Motor Milestones Research Articles

Motor phenotypes associated with genetic neurodevelopmental disorders.

There is a growing number of monogenic disorders implicated in neurodevelopmental disorders (NDDs), including autism spectrum disorder and intellectual disability. Motor impairment is frequently seen in these disorders, although not clearly defined. We aimed to characterize the motor phenotype of genetic NDDs. We analyzed data from Simons Searchlight, collecting information on patients with genetic NDDs. Data analyzed included Vineland Adaptive Behavior Scales Second Edition (Vineland-II) motor standard scores, motor milestones and tone abnormalities. In total, 959 patients with 57 genetic disorders were included. Disorders associated with Vineland-II motor standard score <56 included GRIN2B-related disorder (mean standard score = 53.5), HNRNPH2-related disorder (mean standard score = 55.8) and SCN2A-related disorder (mean standard score = 49.9). The only genetic condition with a mean age of sitting unsupported ≥18 months was GRIN1-related disorder (mean age = 26.3 months). Genetic conditions with a mean age of walking independently ≥36 months included CTNNB1-related disorder (mean age = 37.4 months) and HNRNPH2-related disorder (mean age = 41.9 months). Tone abnormalities included hypotonia in 83% (577/696), hypertonia in 16% (112/696), a diagnosis of cerebral palsy (CP) in 10% (73/696) and a diagnosis specifically of spastic CP in 3% (23/696). Patients with genetic NDDs have a spectrum of motor impairment, which warrant further characterization.

Corrigendum: Association among biomarkers, phenotypes, and motor milestones in Chinese patients with 5q spinal muscular atrophy types 1–3

Corrigendum: Association among biomarkers, phenotypes, and motor milestones in Chinese patients with 5q spinal muscular atrophy types 1–3

Infant Motor Milestones: Analysis of Content and Variability Among Popular Sources for Parents.

Evaluate the content and variability of infant motor milestone education provided to parents in popular sources. Sources were screened for inclusion, and their motor milestone content was coded. Descriptive and inferential analyses were performed. Content from 241 websites, applications, and books was evaluated; 6984 motor milestones were extracted, representing 146 unique milestone codes across 14 categories. Books and applications had more milestone content than websites. There was variability in the milestones mentioned and their associated ages across the sources and relative to the American Academy of Pediatrics (AAP) and Centers for Disease Control and Prevention (CDC) content. Several frequently mentioned milestones were behaviors that facilitate early learning. There is variability among sources in the motor milestones they provide to parents of infants. The AAP and CDC content likely has some influence on the broader content available, but there is substantial deviation from the information they provide.

Delayed Milestones and Demographic Factors Relate to the Accuracy of Autism Screening in Females Using Spoken Language.

Examine how milestone development, demographics, and emotional/behavioral functioning predict autistic females meeting the cutoff on a commonly used Autism screening tool (Social Communication Questionnaire: SCQ). We hypothesized that autistic girls with fewer developmental delays, whose parents have lower education, or are Black or Multiracial would be less likely to meet the SCQ cutoff. Further, those with more symptoms of Withdrawal/Depression, Social Problems, Thought Problems, and Attention Problems on the (Child Behavioral Checklist: CBCL) would be more likely to screen positive. A subset of participants enrolled in a large national cohort (SPARK) were included (5,946 autistic females). A cutoff score on the SCQ of 11was used to form groups: Meet (M: N = 5,186) and Not Meeting (NM: N = 760). Autistic girls who had delayed toileting and motor milestones and whose parents attained higher education were more likely to screen positive. Girls who scored within the clinical range on the CBCL Thought Problems and Attention Problems syndrome scales were more likely to screen positive. Race and reported symptoms on the Withdrawn/Depressed and Social Problems syndrome scales did not relate to screening status. Results further support the existing literature suggesting that autistic girls must present with more significant delays/symptoms to be screened and diagnosed with autism, which can could impact their access to early intervention services and future skill development. Future research should examine additional factors that specifically put females at a disadvantage for being accurately identified, particularly for those who are speaking and/or of average cognitive ability.

