19 results on '"Arlene D’Silva"'
Search Results
2. The Carrier Frequency of Two SMN1 Genes in Parents of Symptomatic Children with SMA and the Significance of SMN1 Exon 8 in Carriers
- Author
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Joanne E Davidson, Jacqueline S Russell, Noelia Nunez Martinez, David R Mowat, Kristi J Jones, Edwin P Kirk, Didu Kariyawasam, Michelle Farrar, and Arlene D’Silva
- Subjects
spinal muscular atrophy ,carrier frequency ,silent carrier ,reproductive carrier screening ,Genetics ,QH426-470 - Abstract
Background: Current carrier screening methods do not identify a proportion of carriers that may have children affected by spinal muscular atrophy (SMA). Additional genetic data is essential to inform accurate risk assessment and genetic counselling of SMA carriers. This study aims to quantify the various genotypes among parents of children with SMA. Method: A retrospective cohort study was undertaken at Sydney Children’s Hospital Network, the major SMA referral centre for New South Wales, Australia. Participants included children with genetically confirmed SMA born between 2005 and 2021. Data was collected on parent genotype inclusive of copy number of SMN1 exons 7 and 8. The number of SMN2 exon 7 copies were recorded for the affected children. Descriptive statistics were used to determine the proportion of carriers of 2+0 genotype classified as silent carriers. Chi-square test was used to correlate the association between parents with a heterozygous SMN1 exon 7 deletion and two copies of exon 8 and ≥3 SMN2 copy number in the proband. Results: SMA carrier testing was performed in 118/154 (76.6%) parents, incorporating 59 probands with homozygous SMN1 deletions and one proband with compound heterozygote pathogenic variants. Among parents with a child with SMA, 7.6% had two copies of SMN1 exon 7. When only probands with a homozygous SMN1 exon 7 deletion were included, 6.9% of parents had two copies of SMN1 exon 7. An association was observed between heterozygous deletion of SMN1 exon 7 with two copies of exon 8 in a parent and ≥3 SMN2 copy number in the affected proband (p = 0.07). Conclusions: This study confirmed a small but substantial proportion of silent carriers not identified by conventional screening within an Australian context. Accordingly, the effectiveness of carrier screening for SMA is linked with genetic counselling to enable health literacy regarding high and low risk results and is complemented by new-born screening and maintaining clinical awareness for SMA. Gene conversion events may underpin the associations between parent carrier status and proband SMN2 copy number.
- Published
- 2023
- Full Text
- View/download PDF
3. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review
- Author
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Hamish W. Y. Wan, Kate A. Carey, Arlene D’Silva, Steve Vucic, Matthew C. Kiernan, Nadine A. Kasparian, and Michelle A. Farrar
- Subjects
Spinal muscular atrophy ,Adult ,Healthcare ,Mental health ,Natural history ,Medicine - Abstract
Abstract Background Spinal muscular atrophy (SMA) is a neurodegenerative disease that has a substantial and multifaceted burden on affected adults. While advances in supportive care and therapies are rapidly reshaping the therapeutic environment, these efforts have largely centered on pediatric populations. Understanding the natural history, care pathways, and patient-reported outcomes associated with SMA in adulthood is critical to advancing health policy, practice and research across the disease spectrum. The aim of this study was to systematically review research investigating the healthcare, well-being and lived experiences of adults with SMA. Methods In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analysis guidelines, seven electronic databases were systematically searched until January 2020 for studies examining clinical (physical health, natural history, treatment) and patient-reported (symptoms, physical function, mental health, quality of life, lived experiences) outcomes in adults with SMA. Study risk of bias and the level of evidence were assessed using validated tools. Results Ninety-five articles met eligibility criteria with clinical and methodological diversity observed across studies. A heterogeneous clinical spectrum with variability in natural history was evident in adults, yet slow declines in motor function were reported when observational periods extended beyond 2 years. There remains no high quality evidence of an efficacious drug treatment for adults. Limitations in mobility and daily activities associated with deteriorating physical health were commonly reported, alongside emotional difficulties, fatigue and a perceived lack of societal support, however there was no evidence regarding effective interventions. Conclusions This systematic review identifies the many uncertainties regarding best clinical practice, treatment response, and long-term outcomes for adults with SMA. This comprehensive identification of the current gaps in knowledge is essential to guide future clinical research, best practice care, and advance health policy with the ultimate aim of reducing the burden associated with adult SMA.
