Motor Developmental Milestones Research Articles

Early neurological signs in infants identified through neonatal screening for SMA: do they predict outcome?

Neonatal screening for SMA has allowed the identification of infants who may present with early clinical signs. Our aim was to establish whether the presence and the severity of early clinical signs have an effect on the development of motor milestones. Infants identified through newborn screening were prospectively assessed using a structured neonatal neurological examination and an additional module developed for the assessment of floppy infants. As part of the follow-up, all infants were assessed using the HINE-2 to establish developmental milestones. Only infants with at least 24months of follow-up were included. Normal early neurological examination (n = 11) was associated with independent walking before the age of 18months while infants with early clinical signs of SMA (n = 4) did not achieve ambulation (duration follow-up 33.2months). Paucisymptomatic patients (n = 3) achieved ambulation, one before the age of 18months and the other 2 between 22 and 24months. Conclusion: Our findings suggest that early clinical signs may contribute to predict motor milestones development. What is Known: • There is increasing evidence of heterogeneity among the SMA newborns identified via NBS. • The proposed nosology describes a clinically silent disease, an intermediate category ('paucisymptomatic') and 'symptomatic SMA'. What is New: • The presence of minimal clinical signs at birth does not prevent the possibility to achieve independent walking but this may occur with some delay. • The combination of genotype at SMN locus and clinical evaluation may better predict the possibility to achieve milestones.

COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum

BackgroundCongenital myasthenic syndrome (CMS) is a group of neuromuscular disorders caused by abnormal signal transmission at the motor endplate. Mutations in the collagen-like tail subunit gene (COLQ) of acetylcholinesterase are responsible for recessive forms of synaptic congenital myasthenic syndromes with end plate acetylcholinesterase deficiency. Clinical presentation includes ptosis, ophthalmoparesis, and progressive weakness with onset at birth or early infancy.MethodsWe followed 26 patients with COLQ-CMS over a mean period of 9 years (ranging from 3 to 213 months) and reported their clinical features, electrophysiologic findings, genetic characteristics, and therapeutic management.ResultsIn our population, the onset of symptoms ranged from birth to 15 years. Delayed developmental motor milestones were detected in 13 patients (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\sim$$\\end{document} 52%), and the most common presenting signs were ptosis, ophthalmoparesis, and limb weakness. Sluggish pupils were seen in 8 (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\sim$$\\end{document} 30%) patients. All patients who underwent electrophysiologic study showed a significant decremental response (> 10%) following low-frequency repetitive nerve stimulation. Moreover, double compound muscle action potential was evident in 18 patients (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\sim$$\\end{document} 75%). We detected 14 variants (eight novel variants), including six missense, three frameshift, three nonsense, one synonymous and one copy number variation (CNV), in the COLQ gene. There was no benefit from esterase inhibitor treatment, while treatment with ephedrine and salbutamol was objectively efficient in all cases.ConclusionDespite the rarity of the disease, our findings provide valuable information for understanding the clinical and electrophysiological features as well as the genetic characterization and response to the treatment of COLQ-CMS.

Neurodevelopmental disorders and the role of PSD-95: Understanding pathways and pharmacological interventions