Yellow Fever Vaccine-Associated Neurotropic Disease: A Case Report Of A 9-Month Old Infant And Review Of Literature

Introduction Yellow fever vaccine-associated neurotropic disease (YEL-AND) is a rare and serious complication following vaccination with the 17D live attenuated yellow fever vaccine. Cases of YEL-AND present as acute inflammatory demyelinating polyneuropathy, acute disseminated encephalomyelitis, and meningoencephalitis and encephalitis. To date, only a few cases have been reported in the literature in children. Methods/Subject We present the case of a 9-month-old male who developed YEL-AND. He suffered "3 episodes of unprovoked generalized tonicclonic seizure," the first occurring within 2 hours of receiving a dose of the Yellow Fever vaccine, Measles, and Meningococcal vaccines. He was lethargic for 28 hours and had intermittent inconsolable cries for 48 hours, low-grade fever, and loss of motor milestones (sitting and standing). Available laboratory investigations and neuroimaging ruled out other possible causes. He was treated with anticonvulsants and IV Methylprednisolone and made a significant recovery and was discharged on the sixth day and has remained stable on follow-up. His clinical presentation, neuroimaging, and challenges in his management are discussed in this case report. Conclusion The licensed Yellow fever vaccines are safe, effective for the prevention of Yellow fever, and highly recommended, however, it is not completely devoid of serious adverse reactions. This case highlights a possibility of a very early onset of YEL-AND in children and should be suspected in individuals with a temporal relationship of symptom onset to vaccination.

Childhood Developmental Milestones and Risk of Adult Cerebrovascular Disease: The Northern Finland Birth Cohort 1966

Introduction: To the best of our knowledge, no previous studies have examined the relationship between childhood developmental milestones and risk of adulthood cerebrovascular disease (CeVD). We studied whether the risk of adult CeVD is associated with delayed attainment of motor and language milestones. Methods: Within the Northern Finland Birth Cohort 1966, a total of 11,688 persons were followed from birth to either death, moving abroad or 54 years of age. CeVD diagnoses, i.e., ischemic and hemorrhagic strokes and transient ischemic attacks, were extracted from national registers with diagnostic coding based on recommendations of the World Health Organization. Cox proportional hazard models stratified by sex were used to estimate associations of motor development and language milestones between ages 0 and 4 years and adult CeVD women-to-men relative hazard ratios (RHRs) were estimated for each developmental milestone. Analyses were adjusted for family socioeconomic status and birth weight for gestational age. Results: Altogether 498 (4.3%) CeVDs were recorded during follow-up. Among both sexes, later turning from back to tummy was associated with ischemic CeVD in adulthood with an adjusted hazard ratio (aHR) of 1.25 and 95% confidence interval (CI) 1.06–1.46 for men and an aHR: 1.20 (CI: 1.02–1.42) for women per 1 month delay in achievement. Delayed overall motor development, modeled by motor milestone principal component score, was related to increased risk of ischemic CeVD (aHR: 1.50; CI: 1.03–2.19) among men. Later achievement of making sounds was associated with any CeVD (aHR: 2.74; CI: 1.39–5.40) and especially ischemic CeVD (aHR: 3.41; CI: 1.65–7.06) among men with women-to-men RHR’s of 0.17 (95% CI: 0.04–0.81) for any CeVD and RHR 0.18 (95% CI: 0.04–0.89) for ischemic stroke indicating risk to be lower in women compared to men. Conclusions: These findings suggest that later achievement of childhood milestones could be a predictor for development of CeVD risk. The results point toward a common neurodevelopmental background and could in part explain lifetime CeVD risk accumulation.

