Michelle A. Farrar

Since 2016/17, three disease modifying therapies for spinal muscular atrophy (SMA) have been translated into clinical practice. This has driven the implementation of newborn screening to transform health outcomes and clinical practice. SMA registries have provided important sources of data on the evolution of novel phenotypes within the therapeutic era, treatment patterns, epidemiology, genotype-phenotype correlations, care and lived experiences of people living with SMA, to enrich knowledge and learnings of the condition in this changed landscape. In this state-of-the-art review, we consider the utility and outcomes of SMA registries and evaluate their role and importance. In 2024 there are more than 35 national registries cataloguing over 8000 individuals with SMA. Additional registries are operated by advocacy groups and pharmaceutical companies, compiling data for more than 10,000 individuals with this condition. This review highlights the essential role of registries in supporting clinical trial recruitment, defining the changing incidence and prevalence of SMA in an age of reproductive carrier and newborn screening, establishing natural history data, contributing to post market drug surveillance, assessing real world clinical and cost effectiveness and capturing patient-reported outcome measures (PROMS) and experience measures (PREMS). Whilst their utility is broad, barriers to effective data curation and management are evaluated including challenges of data curation and fragmentation, quality and sharing, alongside resource constraints and sustainability. Strategies to enhance the value of registries include the imperative to collaborate across clinical research networks and the value of interoperability, enabled by standardization of data collection and entry, sharing procedures and public and patient involvement. As new phenotypes and unmet needs emerge in the post therapeutic era, registries remain central tools in generating new insights now and into the future and are poised to respond meaningfully to the priorities of individuals living with SMA.

Objective: Enhanced efficacy with spinal muscular atrophy (SMA) treatments is demonstrated with earlier initiation, ideally before the onset of symptoms. High-quality pregnancy and postnatal care for mother-baby dyads with SMA are important to ensure optimal outcomes. The aim of this study was to investigate obstetric and postnatal factors that could modify clinical outcomes of mother-baby dyads with SMA. Methods: This is an Australian dual-center prospective cohort study of 42 consecutive mother-baby dyads with SMA (≤4 survival motor neuron 2 [SMN2] copies) identified through a statewide newborn screening program or prenatal testing for SMA from 2018 to 2025. Sociodemographic, clinical, and genetic data were collated. For the group with 2 SMN2 copies, regression models examined differences in gestational age at birth with study outcomes at diagnostic assessment, including clinical manifestations of SMA, motor function scores assessed with the CHOP-INTEND scale, and compound muscle action potential (CMAP). Results: Forty-two mother-baby dyads participated (n = 1 with 1 SMN2; n = 21 with 2 SMN2, gestational age at birth 39.9 ± 1.8 weeks; n = 20 with 3 or 4 SMN2, gestational age at birth 39.4 ± 0.8 weeks). All neonates with 3 or 4 SMN2 copies were clinically silent at diagnostic assessment while 7 of 21 (33.3%) with 2 SMN2 copies had clinical manifestations of SMA (p = 0.009). In newborns with 2 SMN2 copies, higher gestational age at birth was associated with clinical manifestations of SMA (odds ratio 4.37, 95% CI 1.19-16.12, p = 0.001) and lower motor function (CHOP-INTEND: β = -4.52, 95% CI -7.018 to -2.019, p = 0.001) and strongly correlated with lower CMAP (R = -0.800, p < 0.001). High medical acuity was common in the obstetric and postnatal care of mothers and babies with SMA, occurring in 12 of 42 (29.3%) and 8 of 41 (19.5%), respectively, and mostly in those with 1 or 2 SMN2 copies. Conclusions: Early detection and timely administration of treatments are imperative in managing the rapid and severe loss of motor function that can occur in neonates with SMA. A personalized obstetric health care approach, prenatal testing, and planning the timing of delivery and initiation of treatment for newborns with genetically diagnosed SMA may improve outcomes.