Neurodevelopmental disorders (NDDs) are often linked to disruption in brain development and present challenges for affected individuals in achieving their cognitive, emotional, and motor developmental milestones. NDDs encompass a spectrum of conditions, including autism spectrum disorder (ASD), schizophrenia (SCZ), attention-deficit hyperactivity disorder (ADHD), and epilepsy. The unequivocal diagnosis of an NDD is often challenging due to overlapping signs and symptoms across different conditions. Synaptic plasticity, the activity-driven modification of synaptic strength and efficacy, plays a crucial role in brain network formation and organization and is frequently altered in NDDs. Here, we explore the multifaceted roles of postsynaptic density-95 kDa (PSD-95) in NDDs. Psd-95 is a scaffolding protein belonging to the membrane-associated guanylate kinases (MAGUKs) family, located at the core of synapses, and is central to synaptic plasticity. Dysregulation of PSD-95 is linked to various neuropsychiatric disorders. In SCZ, decreased PSD-95 expression affects synaptic plasticity, thereby impacting learning and memory. Genes associated with ASD interact with PSD-95, and its removal in mice leads to ASD-like behavioral abnormalities. Furthermore, PSD-95 is implicated in ADHD, where its modulation influences neurotransmission. Medications used in NDD treatment, such as antipsychotic drugs and selective serotonin reuptake inhibitors (SSRIs), can alter PSD-95 levels, potentially influencing synapse formation. Alpha-2 adrenergic agonists might enhance synaptic integrity by impacting PSD-95. Alternative pharmacotherapies such as memantine, allopurinol, and ketamine, all influencing PSD-95 to a certain extent, hold promise in managing NDDs. Understanding the role of PSD-95 in these disorders can deepen our biological comprehension and pave the way for targeted therapies. Specifically, exploring how PSD-95 affects synaptic plasticity and dendritic spine development could uncover opportunities for repurposing drugs to treat NDDs associated with mutations in the DLG4 gene encoding PSD-95.

The potential and importance of exercise therapy in pediatric oncology – The PrepAIR study

Introduction Modern therapy has improved survival for children with cancer. However, treatment takes its toll. Children experience delays in motor development milestones such as walking, running, jumping or climbing, diminishing children’s quality of life and affecting their social reintegration. One side-effect of chemotherapy and crucial cause of the many dysfunctions is a peripheral neuropathy (CIPN). Depending on the neurotoxic agent, 52%-100% of children are affected (Kandula et al. 2016). It causes severe symptoms such as loss of sensation, numbness, pain, absent reflexes as well as loss of balance control. It is also of high clinical relevance as it affects medical therapy. Additionally, recovery is poor and there are currently no treatment options (Loprinzi et al. 2020). Previous research has shown (Streckmann et al. 2022) promising results: Specific exercises can reduce symptoms of CIPN and improve patients’ quality of life. In our most recent study in adults, we were also able to prevent the onset of CIPN with clinical impact. We hypothesize that CIPN could be the root of many problems children experience during therapy. Our aim is to maintain relevant sensory and motor functions in children in order for them to receive their planned medical therapy and become fitter and socially better integrated survivors. Methods We are therefore currently running a large, prospective, multicenter, randomized controlled trial (Basel, Bern, Aarau, St. Gallen, Freiburg (D) and Berlin (D)), randomizing N = 131 children planned to receive a neurotoxic chemotherapy into an intervention group or a treatment as usual group and accompanying them throughout their oncological therapy. After therapy the control group will also be shown the training. Primary endpoint is the incidence of CIPN, secondary endpoints are postural control, dorsiflexion function, knee extension strength, lower limb power, walk to run transition time, CIPN-related pain, participation of exercise-related leisure activities, children’s’ physical self-concept and quality of life. Discussion/Conclusion We hypothesize that less children in the intervention group will develop symptoms of CIPN and will be able to maintain relevant motor and sensory functions which will enable them to receive their planned medical therapy but also to stay on the age-appropriate motor development level, improve their quality life and enhance social reintegration after therapy. This would show that specific exercise therapy is more than just a lifestyle intervention, it could be a therapy option without further side- effects, changing supportive care in oncology. This study will therefore contribute to our endeavors to implement exercise therapy in pediatric oncology long-term empowering patients to return to an active lifestyle and additionally reduce the risk of long-term secondary diseases.

A position statement on the post gene-therapy rehabilitation of aromatic I-amino acid decarboxylase deficiency patients