Longitudinal Change in Physical Activity in Children 6 to 36 Months of Age

To describe the developmental pattern for physical activity (PA) in children 6-36 months of age and to identify factors that are longitudinally associated with PA as children transition from infancy to preschool age. The study employed a prospective, longitudinal design with baseline data collected when children were approximately 6 months of age. Mothers and infants (n = 124) were recruited through community and educational settings in South Carolina. Data were collected at 6-month intervals from 6 through 36 months. PA was measured via accelerometry. Mothers completed questionnaires that assessed independent variables, including parent characteristics, the child's sex, race, and ethnicity, birth/delivery type, motor milestones, sleep habits, dietary practices, childcare setting, and home environmental factors. Trained research staff administered anthropometric measures and assessed motor developmental status. Growth curve models described the age-related pattern for PA and evaluated relationships between independent variables and change in PA. PA increased by approximately 45% between 6 and 36 months of age and followed a curvilinear pattern, with most of the increase occurring between 6 and 24 months. The child's exposure to television/electronic media was negatively associated with change in PA, and the presence of older siblings in the home was positively associated with change in PA. As children develop from infancy to early childhood, their PA increases substantially, with most of the increase occurring by 24 months of age.

CHRNE-related Congenital Myasthenic Syndrome in Iran: Clinical and Molecular Insights

Variants in the CHRNE gene can lead to a condition called congenital myasthenic syndrome (CMS), which affects the neuromuscular junction (NMJ). CHRNE mutations are the most common cause of CMS. Seventy-seven patients with a possible diagnosis of CMS were referred to the neuromuscular clinic of Shariati Hospital affiliated with the Tehran University of Medical Sciences. We performed whole-exome sequencing (WES) to determine the underlying defect in a group of individuals with a possible diagnosis of CMS. Clinical features and morphological and molecular data on 33 patients with mutations in CHRNE were described. Age of onset, age at diagnosis, consanguinity, family history, motor milestone delay, ophthalmoparesis, generalized fatigue, dysphagia, neurophysiologic findings, and response to treatment of the patients were assessed. Nineteen CHRNE variants including 10 novel ones were identified. The most common mutations were c.1327del; (p.Glu443LysfsTer64) in four different families and c.1252-1267dup; (p.Cys423SerfsTer38) in three families. Clinical onset was mostly at birth or under one year with bilateral fatigable ptosis, ophthalmoplegia, bulbar weakness, and proximal muscle weakness. All patients were treated with pyridostigmine ± salbutamol, which resulted in improvement of motor function, dysphagia, and breathing.

A Rare Case of Paroxysmal Kinesigenic Dyskinesia with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Abstract Paroxysmal kinesigenic dyskinesia (PKD) represents a rare subset of movement disorders characterized by involuntary movements triggered by sudden voluntary actions, without loss of consciousness. Typically manifesting in the first or second decade of life, PKD can present as either familial or sporadic, with the most common mutation identified in familial cases being in the proline-rich transmembrane protein 2 gene. This abstract presents a unique case of PKD accompanied by a progressive spastic ataxic syndrome in a 17-year-old male with a history of consanguinity. The patient exhibited a constellation of symptoms including delayed motor milestones, unsteady gait, slurred speech, and dystonic movements, alongside neurological findings consistent with cerebellar dysfunction and peripheral neuropathy. Genetic testing revealed pathogenic variants in the SACS gene, confirming the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. This case underscores the importance of thorough neurological evaluation, including consideration of atypical presentations, in patients with PKD. In addition, it sheds light on the association between SACS gene mutations and an autosomal recessive variant of PKD, emphasizing the need for awareness and recognition of such rare manifestations in clinical practice.

