RESUMEN
INTRODUCTION/AIMS: Obesity disproportionately affects children and adolescents with Duchenne muscular dystrophy (DMD) and with adverse consequences for disease progression. This study aims to: explore barriers, enablers, attitudes, and beliefs about nutrition and weight management; and to obtain caregiver preferences for the design of a weight management program for DMD. METHODS: We surveyed caregivers of young people with DMD from four Australian pediatric neuromuscular clinics. Survey questions were informed by the Theoretical Domains Framework and purposefully designed to explore barriers and enablers to food and weight management. Caregivers were asked to identify their preferred features in a weight management program for families living with DMD. RESULTS: Fifty-three caregivers completed the survey. Almost half (48%) perceived their son as above healthy weight. Consequences for those children were perceived to be self-consciousness (71%), a negative impact on self-esteem (64%) and movement (57%). Preventing weight gain was a common reason for providing healthy food and healthy eating was a high priority for families. Barriers to that intention included: time constraints, selective food preferences, and insufficient nutrition information. Caregivers preferred an intensive six-week weight management program addressing appetite management and screen time. DISCUSSION: Managing weight is an important issue for caregivers of sons with DMD; yet several barriers exist. Individualized 6 week programs are preferred by caregivers to improve weight management for DMD.
Asunto(s)
Cuidadores , Distrofia Muscular de Duchenne , Adolescente , Humanos , Niño , Distrofia Muscular de Duchenne/terapia , Australia , Estado de Salud , Encuestas y CuestionariosRESUMEN
Childhood dementia is a devastating and under-recognized group of disorders with a high level of unmet need. Typically monogenic in origin, this collective of individual neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in childhood and adolescence. This scoping review aims to clarify definitions and conceptual boundaries of childhood dementia and quantify the collective disease burden. A literature review identified conditions that met the case definition. An expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective burden modelled. One hundred and seventy genetic childhood dementia disorders were identified. Of these, 25 were analysed separately as treatable conditions. Collectively, currently untreatable childhood dementia was estimated to have an incidence of 34.5 per 100 000 (1 in 2900 births), median life expectancy of 9 years and prevalence of 5.3 per 100 000 persons. The estimated number of premature deaths per year is similar to childhood cancer (0-14 years) and approximately 70% of those deaths will be prior to adulthood. An additional 49.8 per 100 000 births are attributable to treatable conditions that would cause childhood dementia if not diagnosed early and stringently treated. A relational database of the childhood dementia disorders has been created and will be continually updated as new disorders are identified (https://knowledgebase.childhooddementia.org/). We present the first comprehensive overview of monogenic childhood dementia conditions and their collective epidemiology. Unifying these conditions, with consistent language and definitions, reinforces motivation to advance therapeutic development and health service supports for this significantly disadvantaged group of children and their families.
Asunto(s)
Demencia , Neoplasias , Enfermedades Neurodegenerativas , Niño , Adolescente , Humanos , Costo de Enfermedad , Prevalencia , Demencia/epidemiologíaRESUMEN
Success in the treatment of infants with spinal muscular atrophy (SMA) underscores the potential of vectors based on adeno-associated virus (AAV). However, a major obstacle to the full realization of this potential is pre-existing natural and therapy-induced anti-capsid humoral immunity. Structure-guided capsid engineering is one possible approach to surmounting this challenge but necessitates an understanding of capsid-antibody interactions at high molecular resolution. Currently, only mouse-derived monoclonal antibodies (mAbs) are available to structurally map these interactions, which presupposes that mouse and human-derived antibodies are functionally equivalent. In this study, we have characterized the polyclonal antibody responses of infants following AAV9-mediated gene therapy for SMA and recovered 35 anti-capsid mAbs from the abundance of switched-memory B (smB) cells present in these infants. For 21 of these mAbs, seven from each of three infants, we have undertaken functional and structural analysis measuring neutralization, affinities, and binding patterns by cryoelectron microscopy (cryo-EM). Four distinct patterns were observed akin to those reported for mouse-derived mAbs, but with early evidence of differing binding pattern preference and underlying molecular interactions. This is the first human and largest series of anti-capsid mAbs to have been comprehensively characterized and will prove to be powerful tools for basic discovery and applied purposes.