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder of monoamine neurotransmitter synthesis that presents with a range of symptoms, including motor dysfunction and limited attainment of developmental motor milestones. The approval of eladocagene exuparvovec, a gene therapy for AADC deficiency with demonstrated efficacy for motor improvements, now expands the range of motor outcomes possible for patients with this disorder. However, recommendations and guidelines for therapy following treatment with gene therapy are lacking. To ensure patients can reach their full potential following treatment with gene therapy, it is essential they receive rehabilitation therapies designed specifically with their impairments and goals in mind. Therefore, we highlight specific rehabilitative needs of patients following gene therapy and propose a set of recommendations for the post-treatment period based on collective experiences of therapists, physicians, and caregivers treating and caring for patients with AADC deficiency who have been treated with gene therapy. These recommendations include a focus on periods of intensive therapy, facilitating active movements, training for functional abilities, cognitive and communication training, parent/caregiver empowerment, collaboration between therapists and caregivers to develop in-home programs, and the incorporation of supplemental forms of therapy that patients and their families may find more enjoyable and engaging. Many of these rehabilitative strategies may be employed prior to gene therapy. However, these recommendations will be valuable for therapists, caregivers, and wider treatment teams as they prepare for the post-treatment journey with these patients. Furthermore, the considerations and recommendations presented here may prove beneficial outside the AADC deficiency community as gene therapies and other treatments are developed and approved for other rare diseases.

Reduced corticospinal drive to antagonist muscles of upper and lower limbs during hands-and-knees crawling in infants with cerebral palsy: Evidence from intermuscular EMG-EMG coherence

BackgroundThere is growing interest in understanding the central control of hands-and-knees crawling, especially as a significant motor developmental milestone for early assessment of motor dysfunction in infants with cerebral palsy (CP) who have not yet acquired walking ability. In particular, CP is known to be associated with walking dysfunctions caused by early damage and incomplete maturation of the corticospinal tract. However, the extent of damage to the corticospinal connections during crawling in infants with CP has not been fully clarified. Therefore, this study aimed to investigate the disparities in intermuscular EMG-EMG coherence, which serve as indicators of corticospinal drives to antagonist muscles in the upper and lower limbs during crawling, between infants with and without CP. MethodsThis study involved 15 infants diagnosed with CP and 20 typically developing (TD) infants. Surface EMG recordings were obtained from two pairs of antagonist muscles in the upper limbs (triceps brachii (TB) and biceps brachii (BB)) and lower limbs (quadriceps femoris (QF) and hamstrings (HS)), while the infants performed hands-and-knees crawling at their self-selected velocity. Intermuscular EMG-EMG coherence was computed in two frequency bands, the beta band (15–30 Hz) and gamma band (30–60 Hz), which indicate corticospinal drive. Additionally, spatiotemporal parameters, including crawling velocity, cadence, duration, and the percentage of stance phase time, were calculated for comparison. Spearman rank correlations were conducted to assess the relationship between EMG-EMG coherence and crawling spatiotemporal parameters. ResultsInfants with CP exhibited significantly reduced crawling velocity, decreased cadence, longer cycle duration, and a higher percentage of stance phase time compared to TD infants. Furthermore, CP infants demonstrated decreased coherence in the beta and gamma frequency bands (indicators of corticospinal drive) in both upper and lower limb muscles. Regarding limb-related differences in the beta and gamma coherence, significant disparities were found between upper and lower limb muscles in TD infants (p < 0.05), but not in infants with CP (p > 0.05). Additionally, significant correlations between coherence metrics and crawling spatiotemporal parameters were identified in the TD group (p < 0.05), while such correlations were not evident in the CP group. ConclusionsOur findings suggest that the corticospinal drive may functionally influence the central control of antagonist muscles in the limbs during typical infant crawling. This functional role could be impaired by neurological conditions such as cerebral palsy. The neurophysiological markers of corticospinal drive, specifically intermuscular EMG-EMG coherence during crawling in infants with cerebral palsy, could potentially serve as a tool to assess developmental response to therapy.

Access to Care Limitations: When Distance and Lack of Evidence Meet.