Cognitive, emotional, communicative, and motor development in children born from couple’s gametes cryopreserved oocytes. A 20 years single-center experience

ObjectiveTo study if social and emotional, communicative, cognitive, motor development of children born from cryopreserved oocytes are comparable to general population. DesignSurvey study. ExposureThis is a single-center population study, focusing on all children born from cycles of in vitro fertilization of cryopreserved oocytes at Humanitas Fertility Center from January 1st,2003, until December 31st, 2021. Main outcome measuresGeneral information about birth history were collected from all parents. Then, screening for developmental delay was performed by administration of a questionnaire, edited according to milestones set for age by the Center for Disease Control and Prevention.Primary outcomes included the percentage of children, for each age range, that reached related milestones. In children younger than 6 years of age, milestones were considered to be reached by each age-based population subgroup studied when ≥ 75 % of included children expressed the tested competences. ResultsA total of 355 live births fulfilled the inclusion and exclusion criteria and were included in the study. Results showed that each age-based population subgroup, younger than 6 years of age, scored ≥ 75 % in all the milestones included in the questionnaire.In preadolescents and adolescents, it was noted a decrease in unstructured in-person socializing. Indeed, milestones that scored the lowest values, based on parents’ judgement, included tasks concerning peer-to-peer interaction (72.31%) and sexuality and sentimental relationships (63.08%). ConclusionsResults indicated that the achievement of emotional, communicative, cognitive, and motor milestones in infants, toddlers, and preschoolers was comparable to the general pediatric population. Similarly, emotional wellbeing and social engagement in school-aged children, preadolescents, and adolescents were in line with their peers.

Real-world multidisciplinary outcomes of onasemnogene abeparvovec monotherapy in patients with spinal muscular atrophy type 1: experience of the French cohort in the first three years of treatment

BackgroundSpinal muscular atrophy type 1 (SMA1) is the most severe and early form of SMA, a genetic disease with motor neuron degeneration. Onasemnogene abeparvovec gene transfer therapy (GT) has changed the natural history of SMA1, but real-world data are scarce.MethodsA French national expert committee identified 95 newly diagnosed treatment-naive SMA1 patients between June 2019 and June 2022. We prospectively report on children treated with GT as the first and only therapy who had more than one-year of follow-up.ResultsForty-six SMA1 patients received GT. Twelve patients received other treatments. Patients with respiratory insufficiency were oriented toward palliative care after discussion with families. Twenty-nine of the treated patients with more than 12 months of follow-up were included in the follow-up analysis. Among them, 17 had 24 months of follow-up. The mean age at treatment was 7.5 (2.1–12.5) months. Twenty-two patients had two SMN2 copies, and seven had three copies. One infant died in the month following GT due to severe thrombotic microangiopathy, and another died due to respiratory distress. Among the 17 patients with 24 months of follow-up, 90% required spinal bracing (15/17), three patients required nocturnal noninvasive ventilation, and two needed gastrostomy. Concerning motor milestones at the 24-month follow-up, all patients held their head, 15/17 sat for 30 s unassisted, and 12/17 stood with aid. Motor scores (CHOPINTEND and HINE-2) and thoracic circumference significantly improved in all patients.ConclusionsOur study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by GT as the first and only therapy before respiratory and bulbar dysfunctions occurred. Nevertheless, almost all patients developed spinal deformities.

A - 63 Sotos Syndrome: a Case Study

Abstract Objective Sotos syndrome is a genetic disorder characterized by pre and postnatal overgrowth and a non-progressive neurological disorder frequently accompanied by intellectual disability. The estimated prevalence is 1:14,000 live births; however, misdiagnosis is common due to features being attributable to other conditions. This case study highlights the broad range of symptom presentation in individuals with Sotos syndrome and adds to the limited available literature on this rare condition. Method The patient is a 26-year-old female with no prior neuropsychological testing presenting with concerns for cognitive functioning, regression of skills, and emotional/behavioral dysregulation. Concerns were raised for an underlying autism spectrum disorder. She presents with large stature, prominent facial configuration, and hypotonia. Developmental history was significant for delayed motor and language milestones. She has a history of absence seizures in childhood and was evaluated by neurology and medical genetics and diagnosed with Sotos syndrome. Results The patient’s overall intellectual functioning was in the exceptionally low range with a personal strength in verbal skills. Her neurocognitive results and low adaptive skills are indicative of a moderate intellectual disability. The patient’s developmental history, social difficulties, restrictive interests, and repetitive behaviors met criteria for autism spectrum disorder. Another notable finding was frequent starring spells in which she became unresponsive for approximately 15 seconds. Conclusion Delayed motor and language milestones, hypotonia, behavioral problems, and intellectual disability are common in individuals with Sotos syndrome and were present in the patient. Seizures and scoliosis are less common in individuals diagnosed, for which she was referred to a neurologist for further work-up.