Asunto(s)
Anticuerpos Monoclonales , Cápside , Lactante , Humanos , Animales , Ratones , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/genética , Microscopía por Crioelectrón , Cápside/química , Proteínas de la Cápside/química , Dependovirus , Terapia Genética , Vectores Genéticos/genéticaRESUMEN
INTRODUCTION: Advanced therapies offer unprecedented opportunities for treating rare neurological disorders (RNDs) in children. However, health literacy, perceptions and understanding of novel therapies need elucidation across the RND community. This study explored healthcare professionals' and carers' perspectives of advanced therapies in childhood-onset RNDs. METHODS: In this mixed-methodology cross-sectional study, 20 healthcare professionals (clinicians, genetic counsellors and scientists) and 20 carers completed qualitative semistructured interviews and custom-designed surveys. Carers undertook validated psychosocial questionnaires. Thematic and quantitative data analysis followed. RESULTS: Participants described high positive interest in advanced therapies, but low knowledge of, and access to, reliable information. The substantial 'therapeutic gap' and 'therapeutic odyssey' common to RNDs were recognised in five key themes: (i) unmet need and urgency for access; (ii) seeking information; (iii) access, equity and sustainability; (iv) a multidisciplinary and integrated approach to care and support and (v) difficult decision-making. Participants were motivated to intensify RND clinical trial activity and access to advanced therapies; however, concerns around informed consent, first-in-human trials and clinical trial procedures were evident. There was high-risk tolerance despite substantial uncertainties and knowledge gaps. RNDs with high mortality, increased functional burdens and no alternative therapies were consistently prioritised for the development of advanced therapies. However, little consensus existed on prioritisation to treatment access. CONCLUSIONS: This study highlights the need to increase clinician and health system readiness for the clinical translation of advanced therapeutics for RNDs. Co-development and use of educational and psychosocial resources to support clinical decision-making, set therapeutic expectations and promotion of equitable, effective and safe delivery of advanced therapies are essential. PATIENT OR PUBLIC CONTRIBUTION: Participant insights into the psychosocial burden and information need to enhance the delivery of care in this formative study are informing ongoing partnerships with families, including co-production and dissemination of psychoeducational resources featuring their voices hosted on the Sydney Children's Hospitals Network website SCHN Brain-Aid Resources.
Asunto(s)
Enfermedades del Sistema Nervioso , Enfermedades Raras , Humanos , Enfermedades Raras/terapia , Estudios Transversales , Enfermedades del Sistema Nervioso/terapia , Femenino , Masculino , Australia , Adulto , Cuidadores/psicología , Encuestas y Cuestionarios , Entrevistas como Asunto , Participación de los Interesados , Persona de Mediana Edad , Personal de Salud/psicología , Investigación Biomédica Traslacional , Investigación CualitativaRESUMEN
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.
Asunto(s)
Atrofia Muscular Espinal , Oligonucleótidos , Potenciales de Acción , Axones , Niño , Preescolar , Humanos , Atrofia Muscular Espinal/tratamiento farmacológicoRESUMEN
BACKGROUND AND OBJECTIVES: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally. METHODS: Development of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations. RESULTS: The final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research. CONCLUSIONS: This clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Adolescente , Adulto , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/terapia , Niño , Consenso , Humanos , Calambre Muscular , Debilidad Muscular , Guías de Práctica Clínica como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
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.
Asunto(s)
Atrofia Muscular Espinal , Tamizaje Neonatal , Australia , Atención a la Salud , Humanos , Recién Nacido , Atrofia Muscular Espinal/diagnóstico , Proyectos PilotoRESUMEN
AIM: To understand the factors that most influence decision-making in the treatment of infantile spinal muscular atrophy (SMA). METHOD: A discrete choice experiment was conducted among parents of people with SMA (parents), healthcare professionals (HCPs), and members of the Australian general population (GenPop). Respondents were asked to accept/reject treatment for an infant newly diagnosed with SMA in eight hypothetical scenarios, characterized by different combinations of the attributes of the treatment offered. The results were analyzed using probability analysis. RESULTS: Completed responses were provided from 1113 individuals (1024 GenPop, 21 parents, 68 HCPs). Respondents were more likely to accept treatments that improved functioning and mobility. Treatments with higher costs, invasive delivery, and risks of adverse events were accepted less often. Cost most affected treatment choices by HCPs and GenPop, while change in mobility and mode of administration were most influential for parents. INTERPRETATION: These results highlight the importance of understanding value for money and clinical impact in affecting treatment choice, which are crucial for effective planning of healthcare and the successful implementation of treatment programmes for SMA. What this paper adds Spinal muscular atrophy (SMA) treatments with a higher chance of improving functioning and mobility are preferred by the general population, parents, and healthcare professionals. Treatments with higher costs, invasive delivery, and risk of adverse events are less preferred. Willingness to pay for SMA treatments increases with impact on functioning.