Jimmy is a 13-year-old adolescent boy who was diagnosed with Down syndrome (trisomy 21) prenatally. Jimmy is the only individual with Down syndrome in the small, rural community where he lives with his parents. He has mild sleep apnea, and his gross and fine motor developmental milestones were generally consistent with those expected among children with Down syndrome. At age 4, his parents raised concerns about his limited language, strong preference to be alone, and refusal to leave the house. Parents had observed his marked startle response to loud laughter and adult male voices. At age 7, his preferred activities consisted of dangling necklaces or shoelaces in front of his face and rocking his body forward and backward when seated. After limited progress in special education, speech, and occupational therapies, he was referred, at age 8, to a specialty center 3 hours from his home for a multidisciplinary evaluation. There, he received a diagnosis of co-occurring autism spectrum disorder (ASD).Over the last year, his repetitive behaviors have become more intense. He hits the side of his head with his fist and presses his thumbs into his eyes, causing bruising. Any attempts to remove his dangle objects are met with aggressive behaviors, including hitting, kicking, scratching, and elopement. At school, he refuses to complete work and sometimes hits his teacher. Aggression stops in the absence of educational demands. School staff informed parents they are not equipped to handle Jimmy's behaviors.Jimmy recently presented to the specialty center for developmental-behavioral pediatric and psychology support at the request of his primary care clinician. The developmental pediatrician discussed with Jimmy's parents the possibility of a trial of medication to address disruptive/aggressive behavior if there is not improvement with initiation of behavioral strategies. The psychologist began weekly behavioral parent training visits through telehealth, including prevention strategies, reinforcement, and functional communication training. The strategies have helped decrease the frequency of elopement and aggressive behaviors. Self-injurious behaviors and refusal at school have remained constant.Despite some stabilization, limited local resources as well as the lack of evidence-based guidelines for people with both Down syndrome and ASD have impeded improvements in Jimmy's significant behavioral and developmental challenges. His parents have become increasingly isolated from critical family and community support as well. In what ways could the clinicians and community support this child and his family and prevent others from experiencing similar hardships?

Motor development of first born compared to later born children in the first two years of life – A replication

PurposeThe motor development of firstborns compared to children having an older sibling in the first two years of life was examined. MethodThe data of the study come from an ongoing research project with citizen participation, which is investigating the development of motor milestones in the first and second years of life. Parents report online their children's developmental progress using a development calendar. 18 motor skills from birth until children manage walking alone are recorded, 14 relate to gross motor skills and four to hand motor skills. ResultsChildren with siblings achieved higher values at birth in terms of Apgar-score, height, weight, BMI and parental satisfaction with the health and development of the child compared to firstborns. However, no differences could be found at the ages of 10–12 months and 14 months. Firstborns reached five fine motor and manual dexterity milestones earlier than children with siblings. In contrast, when mastering 13 gross motor milestones, no differences could be found between firstborns and children with siblings. ConclusionMotor development at an early age is considered to be largely genetically controlled, analogous to physical development. However, the faster development of the fine motor skills of the firstborns could be related to the fact that parents interact more intensively with their firstborn than with later born children and – unlike gross motor skills – in fine motor skills not only genetic factors but also learning processes are effective from a very early age.

Familial and genetic association with neurodevelopmental disorders caused by a heterozygous variant in the SRRM2 gene.

Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain development and function, characterized by an inability to reach cognitive, emotional, and motor developmental milestones. The pathology of NDDs is complex. A recent study found that variants in the SRRM2 gene cause NDDs. However, genetic conditions play the most important role in the etiology of NDD. The genetic causes of NDD are extremely heterogeneous, leading to certain challenges in clinical diagnosis. A pregnant woman with congenital intelligence disorder came to our hospital for genetic diagnosis to predict the status of her fetus. Her mother and a brother also suffer from congenital intelligence disorder. She has a daughter with speech delay. Whole exome sequencing was used to identify a mutation (c.1415C>G) in the SRRM2 gene of this family that resulted in a change in the 472nd amino acid residue of the SRRM2 protein from serine to terminated. We report a family with an autosomal dominant genetic disorder caused by variants in the SRRM2 gene causing NDDs. Prenatal diagnosis can help patients with this genetic disorder to have healthy offspring.

Phenotype Genotype Characterization of FKRP-related Muscular Dystrophy among Indian Patients.

