correlates with disability. A minority of patients have findings consistent with axonal neuropathy (18%). Muscle Nerve, 2019.
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http://dx.doi.org/10.1002/mus.26613DOI Listing
September 2019

Prevalence of Charcot-Marie-Tooth disease across the lifespan: a population-based epidemiological study.

BMJ Open 2019 06 14;9(6):e029240. Epub 2019 Jun 14.

Auckland City Hospital, Auckland, New Zealand.

Objectives: This population-based study aimed to determine age-standardised prevalence of Charcot-Marie-Tooth disease (CMT) across the lifespan using multiple case ascertainment sources.

Design: Point-prevalence epidemiological study in the Auckland Region of New Zealand (NZ).

Setting: Multiple case ascertainment sources including primary care centres, hospital services, neuromuscular disease registry, community-based organisations and self-referral were used to identify potentially eligible participants.

Participants: Adults (≥16 years, n=207, 87.7%) and children (<16 years, n=29, 12.3%) with a confirmed clinical or molecular diagnosis of CMT, hereditary sensory neuropathy, hereditary motor neuropathy or hereditary neuropathy with liability to pressure palsies who resided in the Auckland Region of NZ on 1 June 2016.

Primary Outcome: Prevalence per 100 000 persons with 95% CIs by subtype, age and sex were calculated and standardised to the world population.

Results: Age-standardised point prevalence of all CMT cases was 15.7 per 100 000 (95% CI 11.6 to 21.0). Highest prevalence was identified in those aged 50-64 years 25.2 per 100 000 (95% CI 19.4 to 32.6). Males had a higher prevalence (16.6 per 100 000, 95% CI 10.9 to 25.2) than females (14.6 per 100 000, 95% CI 9.6 to 22.4). Prevalence of CMT1A was 6.9 per 100 000 (95% CI 5.6 to 8.4). The majority (93.2%) of cases were identified through medical records, with 6.8% of cases uniquely identified through community sources.

Conclusions: A small but significant proportion of people with CMT are not connected to healthcare services. Epidemiological studies using medical records alone to identify cases may risk underestimating prevalence. Further studies using population-based methods and reporting age-standardised prevalence are needed to improve global understanding of the epidemiology of CMT.
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http://dx.doi.org/10.1136/bmjopen-2019-029240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585838PMC
June 2019

A Nationwide, Population-Based Prevalence Study of Genetic Muscle Disorders.

Neuroepidemiology 2019 18;52(3-4):128-135. Epub 2019 Jan 18.

Department of Neurology, Auckland City Hospital, Auckland, New Zealand.

Background: Previous epidemiological studies of genetic muscle disorders have relied on medical records to identify cases and may be at risk of selection biases or have focused on selective population groups.

Objectives: This study aimed to determine age-standardised prevalence of genetic muscle disorders through a nationwide, epidemiological study across the lifespan using the capture-recapture method.

Methods: Adults and children with a confirmed clinical or molecular diagnosis of a genetic muscle disorder, resident in New Zealand on April 1, 2015 were identified using multiple overlapping sources. Genetic muscle disorders included the muscular dystrophies, congenital myopathies, ion channel myopathies, GNE myopathy, and Pompe disease. Prevalence per 100,000 persons by age, sex, disorder, ethnicity and geographical region with 95% CIs was calculated using Poisson distribution. Direct standardisation was applied to age-standardise prevalence to the world population. Completeness of case ascertainment was determined using capture-recapture modelling.

Results: Age standardised minimal point prevalence of all genetic muscle disorders was 22.3 per 100,000 (95% CI 19.5-25.6). Prevalence in Europeans of 24.4 per 100,000, (95% CI 21.1-28.3) was twice that observed in NZ's other 3 main ethnic groups; Māori (12.6 per 100,000, 95% CI 7.8-20.5), Pasifika (11.0 per 100,000, 95% CI 5.4-23.3), and Asian (9.13 per 100,000, 95% CI 5.0-17.8). Crude prevalence of myotonic dystrophy was 3 times higher in Europeans (10.5 per 100,000, 9.4-11.8) than Māori and Pasifika (2.5 per 100,000, 95% CI 1.5-4.2 and 0.7 per 100,000, 95% CI 0.1-2.7 respectively). There were considerable regional variations in prevalence, although there was no significant association with social deprivation. The final capture-recapture model, with the least deviance, estimated the study ascertained 99.2% of diagnosed cases.

