Infantile onset transient hypomyelination (IOTH) is a rare form of leukodystrophy that is associated with transient motor impairment and delayed central nervous system myelination. Here, we report a case of a new mutation in the transmembrane protein 63A (TMEM63A) gene identified using Whole-Exome Sequencing (WES) in an 8.5-year-old boy with clinical symptoms similar to IOTH. The patient exhibited a mild developmental delay, including hypotonia and delayed motor milestones, as well as some notable phenotypic characteristics, such as macrocephaly and macrosomia. Despite the absence of early neuroimaging, genetic testing revealed a paternally inherited variant in TMEM63A (NM_14698.3:c.220A>T;p:(Arg74*)), potentially linked to infantile transient hypomyelinating leukodystrophy type 19. Our findings in this study and the patient\'s favorable clinical course underscore the potential for successful myelination even with delayed initiation and may contribute to a better understanding of the genotype-phenotype correlation in IOTH, emphasizing the importance of genetic analysis in unresolved developmental delay cases and providing critical insights for accurate diagnosis, prognosis and potential therapeutic strategies in rare leukodystrophies.

UNASSIGNED: Autosomal recessive intellectual developmental disorder-3 is caused by homozygous or compound heterozygous mutations in the CC2D1A gene. The disorder is characterized by intellectual disability (ID) and autism spectrum disorder (ASD). To date, 39 patients from 17 families with CC2D1A -related disorders have been reported worldwide, in whom only six pathogenic or likely pathogenic loss-of-function variants and three variants of uncertain significance (VUS) in the CC2D1A gene have been identified in these patients.
UNASSIGNED: We described a patient with ID from a non-consanguineous Chinese family and whole-exome sequencing (WES) was used to identify the causative gene.
UNASSIGNED: The patient presented with severe ID and ASD, speech impairment, motor delay, hypotonia, slight facial anomalies, and finger deformities. Threatened abortion and abnormal fetal movements occurred during pregnancy with the proband but not his older healthy sister. WES analysis identified a homozygous nonsense variant, c.736C > T (p.Gln246Ter), in the CC2D1A gene. In addition, six novel likely pathogenic CC2D1A variants were identified by a retrospective review of the in-house database.
UNASSIGNED: This study expands the genetic and clinical spectra of CC2D1A-associated disorders, and may aid in increasing awareness of this rare condition. Our findings have provided new insights into the clinical heterogeneity of the disease and further phenotype-genotype correlation, which could help to offer scope for more accurate genetic testing and counseling to affected families.

BACKGROUND: Children with motor delays are at increased risk for delayed means-end problem-solving (MEPS) performance.
OBJECTIVE: To evaluate children with motor delays: 1) the impact of motor delay severity and MEPS mastery timing on developmental trajectories of MEPS; and 2) the effectiveness of Sitting Together And Reaching To Play (START-Play) intervention for improving MEPS.
METHODS: This represents a secondary analysis from a multi-site randomized controlled trial, with blinded assessors and prospective registration. Children with mild or significant motor delays (n = 112, mean age=10.80, SD=2.59 months at baseline) were randomly assigned to START-Play or usual care early intervention (UC-EI) and assessed at five visits across one year using the Means-End Problem-Solving Assessment Tool that included three 30-second MEPS trials per visit. Task mastery occurred at the first visit the child achieved the highest level of performance in at least two of the three trials. Multilevel analyses evaluated trajectories of MEPS outcomes dependent upon the timing of MEPS mastery, motor delay severity, and intervention group.
RESULTS: At baseline, children with mild motor delays demonstrated better MEPS than children with significant delays, but this difference was only observed for children who achieved mastery late. Children with significant delays demonstrated greater improvements in MEPS in the post-intervention phase compared to children with mild delays. No MEPS differences were found between START-Play and UC-EI.
CONCLUSIONS: Motor delay severity and timing of task mastery impacted MEPS trajectories, whereas START-Play intervention did not impact MEPS for children with motor delays.
UNASSIGNED: NCT02593825 (https://clinicaltrials.gov/ct2/show/NCT02593825).

NUDT2 is an enzyme important for maintaining the intracellular level of the diadenosine tetraphosphate (Ap4A). Bi-allelic loss of function variants in NUDT2 has recently been reported as a rare cause of intellectual disability (ID). Herein, we describe a Chinese girl with ID, attention deficit hyperactivity disorder (ADHD), and motor delays with abnormal walking posture and difficulty climbing stairs, who bears compound heterozygous variants c.34 C > T (p.R12*) and c.194T > G (p.I65R) in NUDT2. Homozygous variants c.34 C > T (p.R12*) or c.186del (p.A63Qfs*3) in NUDT2 were previously reported to cause ID. This is the first patient with ID due to compound heterozygous variants in NUDT2 and p.I65R is a novel missense variant. This study enriched the genotype and phenotype of NUDT2-related ID and supported the critical developmental involvement of NUDT2.

Kabuki syndrome (KS) is a multiple congenital anomaly syndrome that is characterized by postnatal growth deficiency, hypotonia, short stature, mild-to-moderate intellectual disability, skeletal abnormalities, persistence of fetal fingertip pads, and distinct facial appearance. It is mainly caused by pathogenic/likely pathogenic variants in the KMT2D or KDM6A genes. Here, we described the clinical features of nine sporadic KS patients with considerable phenotypic heterogeneity. In addition to intellectual disability and short stature, our patients presented with a high prevalence of motor retardation and recurrent otitis media. We recommended that KS should be strongly considered in patients with motor delay, short stature, intellectual disability, language disorder and facial deformities. Nine KMT2D variants, four of which were novel, were identified by whole-exome sequencing. The variants included five nonsense variants, two frameshift variants, one missense variant, and one non-canonical splice site variant. In addition, we reviewed the mutation types of the pathogenic KMT2D variants in the ClinVar database. We also indicated that effective mRNA analysis, using biological materials from patients, is helpful in classifying the pathogenicity of atypical splice site variants. Pedigree segregation analysis may also provide valuable information for pathogenicity classification of novel missense variants. These findings extended the mutation spectrum of KMT2D and provided new insights into the understanding of genotype-phenotype correlations, which are helpful for accurate genetic counseling and treatment optimization.