The phenotypic spectrum of Fukutin-related protein (FKRP) mutations is highly variable and comprises of limb girdle muscular dystrophy (LGMD) R9 (previously LGMD 2I) and FKRP related congenital muscular dystrophies. To identify the distinct genotype phenotype pattern in Indian patients with FKRP gene mutations. We retrospectively reviewed the case files of patients with muscular dystrophy having a genetically confirmed FKRP mutation. All patients had undergone genetic testing using next-generation sequencing. Our patients included five males and four females presenting between 1.5 years and seven years of age (median age - 3 years). The initial symptom was a delayed acquisition of gross motor developmental milestones in seven patients and recurrent falls and poor sucking in one patient each. Two patients had a language delay, with both having abnormalities on the brain MRI. Macroglossia, scapular winging, and facial weakness were noted in one, three and four patients respectively. Calf muscle hypertrophy was seen in eight patients and ankle contractures in six. At the last follow-up, three patients had lost ambulation (median age - 7 years; range 6.5-9 years) and three patients had not attained independent ambulation. Creatine kinase levels ranged between 2793 and 32,396 U/L (mean 12,120 U/L). A common mutation - c.1343C>T was noted in 5 patients in our cohort. Additionally, four novel mutations were identified. Overall, six patients had an LGMD R9 phenotype, and three had a congenital muscular dystrophy phenotype. Patients with FKRP mutations can have varied presentations. A Duchenne-like phenotype was the most commonly encountered pattern in our cohort, with c.1343C>T being the most common mutation.

Pregnancy, pregnancy outcomes, and infant growth and development after recovery from Ebola virus disease in Liberia: an observational cohort study

Minimal data exist on pregnancy following recovery from Ebola in people of child-bearing potential (females aged roughly 18-45 years). The aim of this study was to assess viral persistence or reactivation in pregnancy, the frequency of placental transfer of anti-Ebola IgG antibodies, and pregnancy outcomes in this population. In this observational cohort study, we studied self-reported pregnancies in two groups: seropositive people who had recovered from Ebola virus disease (seropositive group) and seronegative people who had close contact with people with Ebola (seronegative group). Participants had enrolled in the PREVAIL III longitudinal study and were exposed during the 2014-2016 Liberian Ebola outbreak. The primary outcome was pregnancy result. We assessed rates of livebirths and other pregnancy results in both study groups, and presence of Ebola RNA by PCR in samples of placenta, maternal and cord blood, breastmilk, and vaginal secretions from people who had recovered from Ebola who conceived a median of 14 months after acute Ebola virus disease. Mixed-model logistic regression evaluated associations between first-reported pregnancy outcome, age, and study group. Growth and neurodevelopment in the infants born to people in the seropositive group were assessed at 6-month intervals for 2 years. Data were accrued by PREVAIL III study staff. 1566 participants were enrolled between June 17, 2015, and Dec 14, 2017, of whom 639 became pregnant (215 seropositive, 424 seronegative) and 589 reported pregnancy outcomes (206 seropositive, 383 seronegative). 105 infants born to 98 mothers in the seropositive group were enrolled in the birth cohort. Ebola RNA was not detected in 205 samples of placenta, cord blood, or maternal blood taken at birth from 54 mothers in the seropositive group, nor in 367 vaginal swabs. Viral RNA was found in two of 354 longitudinal breastmilk samples. All but one of 57 infants born during these 54 births were seropositive for anti-Ebola antibodies. Neonates showed high concentrations of anti-Ebola IgG, which declined after 6 months. Odds of adverse pregnancy outcome among the two groups were indistinguishable (OR 1·13, 95% CI 0·71-1·79). Compared with WHO standards, infants born to those in the seropositive group had lower median weight and length, and larger median head circumference over 2 years. Compared with a cohort from the USA accrual of gross motor developmental milestones was similar, whereas attainment of pincer grasp and early vocalisation were mildly delayed. The risks of Ebola virus reactivation in the peripartum and postpartum period and of adverse birth outcomes are low in those who have recovered from Ebola virus disease and become pregnant approximately 1 year after acute Ebola virus disease. The implication for clinical practice is that care of people who are pregnant and who have recovered from Ebola can be offered without risks to health-care providers or stigmatisation of the mothers and their offspring. The implication for prospective mothers is that safe pregnancies are entirely possible after recovery from Ebola. National Institute of Allergy and Infectious Diseases and Liberia Ministry of Health.