Conclusions: Ethnic and regional differences in the prevalence of genetic muscle disorders need to be considered in service delivery planning, evaluation, and decision making.
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http://dx.doi.org/10.1159/000494115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518995PMC
December 2019

Whole-body vibration on leg muscles thermography and femoral resistive index of in adult healthy dogs.

Res Vet Sci 2019 Feb 12;122:118-123. Epub 2018 Nov 12.

School of Veterinary Medicine and Animal Science, University Estadual Paulista, Prof. Doutor Walter Mauricio Correa street, s/n, Unesp Campus de Botucatu, 18618-681, Rubião Jr., Botucatu, São Paulo, Brazil.

This study aimed to assess the influence of WBV exercise on muscles by means of infrared thermography and on resistive index (RI) of the femoral artery. The hypothesis was that WBV exercise protocol will induce increase of the muscle activity detected through skin surface temperature change and decreased of RI with WBV exercise. Ten adult healthy medium dogs, were submitted to WBV session. Thermographic images were taken from regions of biceps femoris and vastus lateralis muscles. Triplex Doppler was used to assess RI of the femoral artery. Exams were performed before and immediately after WBV exercise sessions for five days, and RI of the femoral artery was evaluated 24 h after the last WBV session. There were no statistically significant differences between thermographic temperatures of regions of biceps femoris muscle and vastus lateralis muscle before and immediately after the WBV sessions. Significant differences were observed between the mean RI values before WBV sessions between day 1 and day 3, day 3 and day 5, and before and immediately after session on day 3; between before and immediately after session on day 2, day 3, day 4 and day 5; between before session between day 2 and day 6, day 3 and day 6, day 5 and day 6; and before and immediately after session on day 5. The WBV exercises during five uninterrupted days in adult healthy dogs do not alter significantly the skin temperatures over regions of biceps femoris and vastus lateralis muscles, and increase the femoral RI.
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http://dx.doi.org/10.1016/j.rvsc.2018.11.003DOI Listing
February 2019

Establishment and 12-month progress of the New Zealand Motor Neurone Disease Registry.

J Clin Neurosci 2019 Feb 22;60:7-11. Epub 2018 Nov 22.

Department of Neurology, Auckland City Hospital, Private Bag 92024, Auckland 1142, New Zealand; Centre for Brain Research, Neurogenetics Research Clinic, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1023, New Zealand.

There are only limited treatments currently available for Motor Neurone Disease, each with modest benefits. However, there is a large amount of research and drug discovery currently underway worldwide. The New Zealand Motor Neurone Disease Registry was established in 2017 to facilitate participation in research and clinical trials, and to aid researchers in planning and recruitment. The NZ MND Registry is an opt in patient registry which collects demographic, contact and clinical data for those who choose to enrol. We report anonymised aggregated data from the first year's enrolment. 12th July 2018, there were 142 participants enrolled in the NZ MND Registry. Participant sex distribution reflects the demographics reported worldwide, but ethnicity is divergent from what is seen in New Zealand overall, with an over-representation of people who identify as New Zealand European. 85.5% of participants are diagnosed with sporadic MND and 6.1% with familial MND. The remainder were participants who have not been diagnosed but have a family history, or positive genetic test for a MND-causing mutation. Levels of disability are reported using ALSFRS-R scores, and show that the majority of participants are within the higher range of the scale. The registry has facilitated entry of patients into three studies to date. The establishment of the NZ MND Registry illustrates a swift launch of a rare disease patient registry. The role of patient registries is an ever changing one, but with clear utility at every point of along the pathway to drug discovery.
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http://dx.doi.org/10.1016/j.jocn.2018.11.034DOI Listing
February 2019

Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease.

Orphanet J Rare Dis 2018 09 5;13(1):155. Epub 2018 Sep 5.

Neurology, Auckland City Hospital, Private Bag 92024, Auckland, 1142, New Zealand.

Background: Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania).

Results: The registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact.

Conclusions: The community should consider how to maximise this collective resource in future therapeutic programmes.
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http://dx.doi.org/10.1186/s13023-018-0889-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126043PMC
September 2018

Impacts for Children Living with Genetic Muscle Disorders and their Parents - Findings from a Population-Based Study.

