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Background: GTPases of the Rab family are important orchestrators of membrane trafficking, and their dysregulation has been linked to a variety of neuropathologies. In 2017, we established a causal link between RAB11A variants and developmental and epileptic encephalopathy. In this study, we expand the phenotype of RAB11A-associated neurodevelopmental disorder and explore genotype-phenotype correlations., Methods: We assessed 16 patients with pathogenic or likely pathogenic RAB11A variants, generally de novo, heterozygous missense variants. One individual had a homozygous nonsense variant, although concomitant with a pathogenic LAMA2 variant, which made their respective contributions to the phenotype difficult to discriminate., Results: We reinforce the finding that certain RAB11A missense variants lead to intellectual disability and developmental delays. Other clinical features might include gait disturbances, hypotonia, magnetic resonance imaging abnormalities, visual anomalies, dysmorphisms, early adrenarche, and obesity. Epilepsy seems to be less common and linked to variants outside the binding sites. Individuals with variants in the binding sites seem to have a more multisystemic, nonepileptic phenotype., Conclusions: Similar to other Rab-related disorders, RAB11A-associated neurodevelopmental disorder can also impact gait, tonus, brain anatomy and physiology, vision, adrenarche, and body weight and structure. Epilepsy seems to affect the minority of patients with variants outside the binding sites., Competing Interests: Declaration of competing interest The Department of Molecular & Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. Sureni V. Mullegama is an employee of GeneDx, LLC. Otherwise, we have no conflict of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Biallelic SUFU variants have originally been linked to Joubert syndrome, comprising cerebellar abnormalities, dysmorphism, and polydactyly. In contrast, heterozygous truncating variants have recently been associated with developmental delay and ocular motor apraxia, but only a limited number of patients have been reported. Here, we aim to delineate further the mild end of the phenotypic spectrum related to SUFU haploinsufficiency., Methods: Nine individuals (from three unrelated families) harboring truncating SUFU variants were investigated, including two previously reported individuals (from one family). We provide results from a comprehensive assessment comprising neuroimaging, neuropsychology, video-oculography, and genetic testing., Results: We identified three inherited or de novo truncating variants in SUFU (NM_016169.4): c.895C>T p.(Arg299∗), c.71dup p.(Ala25Glyfs∗23), and c.71del p.(Pro24Argfs∗72). The phenotypic expression showed high variability both between and within families. Clinical features include motor developmental delay (seven of nine), axial hypotonia (five of nine), ocular motor apraxia (three of nine), and cerebellar signs (three of nine). Four of the six reported children had macrocephaly. Neuropsychological and developmental assessments revealed mildly delayed language development in the youngest children, whereas general cognition was normal in all variant carriers. Subtle but characteristic SUFU-related neuroimaging abnormalities (including superior cerebellar dysplasia, abnormalities of the superior cerebellar peduncles, rostrally displaced fastigium, and vermis hypoplasia) were observed in seven of nine individuals., Conclusions: Our data shed further light on the mild but recognizable features of SUFU haploinsufficiency and underline its marked phenotypic variability, even within families. Notably, neurodevelopmental and behavioral abnormalities are mild compared with Joubert syndrome and seem to be well compensated over time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Research indicates that preterm infants requiring prolonged mechanical ventilation often exhibit suboptimal neurodevelopment at follow-up, coupled with altered brain development as detected by magnetic resonance imaging (MRI) at term-equivalent age (TEA). However, specific regions of brain dysmaturation and the subsequent neurodevelopmental phenotype following early-life adverse respiratory exposures remain unclear. Additionally, it is uncertain whether brain dysmaturation mediates neurodevelopmental outcomes after respiratory adversity. This study aims to investigate the relationship between early-life adverse respiratory exposures, brain dysmaturation at TEA, and the developmental phenotype observed during follow-up in extremely preterm infants., Methods: 89 infants born < 29 weeks' gestation from 2019 to 2021 received MRI examinations at TEA for structural and lobe brain volumes, which were adjusted with sex-and-postmenstrual-age expected volumes for volume residuals. Assisted ventilation patterns in the first 8 postnatal weeks were analyzed using kmlShape analyses. Patterns for motor, cognition, and language development were evaluated from corrected age 6 to 12 months using Bayley Scales of Infant Development, third edition. Mediation effects of brain volumes between early-life respiratory exposures and neurodevelopmental phenotypes were adjusted for sex, gestational age, maternal education, and severe brain injury., Results: Two distinct respiratory trajectories with varying severity were identified: improving (n = 35, 39%) and delayed improvement (n = 54, 61%). Compared with the improving group, the delayed improvement group exhibited selectively reduced brain volume residuals in the parietal lobe (mean - 4.9 cm 3 , 95% confidence interval - 9.4 to - 0.3) at TEA and lower motor composite scores (- 8.7, - 14.2 to - 3.1) at corrected age 12 months. The association between delayed respiratory improvement and inferior motor performance (total effect - 8.7, - 14.8 to - 3.3) was partially mediated through reduced parietal lobe volume (natural indirect effect - 1.8, - 4.9 to - 0.01), suggesting a mediating effect of 20%., Conclusions: Early-life adverse respiratory exposure is specifically linked to the parietal lobe dysmaturation and neurodevelopmental phenotype of motor delay at follow-up. Dysmaturation of the parietal lobe serves as a mediator in the connection between respiratory adversity and compromised motor development. Optimizing respiratory critical care may emerge as a potential avenue to mitigate the consequences of altered brain growth and motor developmental delay in this extremely preterm population., (© 2024. The Author(s).)