Contributions of Screen Use on Early Language and Development Milestones in Argentinean Toddlers from Different Socioeconomic Contexts

The objective of the following research was to describe the use of digital media (i.e., TV, background TV, cell phone, PC, and Tablet), presence of the adults during this activity, and its association with language, motor, and language developmental milestones and SES in the first years of life. Participants were 114 primary caregivers of toddlers between 12 and 36 months (M = 27.48 months, SD = 7.31, female = 58, low SES = 56). Parental reports of infant media use, motor and language development milestones, the Inventory of Skills Development (CDI), and the INDEC Scale (for SES) were used. The results showed that, on average, toddlers engaged for 1 h per day with TV and were passive recipients of background TV for 2 h a day, which was the most used screen. In addition, parents tend to share TV with toddlers. Language positively related with child Tablet use, book use, and TV shared with an adult, and there were negative associations with children’s cell phone and PC use alone and with an adult. For SES, having at least one basic need unsatisfied or less parental educational and occupancy was related with more background TV and use, less time sharing this type of media with toddlers, and less use and quantity of books at home. In general, there were no relations between digital media use and developmental milestones. This indicates that the excessive use of screens could relate to some early language skills, although it is necessary to investigate the context in which they are used.

Hypermanganesemia with Dystonia Type 2: A Rare Entity. (P12-11.001)

<h3>Objective:</h3> NA <h3>Background:</h3> Hypermanganesemia with dystonia type 2 is an established, rare autosomal recessive partially reversible neurodegenerative condition characterised by mutations in the SLC39A14 gene. Manganese deposition in such cases has a special predilection for the basal ganglia structures leading to dystonia and parkinsonian features. We report such a case of hypermanganesemia in a 1 year old child presenting with extrapyramidal features. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 1 year old female child presented with regression of developmental milestones for the past 2 months, losing the ability to stand or even sit without support—skills that she had previously acquired at an appropriate time. This was associated with dystonic posturing of her neck and limbs for the last 1 month. Cognitive skills were normal as per her age without any history of convulsions or other systemic features. Her birth and family history were unremarkable. Her neurological examination was remarkable only for generalised dystonia of her limbs, neck and trunk. Magnetic resonance imaging was suggestive of paramagnetic substance deposition in bilateral basal ganglia and dentate nucleus. Normal routine blood parameters were followed by extensive investigations to rule out Wilson’s disease, NBIA and other autoimmune pathologies. Her blood manganese levels were significantly elevated and her genetic sequencing revealed compound heterozygous mutations of the SLC39A14 gene at exons 7 and 8. She was started on chelation therapy with Penicillamine and oral iron. Dystonia resolved significantly by the end of 6 months of therapy with marked improvement in her motor developmental milestones. <h3>Conclusions:</h3> Hypermanganesemia with dystonia type 2 (HMNDYT2) is a rare genetic disorder characterised by neuronal manganese deposition without other systemic features. This case highlights the importance of recognising this potentially rare treatable condition and with adequate chelation therapy at the right time, near total restoration of motor symptomatology is possible. <b>Disclosure:</b> Dr. Bhattacharya has nothing to disclose. Dr. Chintha has nothing to disclose. Dr. Biswas has nothing to disclose. Dr. Das has nothing to disclose. Dr. Chakraborty has nothing to disclose. Dr. Mukherjee has nothing to disclose.