J Neuromuscul Dis 2018;5(3):341-352

National Institute for Stroke and Applied Neurosciences, School of Public Health and Psychosocial Studies, Faculty of Health and Environmental Studies, Auckland University of Technology, Auckland, New Zealand.

Background: Genetic muscle disorders, including muscular dystrophies, congenital myopathies, and ion channel muscle diseases can be associated with significant disability.

Objective: This study aimed to explore child and parent perspectives of the impact of living with a genetic muscle disorder.

Methods: Eighty-three children (<16 years) with a clinical or molecular diagnosis were identified as part of a national prevalence study. Parents' experiences and needs were assessed using a study-specific questionnaire. Additional outcome measures included parent and child self-report versions of the Behavior Assessment System for Children and the Pediatric Quality of Life Inventory. Parents also completed the Hospital Anxiety and Depression Scale and Activlim.

Results: Sixty-four percent of families had a combined annual household income below $60,000 NZD ($43,650 USD), being less than the national median income of $73,000 NZD ($53,112 USD). Parents reported needing more support than they were currently receiving (40%), particularly with household chores (23%) and transportation (17%). Few parents (13%) or children (4%) reported significant child behavioral difficulties. Risks of impaired quality of life were high (parent proxy 71%, child report 70%), and associated with co-morbid health conditions (p = 0.008), functional status (p = 0.001), wheelchair use (p = 0.001) and mechanical ventilation (p = 0.01).

Conclusions: Findings are relevant to those involved in the care and support of children, and their families, who are impacted by genetic muscle disorders. Targeted guidelines are required to inform the provision of services, alongside promotion of existing community services to improve access to financial support, and assistance with day-to-day functioning. Future research should examine intervention and treatment options aimed at maximising affected children's quality of life.
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http://dx.doi.org/10.3233/JND-170287DOI Listing
November 2018

Peripheral nerve ultrasound in Friedreich ataxia.

Muscle Nerve 2018 05 27;57(5):852-856. Epub 2017 Nov 27.

Department of Neurology, Auckland District Health Board, Auckland, New Zealand.

Introduction: Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionopathy. The degree of contribution from axonal pathology remains a matter of debate. Nerve ultrasound may be able to differentiate these processes.

Methods: The ultrasound cross-sectional area of median, ulnar, tibial, and sural nerves of 8 patients with FRDA was compared with 8 age- and gender-matched healthy controls and with reference values in our population.

Results: The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs.

Discussion: Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role. Muscle Nerve 57: 852-856, 2018.
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http://dx.doi.org/10.1002/mus.26012DOI Listing
May 2018

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database.

J Neuromuscul Dis 2017;4(4):293-306

Kanchi Kamakoti CHILDS Trust and Apollo Children's Hospitals, Chennai, India.

Background: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population.

Objective: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients.

Methods: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age.

Results: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions.

Conclusions: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field.
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http://dx.doi.org/10.3233/JND-170280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701764PMC
July 2019

Neuronopathy and neuropathy in autosomal dominant spino-cerebellar ataxia (SCA): A preliminary peripheral nerve ultrasound study.

Clin Neurophysiol 2017 12 12;128(12):2436-2437. Epub 2017 Oct 12.

Auckland District Health Board (ADHB), Auckland, New Zealand; School of Medicine, University of Auckland, New Zealand.

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http://dx.doi.org/10.1016/j.clinph.2017.09.114DOI Listing
December 2017

The New Zealand Neuromuscular Disease Patient Registry; Five Years and a Thousand Patients.

J Neuromuscul Dis 2017;4(3):183-188

Neurology, Auckland City Hospital, Auckland, New Zealand.

The New Zealand Neuromuscular Disease Patient Registry has been recruiting for five years. Its primary aim is to enable people with neuromuscular disease to participate in research including clinical trials. It has contributed data to large anonymised cohort studies and many feasibility studies, and has provided practical information and advice to researchers wanting to work with people with neuromuscular conditions. 1019 people have enrolled since the Registry's launch in August 2011 with over 70 different diagnoses. Of these; 8 patients have been involved in clinical trials, 134 in other disease-specific research and 757 have contributed anonymised data to cohort studies. As a result the Registry is now effectively facilitating almost all neuromuscular research currently taking place in New Zealand.
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http://dx.doi.org/10.3233/JND-170240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611797PMC
April 2018

A 'limb-girdle muscular dystrophy' responsive to asthma therapy.