Purpose: Post-hemorrhagic ventricular dilation (PHVD) leads to developmental delays in premature infants, yet the optimal timing of neurosurgical interventions is unknown. Neuroimaging modalities have emerged to delineate injury and follow the progression of PHVD. Fronto-temporal horn ratio (FTHR) is used as a marker of ventricular dilation and can be a standardized tool to direct the timing of neurosurgical intervention. Our study determined a pre-operative FTHR measurement threshold to predict short- and long-term outcomes., Methods: This is a retrospective cohort study of premature infants with severe intraventricular hemorrhage (IVH) who developed PHVD requiring neurosurgical intervention and were treated in a level IV NICU between 2012 and 2019. Receiver operating characteristic (ROC) curve and area under the curve (AUC) analyses were performed to evaluate the accuracy of pre-operative FTHR for predicting developmental delay. In-hospital outcomes and developmental assessments were analyzed., Results: We reviewed 121 charts of infants with IVH and identified 43 infants with PHVD who required neurosurgical intervention. We found FTHR measurements were an excellent predictor of cognitive and motor delay with an AUC of 0.89 and 0.88, respectively. An average pre-operative FTHR of ≥ 0.67 was also associated with worse lung and feeding outcomes. There was excellent inter-observer reliability of individual components of FTHR measurements., Conclusions: Early intervention for PHVD is ideal but not always practical. Identification of ventricular size thresholds associated with better outcomes is needed to direct timing of neurosurgical intervention., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mutations in ARCN1 give rise to a syndromic disorder with rhizomelic short stature with microretrognathia and developmental delay. ARCN1 encodes the delta subunit of the coat protein I complex, which is required for intracellular trafficking of collagen 1 and which may also be involved in the endoplasmic reticulum (ER) stress response. In this paper we describe for the first time the skeletal histological abnormalities in an 18-week-old fetus with an ARCN1 mutation, and we suggest that the skeletal phenotype in ARCN1 -related syndrome has more resemblance with ER stress than with a defect in collagen 1 metabolism., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: B-Cell CLL/Lymphoma 11B (BCL11B) is a C 2 H 2 zinc finger transcription factor that has broad biological functions and is essential for the development of the immune system, neural system, cardiovascular system, dermis, and dentition. Variants of BCL11B have been found in patients with neurodevelopmental disorders and immunodeficiency., Materials and Methods: Whole-exome sequencing (WES) and clinical examinations were performed to identify the etiology of our patient. A variant in the BCL11B gene, NM&#95;138576.4: c.1206delG (p.Phe403Serfs*2) was found and led to frameshift truncation., Results: We reported a male patient with developmental delay and cerebral palsy who carried the BCL11B variant. The detailed clinical features, such as brain structure and immune detection, were described and reviewed in comparison to previous patients., Conclusions: The BCL11B-related neurodevelopmental disorders are rare, and only 17 variants in 25 patients have been found to date. Our report expands the variants spectrum of BCL11B and increases the case of neurodevelopmental abnormalities., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

We report the clinical case of AB, a right-handed 19-year-old woman who presents severe developmental topographical disorientation, a relatively rare syndrome, leading to difficulties in navigating in familiar (and novel) environments. This symptomatology appears without acquired cerebral damage (MRI described as normal) nor more global cognitive disability (high degree of education achieved). An extensive assessment of spatial cognition with different aspects of underlying cognitive processes is first presented. Second, the patient's preserved cognitive abilities and her major difficulties in calculation, as well as her attention deficit, as seen in a detailed neuropsychological assessment, are reported. For the first time to our knowledge, we show that developmental topographical disorientation can be associated with other developmental cognitive disorders affecting number processing (dyscalculia) and attention (Attention Deficit-Hyperactivity Disorder (ADHD)). We discuss the links between these different cognitive processes in relation to visuo-spatial working memory and magnitude representation, which could represent common denominators for all these syndromes. This case report highlights the importance of thoroughly assessing potentially associated neurocognitive disorders in developmental topographical disorientation. In addition, it highlights the necessity to keep in mind the prevalence of spatial difficulties in the assessment of children and adolescents with other neurodevelopmental syndromes. Finally, this case study raises a new question about the nosology of developmental disorders affecting the visuo-spatial and spatial domains., Competing Interests: Declarations of interest None., (Copyright © 2022. Published by Elsevier Ltd.)

