Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible. Clinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3–12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort. Our findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.

Objective: The aim of this project is to study the effect of a physical therapist intervention provided in the first months of life on developmental outcomes of infants born very preterm. Secondary aims are to investigate the impact of intervention timing on the efficacy and impact of the intervention on infants with and without cerebral palsy. Methods: This study is a multisite longitudinal controlled trial comparing developmental outcomes from infants in the Supporting Play, Exploration, and Early Development Intervention (SPEEDI)_Late or SPEEDI_Early group to a usual care group. Settings are urban: Urban and rural areas surrounding 2 academic medical centers. There will be 90 preterm infants enrolled in this study born at <29 weeks of gestation. SPEEDI is a developmental intervention provided by collaboration between a physical therapist and parent to support a child’s motor and cognitive development. The primary outcome measure is the Bayley Scale of Infant and Toddler Development Cognitive and Gross Motor Scaled Scores. Secondary measures include behavioral coding of early problem solving skills, the Gross Motor Function Measure, and Test of Infant Motor Performance. Impact: More than 270,000 infants are born very preterm in the United States each year, 50% of whom will have neurological dysfunction that limits their ability to keep pace with peers who are typically developing. This study is a step toward understanding the impact that intensive developmental intervention could have in this population in the first months of life.

The development of therapeutics for muscle diseases such as facioscapulohumeral dystrophy (FSHD) is impeded by a lack of objective, minimally invasive biomarkers. Here we identify circulating miRNAs and proteins that are dysregulated in early-onset FSHD patients to develop blood-based molecular biomarkers. Plasma samples from clinically characterized individuals with early-onset FSHD provide a discovery group and are compared to healthy control volunteers. Low-density quantitative polymerase chain reaction (PCR)-based arrays identify 19 candidate miRNAs, while mass spectrometry proteomic analysis identifies 13 candidate proteins. Bioinformatic analysis of chromatin immunoprecipitation (ChIP)-seq data shows that the FSHD-dysregulated DUX4 transcription factor binds to regulatory regions of several candidate miRNAs. This panel of miRNAs also shows ChIP signatures consistent with regulation by additional transcription factors which are up-regulated in FSHD (FOS, EGR1, MYC, and YY1). Validation studies in a separate group of patients with FSHD show consistent up-regulation of miR-100, miR-103, miR-146b, miR-29b, miR-34a, miR-454, miR-505, and miR-576. An increase in the expression of S100A8 protein, an inflammatory regulatory factor and subunit of calprotectin, is validated by Enzyme-Linked Immunosorbent Assay (ELISA). Bioinformatic analyses of proteomics and miRNA data further support a model of calprotectin and toll-like receptor 4 (TLR4) pathway dysregulation in FSHD. Moving forward, this panel of miRNAs, along with S100A8 and calprotectin, merit further investigation as monitoring and pharmacodynamic biomarkers for FSHD.

Infants born very preterm (VPT; ≤29 weeks of gestation) are at high risk of developmental disabilities and abnormalities in neural white matter characteristics. Early physical therapy interventions such as Supporting Play Exploration and Early Development Intervention (SPEEDI2) are associated with improvements in developmental outcomes. Six VPT infants were enrolled in a randomised clinical trial of SPEEDI2 during the transition from the neonatal intensive care unit to home over four time points. Magnetic resonance imaging scans and fixel-based analysis were performed, and fibre density (FD), fibre cross-section (FC), and fibre density and cross-section values (FDC) were computed. Changes in white matter microstructure and macrostructure were positively correlated with cognitive, motor, and motor-based problem solving over time on developmental assessments. In all infants, the greatest increase in FD, FC, and FDC occurred between Visit 1 and 2 (mean chronological age: 2.68–6.22 months), suggesting that this is a potential window of time to optimally support adaptive development. Results warrant further studies with larger groups to formally compare the impact of intervention and disparity on neurodevelopmental outcomes in infants born VPT.

Understanding the type and frequency of current neonatal intensive care unit (NICU) therapy services and predictors of referral for therapy services is a crucial first step to supporting positive long-term outcomes in very preterm infants. This study enrolled 83 very preterm infants (<32 weeks, gestational age mean 26.5 ± 2.0 weeks; 38 male) from a longitudinal clinical trial. Race, neonatal medical index, neuroimaging, and frequency of therapy sessions were extracted from medical records. The Test of Infant Motor Performance and the General Movement Assessment were administered. Average weekly sessions of occupational therapy, physical therapy, and speech therapy were significantly different by type, but the magnitude and direction of the difference depended upon the discharge week. Infants at high risk for cerebral palsy based on their baseline General Movements Assessment scores received more therapy sessions than infants at low risk for cerebral palsy. Baseline General Movements Assessment was related to the mean number of occupational therapy sessions but not physical therapy or speech therapy sessions. Neonatal Medical Index scores and Test of Infant Motor Performance scores were not predictive of combined therapy services. Medical and developmental risk factors, as well as outcomes from therapy assessments, should be the basis for referral for therapy services in the neonatal intensive care unit.