Pract Neurol 2017 Aug 22;17(4):327-331. Epub 2017 Apr 22.

Department of Neurology, Auckland City Hospital, Auckland, New Zealand.

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http://dx.doi.org/10.1136/practneurol-2017-001598DOI Listing
August 2017

Knowledge of Sub-Types Important to Understanding of the Prevalence of Myotonic Dystrophy.

Neuroepidemiology 2016 15;46(3):228. Epub 2016 Mar 15.

National Institute for Stroke and Applied Neuroscience, Auckland University of Technology, Auckland, New Zealand.

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http://dx.doi.org/10.1159/000444469DOI Listing
August 2016

Load dissipation by corn residue on tilled soil in laboratory and field-wheeling conditions.

J Sci Food Agric 2016 Jun 24;96(8):2705-14. Epub 2015 Sep 24.

Fronteira Sul Federal University (Universidade Federal da Fronteira Sul - UFFS), Chapecó, SC, Brazil.

Crop residues may partially dissipate applied loads and reduce soil compaction. We evaluated the effect of corn residue on energy-applied dissipation during wheeling. The experiment consisted of a preliminary laboratory test and a confirmatory field test on a Paleaudalf soil. In the laboratory, an adapted Proctor test was performed with three energy levels, with and without corn residue. Field treatments consisted of three 5.1 Mg tractor wheeling intensities (0, 2, and 6), with and without 12 Mg ha(-1) corn residue on the soil surface. Corn residue on the soil surface reduced soil bulk density in the adapted Proctor test. By applying energy of 52.6 kN m m(-3) , soil dissipated 2.98% of applied energy, whereas with 175.4 kN m m(-3) a dissipation of 8.60% was obtained. This result confirms the hypothesis that surface mulch absorbs part of the compaction effort. Residue effects on soil compaction observed in the adapted Proctor test was not replicated under subsoiled soil field conditions, because of differences in applied pressure and soil conditions (structure, moisture and volume confinement). Nevertheless, this negative result does not mean that straw has no effect in the field. Such effects should be measured via stress transmission and compared to soil load-bearing capacity, rather than on bulk deformations. Wheeling by heavy tractor on subsoiled soil increased compaction, independently of surface residue. Two wheelings produced a significantly increase, but six wheelings did not further increase compaction. Reduced traffic intensity on recently tilled soil is necessary to minimize soil compaction, since traffic intensity show a greater effect than surface mulch on soil protection from excessive compaction. © 2015 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.7389DOI Listing
June 2016

The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations.

Hum Mutat 2015 Apr 17;36(4):395-402. Epub 2015 Mar 17.

The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases Institute of Genetic Medicine, University of Newcastle, Central Parkway, Newcastle upon Tyne, UK.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).
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http://dx.doi.org/10.1002/humu.22758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405042PMC
April 2015

Prevalence of muscular dystrophies: a systematic literature review.

Neuroepidemiology 2014 16;43(3-4):259-68. Epub 2014 Dec 16.

National Institute for Stroke and Applied Neuroscience, Auckland University of Technology, Auckland, New Zealand.

Background: Determining the prevalence of neuromuscular disorders for the general population is important to identify the scope of burden on society and enable comparisons with other health conditions. This systematic review aims to identify and collate the findings of studies published between 1960 and 2013 on the prevalence of all types of muscular dystrophies.

Summary: Relevant articles were identified through electronic database searches and manual searches of reference lists. There were 38 articles from across 19 countries that met the inclusion criteria. The total combined prevalence for all muscular dystrophies for studies classified as having a low risk of bias ranged between 19.8 and 25.1 per 100,000 person-years. Myotonic dystrophy (0.5-18.1 per 100,000), Duchenne muscular dystrophy (1.7-4.2) and facioscapulohumeral muscular dystrophy (3.2-4.6 per 100,000) were found to be the most common types of disorder. There was wide variation in study methodology, case ascertainment, and verification procedures and populations studied, all of which may contribute to the wide prevalence range, in addition to the likely variation in prevalence by country. Key Messages: Greater consistency in the conduct and reporting of neuroepidemiological studies is urgently needed to enable comparisons to be made between studies, countries, and over time.
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http://dx.doi.org/10.1159/000369343DOI Listing
September 2015

The New Zealand Neuromuscular Disease Registry: rate of diagnoses confirmed by molecular testing.