Association among biomarkers, phenotypes, and motor milestones in Chinese patients with 5q spinal muscular atrophy types 1-3.

Biomarkers can be used to assess the severity of spinal muscular atrophy (5q SMA; SMA). Despite their potential, the relationship between biomarkers and clinical outcomes in SMA remains underexplored. This study aimed to assess the association among biomarkers, phenotypes, and motor milestones in Chinese patients diagnosed with SMA. We collected retrospective clinical and follow-up data of disease-modifying therapy (DMT)-naïve patients with SMA at our center from 2019 to 2021. Four biomarkers were included: survival motor neuron 2 (SMN2) copies, neuronal apoptosis inhibitory protein (NAIP) copies, full-length SMN2 (fl-SMN2), and F-actin bundling protein plastin 3 (PLS3) transcript levels. Data were analyzed and stratified according to SMA subtype. Of the 123 patients, 30 were diagnosed with Type 1 (24.3%), 56 with Type 2 (45.5%), and 37 with Type 3 (30.1%). The mortality rate for Type 1 was 50%, with median survival times of 2 and 8 months for types 1a and 1b, respectively. All four biomarkers were correlated with disease severity. Notably, fl-SMN2 transcript levels increased with SMN2 copies and were higher in Type 2b than those in Type 2a (p = 0.028). Motor milestone deterioration was correlated with SMN2 copies, NAIP copies, and fl-SMN2 levels, while PLS3 levels were correlated with standing and walking function. Our findings suggest that SMN2 copies contribute to survival and that fl-SMN2 may serve as a valuable biomarker for phenotypic variability in SMA Type 2 subtypes. These insights can guide future research and clinical management of SMA.

Outcomes for patients in the RESTORE registry with spinal muscular atrophy and four or more SMN2 gene copies treated with onasemnogene abeparvovec

ObjectiveWe describe outcomes following onasemnogene abeparvovec monotherapy for patients with ≥four survival motor neuron 2 (SMN2) gene copies in RESTORE, a noninterventional spinal muscular atrophy patient registry. MethodsWe evaluated baseline characteristics, motor milestone achievement, post-treatment motor function, use of ventilatory/nutritional support, and adverse events as of December 22, 2022. ResultsAt data cutoff, 19 patients in RESTORE had ≥four SMN2 copies and were treated with onasemnogene abeparvovec monotherapy (n=12 [63.2%] four copies; n=7 [36.8%] >four copies). All patients were identified by newborn screening and were reported as asymptomatic at diagnosis. Median age at onasemnogene abeparvovec administration was 3.0 months. Median time from treatment to last recorded visit was 15.4 months, with a range of post-treatment follow-up of 0.03–39.4 months. All 12 children who were assessed for motor development achieved new milestones, including standing alone (n=2) and walking alone (n=5). Five children reported one or more treatment-emergent adverse events (one Grade 3 or greater). No deaths or use of ventilatory/nutritional support were reported. ConclusionsReal-world findings from the RESTORE registry indicate that patients with ≥four SMN2 gene copies treated with onasemnogene abeparvovec monotherapy demonstrated improvements in motor function. Adverse events experienced by these patients were consistent with previously reported findings.

An International Retrospective Early Natural History Study of LAMA2-Related Dystrophies.