Background: With the rapid development of genetic detection technology, especially next-generation sequencing, identification of the aetiology of unexplained intellectual disabilities accompanied by seizures and other dysmorphic features has become possible. The purpose of our paper is to make a definitive diagnosis of a girl with neonatal hypotonia, severe global developmental delay, seizures and mild facial dysmorphism., Methods: The clinical data of the patient were retrospectively studied. Whole-exome sequencing was performed on a blood sample from the patient. Subsequently, Sanger sequencing was utilized for validation of variants and parental validation., Results: The patient had hypotonia since the neonatal period. She showed a significant delay in physical and psychomotor development. She did not have any speech until the age of 2 years and 6 months. She had seizures that were easy to control with levetiracetam. The craniocerebral magnetic resonance imaging (MRI) then showed mild delayed myelination, enlarged bilateral ventricles and widened frontotemporal extracerebral space. Interictal video electroencephalogram (VEEG) was normal. She had esotropia and mild facial abnormalities with a flat nasal bridge and a short nose. She showed no abnormalities in the heart, genitourinary or skeletal systems. Whole-exome sequencing revealed a novel de novo variant c.5334&#95;5335delAG (p. Arg1778Serfs*11) in the SON gene., Conclusion: Our paper reports a novel variant in the SON gene and provides a definitive diagnosis of a female with neonatal hypotonia, severe global developmental delay, seizures and mild facial abnormalities, which are symptoms consistent with Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome)., (© 2022 International Society for Developmental Neuroscience.)

Aim: To assess the relationship between neonatal brain development and injury with early motor outcomes in infants with critical congenital heart disease (CCHD)., Method: Neonatal brain magnetic resonance imaging was performed after open-heart surgery with cardiopulmonary bypass. Cortical grey matter (CGM), unmyelinated white matter, and cerebellar volumes, as well as white matter motor tract fractional anisotropy and mean diffusivity were assessed. White matter injury (WMI) and arterial ischaemic stroke (AIS) with corticospinal tract (CST) involvement were scored. Associations with motor outcomes at 3, 9, and 18 months were corrected for repeated cardiac surgery., Results: Fifty-one infants (31 males, 20 females) were included prospectively. Median age at neonatal surgery and postoperative brain magnetic resonance imaging was 7 days (interquartile range [IQR] 5-11d) and 15 days (IQR 12-21d) respectively. Smaller CGM and cerebellar volumes were associated with lower fine motor scores at 9 months (CGM regression coefficient=0.51, 95% confidence interval [CI]=0.15-0.86; cerebellum regression coefficient=3.08, 95% CI=1.07-5.09) and 18 months (cerebellum regression coefficient=2.08, 95% CI=0.47-5.12). The fractional anisotropy and mean diffusivity of white matter motor tracts were not related with motor scores. WMI was related to lower gross motor scores at 9 months (mean difference -0.8SD, 95% CI=-1.5 to -0.2). AIS with CST involvement increased the risk of gross motor problems and muscle tone abnormalities. Cerebral palsy (n=3) was preceded by severe ischaemic brain injury., Interpretation: Neonatal brain development and injury are associated with fewer favourable early motor outcomes in infants with CCHD., (© 2021 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

KIRREL3 is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with CASK gene. Alterations of KIRREL3 have been linked to neurodevelopmental disorders, ranging from developmental delay, to autism spectrum disorder, to attention deficit/hyperactivity disorder. The underlying mechanism is not yet fully understood, as it has been hypothesized a fully dominant effect, a risk factor role of KIRREL3 partially penetrating variants, and a recessive inheritance pattern. We report a novel and de novo KIRREL3 mutation in a child affected by severe neurodevelopmental disorder and with brain magnetic resonance imaging evidence of mega cisterna magna and mild cerebellar hypoplasia. This case strengthens the hypothesis that dominant KIRREL3 variants may lead to neurodevelopmental disruption; furthermore, given the strong interaction between KIRREL3 and CASK , we discuss as posterior fossa anomalies may also be part of the phenotype of KIRREL3 -related syndrome., Competing Interests: None declared., (Thieme. All rights reserved.)