Asunto(s)
Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Australia , Atención a la Salud , Personal de Salud , Humanos , Lactante , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofias Musculares Espinales de la Infancia/terapiaRESUMEN
Precision medicine refers to treatments that are targeted to an individual's unique characteristics. Precision medicine for neurodevelopmental disorders (such as cerebral palsy, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, Tourette syndrome, and autism spectrum disorder) in children has predominantly focused on advances in genomic sequencing technologies to increase our ability to identify single gene mutations, diagnose a multitude of rare neurodevelopmental disorders, and gain insights into pathogenesis. Although targeting specific gene variants with high penetrance will help some children with rare disease, this approach will not help most children with neurodevelopmental disorders. A 'pathway' driven approach targeting the cumulative influence of psychosocial, epigenetic, or cellular factors is likely to be more effective. To optimize the therapeutic potential of precision medicine, we present a biopsychosocial integrated framework to examine the 'gene-environment neuroscience interaction'. Such an approach would be supported through harnessing the power of big data, transdiagnostic assessment, impact and implementation evaluation, and a bench-to-bedside scientific discovery agenda with ongoing clinician and patient engagement. WHAT THIS PAPER ADDS: Precision medicine has predominantly focused on genetic risk factors. The impact of environmental risk factors, particularly inflammatory, metabolic, and psychosocial risks, is understudied. A holistic biopsychosocial model of neurodevelopmental disorder causal pathways is presented. The model will provide precision medicine across the full spectrum of neurodevelopmental disorders.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastornos del Neurodesarrollo , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/terapia , Niño , Genómica , Humanos , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/terapia , Medicina de PrecisiónRESUMEN
INTRODUCTION: Biomedical progress has facilitated breakthrough advanced neurotherapeutic interventions, whose potential to improve outcomes in rare neurological diseases has increased hope among people with lived experiences and their carers. Nevertheless, gene, somatic cell and other advanced neurotherapeutic interventions carry significant risks. Rare disease patient organizations (RDPOs) may enhance patient experiences, inform expectations and promote health literacy. However, their perspectives are understudied in paediatric neurology. If advanced neurotherapeutics is to optimize RDPO contributions, it demands further insights into their roles, interactions and support needs. METHODS: We used a mixed-methodology approach, interviewing 20 RDPO leaders representing paediatric rare neurological diseases and following them up with two online surveys featuring closed and open-ended questions on advanced neurotherapeutics (19/20) and negative mood states (17/20). Qualitative and quantitative data were analysed using thematic discourse analysis and basic descriptive statistics, respectively. RESULTS: Leaders perceived their roles to be targeted at educational provision (20/20), community preparation for advanced neurotherapeutic clinical trials (19/20), information simplification (19/20) and focused research pursuits (20/20). Although most leaders perceived the benefits of collaboration between stakeholders, some cited challenges around collaborative engagement under the following subthemes: conflicts of interest, competition and logistical difficulties. Regarding neurotherapeutics, RDPO leaders identified support needs centred on information provision, valuing access to clinician experts and highlighting a demand for co-developed, centralized, high-level and understandable, resources that may improve information exchange. Leaders perceived a need for psychosocial support within themselves and their communities, proposing that this would facilitate informed decision-making, reduce associated psychological vulnerabilities and maintain hope throughout neurotherapeutic development. CONCLUSION: This study provides insights into RDPO research activities, interactions and resource needs. It reveals a demand for collaboration guidelines, central information resources and psychosocial supports that may address unmet needs and assist RDPOs in their advocacy. PATIENT OR PUBLIC CONTRIBUTION: In this study, RDPO leaders were interviewed and surveyed to examine their perspectives and roles in advanced neurotherapeutic development. Some participants sent researchers postinterview clarification emails regarding their responses to questions.
Asunto(s)
Alfabetización en Salud , Enfermedades Raras , Humanos , Niño , Enfermedades Raras/terapia , Promoción de la Salud/métodos , Encuestas y Cuestionarios , CuidadoresRESUMEN
Spinal muscular atrophy is treated with onasemnogene abeparvovec, which replaces the missing survival motor neuron 1 gene via an adeno-associated virus vector. As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec. Early recognition and treatment of drug-induced thrombotic microangiopathy may lessen mortality and morbidity.