Early Motor Developmental Milestones and Personality Traits in Midlife: A 50-Year Follow-Up Study

Background The purpose of this study was to investigate if infants' age at attaining motor developmental milestones is associated with the big five personality traits 50 years later. Methods Mothers of 8395 infants from the Copenhagen Perinatal Cohort recorded a total of 12 motor developmental milestones during the first year of their infant's life. Information on at least one milestone was available for 1307 singletons with adult follow-up scores on the NEO-Five-Factor Inventory. The mean age at personality testing was 50.1 years. Results Slower attainment of motor milestones was associated with increased neuroticism and lower conscientiousness in midlife. All 12 motor developmental milestones explained a total of 2.4% of the variance in neuroticism, while they explained 3.2% of the variance in conscientiousness. These results remained significant after adjustment for the included family and perinatal covariates, as well as adult intelligence. Discussion The personality trait of neuroticism is a general risk factor for psychopathology and has in young adulthood been found to be associated with early motor development. However, evidence on associations of motor developmental milestones with other personality traits has been non-existent. These findings suggest that delays in early motor development may not only characterise individuals with later psychopathology, including schizophrenia, but may also be associated with personality traits such as neuroticism and conscientiousness through the life course.

Exclusive Breastfeeding Measured by Deuterium-Oxide Turnover Method is Associated with Motor Development in Rural Senegalese Infants

BackgroundThe findings on the relationship between breastfeeding and children’s motor development are very poor, particularly in low and middle income countries, because of the use of inadequate measures of breastfeeding practices. ObjectivesTo assess the relationship between exclusive breastfeeding, measured by the deuterium-oxide turnover method (DTM), and the acquisition of motor development in a cohort of Senegalese children. MethodsOne hundred forty mother-infant (4–5 mo) pairs were recruited and monitored up to 18 mo. Breast milk intake and breastfeeding practices were measured by DTM. Six stages of motor development were assessed: “sitting without support,” “hands-and-knees crawling,” “standing with assistance,” “walking with assistance,” “standing alone,” and “walking alone.” Acquisition age of motor milestones between exclusively breastfed (EBF) and not exclusively breastfed (non-EBF) infants was compared using Student’s and Wilcoxon’s tests. Mixed linear regression, adjusted with confounding factors, was used to determine the association between EBF and motor development. ResultsOverall, 32.9% of infants were EBF at the enrollment at 4–5 mo of age. Breast milk intake of EBF infants was significantly higher than that of non-EBF infants (1039 ± 193 g/d compared with 915 ± 211 g/d; P < 0.01). At 4–5 mo of age, only “sitting without support” (67.4% compared with 47.9%, P = 0.02) and “hands-and-knees crawling” (17.4% compared with 4.3%, P = 0.01) were completed significantly in the EBF group. At 18 mo, all children had completed all 6 motor developmental milestones. However, their acquisition age was significantly earlier in the EBF group after adjustment. Non-EBF infants had a delay of 0.4 to 0.5 mo on the acquisition of the first 5 stages compared to EBF infants. For “walking alone,” no difference was found after adjustment. ConclusionsMotor skill acquisition is earlier in EBF infants compared to non-EBF infants. This finding highlights the need to strengthen the advocacy for EBF up to 6 mo.

A novel homozygous SLC39A14 variant in an infant with hypermanganesemia and a review of the literature.

Manganese (Mn) is an essential trace metal necessary for good health; however, excessive amounts in the body are neurotoxic. To date, three genes (SLC30A10, SLC39A8, and SLC39A14) have been discovered to cause inborn errors in Mn metabolism in humans. As very rare diseases, the clinical features require further clarification. A male Chinese patient who mainly presented with hypermanganesemia and progressive parkinsonism-dystonia was recruited for this study. We collected and analyzed clinical information, performed whole-exome sequencing (WES), and reviewed the relevant literature. The motor-developmental milestones of the patient were delayed at the age of 4 months, followed by rapidly progressive dystonia. The patient displayed elevated Mn concentrations in blood and urine, and brain magnetic resonance imaging (MRI) showed symmetrical hyperintensity on T1-weighted images and hypointensity on T2-weighted images in multiple regions. A novel homozygous variant of the SLC39A14 gene (c.1058T > G, p.L353R) was identified. The patient was treated with disodium calcium edetate chelation (Na2CaEDTA). Three months later, mild improvement in clinical manifestation, blood Mn levels, and brain MRI was observed. To date, 15 patients from 10 families have been reported with homozygous mutations of SLC39A14, with a mean age of onset of 14.9 months. The common initial symptom is motor regression or developmental milestone delay, with a disease course for nearly all patients involving development of progressive generalized dystonia and loss of ambulation before treatment. Additionally, hypermanganesemia manifests as Mn values ranging from 4- to 25-fold higher than normal baseline levels, along with brain MRI results similar to those observed in the recruited patient. Nine SLC39A14 variants have been identified. Seven patients have been treated with Na2CaEDTA, and only one patient achieved obvious clinical improvement. We identified a novel SLC39A14 mutation related to autosomal recessive hypermanganesemia with dystonia-2, which is a very rare disease. Patients present motor regression or delay of developmental milestones and develop progressive generalized dystonia. Chelation therapy with Na2CaEDTA appears to effectively chelate Mn and increase urinary Mn excretion in some cases; however, clinical response varies. The outcome of the disease was unsatisfactory. This study expands the genetic spectrum of this disease.