Dental radiographs are essential for diagnosis and treatment planning, but are sometimes difficult to acquire for patients with developmental disabilities (PDD). Optical Coherence Tomography (OCT) is a non-ionizing imaging modality that has the potential application as an alternative to dental radiographs for PDD. This study aimed to determine the feasibility of intraoral OCT imaging for PDD. Ten participants were recruited in the Dental Education in the Care of Persons with Disabilities (DECOD) Clinic to explore the utility of dental OCT. The prototype system (Yoshida Dental) creates in-depth and three-dimensional images of teeth. The participants indicated their degree of pain during imaging on the Wong-Baker FACES Pain Rating Scale, and the degree of discomfort after imaging on a visual analog scale. OCT can be used for patients with developmental disabilities with minimal levels of pain and discomfort, without ionizing radiation.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of γ-aminobutyric acid (GABA) degradation, resulting in elevations of brain GABA and γ-hydroxybutyric acid (GHB). Previous magnetic resonance (MR) spectroscopy studies have shown increased levels of Glx in SSADH deficiency patients. Here in this work, we measure brain GABA in a large cohort of SSADH deficiency patients using advanced MR spectroscopy techniques that allow separation of GABA from overlapping metabolite peaks. We observed significant increases in GABA concentrations in SSADH deficiency patients for all 3 brain regions that were evaluated. Although GABA levels were higher in all 3 regions, each region had different patterns in terms of GABA changes with respect to age. We also report results from structural magnetic resonance imaging (MRI) of the same cohort compared with age-matched controls. We consistently observed signal hyperintensities in globus pallidus and cerebellar dentate nucleus.

Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2 +/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2 +/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2 +/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis., Competing Interests: Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives financial support from Baylor Genetics. Dr. Brendan Lee serves on the Board of Directors of Baylor Genetics and chairs its Scientific Advisory Board but receives no personal income from these positions., (Copyright © 2021 American Society of Human Genetics. All rights reserved.)

Background: Deletion and duplication of the 3.7 Mb region in 17p11.2 result in two syndromes, Smith-Magenis syndrome and Potocki-Lupski syndrome, which are well-known development disorders. The purpose of this study was to determine the prevalence, genetic characteristics and clinical phenotypes of 17p11.2 deletion/duplication in Chinese children with development delay and in fetuses with potential congenital defects., Methods: 7077 children with development delay and/or intellectual disability were screened by multiplex ligation-dependent probe amplification P245 assay. 7319 fetuses with potential congenital defects were tested using next generation sequencing technique., Results: 417 of 7077 pediatric patients were determined to carry chromosome imbalance. 28 (28/7077, 0.4%) cases had imbalance at chromosome 17p11.2. Among them, 12 cases (42.9%) had heterozygous deletions and 16 cases (57.1%) had heterozygous duplications. The clinical phenotypes were variable, including neurobehavioral disorders, craniofacial/skeletal anomalies, immunologic defects, ocular problems and organ malformations. 263 of 7319 fetuses were recognized to have genomic copy number variations. Only 2 of them were found to harbor 17p11.2 imbalance. The fetus with deletion presented with ventricular septal defect and the fetus with duplication had cerebral ventricle dilation., Conclusion: Our study highlights the phenotypic variability associated with 17p11.2 variations in China. The results further expand the phenotypic spectrum of SMS/PTLS and increase awareness of these disruptive mutations among clinicians., (© 2021. The Author(s).)

Many major neuropsychiatric pathologies, some of which appear in adolescence, show differentiated prevalence, onset, and symptomatology across the biological sexes. Therefore, mapping differences in brain structure between males and females during this critical developmental period may provide information about the neural mechanisms underlying the dimorphism of these pathologies. Utilizing a large dataset collected through the Adolescent Brain Cognitive Development study, we investigated the differences of adolescent (9-10 years old) male and female brains (n = 8325) by using a linear Support-Vector Machine Classifier to predict sex based on morphometry and image intensity values of structural brain imaging data. The classifier correctly classified the sex of 86% individuals with the insula, the precentral and postcentral gyri, and the pericallosal sulcus as the most discernable features. These results demonstrate the existence of complex, yet robustly measurable morphometrical brain markers of sex difference., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: We assessed in extremely preterm born (EPB) children whether secondary somatosensory cortex (SII) responses recorded with magnetoencephalography (MEG) at term-equivalent age (TEA) correlate with neurodevelopmental outcome at age 6 years. Secondly, we assessed whether SII responses differ between 6-year-old EPB and term-born (TB) children., Methods: 39 EPB children underwent MEG with tactile stimulation at TEA. At age 6 years, 32 EPB and 26 TB children underwent MEG including a sensorimotor task requiring attention and motor inhibition. SII responses to tactile stimulation were modeled with equivalent current dipoles. Neurological outcome, motor competence, and general cognitive ability were prospectively evaluated at age 6 years., Results: Unilaterally absent SII response at TEA was associated with abnormal motor competence in 6-year-old EPB children (p = 0.03). At age 6 years, SII responses were bilaterally detectable in most EPB (88%) and TB (92%) children (group comparison, p = 0.69). Motor inhibition was associated with decreased SII peak latencies in TB children, but EPB children lacked this effect (p = 0.02)., Conclusions: Unilateral absence of an SII response at TEA predicted poorer motor outcome in EPB children., Significance: Neurophysiological methods may provide new means for outcome prognostication in EPB children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Ferredoxin reductase (FDXR), located in 17q25.1, encodes for a mitochondrial NADPH: adrenodoxin oxidoreductase or ferredoxin reductase, the sole human ferredoxin reductase involved in the biosynthesis of iron-sulfur (Fe-S) clusters and heme formation. Iron-sulfur (Fe-S) clusters are involved in enzymatic catalysis, gene expression, and DNA replication and repair. Variants in FDXR lead to sensorial neuropathies, damage optic, and auditory neurons. Here, we report a Chinese boy with hearing loss, visual impairment, and motor retardation, with two novel compound heterozygous variants in FDXR (NM&#95;004110), namely, c.250C > T (p.P84S) and c.634G > C (p.D212H), identified by whole-exome sequencing. Compared with the reported cases, except hearing loss and visual impairment, the clinical manifestations of this boy were more serious, who also had motor retardation and died in infancy after infection. The present study expands our knowledge of FDXR variants and related phenotypes, and provides new information on the genetic defects associated with this disease for clinical diagnosis., (© 2021 International Society for Developmental Neuroscience.)