Asunto(s)
Productos Biológicos/efectos adversos , Atrofia Muscular Espinal/tratamiento farmacológico , Proteínas Recombinantes de Fusión/efectos adversos , Microangiopatías Trombóticas/inducido químicamente , Productos Biológicos/uso terapéutico , Femenino , Humanos , Lactante , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
OBJECTIVE: To assess cost-effectiveness of newborn screening (NBS) for spinal muscular atrophy (SMA) and early treatment with nusinersen or onasemnogene abeparvovec (gene therapy), compared with nusinersen without SMA screening. METHODS: Informed by an Australian state-wide SMA NBS programme, a decision analytical model nested with Markov models was constructed to evaluate costs and quality-adjusted life-years (QALYs) from a societal perspective with sensitivity analyses. RESULTS: By treating one presymptomatic SMA infant with nusinersen or gene therapy, an additional 9.93 QALYs were gained over 60 years compared with late treatment in clinically diagnosed SMA. The societal cost was $9.8 million for early nusinersen treatment, $4.4 million for early gene therapy and $4.8 million for late nusinersen treatment. Compared with late nusinersen treatment, early gene therapy would be dominant, gaining 9.93 QALYs while saving $360 000; whereas early nusinersen treatment would result in a discounted incremental cost-effectiveness ratio (ICER) of $507 000/QALY.At a population level, compared with no screening and late treatment with nusinersen, NBS and early gene therapy resulted in 0.00085 QALY gained over 60 years and saving $24 per infant screened (85 QALYs gained and $2.4 million saving per 100 000 infants screened). More than three quarters of simulated ICERs by probability sensitivity analyses showed NBS and gene therapy would be dominant or less than $50 000/QALY, compared with no screening and late nusinersen treatment. CONCLUSION: NBS coupled with gene therapy improves the quality and length of life for infants with SMA and would be considered value-for-money from an Australian clinical and policy context.
Asunto(s)
Productos Biológicos/uso terapéutico , Atrofia Muscular Espinal/diagnóstico , Tamizaje Neonatal , Oligonucleótidos/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Análisis Costo-Beneficio , Femenino , Humanos , Recién Nacido , Masculino , Atrofia Muscular Espinal/tratamiento farmacológicoRESUMEN
Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disease caused by biallelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is characterized by motor neuron degeneration, resulting in progressive muscle atrophy and weakness. Before the emergence of disease-modifying therapies, children with the most severe form of SMA would never achieve the ability to sit independently. Only 8% survived beyond 20 months of age without permanent ventilator support. One such therapy, onasemnogene abeparvovec, an adeno-associated virus-based gene replacement therapy, delivers functional human SMN through a one-time intravenous infusion. In addition to substantially improving survival, onasemnogene abeparvovec was found to increase motor milestone attainment and reduce the need for respiratory or nutritional support in many patients. This expert opinion provides recommendations and practical considerations on the patient-centered decisions to use onasemnogene abeparvovec. Recommendations include the need for patient-centered multidisciplinary care and patient selection to identify those with underlying medical conditions or active infections to reduce risks. We also describe the importance of retesting patients with elevated anti-adeno-associated virus serotype 9 antibodies. Recommendations for prednisolone tapering and monitoring for potential adverse events, including hepatotoxicity and thrombotic microangiopathy, are described. The need for caregiver education on managing day-to-day care at time of treatment and patient- and family-centered discussions on realistic expectations are also recommended. We detail the importance of following standard-of-care guidance and long-term monitoring of all children with SMA who have received one or more disease-modifying therapy using registries. We also highlight the need for presymptomatic or early symptomatic treatment of this disorder.
Asunto(s)
Productos Biológicos/administración & dosificación , Toma de Decisiones Clínicas/métodos , Testimonio de Experto/métodos , Terapia Genética/métodos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Proteínas Recombinantes de Fusión/administración & dosificación , Humanos , Atención Dirigida al Paciente/métodosRESUMEN
BACKGROUND: Literature regarding congenital subependymal giant cell astrocytomas (SEGA) is limited, and suggests they are at risk of rapid growth and complications. We sought to characterise the growth patterns of congenital SEGA. The second part of the study was an exploratory analysis of congenital SEGA as a possible biomarker for poor neurological outcome. METHODS: This single-centre case series describes ten patients with TSC who had SEGA diagnosed before 12 months. SEGA diameter and volumetric growth were analysed using serial MRIs. Neurological outcomes were compared to a genotype-matched group. RESULTS: All children with congenital SEGA had a TSC2 mutation. Patients were followed for 1-8.7 years, during which median SEGA growth rate was 1.1 mm/yr in diameter or 150 mm3/yr volumetrically. SEGA with volume > 500 mm3 had a significantly higher growth rate compared with smaller SEGA (462 mm3/yr vs. 42 mm3/yr, p = 0.0095). Children with congenital SEGA had a high prevalence of severe epilepsy, developmental disability and autism spectrum disorder. CONCLUSION: Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Frequent neuroimaging surveillance is recommended for congenital SEGA with volumes exceeding 500 mm3. IMPACT: Congenital SEGA occur in 9.2% of paediatric patients with tuberous sclerosis complex. There are few published cases of congenital SEGA to date. This case series of ten patients adds our experience seen in a tertiary referral hospital over 10 years. Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Congenital SEGA with volume exceeding 500 mm3 had a significantly higher growth rate compared with smaller SEGA and should have more frequent neuroimaging surveillance.