- Published
- 2020
- Full Text
- View/download PDF
4. 'Getting ready for the adult world': how adults with spinal muscular atrophy perceive and experience healthcare, transition and well-being
- Author
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Hamish W. Y. Wan, Kate A. Carey, Arlene D’Silva, Nadine A. Kasparian, and Michelle A. Farrar
- Subjects
Spinal muscular atrophy ,Patient-centered care ,Family-centered care ,Health services ,Lived experience ,Quality of life ,Medicine - Abstract
Abstract Background Spinal muscular atrophy (SMA) has profound implications across a lifetime for people with the condition and their families. Those affected need long-term multidisciplinary medical and supportive care to maintain functional mobility, independence and quality of life. Little is known about how adults with SMA experience healthcare, or the components of care perceived as important in promoting well-being. The purpose of this study was to use qualitative research methodology to explore the lived experiences of healthcare and wellbeing of adults with SMA. Purposive sampling was used to recruit adolescents and adults with SMA, their parents and partners. Face-to-face or telephone-based semi-structured interviews were recorded and analysed using inductive thematic analysis. Results Across a total of 25 interviews (19 people with SMA, 5 parents, 1 partner) many participants described disengagement from health services and major gaps in care throughout adulthood. Disengagement was attributed to the perceived low value of care, as well as pragmatic, financial and social barriers to navigating the complex healthcare system and accessing disability services. Adults with SMA valued healthcare services that set collaborative goals, and resources with a positive impact on their quality of life. Mental health care was highlighted as a major unmet need, particularly during times of fear and frustration in response to loss of function, social isolation, stigma, and questions of self-worth. Alongside this, participants reported resilience and pride in their coping approaches, particularly when supported by informal networks of family, friends and peers with SMA. Conclusions These findings provide insight into the lived experiences, values and perspectives of adults with SMA and their carers, revealing major, ongoing unmet healthcare needs, despite many realising meaningful and productive lives. Findings indicate the necessity of accessible, patient- and family-centered multidisciplinary care clinics that address currently unmet physical and mental health needs. Understanding the lived experiences of people with SMA, particularly during times of transition, is critical to advancing health policy, practice and research. Future studies are needed to quantify the prevalence, burden and impact of mental health needs whilst also exploring potential supportive and therapeutic strategies.
- Published
- 2019
- Full Text
- View/download PDF
5. Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy
- Author
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Didu S. T. Kariyawasam, Arlene D'Silva, Cindy Lin, Monique M. Ryan, and Michelle A. Farrar
- Subjects
biomarker ,spinal muscular atrophy ,motor unit number estimation ,compound muscle action potential ,SMN2 ,neurofilament ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Recent unprecedented advances in treatment for spinal muscular atrophy (SMA) enabled patients to access the first approved disease modifying therapy for the condition. There are however many uncertainties, regarding timing of treatment initiation, response to intervention, treatment effects and long-term outcomes, which are complicated by the evolving phenotypes seen in the post-treatment era for patients with SMA. Biomarkers of disease, with diagnostic, prognostic, predictive, and pharmacodynamic value are thus urgently required, to facilitate a wider understanding in this dynamic landscape. A spectrum of these candidate biomarkers, will be evaluated in this review, including genetic, epigenetic, proteomic, electrophysiological, and imaging measures. Of these, SMN2 appears to be the most significant modifier of phenotype to date, and its use in prognostication shows considerable clinical utility. Longitudinal studies in patients with SMA highlight an emerging role of circulatory markers such as neurofilament, in tracking disease progression and response to treatment. Furthermore, neurophysiological biomarkers such as CMAP and MUNE values show considerable promise in the real word setting, in following the dynamic response and output of the motor unit to therapeutic intervention. The specific value for these possible biomarkers across diagnosis, prognosis, prediction of treatment response, efficacy, and safety will be central to guide future patient-targeted treatments, the design of clinical trials, and understanding of the pathophysiological mechanisms of disease and intervention.