The long-term effects of a Cesarean section (CS) birth on child neurodevelopment are of increasing interest. In this study, we examined the associations between mode of delivery and presence of neurodevelopmental disorders in toddlers. Moreover, given that the prevalence of several neurodevelopmental disorders such as autism spectrum disorder (ASD) is known to differ by sex, we also investigated these associations separately in male and female toddlers.
We investigated 65,701 mother-toddler pairs from the Japan Environment and Children\'s Study, a nationally representative children\'s cohort study. To investigate the associations between mode of delivery (CS or vaginal delivery) and neurodevelopmental disorders (motor delay, intellectual disability, and ASD) in 3-year-old toddlers as a whole and stratified by sex, we used logistic regression models to calculate adjusted odds ratios (aORs) with 95% confidence intervals (CIs).
The morbidity of ASD at age 3 years was higher for children delivered by CS than those delivered vaginally (aOR 1.38, 95% CI 1.04-1.83). However, no such difference was evident in the case of motor delay or intellectual disability (aOR 1.33, 95% CI 0.94-1.89; aOR 1.18, 95% CI 0.94-1.49, respectively). In the analysis by sex, CS was not associated with increased risk of any of the neurodevelopmental disorders in males, but it was associated with increased risks of motor delay (aOR 1.88, 95% CI 1.02-3.47) and ASD (aOR 1.82, 95% CI 1.04-3.16) in females.
This study provides evidence of significant associations between mode of delivery and neurodevelopmental disorders in early childhood. Females may be more sensitive to the effects of CS than males.

Parkinson\'s disease (PD) is a prevalent neurodegenerative disorder that occurs in old age due to a decrease in dopamine, which causes nerve cell destruction. This disease is difficult to diagnose since its symptoms are similar to those of the aging process. Those with PD have impaired motor control and function, dyskinesia, and tremors. To treat PD, drugs that enhance the amount of dopamine given to the brain are administered to alleviate symptoms. This inquiry examines the prescription of rotigotine to achieve this objective. The primary objective of this review is to examine the usage of rotigotine in both the late and early stages of PD. The statistical model utilized in the review found that there was not a significant difference in the dosage of rotigotine prescribed to late and early-stage PD patients, however, there were some confounding variables that may have skewed this result; therefore, further research is necessary to validate or nullify this hypothesis.

UNASSIGNED: To systematically examine the effect of early motor interventions on motor and locomotor development in infants <1 year of age with motor developmental disability or at risk of motor delay.
UNASSIGNED: Pertinent literature from January 2000 to September 2021 was identified by searching the PubMed, Embase, Cochrane, Pedro and Web of Science databases. Selection criteria included interventions starting before 12 months corrected age. Methodological quality was assessed with AACPDM criteria, Mallen score and Cochrane risk of bias methodology. Evaluation procedure was performed using PRISMA protocol (PICO approach) and AMSTAR-2. This review was preregistered in PROSPERO (CRD42021286445).
UNASSIGNED: Ten articles met the inclusion criteria; seven had moderate to strong methodological quality. The interventions included treadmill training (n = 3), crawling training (n = 1), \"tummy time\" (n = 1), physical therapy with neonatal developmental program (n = 1) or Bobath approach (n = 1), treadmill training combined with active leg movements (n = 2) or Bobath physiotherapy (n = 1). The three key characteristics of effective interventions that emerged from the review were: (1) the infants\' disability or risk of delay was well-defined; (2) the protocol was standardized and easy to replicate; (3) infants were required to make active movements.
UNASSIGNED: There is an urgent need for additional high-quality studies on the effects of early motor interventions on the gross motor and locomotor development of infants with a range of disabilities or risks for delay. Suggestions for future research are outlined.

Objective: This study was conducted to determine the gross and fine motor profiles of children with autism spectrum disorder compared to typically developing children. Additionally, we also assessed if the motor delay was more pronounced with increasing age. Method: This was a retrospective study involving children aged 12-60 months of age comparing motor development in children with autism spectrum disorder with typically developing children. Their developmental profile was assessed using Schedule of Growing Skills II. Descriptive statistics was used to analyse the developmental profile between the groups. Results: ASD children had significant gross motor (6.7%) and fine motor delay (38.5%) compared to typically developing children, who did not show any delay. The motor delay in ASD children was more prominent in older children. Conclusion: It is important to assess motor development in ASD children as there is significant motor delay in these children compared to typically developing children, and the delay becomes more prominent with age. Early detection of motor delay could allow provision of early intervention services to optimize developmental outcomes.

The kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by hyperextensible skin and joints, kyphoscoliosis, and severe muscle hypotonia at birth. Causal variants have been identified in PLOD1 resulting in lysyl hydroxylase deficiency responsible for kEDS. However, the detailed phenotype of kEDS during the perinatal period is still poorly recognized. Here, we describe a case of a female newborn presenting with prenatal hydrocephalus and severe hypotonia after birth with two novel compound heterozygous variants, c.2T > C (p.?) and c.1462del (p. Arg488Glyfs*9) in the PLOD1 gene. Our case suggests that in addition to the reported phenotype during the neonatal period, prenatal hydrocephalus should also be differentially diagnosed to exclude the potential of kEDS.