Global developmental delay / intellectual disability are common pediatric conditions. Brain magnetic resonance imaging (MRI), although an important diagnostic tool in the evaluation of these patients, often requires general anesthesia. Recent literature suggests that unnecessary general anesthesia exposure should be avoided in early years because of possible long-term negative neurodevelopmental sequelae. This study sought to identify clinical clues associated with brain MRI abnormalities in children with global developmental delay / intellectual disability in an attempt to provide guidance to physicians on selecting patients who would benefit from an MRI. Retrospective chart review analysis was conducted for patients presenting to a pediatric neurology tertiary care center between 2014 and 2017 for a first clinic evaluation for global developmental delay / intellectual disability. Detailed clinical history and physical examination findings were analyzed and correlated with brain MRI findings. The majority (218/327, 67%) of children referred for evaluation of global developmental delay / intellectual disability underwent complete clinical and radiologic evaluations. Mean age was 37.9 months (±32.5 standard deviation) and 116 were males (53%). Motor deficits were predominant in most subjects (122/218, 56%). Abnormal MRI findings were observed in 153 children (70%), with the most prevalent abnormalities noted within the white matter (104/153, 68%), corpus callosum (77/153, 50%), and the hippocampus (50/153, 33%). Abnormal MRI findings were prevalent in children with predominant motor delay (84, 69%) and cognitive disability (3, 100%) as well as those with visual and hearing impairment ( P < .05). The presence of facial dysmorphisms (57/71, P = .02); cranial nerve abnormalities (79/100; P = .007) and abnormal reflexes (16, P = .01) on examination also correlated significantly with increased MRI abnormalities.

Microcephaly, disproportionate pontine and cerebellar hypoplasia (MICPCH) syndrome is a rare and genetic disorder, which is mainly caused by mutations in the CASK gene. We described four variations in the CASK gene in Chinese female patients with MICPCH, who presented with microcephaly, developmental delay, and motor disorder. The CASK mutations were identified using NGS (the next-generation sequencing), copy number variation sequencing. Two novel variations in the CASK gene were revealed including a frameshift mutation c.1000&#95;1001insG (p.Asp334GlyfsTer32) and a nonsense mutation c.2110A > T (p.Lys704Ter). Two other aberrations were c.316C > T (p.Arg106Ter) and Xp11.4-p11.3 (41,700,001-44,660,000) × 1 loss. We provided clinical manifestations and neuroimaging findings of the four patients. The genetic variation spectrum of MICPCH caused by CASK was updated. Furthermore, we expounded on the molecular mechanism of the disease and noticed that it was not possible to relate the magnitude of the genetic alteration to a particular phenotype., (© 2021 International Society for Developmental Neuroscience.)