- Published
- 2019
- Full Text
- View/download PDF
6. Structural and functional characterization of capsid binding by anti-AAV9 monoclonal antibodies from infants after SMA gene therapy
- Author
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Grant J. Logan, Mario Mietzsch, Neeta Khandekar, Arlene D’Silva, Daniel Anderson, Mawj Mandwie, Jane Hsi, Austin R. Nelson, Paul Chipman, Jennifer Jackson, Peter Schofield, Daniel Christ, Christopher C. Goodnow, Joanne H. Reed, Michelle A. Farrar, Robert McKenna, and Ian E. Alexander
- Subjects
Pharmacology ,Drug Discovery ,Genetics ,Molecular Medicine ,Molecular Biology - Published
- 2023
7. Incidence of Duchenne muscular dystrophy in the modern era; an Australian study
- Author
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Didu Kariyawasam, Arlene D’Silva, David Mowat, Jacqui Russell, Hugo Sampaio, Kristi Jones, Peter Taylor, and Michelle Farrar
- Subjects
Male ,Muscular Dystrophy, Duchenne ,Cohort Studies ,Pregnancy ,Incidence ,Australia ,Genetics ,Humans ,Female ,Genetics (clinical) ,Retrospective Studies - Abstract
Duchenne muscular dystrophy (DMD), an X-linked recessive condition is maternally inherited in two-thirds of affected boys. It is important to establish carrier status of female relatives to restore reproductive confidence for non-carriers and facilitate reproductive options and cardiac surveillance for carriers. This study investigates disease incidence within an Australian model of cascade screening and evolving genetic diagnostic technologies. A retrospective population-based cohort study of all genetically and/or histopathologically confirmed males with DMD, born in New South Wales and the Australian Capital Territory was undertaken from 2002–2012. Cases were identified using state-wide molecular laboratory and clinical databases. The annual disease incidence and “theoretically” preventable cases were extrapolated over the study period. Proband genotype/phenotype, pedigree analysis, carrier-risk and extent of cascade screening were also determined. The cumulative incidence of disease was 19.7 per 100,000 male live births and 1 in 5076 live born males were diagnosed with DMD. Differences in disease incidence were not statistically different when compared between 2002–2007 and 2008–2012 (incidence rate ratio = 1.13, 95% CI 0.76–1.69, p = 0.52). The incidence rate ratio of theoretically preventable cases did not significantly change between 2002–2007 and 2008–2012 (incidence rate ratio = 2.07, 95% CI 0.58–9.21, p = 0.23). Current diagnostic and cascade screening models have limitations in their impact on disease incidence, due to a spectrum of logistical, patient and condition related factors. Innovative approaches to reduce DMD incidence may be better achieved by preconception or early pregnancy carrier screening, prenatal exome sequencing and newborn screening.
