Characterizing Common Phenotypes Across the Childhood Dementia Disorders: A Cross-sectional Study From Two Australian Centers.

BACKGROUND: Childhood dementias are a group of rare pediatric conditions characterized by progressive neurocognitive decline. Quantifying and characterising phenotypes to identify similarities between specific conditions is critical to inform opportunities to optimize care and advance research. METHODS: This cross-sectional study recruited primary caregivers of children (<18 years) living with a dementia syndrome from neurology and metabolic clinics in Sydney and Adelaide, Australia. Sociodemographic and clinical data were collated. Behavior, eating, sleep, pain, and neurological disability were assessed using validated tools, including Strengths and Difficulties, Child Eating Behaviour, and Children's Sleep Habits questionnaires and visual analog of pain and modified Rankin scales. Data were analyzed with descriptive statistics. RESULTS: Among 45 children with 23 different dementia syndromes, the modified Rankin Scale demonstrated at least moderate neurological disability and functional dependence in 82% (37/45). Families reported delays in receiving an accurate diagnosis following initial symptoms (mean: 1.6 ± 1.4 years, range: 0-5 years). The most prevalent phenotypes included communication, comprehension, or recall difficulties (87%, 39/45); disturbances in sleep (80%, 36/45); appetite changes (74%, 29/39); mobility issues (53%, 24/45); and hyperactive behavior (53%, 21/40). Behavioral problems had a "high" or "very high" impact on everyday family life in 73% (24/33). CONCLUSIONS: Childhood dementia disorders share substantial behavioral, motor, sensory, and socioemotional symptoms, resulting in high care needs, despite their vast heterogeneity in age of onset and progression. Considering their unifying characteristics under one collective term is an opportunity to improve treatment, provide quality care, and accelerate research.

The Carrier Frequency of Two SMN1 Genes in Parents of Symptomatic Children with SMA and the Significance of SMN1 Exon 8 in Carriers.

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.

Decision-making and challenges within the evolving treatment algorithm in spinal muscular atrophy: a clinical perspective.

INTRODUCTION: The clinical application of disease modifying therapies has dramatically changed the paradigm of the management of people with spinal muscular atrophy (SMA), from sole reliance on symptomatic care directed toward the downstream consequences of muscle weakness, to proactive intervention and even preventative care. AREAS COVERED: In this perspective, the authors evaluate the contemporary therapeutic landscape of SMA and discuss the evolution of novel phenotypes and the treatment algorithm, including the key factors that define individual treatment choice and treatment response. The benefits achieved by early diagnosis and treatment through newborn screening are highlighted, alongside an appraisal of emerging prognostic methods and classification frameworks to inform clinicians, patients, and families about disease course, manage expectations, and improve care planning. A future perspective of unmet needs and challenges is provided, emphasizing the key role of research. EXPERT OPINION: SMN-augmenting therapies have improved health outcomes for people with SMA and powered the practice of personalized medicine. Within this new proactive diagnostic and treatment paradigm, new phenotypes and different disease trajectories are emerging. Ongoing collaborative research efforts to understand the biology of SMA and define optimal response are critical to refining future approaches.

The outlook for individuals with Spinal Muscular Atrophy (SMA) has transformed with the approval of three effective disease modifying therapies in the past seven years. This group of genetic diseases that cause progressive muscle weakness and present as a broad range of severity ­ from mild disease with near normal lifespan to severe with abbreviated lifespan and comorbidities ­ now have gene-based therapies that have shown (motor) functional gains, ameliorated comorbidities, and improved overall quality of life of patients and prolonged survival. With the rapid translation of early diagnostic paradigms through newborn screening and the acceleration of a therapeutic pipeline, uncertainties within clinical practice arise including the optimal time to treat, the changing clinical characteristics of the treated population, monitoring of disease progression and therapeutic response in the post-treatment era. In this article, we review the evidence base to address these challenges. The key factors that determine individual treatment choice and response are discussed. The changed clinical characteristics in treated children that need early identification and appropriate management are discussed in depth. A new classification system in keeping with the changed paradigm is provided. In these early times of the treatment era, the evidence from clinical trials and real world is combined to generate evidence base to guide management. The reader would be apprised of the recent therapeutic developments, their applications, and outcomes. Finally, the challenges to be expected along the uncharted path of prolonged lifespan are discussed and care guidelines provided.

Structural and functional characterization of capsid binding by anti-AAV9 monoclonal antibodies from infants after SMA gene therapy.

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.

Identification of Novel CSF-Derived miRNAs in Treated Paediatric Onset Spinal Muscular Atrophy: An Exploratory Study.