This paper discusses the clinical value of standardized early pregnancy ultrasound structure screening in the diagnosis of fetal central nervous system (CNS) malformations. In this paper, 6902 cases (8336 fetuses) of 11～13 + 6 weeks of gestation (5468 cases of singleton pregnancy and 1434 cases of twin pregnancy) underwent standardized early pregnancy ultrasound structure screening. While tracking the pregnancy process and clinical outcome, we found that 13 cases of CNS malformations (10 cases of single pregnancy, 3 cases of twin pregnancy) were detected by prenatal ultrasound in 6902 cases (8336 fetuses) 11～13 + 6 weeks of gestation including 5 cases of exposed brain malformations. There were 4 cases of children with cerebral sickle disease, 2 cases of forebrain without splitting, 1 case of meningocele, and 1 case of open spina bifida. There were 4 cases with other structural abnormalities and 3 cases with abnormal karyotype. Follow-up results of 13 fetuses indicated that except for 3 cases of twin malformed fetuses who continued to be pregnant after selective reduction, ultrasound results of the remaining fetuses were consistent with autopsy results after the induction of labor. For this reason, it can be concluded that standardized ultrasound structural screening during early pregnancy can detect fetal CNS malformations early and has important clinical value in reducing the birth rate of malformed fetuses and guiding obstetric treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Developmental delay (DD) is an important long-term neuromorbidity owing to various insults to the developing brain and neuroimaging plays a key role in evaluating these children. Magnetic resonance spectroscopy (MRS) is the only noninvasive method to determine the levels of various metabolites in the brain which aids in delineating the underlying abnormalities. A total of 48 children aged between 6 months to 6 years with developmental delay were included and evaluated with neuroimaging in our study. Sensitivity of MRS in children with DD and DD plus (DD along with seizures, abnormal motor findings, behavior, brainstem evoked response audiometry, visual assessment, and microcephaly) was 81.2% and 89.6% respectively. 86.6% of children with microcephaly had abnormal MRS. MRS detected abnormalities in two-thirds of children with normal magnetic resonance imaging (MRI). Children with behavioral abnormalities had significantly lower N -acetyl aspartate (NAA)-creatine and NAA-choline ratios on MRS. Thus, MRS is additive to MRI in delineating the underlying pathophysiology in children with DD.