- Published
- 2022
8. Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen
- Author
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Michelle A. Farrar, Arlene D’Silva, James Howells, Didu S T Kariyawasam, Karen Herbert, Cindy S.-Y. Lin, Tejaswi Kandula, and Kate A. Carey
- Subjects
Physiology ,business.industry ,Neurodegeneration ,Oligonucleotides ,Action Potentials ,Motor nerve ,Spinal muscular atrophy ,SMA ,medicine.disease ,Spinal cord ,Axons ,Muscular Atrophy, Spinal ,medicine.anatomical_structure ,Rheobase ,nervous system ,Child, Preschool ,medicine ,Humans ,Nusinersen ,Axon ,Child ,business ,Neuroscience - Abstract
Spinal muscular atrophy (SMA) is associated with developmental disruption of motor axons in ventral roots of the spinal cord alongside motor axon degeneration. The pathogenesis of peripheral axonal change during development is pertinent to understand treatment response. Nerve excitability techniques, stimulating the median motor nerve at the wrist, were utilised to investigate axonal change during neurodevelopment in 24 children with SMA, compared with 71 age-matched controls. Longitudinal axonal response to nusinersen treatment in 18 children was also investigated. Significant differences in axonal development were noted in the youngest children with SMA, signified by reduced compound muscle action potential (CMAP) (P = 0.030), higher axonal threshold (P = 0.016), rheobase (minimal current amplitude of infinite duration, required to generate an action potential) (P = 0.012) and greater changes in depolarising and hyperpolarising threshold electrotonus. Subexcitability increased in all children with SMA, compared to controls. With treatment, nerve excitability changes were observed prominently in young children, with increases in CMAP, reduction in axonal threshold, fanning-in of threshold electrotonus, increase in resting current-threshold slope and reduction in subexcitability. Whilst motor axons continue to mature in SMA, developmental delays in passive and active membrane properties occur especially in early childhood. Concurrently, motor axons actively undergo degeneration. Nusinersen restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation. Our findings move the field forward in understanding the developmental aspect of childhood-onset motor neurone diseases and changes in axonal function associated with disease modification. KEY POINTS: Pathomechanisms in spinal muscular atrophy involve concurrent neurodevelopmental and neurodegenerative processes. The greatest delays in maturation of the passive and active properties of the peripheral motor axon are seen in early childhood. Nusinersen facilitates developmental recovery of the motor axon whilst also reducing neurodegeneration. Axonal dysfunction is reversed with SMN repletion particularly when intervention occurs early in development.
- Published
- 2021
9. Real-world respiratory and bulbar comorbidities of SMA type 1 children treated with nusinersen: 2-Year single centre Australian experience
- Author
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John Widger, Arlene D’Silva, Kerrie-Anne Chen, Dominic A. Fitzgerald, Arthur Teng, and Michelle A. Farrar
- Subjects
Male ,Pulmonary and Respiratory Medicine ,Pediatrics ,medicine.medical_specialty ,medicine.medical_treatment ,Oligonucleotides ,Comorbidity ,Spinal Muscular Atrophies of Childhood ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Respiratory morbidity ,medicine ,Humans ,Respiratory system ,Child ,business.industry ,Australia ,SMA ,Gastrostomy ,Observational Studies as Topic ,Single centre ,030228 respiratory system ,Pediatrics, Perinatology and Child Health ,Female ,Nusinersen ,Noninvasive ventilation ,business ,Cohort study - Abstract
To describe the respiratory and nutritional supportive care and hospitalisations required in the real-world scenario in children with SMA type 1 treated with nusinersen.Single-centre observational cohort study of children with SMA1 commencing nusinersen from November 2016 to September 2018. Motor, respiratory and nutritional clinical characteristics and management are described from initiation of nusinersen for a minimum of two years.Nine children (5 females, 4 males), median age 10.7 months (range 2.7-181.2) commenced treatment with nusinersen and outcomes were assessed over a total of 270.5 patient months and 209 hospital admissions. Supportive care in newly-diagnosed patients (n = 7) included gastrostomy insertion (n = 4) and commencement of noninvasive ventilation (n = 4) at an average of 8.3 and 4.5 months after diagnosis, respectively. The annualised hospitalisation rate was 9.3/patient/year, average length of stay (LOS) of 3.3 days (SD = 5.6). Children with two SMN2 copies required more gastrostomies (p 0.05) and had more frequent admissions (p 0.05). Number of total admissions halved from the first to the second year of treatment in all patients (p 0.005).Children with treated SMA1 experienced considerable respiratory and bulbar comorbidities, necessitating substantial respiratory and nutritional supportive care. Proactive respiratory and nutritional surveillance and management is essential in SMA1 patients treated with nusinersen.