Asunto(s)
Astrocitoma/diagnóstico , Esclerosis Tuberosa/diagnóstico , Astrocitoma/complicaciones , Astrocitoma/patología , Niño , Femenino , Humanos , Lactante , Masculino , Resultado del Tratamiento , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/patologíaRESUMEN
AIM: 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. METHODS: 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. RESULTS: Nine children (5 females, 4 males), median age 10.7â¯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 (nâ¯=â¯7) included gastrostomy insertion (nâ¯=â¯4) and commencement of noninvasive ventilation (nâ¯=â¯4) at an average of 8.3 and 4.5â¯months after diagnosis, respectively. The annualised hospitalisation rate was 9.3/patient/year, average length of stay (LOS) of 3.3â¯days (SDâ¯=â¯5.6). Children with two SMN2 copies required more gastrostomies (pâ¯<â¯0.05) and had more frequent admissions (pâ¯<â¯0.05). Number of total admissions halved from the first to the second year of treatment in all patients (pâ¯<â¯0.005). INTERPRETATION: 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.
Asunto(s)
Atrofias Musculares Espinales de la Infancia , Australia/epidemiología , Niño , Comorbilidad , Femenino , Humanos , Masculino , Estudios Observacionales como Asunto , OligonucleótidosRESUMEN
PURPOSE: To evaluate the implementation of the first statewide newborn screening (NBS) program for spinal muscular atrophy (SMA) in Australia. Processes that hinder and support clinical development, translation, and sustainability of the first primary genetic screening program in Australia are appraised. METHODS: The study prospectively describes the course (timelines, health processes, and preliminary clinical outcomes) for SMA screen-positive newborns from 1 August 2018 to 31 July 2019 in New South Wales and Australian Capital Territory, Australia. RESULTS: In the first year of the program, 103,903 newborns were screened. Ten newborns screened positive for SMA. Genetic confirmation of SMA occurred in 9/10 (90%) of infants. Clinical signs of SMA evolved in 4/9 (44%) within 4 weeks of life, heralded by hypotonia and weakness initially recognized in the neck. Median time to implementing a care plan (including commencement of disease-modifying therapies) was 26.5 days (16-37 days) from birth. CONCLUSION: NBS is essential for early and equitable identification of patients with SMA. Expedient diagnosis and management are vital, as disease latency appears brief in some cases. NBS shows significant clinical utility to support early parental decision making, improve access to specialist neuromuscular expertise, and facilitate initiation of personalized therapeutic strategies.
Asunto(s)
Pruebas Genéticas , Atrofia Muscular Espinal/genética , Tamizaje Neonatal , Australia/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/epidemiología , PadresRESUMEN
Gene therapy (GT) has tremendous potential for the treatment of neurological disorders to transform patient care. The successful application of virus-mediated GT to treat spinal muscular atrophy is a significant milestone, serving to accelerate similar progress in a spectrum of neurological conditions, with more than 50 clinical trials currently underway, across neurodevelopmental, neurodegenerative, muscular dystrophy, epilepsy, chronic pain and neoplastic diseases. This review provides an overview of the key features of virus-mediated GT, paradigms of delivery and dosing, potential risks and highlights ongoing research to optimise safe and effective delivery of vectors into the nervous system. Examples of the application of GT in various neurological diseases alongside clinical development challenges will be presented. As the development and translation of GTs gain pace, success can only ultimately be realised for patients following implementation in the health system. The challenges and controversies of daunting costs, ethics, early diagnosis and health system readiness will require innovative pricing schemes, regulatory policies, education and organisation of a skilled workforce to deliver of high-quality care in clinical practice as we prepare for advanced therapeutics in neurology.
Asunto(s)
Terapia Genética/métodos , Vectores Genéticos/uso terapéutico , Enfermedades del Sistema Nervioso/terapia , Edición Génica , Silenciador del Gen , Humanos , Virus/genéticaRESUMEN
OBJECTIVES: To elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique. METHODS: MScanFit 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). RESULTS: Twenty 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 (p<0.05). Electrophysiological changes delineated children who were functionally stable from those who attained clinically significant gains in motor function. INTERPRETATION: Nusinersen 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.
RESUMEN
OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.