LAMA2-related dystrophies (LAMA2-RDs) represent one of the most common forms of congenital muscular dystrophy and have historically been classified into two subtypes: complete or partial deficiency of laminin-211 (merosin). Patients with LAMA2-RD with the typical congenital phenotype manifest severe muscle weakness, delayed motor milestones, joint contractures, failure to thrive, and progressive respiratory insufficiency. While a comprehensive prospective natural history study has been performed in LAMA2-RD patients over 5 years of age, the early natural history of patients with LAMA2-RD 5 years and younger has not been comprehensively characterized. We extracted retrospective data for patients with LAMA2-RD ages birth through 5 years via the Congenital Muscle Disease International Registry (CMDIR). We analyzed the data using a phenotypic classification based on maximal motor milestones to divide patients into two phenotypic groups: "Sit" for those patients who attained that ability to remain seated and "Walk" for those patients who attained the ability to walk independently by 3.5 years of age. Sixty patients with LAMA2-RD from 10 countries fulfilled the inclusion criteria. Twenty-four patients had initiated non-invasive ventilation by age 5 years. Hospitalizations during the first years of life were often related to respiratory insufficiency. Feeding/nutritional difficulties and orthopedic issues were commonly reported. Significant elevations of creatine kinase (CK) observed during the neonatal period declined rapidly within the first few months of life. This is the largest international retrospective early natural history study of LAMA2-RD to date, contributing essential data for understanding early clinical findings in LAMA2-RD which, along with the data being collected in international, prospective early natural history studies, will help to establish clinical trial readiness. Our proposed nomenclature of LAMA2-RD1 for patients who attain the ability to sit (remain seated) and LAMA2-RD2 for patients who attain the ability to walk independently is aimed at further improving LAMA2-RD classification.

Quantifying the Spectrum of Early Motor and Language Milestones in Sex Chromosome Trisomy.

Sex chromosome trisomy (SCT) is a common chromosomal abnormality associated with increased risks for early developmental delays and neurodevelopmental disorders later in childhood. Our objective was to quantify the spectrum of early developmental milestones in SCT. We hypothesized later milestone achievement in SCT than the general population. Data were collected as part of the eXtraordinarY Babies Study, a prospective natural history of developmental and health trajectories in a prenatally identified sample of infants with SCT. Parent reported, clinician-validated, early motor and language milestones were collected at 2, 6, 12, 18, 24, and 36-months. Age distributions of milestone achievement were compared with normative data. In all SCT conditions, compared with normative data, there was increased variability and a later median age of skill development across multiple gross motor and expressive language milestones. Results also show a significant amount of overlap with the general pediatric population, suggesting that for many children with prenatally identified SCT, early milestones present within, or close to, the expected timeline. As increasing numbers of infants with prenatal SCT diagnoses present at pediatric practices, we provide an evidence-based schedule of milestone achievement in SCT as a tool for pediatricians and families. Detailed data on SCT milestones can support clinical interpretation of milestone achievement. Increased variability and later median age of milestone acquisition in SCT compared to norms support consideration of all infants with SCT as high risk.

Systematic Review of Presymptomatic Treatment for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) causes the degeneration of motor neurons in the spinal cord. Treatments including nusinersen, risdiplam, and onasemnogene abeparvovec have been shown to be effective in reducing symptoms, with recent studies suggesting greater effectiveness when treatment is initiated in the presymptomatic stage. This systematic review synthesises findings from prospective studies of presymptomatic treatment for 5q SMA published up to December 2023. The review identified three single-arm interventional studies of presymptomatic treatment (NURTURE, RAINBOWFISH, and SPR1NT), six observational studies comparing presymptomatic or screened cohorts versus symptomatic cohorts, and twelve follow-up studies of screened cohorts only (i.e., babies identified via newborn screening for SMA). Babies with three SMN2 copies met most motor milestones in the NURTURE study of nusinersen and in the SPR1NT study of onasemnogene abeparvovec. Babies with two SMN2 copies in these two studies met most motor milestones but with some delays, and some required ventilatory or feeding support. The RAINBOWFISH study of risdiplam is ongoing. Naïve comparisons of presymptomatic treatment in SPR1NT, versus untreated or symptomatic treatment cohorts, suggested improved outcomes in patients treated presymptomatically. Comparative observational studies supported the finding that presymptomatic treatment, and early treatment following screening, may improve outcomes compared with treatment at the symptomatic stage. Further research should assess the long-term clinical outcomes and cost-effectiveness of presymptomatic treatment for SMA.