Objective: Far field potentials (FFP) have been proposed as a reliable neurophysiological prognostic biomarker in amyotrophic lateral sclerosis (ALS). This study evaluates the diagnostic utility of ulnar nerve FFP in ALS. Methods: Comprehensive peripheral neurophysiological assessments were conducted in 62 ALS and 43 ALS-mimicking disorder participants. The ulnar nerve was stimulated at the wrist, recording motor responses over the abductor digit minimi (ADM) muscle. Conventional compound muscle action potentials (CMAP), FFP, and near field potential amplitudes were recorded, alongside the split-hand index, neurophysiological index, motor unit number estimation (MScanFit-MUNE), and motor unit index (MUNIX). Diagnostic utility was evaluated using receiver operating characteristic (ROC) analysis. Results: In ALS, FFP amplitude was significantly lower (5.07 ± 0.36 mV) compared to ALS mimics (8.25 ± 0.40 mV, p < 0.001). FFP amplitude exhibited a moderate-to-strong correlation with neurophysiological biomarkers, including CMAP amplitude (ρ = 0.77, p < 0.001), split-hand index (ρ = 0.53, p < 0.001), neurophysiological index (ρ = 0.52, p < 0.001), MUNIX (ρ = 0.69, p < 0.001), and MScanFit-MUNE (ρ = 0.66, p < 0.001). Weak-to-moderate correlations were also observed with clinical measures of disease progression, including upper limb muscle strength, ALS functional rating score-revised (ALSFRS-R) and the rate of decline in the ALSFRS-R fine motor subscore. ROC analysis demonstrated that FFP amplitude reliably distinguished ALS from mimicking disorders (AUC = 0.80, 95% CI: 0.71-0.89), with consistent diagnostic accuracy across ALS phenotypes. Conclusions: The diagnostic capability of FFP amplitude was comparable to established neurophysiological biomarkers utilized in ALS. It is a promising prognostic and diagnostic biomarker for ALS. Its simplicity and reproducibility complement traditional neurophysiological measures, offering potential for clinical application in ALS diagnosis and monitoring.

Newborn Bloodspot Screening (NBS) can detect severe treatable health conditions with onset during infancy. The parents of a newborn baby are vulnerable in the days after birth, and the optimal way to deliver the shocking and distressing news of a potential serious diagnosis is yet to be defined. More data are needed to determine whether access to a genetic counsellor (GC) improves families' experiences with genetic conditions identified by NBS. This study aimed to explore the similarities and differences for parents who received a positive NBS result for Spinal Muscular Atrophy (SMA) and received access to a GC (GC cohort), to a cohort of parents who received a diagnosis for inborn errors of metabolism (IEM) and did not have access to a GC (non-GC cohort). Semi-structured interviews explored the retrospective experiences of receiving the NBS result, including diagnosis implications and subsequent adaptation to respective genetic diagnoses. Inductive thematic analysis was used from group comparison. 7 SMA families and 5 IEM families were included in the study. Four themes were identified: 1. minimal pre-test counselling; 2. perceived lack of local healthcare team knowledge; 3. enabling factors for adaptation; 4. implications for both individuals and their families. Both the GC and non-GC cohorts reported insufficient counselling in the pre-test period and described feeling traumatised at the time of the diagnosis delivery. Families without subsequent GC input described limited understanding of the disease due to the use of medicalized terms, as well as a decreased understanding of reproductive options, familial communication and subsequent cascade screening. GCs can support information needs and adaptation following a NBS diagnosis.

Objective: To explore quality of life outcomes for caregivers of children with childhood dementia including the positive and negative impact of caregiving. The secondary aim was to explore caregivers' perspectives on healthcare services for children with dementia. Methods: Cross-sectional, mixed-methods study with analyses of quantitative and qualitative data collected via online survey. Methods: Australian tertiary referral children's hospitals, clinics and community advocacy groups. Methods: 40 caregivers of children with dementia. Methods: The survey was developed by a multidisciplinary team of clinicians including paediatric neurologists and behavioural scientists with experience in caring for families with childhood dementias and mixed-methods research. Methods: Surveys assessed caregiver-reported health-related quality of life, psychological distress, the impacts of caregiving and perspectives on healthcare services and how they may be improved for children with dementia. Results: Psychological distress was reported by 72.5%, caregiver stress by 67%, chronic pain or discomfort by 43% and for 87.5% their child's condition had a moderate or severe impact on their ability to do regular daily activities. Caregivers voiced a desire for more integrated care, increased general awareness and education around childhood dementia and a greater need for more trained support services. Conclusions: Caregivers of children with dementia experience high levels of psychological distress, physical and social consequences. This study highlights the need for integrated care and psychosocial support to efficiently connect children and families with appropriate healthcare services and resources.

A Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Tideglusib Versus Placebo for the Treatment of Children and Adolescents With Congenital Myotonic Dystrophy (REACH CDM)

A Global Study of a Single, One-Time Dose of AVXS-101 Delivered to Infants With Genetically Diagnosed and Pre-symptomatic Spinal Muscular Atrophy With Multiple Copies of SMN2