- Published
- 2021
10. Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen
- Author
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Arlene D’Silva, Cindy S.-Y. Lin, Didu Sanduni Kariyawasam, Karen Herbert, Peter Geelan-Small, James Howells, and Michelle A. Farrar
- Subjects
0303 health sciences ,Abductor pollicis brevis muscle ,business.industry ,Spinal muscular atrophy ,medicine.disease ,SMA ,Median nerve ,Compound muscle action potential ,Motor unit ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Neuromuscular ,Anesthesia ,medicine ,Surgery ,Nusinersen ,Motor unit number estimation ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
ObjectivesTo elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique.MethodsMScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%–100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50).ResultsTwenty children (median age 99 months, range 4–193) were followed for a median of 13.8 (4–33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (pInterpretationNusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.
- Published
- 2020
11. WE-149. Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen
- Author
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Didu Kariyawasam, Arlene D'Silva, Michelle Farrar, and Cindy Shin-Yi Lin
- Subjects
Neurology ,Physiology (medical) ,Neurology (clinical) ,Sensory Systems - Published
- 2022
12. Integrating newborn screening for spinal muscular atrophy into health care systems: an Australian pilot programme
- Author
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Veronica Wiley, Arlene D’Silva, Didu S T Kariyawasam, Michelle A. Farrar, and Stephanie Best
- Subjects
Protocol (science) ,Pediatrics ,medicine.medical_specialty ,Newborn screening ,business.industry ,Australia ,Infant, Newborn ,Pilot Projects ,Spinal muscular atrophy ,medicine.disease ,SMA ,Predictive value ,Muscular Atrophy, Spinal ,Neonatal Screening ,Developmental Neuroscience ,Severe phenotype ,Pediatrics, Perinatology and Child Health ,Health care ,medicine ,Humans ,Pilot test ,Neurology (clinical) ,business ,Delivery of Health Care - Abstract
Aim This study dynamically designed, evaluated, and implemented the components of an Australian newborn bloodspot screening (NBS) pilot programme for spinal muscular atrophy (SMA). Method We used an implementation-effectiveness study design and continuous interdisciplinary review to measure SMA NBS test protocol performance, identify and overcome laboratory and clinical barriers to implementation, and describe progress during the 2-year pilot study. Results The NBS programme screened 252 081 newborn infants from 1st August 2018 to 31st January 2021. Using an NBS pilot test protocol, 21 infants were diagnostically confirmed with SMA. The NBS pilot test protocol had a sensitivity of 100%, specificity greater than 99.9%, false-positive rate less than 0.001%, a false-negative rate of 0%, and positive predictive value of 95.5%. A severe phenotype was predicted on the basis of two copies of SMN2 in 57.2% of newborn infants screening positive for SMA. Clinical signs consistent with SMA were evident in 6 out of 21 screen-positive newborn infants within the first 4 weeks of life. A multidisciplinary team establishing strong partnerships across clinical and laboratory staff was key to implementation. Interpretation This pilot programme suggests that NBS is essential for early identification of newborn infants at risk of SMA and can be effectively translated into clinical practice.
- Published
- 2021
13. 'We needed this': perspectives of parents and healthcare professionals involved in a pilot newborn screening program for spinal muscular atrophy
- Author
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Veronica Wiley, Arlene D’Silva, Claire E. Wakefield, Michelle A. Farrar, Janine Vetsch, and Didu S T Kariyawasam
- Subjects