J Clin Neurosci 2015 Feb 19;22(2):434-6. Epub 2014 Oct 19.

Neurology Department, Auckland City Hospital, Private Bag 92024, Auckland 1142, New Zealand; Centre for Brain Research, University of Auckland, Auckland, New Zealand.

The New Zealand Neuromuscular Disease Registry (NZ NMD Registry) is part of the TREAT NMD Alliance, an international network that provides infrastructure ensuring the most promising new therapies reach neuromuscular patients as quickly as possible. Its main aim is to ensure that the most promising new therapies reach patients as quickly as possible. From the perspective of researchers interested in trialling treatments it is useful to have data on the pool of potential research participants. From a patient's perspective it is important to know what trials they can take part in. Both of these require a confirmed molecular diagnosis in the patient. Some therapeutic strategies not only require knowledge of which gene is affected but are targeted at specific mutations within the gene. In reviewing data held in the NZ NMD Registry it was noted that, of those diagnosed with a genetic condition, only 51% have a confirmed molecular genetic diagnosis. This low rate of genetic diagnosis is a potential barrier to research participation but can be removed with improved genetic technology and with changes in knowledge about and attitudes towards genetic testing.
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http://dx.doi.org/10.1016/j.jocn.2014.06.096DOI Listing
February 2015

Mapping the differences in care for 5,000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe.

J Neurol 2014 Jan 27;261(1):152-63. Epub 2013 Oct 27.

MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK,

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning.
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http://dx.doi.org/10.1007/s00415-013-7154-1DOI Listing
January 2014

The TREAT-NMD Duchenne muscular dystrophy registries: conception, design, and utilization by industry and academia.

Hum Mutat 2013 Nov 26;34(11):1449-57. Epub 2013 Aug 26.

MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine, Newcastle upon Tyne, UK.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.
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http://dx.doi.org/10.1002/humu.22390DOI Listing
November 2013

The New Zealand Neuromuscular Disease Registry.

J Clin Neurosci 2012 Dec 19;19(12):1749-50. Epub 2012 Sep 19.

Neurology Department, Auckland City Hospital, Auckland Mail Centre, Auckland, New Zealand.

The development of effective treatments for neuromuscular diseases is a significant challenge due to difficulties in identifying adequate numbers of patients for clinical trials. Low patient numbers in these rare diseases also has an effect when establishing sound clinical practices based on experience gained from patients with similar diagnosis. The Muscular Dystrophy Association of New Zealand (MDA), working in consort with interested clinicians has established the New Zealand Neuromuscular Disease (NZ NMD) Registry in order to help address these problems. The NZ NMD Registry is exceptional in that it comprises one registry for all neuromuscular conditions and will significantly benefit both patients with neuromuscular disease and their clinicians.
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http://dx.doi.org/10.1016/j.jocn.2012.04.008DOI Listing
December 2012

Blastic CD4 NK cell leukemia/lymphoma: a distinct clinical entity.

Leuk Res 2002 Sep;26(9):803-7

Department of Clinical Medicine, School of Medicine Ribeirão Preto-USP, Ribeirão Preto, SP, Brazil.

We report the findings of three new cases of a distinct clinicopathologic natural killer (NK) cell malignancy characterized by cutaneous, nodal and bone marrow infiltration by CD3-CD4+CD56+ NK blastic cells. Tumor cells were detected in bone marrow and in peripheral blood smears and showed finely distributed nuclear chromatin with nucleoli and a moderate amount of cytoplasm. Epstein-Barr virus (EBV) DNA was negative in the two tested cases. The immunophenotypes determined by flow cytometry were identical concerning mCD3-cytCD3-CD4+weakCD56+ HLA-DR+. The TCR was in germline configuration in the two cases tested. NK cell activity was demonstrated only in one out of the two cases tested. The negative reactions with alpha-naphthyl-acetate-esterase (ANAE), CD11b and CD14 strongly suggested that the tumor cells were not of the monocytic lineage.
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http://dx.doi.org/10.1016/s0145-2126(02)00014-0DOI Listing
September 2002
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