Caffeine, a very widely used and potent neuromodulator, easily crosses the placental barrier, but relatively little is known about the long-term impact of gestational caffeine exposure (GCE) on neurodevelopment. Here, we leverage magnetic resonance imaging (MRI) data, collected from a very large sample of 9157 children, aged 9-10 years, as part of the Adolescent Brain and Cognitive Development sm (ABCD ®) study, to investigate brain structural outcomes at 27 major fiber tracts as a function of GCE. Significant relationships between GCE and fractional anisotropy (FA) measures in the inferior fronto-occipito fasciculus and corticospinal tract of the left hemisphere (IFOF-LH; CST-LH) were detected via mixed effects binomial regression. We further investigated the interaction between these fiber tracts, GCE, cognitive measures (working memory, task efficiency), and psychopathology measures (externalization, internalization, somatization, and neurodevelopment). GCE was associated with poorer outcomes on all measures of psychopathology but had negligible effect on cognitive measures. Higher FA values in both fiber tracts were associated with decreased neurodevelopmental problems and improved performance on both cognitive tasks. We also identified a decreased association between FA in the CST-LH and task efficiency in the GCE group. These findings suggest that GCE can lead to future neurodevelopmental complications and that this occurs, in part, through alteration of the microstructure of critical fiber tracts such as the IFOF-LH and CST-LH. These data suggest that current guidelines regarding limiting caffeine intake during pregnancy may require some recalibration., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours., Study Design: Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age., Results: Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively., Conclusions: MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia-ischemia., Trial Registration: Clinicaltrials.gov: NCT00614744., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder including developmental delay/intellectual disability (DD/ID), hypertrichosis cubiti, short stature, and distinctive facial features, caused by mutation in KMT2A gene, which encodes a histone methyltransferase (H3K4) that regulates chromatin-mediated transcription. Different neurodevelopmental phenotypes have been described within the WDSTS spectrum, including a peculiar Autism Spectrum Disorder (ASDs) subtype in some affected individuals. Here, we report a 9-year-old Caucasian male found by next-generation panel sequencing to carry a novel heterozygous de novo KMT2A frameshift variant (NM&#95;001197104.2:c.4433delG; p. Arg1478LeufsTer108). This boy presented a WDSTS phenotype associated with broad neurodevelopmental features, including an unusual speech difficulty (i.e., palilalia), and brain imaging studies revealed an array of cortical anomalies (e.g., frontal simplified gyration, focal frontal cortical dysplasia). These clinical and radiological observations expand the known WDSTS-related neurodevelopmental phenotypes and further strengthen the important role of KMT2A in brain function and cortical development., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Ververi-Brady syndrome (VBS, # 617982) is a rare developmental disorder, and loss-of-function variants in QRICH1 were implicated in its etiology. Furthermore, a recognizable phenotype was proposed comprising delayed speech, learning difficulties and dysmorphic signs. Here, we present four unrelated individuals with one known nonsense variant (c.1954C > T; p.[Arg652*]) and three novel de novo QRICH1 variants, respectively. These included two frameshift mutations (c.832&#95;833del; p.(Ser278Leufs*25), c.1812&#95;1813delTG; p.(Glu605Glyfs*25)) and interestingly one missense mutation (c.2207G > A; p.[Ser736Asn]), expanding the mutational spectrum. Enlargement of the cohort by these four individuals contributes to the delineation of the VBS phenotype and suggests expressive speech delay, moderate motor delay, learning difficulties/mild ID, mild microcephaly, short stature and notable social behavior deficits as clinical hallmarks. In addition, one patient presented with nephroblastoma. The possible involvement of QRICH1 in pediatric cancer assumes careful surveillance a key priority for outcome of these patients. Further research and enlargement of cohorts are warranted to learn about the genetic architecture and the phenotypic spectrum in more detail., (© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis., Methods: In order to further refine the phenotypical spectrum associated with TUBB2A , clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed., Results: We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy., Conclusion: The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a need for non-invasive prenatal markers of the brain to assess fetuses at risk for poor postnatal neurodevelopmental outcome. Periconceptional maternal conditions and pregnancy complications impact prenatal brain development., Aims: To investigate associations between growth trajectories of fetal brain structures and neurodevelopmental outcome in children in the early life course., Study Design: Periconceptional prospective observational cohort., Subjects: Singleton pregnancies were included in the Rotterdam periconception cohort. Two- and three-dimensional ultrasound scans at 22, 26 and 32 weeks gestational age were analysed., Outcome Measures: Head circumference (HC), cerebellum, corpus callosum (CC), Sylvian fissure, insula and parieto-occipital fissure (POF) were measured. Neurodevelopment was evaluated using the Age-and-Stages-questionnaire-3 (ASQ-3) and the Child-Behaviour-Checklist (CBCL) at 2 years of age. Linear mixed models, used to estimate the prenatal brain growth trajectories, and linear regression models, used to evaluate the associations between prenatal brain structures and neurodevelopmental outcomes, were applied in the total study population, and in subgroups: fetal growth restriction (FGR), preterm birth (PTB), fetal congenital heart disease (CHD), and uncomplicated controls., Results: Consent for participation was received from parents on behalf of their child 138/203 (68%). ASQ-3 was completed in 128/203 children (63%) and CBCL in 93/203 children (46%). Significant smaller subject-specific growth trajectories (growth rate of CC, HC, left insula, left POF and right POF and the baseline size of CC, HC, left POF and right POF) were found in the FGR subgroup, compared to the other subgroups (all p-values <0.05). In the total group (n = 138), the growth rate of the left insula was associated with poorer ASQ-3 score (β = -869.51; p < 0.05). Healthy controls (n = 106) showed a comparable association (β = -1209.87; p < 0.01). FGR (n = 10) showed a larger baseline size of the right Sylvian fissure in association with poorer CBCL-score (β = 4.13; p < 0.01). In CHD (n = 12) the baseline size of the left Sylvian fissure and its growth rate were associated with respectively poorer and better CBCL-scores (β = 3.11; p < 0.01); (β = -171.99; p < 0.01). In PTB (n = 10) no associations were found., Conclusions: This explorative study suggests associations between ultrasound measurements of fetal brain growth and neurodevelopmental outcome at 2 years of age. In future, this non-invasive technique may improve early identification of fetuses at risk for neurodevelopmental outcome and follow-up postnatal clinical care., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Auditory evoked fields (AEFs) are well suited for studies of auditory processing in patients. Their sources have been localized to Heschl's gyri and to the supratemporal auditory cortices. Auditory evoked fields are known to be modulated by peripheral and central lesions of auditory pathways and to reflect group-level pathophysiology of neurodevelopmental and psychiatric disorders. They are useful in lateralization of language processes for planning neurosurgery and for localization of language-related cortex. The recently developed artifact rejection and movement compensation methods will enhance and extend the use of AEFs in studies of clinical patients and pediatric groups. New pediatric magnetoencephalography systems will facilitate clinical AEF studies of developmental disorders. In addition to their established use in planning neurosurgery, AEF findings in several new clinical patient groups suffering, e.g., from developmental, neurodegenerative, or psychiatric disorders have been reported. Several recent investigations report the correlations with clinical symptoms and sensitivity and specificity profiles of AEFs in studies of these disorders; this development is mandatory in gaining wider clinical approval for the use of AEFs in clinical practice dealing with individual patients. Most promising future research lines of clinical applicability of AEFs focus on developmental and psychiatric disorders.

Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2A cause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2A variants (NG&#95;053084.1, NM&#95;032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750&#95;753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386&#95;1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM&#95;032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM&#95;032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2A deficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.

Potocki-Lupski syndrome is a condition mainly characterized by infantile hypotonia, developmental delay/intellectual disability (DD/ID), and congenital anomalies, caused by duplications of the 17p11.2 region, encompassing RAI1 gene. Its clinical presentation is extremely variable, especially for what concerns the cognitive level and the behavioral phenotype. Such aspects, as well as the dysmorphic/malformative ones, have been covered by previous studies; otherwise neurological features have never been systematically described. In order to delineate the neurological phenotype of Potocki-Lupski Syndrome, we collect an 8-patients cohort. Developmental milestones are delayed and a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb. Hypotonia appears a less frequent finding than what previously reported, while motor clumsiness/coordination impairment is frequent. EGG registration demonstrated a common pattern with excess of diffuse rhythmic activity in sleep phases or while the patient is falling asleep. Brain MRI did not reveal common anomalies, although unspecific white matter changes may be present. We discuss such findings and compare them to literature data, offering an overview on the neurological and cognitive-behavioral presentation of the syndrome., (© 2020 Wiley Periodicals LLC.)