lcsh:R5-920 ,Newborn screening ,medicine.medical_specialty ,Health professionals ,business.industry ,010102 general mathematics ,General Medicine ,Spinal muscular atrophy ,SMA ,medicine.disease ,Health outcomes ,01 natural sciences ,03 medical and health sciences ,Scholarship ,0302 clinical medicine ,Quality of life (healthcare) ,Family medicine ,medicine ,030212 general & internal medicine ,0101 mathematics ,Service improvement ,lcsh:Medicine (General) ,business ,Research Paper - Abstract
Background: Newborn screening (NBS) for spinal muscular atrophy (SMA) is a recognised model through which health outcomes can be improved. However, perspectives of parents and healthcare professionals (HCPs) involved in such programs are largely unknown. Methods: A pilot program for SMA ran from August 2018-July 2020. Using a mixed-methods convergent methodology, we used a self-administered questionnaire to understand parents’ perceptions and psychological impact of the program from diagnosis to treatment. We thematically analysed successes/challenges encountered by HCPs and recommendations for service improvement from both participant groups. Findings: 202,388 infants were screened for SMA and the perceptions of 44 parents and HCPs affected by a positive result in eighteen newborns was ascertained. Parents (n=29, 100%) were satisfied with NBS for SMA. Although screen-positive result was distressing for all parents, quality of life improved over time [CarerQoL-7D baseline median score 4 (SD=1.4) vs six-month median score 8 (SD=1.3), p
- Published
- 2021
14. Growth and nutrition in pediatric neuromuscular disorders
- Author
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Rachel Lindeback, Arlene D’Silva, Elle Chou, Michelle A. Farrar, Kristen A Neville, and Hugo Sampaio
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Weakness ,Future studies ,Adolescent ,Dietetics ,Gastrointestinal Diseases ,Psychological intervention ,Nutritional Status ,030209 endocrinology & metabolism ,Disease ,Growth ,Critical Care and Intensive Care Medicine ,Body Mass Index ,03 medical and health sciences ,0302 clinical medicine ,High energy diet ,Swallowing ,Medicine ,Humans ,Child ,030109 nutrition & dietetics ,Nutrition and Dietetics ,business.industry ,Body Weight ,Infant ,Neuromuscular Diseases ,Precision medicine ,Diet ,Muscular Dystrophy, Duchenne ,Cross-Sectional Studies ,Family medicine ,Child, Preschool ,Female ,Nutrition Therapy ,medicine.symptom ,business - Abstract
Little is currently known about the nutrition and growth outcomes in children with neuromuscular disorders (NMDs), and these are likely disease dependent. The aim of this study was to describe the range of nutritional issues in pediatric NMDs and identify similarities and differences in growth outcomes and nutritional needs in children with a variety of NMDs at different ages, with the goal of informing future services.In this cross-sectional study we collected data on growth, dietetic interventions and nutrition-related issues in 160 children who attended a multidisciplinary clinic in a tertiary children's hospital, from February to December 2019. Children with significant weakness affecting mobility before the age of 3 years were clinically grouped into 'early-onset NMDs'.Across our clinic, 42.5% children had a history of chronic gastrointestinal issues, and 34.4% received dietetic care on the day of clinical visit. Children with early-onset NMDs had significantly higher prevalence of swallowing issues, gastroesophageal reflux, and vomiting, as well as higher frequency of dietetic consultations, high energy diet, swallowing assessment and tube-feeding, compared to later-onset NMDs (p 0.05). In total, 49.2% children with NMDs had an abnormal weight, in which the prevalence of underweight (n = 24, 19.2%) was significantly higher compared to normal Australian children (8.2%) (p 0.05). In Duchenne muscular dystrophy, over 50% children were overweight/obese.Among children with NMDs, there were many disease-specific nutrition-related symptoms, growth issues, and dietetic practices that were tailored to individual needs. Future studies should focus on measuring the impact of specific dietetic practices on growth and nutritional outcomes, as well as developing a precision medicine approach tailored to the individual nutritional needs of children with NMDs.