Neurodevelopmental profiles of 14 individuals with phosphomannomutase deficiency (PMM2-CDG).

PMM2-CDG (formerly CDG-1a), the most common type of congenital disorders of glycosylation, is inherited in an autosomal recessive pattern. PMM2-CDG frequently presents in infancy with multisystemic clinical involvement, and it has been diagnosed in over 1000 people worldwide. There have been few natural history studies reporting neurodevelopmental characterization of PMM2-CDG. Thus, a prospective study was conducted that included neurodevelopmental assessments as part of deep phenotyping. This study, Clinical and Basic Investigations into Known and Suspected Congenital Disorders of Glycosylation (NCT02089789), included 14 participants (8 males and 6 females ages 2-33 years) with a confirmed molecular diagnosis of PMM2-CDG. Clinical features of PMM2-CDG in this cohort were neurodevelopmental disorders, faltering growth, hypotonia, cerebellar atrophy, peripheral neuropathy, movement disorders, ophthalmological abnormalities, and auditory function differences. All PMM2-CDG participants met criteria for intellectual disability (or global developmental delay if younger than age 5). The majority never attained certain gross motor and language milestones. Only two participants were ambulatory, and almost all were considered minimally verbal. Overall, individuals with PMM2-CDG present with a complex neurodevelopmental profile characterized by intellectual disability and multisystemic presentations. This systematic quantification of the neurodevelopmental profile of PMM2-CDG expands our understanding of the range in impairments associated with PMM2-CDG and will help guide management strategies.

Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: results from the 36-month TOPAZ study.

At 12 months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36 months. Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20 mg/kg by intravenous infusion every 4 weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3 years). The mean change at 36 months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and + 2.4 (3.24) for RULM score (excluding n = 7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36 months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%). The benefit of apitegromab treatment observed at 12 months was sustained at 36 months with no new safety findings.

Preclinical studies of gene replacement therapy for CDKL5 deficiency disorder

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by a mutation in the X-linked CDKL5 gene. CDKL5 is a serine/threonine kinase that is critical for axon outgrowth and dendritic morphogenesis as well as synapse formation, maturation, and maintenance. This disorder is characterized by early-onset epilepsy, hypotonia, and failure to reach cognitive and motor developmental milestones. Because the disease is monogenic, delivery of the CDKL5 gene to the brain of patients should provide clinical benefit. To this end, we designed a gene therapy vector, adeno-associated virus (AAV)9.Syn.hCDKL5, in which human CDKL5 gene expression is driven by the synapsin promoter. In biodistribution studies conducted in mice, intracerebroventricular (i.c.v.) injection resulted in broader, more optimal biodistribution than did intra-cisterna magna (i.c.m.) delivery. AAV9.Syn.hCDKL5 treatment increased phosphorylation of EB2, a bona fide CDKL5 substrate, demonstrating biological activity invivo. Our data provide proof of concept that i.c.v. delivery of AAV9.Syn.hCDKL5 to neonatal male Cdkl5 knockout mice reduces pathology and reduces aberrant behavior. Functional improvements were seen at doses of 3e11 to 5e11 vector genomes/g brain, which resulted in transfection of ≥50% of the neurons. Functional improvements were not seen at lower doses, suggesting a requirement for broad distribution for efficacy.