Zoledronic Acid Treatment in Infants and Toddlers with Osteogenesis Imperfecta is Safe and Effective: A Tertiary Care Centre Experience.

Osteogenesis imperfecta (OI) is a genetic disorder of the extracellular matrix of bone characterized by low bone mass manifesting as frequent fractures, delayed motor development, pain, and impaired quality of life. The intravenous bisphosphonate, pamidronate is an established treatment for OI. Recently, zoledronic acid (ZA) has been used for the management of OI. To assess the efficacy and safety of ZA in children below five years of age with OI. A hospital-based prospective observational study. Patients with OI aged less than five years attending our centre were treated with intravenous ZA at a dose of 0.05 mg/kg every six months. Subjects were closely monitored for clinical and biochemical variables, adverse events, and new-onset fractures. The response to therapy was assessed by monitoring clinical variables including the degree of bony pains, number of fractures, height/length standard deviation score (SDS), and motor developmental milestones. All patients were analysed at baseline and at the end of two years for biochemical parameters and clinical severity score (CSS) as proposed by Aglan et al. with modifications. After two years of treatment, OI patients showed a significant decline in the rate of fractures (p < 0.001), improvement in ambulation (p = 0.005), alleviation of pain (p < 0.001), and improvement in height SDS (p < 0.05). There was a significant improvement in CSS after two years of therapy. Apart from mild flu-like symptoms and mild asymptomatic hypocalcaemia immediately post-infusion, no other adverse effect was noted. ZA therapy in infants and children below five years of age with OI was effective and safe and a more convenient alternative to pamidronate.

Congenital chloride diarrhea presenting as dilated fetal bowel loops.

Congenital chloride diarrhea presenting as dilated fetal bowel loops.

The associations between stunting and wasting at 12 months of age and developmental milestones delays in a cohort of Cambodian children

Worldwide, over 250 million children under 5 years do not reach their developmental potential due to several causes, including malnutrition. In Cambodia, the prevalence of stunting and wasting among children remains high. This prospective cohort study aimed to assess acquisition of motor and cognitive developmental milestones in early childhood and their associations with stunting and wasting. Children aged from 0 to 24 months were recruited from three provinces in Cambodia and followed up to seven times from March 2016 to June 2019, until their 5 years. Data collection included anthropometry and developmental milestones. Seven motor and seven cognitive milestones were evaluated using the Cambodian Development Milestone Assessment Tool. Associations were assessed with parametric survival models. Hazard ratios (HR) below 1 stood for lower probabilities for achieving developmental milestones. Data were available for 7394 children. At 12 months, the prevalence of stunting and wasting were 23.7% and 9.6% respectively. Both were consistently associated with delays in most motor and cognitive milestones. Stunting was strongly associated with delays in gross motor milestones (HR < 0.85; p < 0.001). Wasting was more strongly associated with delays in fine motor development and most cognitive milestones (HR < 0.75; p < 0.001). Promoting nutritional programs in the first 1000 days to prevent malnutrition is essential to further the optimal growth and motor and cognitive development of Cambodian children.

Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial

Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0·0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%). Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam. F Hoffmann-La Roche.