- Published
- 2020
15. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review
- Author
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Michelle A. Farrar, Arlene D’Silva, Hamish W. Y. Wan, Kate A. Carey, Matthew C. Kiernan, Nadine A. Kasparian, and Steve Vucic
- Subjects
0301 basic medicine ,Gerontology ,Adult ,Activities of daily living ,Natural history ,lcsh:Medicine ,Review ,030105 genetics & heredity ,Muscular Atrophy, Spinal ,03 medical and health sciences ,0302 clinical medicine ,Quality of life (healthcare) ,Health care ,Medicine ,Humans ,Pharmacology (medical) ,Child ,Genetics (clinical) ,Health policy ,Fatigue ,business.industry ,lcsh:R ,Healthcare ,Neurodegenerative Diseases ,General Medicine ,Evidence-based medicine ,Spinal muscular atrophy ,SMA ,Mental health ,Systematic review ,Quality of Life ,business ,030217 neurology & neurosurgery - Abstract
Background Spinal muscular atrophy (SMA) is a neurodegenerative disease that has a substantial and multifaceted burden on affected adults. While advances in supportive care and therapies are rapidly reshaping the therapeutic environment, these efforts have largely centered on pediatric populations. Understanding the natural history, care pathways, and patient-reported outcomes associated with SMA in adulthood is critical to advancing health policy, practice and research across the disease spectrum. The aim of this study was to systematically review research investigating the healthcare, well-being and lived experiences of adults with SMA. Methods In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analysis guidelines, seven electronic databases were systematically searched until January 2020 for studies examining clinical (physical health, natural history, treatment) and patient-reported (symptoms, physical function, mental health, quality of life, lived experiences) outcomes in adults with SMA. Study risk of bias and the level of evidence were assessed using validated tools. Results Ninety-five articles met eligibility criteria with clinical and methodological diversity observed across studies. A heterogeneous clinical spectrum with variability in natural history was evident in adults, yet slow declines in motor function were reported when observational periods extended beyond 2 years. There remains no high quality evidence of an efficacious drug treatment for adults. Limitations in mobility and daily activities associated with deteriorating physical health were commonly reported, alongside emotional difficulties, fatigue and a perceived lack of societal support, however there was no evidence regarding effective interventions. Conclusions This systematic review identifies the many uncertainties regarding best clinical practice, treatment response, and long-term outcomes for adults with SMA. This comprehensive identification of the current gaps in knowledge is essential to guide future clinical research, best practice care, and advance health policy with the ultimate aim of reducing the burden associated with adult SMA.
- Published
- 2020
16. Personalized medicine for children with spinal muscular atrophy: Toward the holy grail
- Author
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Arlene D’Silva and Michelle A. Farrar
- Subjects
Motor Neurons ,Denervation ,Physiology ,business.industry ,Spinal muscular atrophy ,medicine.disease ,Bioinformatics ,Holy Grail ,Muscular Atrophy, Spinal ,Cellular and Molecular Neuroscience ,Physiology (medical) ,medicine ,Humans ,Biomarker (medicine) ,Neurology (clinical) ,Personalized medicine ,Precision Medicine ,Child ,business ,Transcription Factors - Published
- 2020
17. 7. Motor unit changes in children with spinal muscular atrophy treated with nusinersen
- Author
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Peter Geelan-Small, Karen Herbert, Didu Sanduni Kariyawasam, Cindy S.-Y. Lin, Arlene D’Silva, and Michelle A. Farrar
- Subjects
Motor unit ,Neurology ,business.industry ,Physiology (medical) ,medicine ,Nusinersen ,Neurology (clinical) ,Spinal muscular atrophy ,Anatomy ,medicine.disease ,business ,Sensory Systems - Published
- 2020
18. Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy
- Author
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Arlene D’Silva, Monique M. Ryan, Michelle A. Farrar, Didu S T Kariyawasam, and Cindy S.-Y. Lin
- Subjects
0301 basic medicine ,Response to intervention ,Review ,Disease ,neurofilament ,Bioinformatics ,lcsh:RC346-429 ,03 medical and health sciences ,motor unit number estimation ,0302 clinical medicine ,Intervention (counseling) ,medicine ,lcsh:Neurology. Diseases of the nervous system ,spinal muscular atrophy ,business.industry ,Spinal muscular atrophy ,medicine.disease ,SMA ,compound muscle action potential ,Clinical trial ,030104 developmental biology ,Neurology ,biomarker ,Biomarker (medicine) ,Neurology (clinical) ,Personalized medicine ,business ,030217 neurology & neurosurgery ,SMN2 - Abstract
Recent unprecedented advances in treatment for spinal muscular atrophy (SMA) enabled patients to access the first approved disease modifying therapy for the condition. There are however many uncertainties, regarding timing of treatment initiation, response to intervention, treatment effects and long-term outcomes, which are complicated by the evolving phenotypes seen in the post-treatment era for patients with SMA. Biomarkers of disease, with diagnostic, prognostic, predictive, and pharmacodynamic value are thus urgently required, to facilitate a wider understanding in this dynamic landscape. A spectrum of these candidate biomarkers, will be evaluated in this review, including genetic, epigenetic, proteomic, electrophysiological, and imaging measures. Of these, SMN2 appears to be the most significant modifier of phenotype to date, and its use in prognostication shows considerable clinical utility. Longitudinal studies in patients with SMA highlight an emerging role of circulatory markers such as neurofilament, in tracking disease progression and response to treatment. Furthermore, neurophysiological biomarkers such as CMAP and MUNE values show considerable promise in the real word setting, in following the dynamic response and output of the motor unit to therapeutic intervention. The specific value for these possible biomarkers across diagnosis, prognosis, prediction of treatment response, efficacy, and safety will be central to guide future patient-targeted treatments, the design of clinical trials, and understanding of the pathophysiological mechanisms of disease and intervention.
