Sensory impairment secondary to dorsal root ganglion neuronopathy is common, although often subcl... more Sensory impairment secondary to dorsal root ganglion neuronopathy is common, although often subclinical, in X‐linked spinal and bulbar muscular atrophy (SBMA).
Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as ... more 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). 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. 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. 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.
To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, a... more To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, and symptom factors influencing quality of life. 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. 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. 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.
Introduction TREAT-NMD is a neuromuscular network that aims to ensure that the most promising new... more Introduction TREAT-NMD is a neuromuscular network that aims to ensure that the most promising new therapies reach patients as quickly as possible. The TREAT-NMD Global Network of Spinal Muscular Atrophy (SMA) Registries include 50 national registries that collect a common core dataset and are governed by the TREAT-NMD Global Database Oversight Committee (TGDOC). Researchers and industry can request anonymised and aggregate data, offering a single point of access to this extensive dataset. Results The core dataset was established 10 years ago when the main purpose of the registries was clinical trial readiness and recruitment. In the current SMA landscape, with emerging treatments and new therapeutic approaches in development, there is a need for more widespread longitudinal data collection to support future research and post marketing surveillance (PMS) requirements for emerging therapies. To support this, TREAT-NMD are reviewing and expanding the core dataset for their SMA Registri...
Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recen... more 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 cor...
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-on... more 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.
ObjectivesThis population-based study aimed to determine age-standardised prevalence of Charcot-M... more ObjectivesThis population-based study aimed to determine age-standardised prevalence of Charcot-Marie-Tooth disease (CMT) across the lifespan using multiple case ascertainment sources.DesignPoint-prevalence epidemiological study in the Auckland Region of New Zealand (NZ).SettingMultiple 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.ParticipantsAdults (≥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 outcomePrevalence per 100 000 persons with 95% CIs by subtype, age and sex were calculated and standardised to the world population.ResultsAge-standardised point prevale...
Background: Previous epidemiological studies of genetic muscle disorders have relied on medical r... more 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...
Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionop... more 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.
Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimate... more 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). 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 ...
Genetic muscle disorders, including muscular dystrophies, congenital myopathies, and ion channel ... more Genetic muscle disorders, including muscular dystrophies, congenital myopathies, and ion channel muscle diseases can be associated with significant disability. This study aimed to explore child and parent perspectives of the impact of living with a genetic muscle disorder. 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. 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%), pa...
Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicat... more 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. To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. 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. 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 cardiop...
Sensory impairment secondary to dorsal root ganglion neuronopathy is common, although often subcl... more Sensory impairment secondary to dorsal root ganglion neuronopathy is common, although often subclinical, in X‐linked spinal and bulbar muscular atrophy (SBMA).
Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as ... more 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). 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. 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. 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.
To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, a... more To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, and symptom factors influencing quality of life. 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. 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. 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.
Introduction TREAT-NMD is a neuromuscular network that aims to ensure that the most promising new... more Introduction TREAT-NMD is a neuromuscular network that aims to ensure that the most promising new therapies reach patients as quickly as possible. The TREAT-NMD Global Network of Spinal Muscular Atrophy (SMA) Registries include 50 national registries that collect a common core dataset and are governed by the TREAT-NMD Global Database Oversight Committee (TGDOC). Researchers and industry can request anonymised and aggregate data, offering a single point of access to this extensive dataset. Results The core dataset was established 10 years ago when the main purpose of the registries was clinical trial readiness and recruitment. In the current SMA landscape, with emerging treatments and new therapeutic approaches in development, there is a need for more widespread longitudinal data collection to support future research and post marketing surveillance (PMS) requirements for emerging therapies. To support this, TREAT-NMD are reviewing and expanding the core dataset for their SMA Registri...
Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recen... more 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 cor...
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-on... more 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.
ObjectivesThis population-based study aimed to determine age-standardised prevalence of Charcot-M... more ObjectivesThis population-based study aimed to determine age-standardised prevalence of Charcot-Marie-Tooth disease (CMT) across the lifespan using multiple case ascertainment sources.DesignPoint-prevalence epidemiological study in the Auckland Region of New Zealand (NZ).SettingMultiple 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.ParticipantsAdults (≥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 outcomePrevalence per 100 000 persons with 95% CIs by subtype, age and sex were calculated and standardised to the world population.ResultsAge-standardised point prevale...
Background: Previous epidemiological studies of genetic muscle disorders have relied on medical r... more 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...
Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionop... more 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.
Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimate... more 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). 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 ...
Genetic muscle disorders, including muscular dystrophies, congenital myopathies, and ion channel ... more Genetic muscle disorders, including muscular dystrophies, congenital myopathies, and ion channel muscle diseases can be associated with significant disability. This study aimed to explore child and parent perspectives of the impact of living with a genetic muscle disorder. 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. 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%), pa...
Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicat... more 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. To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. 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. 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 cardiop...
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