The availability of disease modifying therapies for spinal muscular atrophy (SMA) have created an urgent need to identify clinically meaningful biomarkers that provide insight into disease progression and therapeutic response. microRNAs (miRNA) have been shown to be involved in the pathogenesis of SMA and have the potential to provide insight within the field of SMA. miRNA-sequencing was utilized to identify differential miRNA expression in the cerebrospinal fluid (CSF) in six children with SMA treated with nusinersen in this exploratory study. Fourteen differentially expressed miRNAs were significantly altered in CSF from baseline to follow-up during treatment with nusinersen. The greatest magnitude of change was noted in miR-7-5p, miR-15a-5p, miR-15b-3p/5p, miR-126-5p, miR-128-2-5p and miR-130a-3p which encompassed a spectrum of functions predominantly in neurogenesis, neuronal differentiation and growth. The dominant signaling pathways identified in this study were the mammalian target of rapamycin and the mitogen-activated protein kinase signaling pathways. This study identified multiple miRNAs that were involved in the complex interplay between neurodevelopment and neurodegeneration.

Newborn screening for spinal muscular atrophy in Australia: a non-randomised cohort study.

BACKGROUND: In light of a new therapeutic era for spinal muscular atrophy (SMA), newborn screening has been proposed as a gateway to facilitate expedient diagnosis and access to therapeutics. However, there is paucity of evidence on health outcomes outside the homogenous populations in clinical trials to justify broader implementation of newborn screening for SMA. In this real-world study, we aimed to investigate the effectiveness of newborn screening coupled with access to disease-modifying therapeutics, as an intervention for SMA. METHODS: In this prospective, non-randomised cohort study done at Sydney Children's Hospital Network (NSW, Australia), we included children younger than 16 years with homozygous exon 7 deletions of survival motor neuron 1 gene (SMN1) mutations, non-selectively assigned to a screening group (incident population diagnosed by newborn screening) from Aug 1, 2018, to Aug 1, 2020, or a comparator group (incident population diagnosed by clinical referral) from Aug 1, 2016, to July 31, 2018. We excluded infants with compound heterozygous SMN1 mutations and those participating in ongoing and unpublished clinical trials. Effectiveness of newborn screening for SMA was compared using motor development milestone attainment defined by WHO Multicentre Growth Reference Study at 2 years post diagnosis. Secondary outcome measures included mortality and change in Hammersmith Infant Neurological Examination-2 (HINE-2) score, ventilation requirements, and enteral requirements 2 years from the time of diagnosis. FINDINGS: 34 children met the study inclusion criteria, but 33 children were included in the study population after one neonate was excluded due to participation in an ongoing unpublished clinical trial. 15 children were included in the screening group (seven [47%] male and eight [53%] female; median age 2·1 weeks [IQR 1·9-2·7]) and 18 children (nine [50%] male and nine [50%] female) were included in the comparator group (median age 47·8 weeks [13·0-99·9]). The 2-year survival rate was 93% (14 of 15 children) in the screening group and 89% (16 of 18) in the comparator group. Among survivors, 11 (79%) of 14 walked independently or with assistance in the screening group, compared with one (6%) of 16 children in the comparator group (χ2=16·27; p<0·0001). A significantly greater change in motor function was observed in the screening group compared with the comparator group over 2 years (HINE-2 score group difference, 12·32; p<0·0001). The requirement for non-intensive ventilation or feeding support at follow-up was higher in the comparator group than in the screening group (odds ratio 7·1 [95% CI 0·7-70·2]). Significant predictors of functional motor outcomes as determined by HINE-2 score at 2 years post diagnosis were HINE-2 score (p=0·0022), CHOP-INTEND (p=0·0001), compound muscle action potential (CMAP; p=0·0006), and disease status (p=0·023) at diagnosis. INTERPRETATION: Newborn screening for SMA, coupled with early access to disease-modifying therapies, effectively ameliorates the functional burden and associated comorbidities for affected children. For children diagnosed through newborn screening, motor score, CMAP, and disease status at diagnosis has clinical utility to determine functional independence. FUNDING: Brain Foundation and National Health and Medical Research Council.

Incidence of Duchenne muscular dystrophy in the modern era; an Australian study.

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.

Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy.

OBJECTIVE: To provide a greater understanding of the tolerability, safety and clinical outcomes of onasemnogene abeparvovec in real-world practice, in a broad population of infants with spinal muscular atrophy (SMA). METHODS: A prospective cohort study of children with SMA treated with onasemnogene abeparvovec at Sydney Children's Hospital Network, Australia was conducted from August 2019 to November 2021. Safety outcomes included clinical and laboratory evaluations. Efficacy assessments included World Health Organisation (WHO) motor milestones, oral and swallowing abilities, and requirements for respiratory support. The implementation of a model of care for onasemnogene abeparvovec administration in health practice is described. RESULTS: 21 children were treated (age range, 0.65-24 months; body weight range, 2.5-12.5 kg) and 19/21 (90.4%) had previous nusinersen. Transient treatment-related side effects occurred in all children; vomiting (100%), transaminitis (57%) and thrombocytopaenia (33%). Incidence of moderate/severe transaminitis was significantly greater in infants weighing ≥8 kg compared with <8 kg (p < 0.05). Duration of prednisolone following treatment was prolonged (mean 87.5 days, range 57-274 days). 16/21 (76%) children gained at least one WHO motor milestone. Stabilisation or improvement in bulbar or respiratory function was observed in 20/21 (95.2%) patients. Implementation challenges were mitigated by developing standard operating procedures and facilitating exchange of knowledge. INTERPRETATION: This study provides real-world evidence to inform treatment decisions and guide therapeutic expectations for onasemnogene abeparvovec and combination therapy for SMA in health practice, especially for children weighing ≥8 kg receiving higher vector loads. Proactive clinical and laboratory surveillance is essential to facilitate individualised management of risks.

Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen.

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.

Integrating newborn screening for spinal muscular atrophy into health care systems: an Australian pilot programme.

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.

"We needed this": perspectives of parents and healthcare professionals involved in a pilot newborn screening program for spinal muscular atrophy.

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<0.001)]. Challenges for HCPs included managing the time-critical nature of the pathway whilst remaining cognisant of limitations associated with the predictive screening test. INTERPRETATION: Interpretation: NBS for SMA fulfils criteria for population-wide screening. Net benefits are acknowledged by stakeholders to optimise lifelong outcomes. Harms including psychological distress associated with a screen-positive result may be managed by targeted psychosocial support, information provision and a personalised model of care together strengthening healthcare systems. FUNDING: The NSW Pilot NBS study was funded by Luminesce Alliance. Dr Kariyawasam received funding from the RTP Scholarship, University of New South Wales and The Freedman Family Foundation Scholarship, Sydney Children's Hospital Foundation.

Growth and nutrition in pediatric neuromuscular disorders.

BACKGROUND & AIMS: 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. METHODS: 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'. RESULTS: 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. CONCLUSION: 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.

Real-world respiratory and bulbar comorbidities of SMA type 1 children treated with nusinersen: 2-Year single centre Australian experience.

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 10.7 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). 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.

Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.

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.

Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review.

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.

First Trimester Protein Biomarkers for Risk of Spontaneous Preterm Birth: Identifying a Critical Need for More Rigorous Approaches to Biomarker Identification and Validation.

BACKGROUND: Spontaneous preterm birth is the leading cause of perinatal morbidity and mortality worldwide and continues to present a major clinical dilemma. We previously reported that a number of protein species were dysregulated in maternal serum collected at 11-13+6 weeks' gestation from pregnancies that continued to labour spontaneously and deliver preterm. OBJECTIVES AND METHODS: In this study, we aimed to validate changes seen in 4 candidate protein species: alpha-1-antitrypsin, vitamin D-binding protein (VDBP), alpha-1beta-glycoprotein and apolipoprotein A-1 in a larger cohort of women using a western blot approach. RESULTS: Serum levels of all 4 proteins were reduced in women who laboured spontaneously and delivered preterm. This reduction was significant for VDBP (p = 0.04), which has been shown to be involved in a plethora of essential biological functions, including actin scavenging, fatty acid transport, macrophage activation and chemotaxis. CONCLUSIONS: The decrease in select proteoforms of VDBP may result in an imbalance in the optimal intrauterine environment for the developing foetus as well as to a successful uncomplicated pregnancy. Thus, certain (phosphorylated) species of VDBP may be of value in developing a targeted approach to the early prediction of spontaneous preterm labour. Importantly, this study raises the importance of a focus on proteoforms and the need for any biomarker validation process to most effectively take these into account rather than the more widespread practice of simply focussing on the primary amino acid sequence of a protein.

Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy.

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.

"Getting ready for the adult world": how adults with spinal muscular atrophy perceive and experience healthcare, transition and well-being.

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.

Proteomic analysis of first trimester maternal serum to identify candidate biomarkers potentially predictive of spontaneous preterm birth.

Spontaneous preterm birth (sPTB) remains a major clinical dilemma; current diagnostics and interventions have not reduced the rate of this serious healthcare burden. This study characterizes differential protein profiles and post-translational modifications (PTMs) in first trimester maternal serum using a refined top-down approach coupling two-dimensional gel electrophoresis (2DE) and mass spectrometry (MS) to directly compare subsequent term and preterm labour events and identify marked protein differences. 30 proteoforms were found to be significantly increased or decreased in the sPTB group including 9 phosphoproteins and 11 glycoproteins. Changes occurred in proteins associated with immune and defence responses. We identified protein species that are associated with several clinically relevant biological processes, including interrelated biological networks linked to regulation of the complement cascade and coagulation pathways, immune modulation, metabolic processes and cell signalling. The finding of altered proteoforms in maternal serum from pregnancies that delivered preterm suggests these as potential early biomarkers of sPTB and also possible mediators of the disorder. BIOLOGICAL SIGNIFICANCE: Identifying changes in protein profiles is critical in the study of cell biology, and disease treatment and prevention. Identifying consistent changes in the maternal serum proteome during early pregnancy, including specific protein PTMs (e.g. phosphorylation, glycosylation), is likely to provide better opportunities for prediction, intervention and prevention of preterm birth. This is the first study to examine first trimester maternal serum using a highly refined top-down proteomic analytical approach based on high resolution 2DE coupled with mass spectrometry to directly compare preterm (<37 weeks) and preterm (≥37 weeks) events and identify select protein differences between these conditions. As such, the data present a promising avenue for translation of biomarker discovery to a clinical setting as well as for future investigation of underlying aetiological processes.