- Published
- 2019
19. 'Getting ready for the adult world': how adults with spinal muscular atrophy perceive and experience healthcare, transition and well-being
- Author
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Arlene D’Silva, Michelle A. Farrar, Kate A. Carey, Nadine A. Kasparian, and Hamish W. Y. Wan
- Subjects
Adult ,Quality of life ,0301 basic medicine ,Gerontology ,Transition to Adult Care ,Adolescent ,Patient-centered care ,Health Services for Persons with Disabilities ,lcsh:Medicine ,Lived experience ,030105 genetics & heredity ,Family centered care ,Life Change Events ,Muscular Atrophy, Spinal ,Complex care ,Young Adult ,03 medical and health sciences ,Family-centered care ,0302 clinical medicine ,Health care ,medicine ,Humans ,Pharmacology (medical) ,Disengagement theory ,Social isolation ,Genetics (clinical) ,Health policy ,Health Services Needs and Demand ,Disability ,business.industry ,Research ,lcsh:R ,General Medicine ,Spinal muscular atrophy ,Mental health ,Health services ,Patient Satisfaction ,Transition ,Well-being ,Perception ,Thematic analysis ,medicine.symptom ,business ,Psychology ,030217 neurology & neurosurgery - Abstract
Background Spinal muscular atrophy (SMA) has profound implications across a lifetime for people with the condition and their families. Those affected need long-term multidisciplinary medical and supportive care to maintain functional mobility, independence and quality of life. Little is known about how adults with SMA experience healthcare, or the components of care perceived as important in promoting well-being. The purpose of this study was to use qualitative research methodology to explore the lived experiences of healthcare and wellbeing of adults with SMA. Purposive sampling was used to recruit adolescents and adults with SMA, their parents and partners. Face-to-face or telephone-based semi-structured interviews were recorded and analysed using inductive thematic analysis. Results Across a total of 25 interviews (19 people with SMA, 5 parents, 1 partner) many participants described disengagement from health services and major gaps in care throughout adulthood. Disengagement was attributed to the perceived low value of care, as well as pragmatic, financial and social barriers to navigating the complex healthcare system and accessing disability services. Adults with SMA valued healthcare services that set collaborative goals, and resources with a positive impact on their quality of life. Mental health care was highlighted as a major unmet need, particularly during times of fear and frustration in response to loss of function, social isolation, stigma, and questions of self-worth. Alongside this, participants reported resilience and pride in their coping approaches, particularly when supported by informal networks of family, friends and peers with SMA. Conclusions These findings provide insight into the lived experiences, values and perspectives of adults with SMA and their carers, revealing major, ongoing unmet healthcare needs, despite many realising meaningful and productive lives. Findings indicate the necessity of accessible, patient- and family-centered multidisciplinary care clinics that address currently unmet physical and mental health needs. Understanding the lived experiences of people with SMA, particularly during times of transition, is critical to advancing health policy, practice and research. Future studies are needed to quantify the prevalence, burden and impact of mental health needs whilst also exploring potential supportive and therapeutic strategies. Electronic supplementary material The online version of this article (10.1186/s13023-019-1052-2) contains supplementary material, which is available to authorized users.
- Published
- 2019
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