The short arm of chromosome 16 (16p) is enriched for segmental duplications, making it susceptible to recurrent, reciprocal rearrangements implicated in the etiology of several phenotypes, including intellectual disability, speech disorders, developmental coordination disorder, autism spectrum disorders, attention deficit hyperactivity disorders, obesity and congenital skeletal disorders. In our clinical study 73 patients were analyzed by chromosomal microarray, and results were confirmed by fluorescence in situ hybridization or polymerase chain reaction. All patients underwent detailed clinical evaluation, with special emphasis on behavioral symptoms. 16p rearrangements were identified in 10 individuals. We found six pathogenic deletions and duplications of the recurrent regions within 16p11.2: one patient had a deletion of the distal 16p11.2 region associated with obesity, while four individuals had duplications, and one patient a deletion of the proximal 16p11.2 region. The other four patients carried 16p variations as second-site genomic alterations, acting as possible modifying genetic factors. We present the phenotypic and genotypic results of our patients and discuss our findings in relation to the available literature., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Survivors following very premature birth (i.e., ≤ 32 weeks gestational age) remain at high risk for neurodevelopmental impairments. Recent advances in deep learning techniques have made it possible to aid the early diagnosis and prognosis of neurodevelopmental deficits. Deep learning models typically require training on large datasets, and unfortunately, large neuroimaging datasets with clinical outcome annotations are typically limited, especially in neonates. Transfer learning represents an important step to solve the fundamental problem of insufficient training data in deep learning. In this work, we developed a multi-task, multi-stage deep transfer learning framework using the fusion of brain connectome and clinical data for early joint prediction of multiple abnormal neurodevelopmental (cognitive, language and motor) outcomes at 2 years corrected age in very preterm infants. The proposed framework maximizes the value of both available annotated and non-annotated data in model training by performing both supervised and unsupervised learning. We first pre-trained a deep neural network prototype in a supervised fashion using 884 older children and adult subjects, and then re-trained this prototype using 291 neonatal subjects without supervision. Finally, we fine-tuned and validated the pre-trained model using 33 preterm infants. Our proposed model identified very preterm infants at high-risk for cognitive, language, and motor deficits at 2 years corrected age with an area under the receiver operating characteristic curve of 0.86, 0.66 and 0.84, respectively. Employing such a deep learning model, once externally validated, may facilitate risk stratification at term-equivalent age for early identification of long-term neurodevelopmental deficits and targeted early interventions to improve clinical outcomes in very preterm infants.

Objective: To characterize the extent of CNS involvement in children with Pompe disease using brain MRI and developmental assessments., Methods: The study included 14 children (ages 6-18 years) with infantile Pompe disease (IPD) (n = 12) or late-onset Pompe disease (LOPD) (n = 2) receiving enzyme replacement therapy. White matter (WM) hyperintense foci seen in the brain MRIs were systematically quantified using the Fazekas scale (FS) grading system with a novel approach: the individual FS scores from 10 anatomical areas were summed to yield a total FS score (range absent [0] to severe [30]) for each child. The FS scores were compared to developmental assessments of cognition and language obtained during the same time period., Results: Mild to severe WM hyperintense foci were seen in 10/12 children with IPD (median age 10.6 years) with total FS scores ranging from 2 to 23. Periventricular, subcortical, and deep WM were involved. WM hyperintense foci were seen throughout the path of the corticospinal tracts in the brain in children with IPD. Two children with IPD had no WM hyperintense foci. Children with IPD had relative weaknesses in processing speed, fluid reasoning, visual perception, and receptive vocabulary. The 2 children with LOPD had no WM hyperintense foci, and high scores on most developmental assessments., Conclusion: This study systematically characterized WM hyperintense foci in children with IPD, which could serve as a benchmark for longitudinal follow-up of WM abnormalities in patients with Pompe disease and other known neurodegenerative disorders or leukodystrophies in children., (© 2020 American Academy of Neurology.)

Background: The objective of this study was to examine how nonverbal skills at age five years relate to visual perception and brain activation during visual perception tasks at age 12 years in very preterm subjects without visual or other neurodevelopmental impairments or major brain pathologies., Methods: At age five years, 36 prematurely born (birth weight ≤1500 g or gestational age less than 32 weeks) and 31 term-born control children were assessed with the nonverbal subtests of the Wechsler Preschool and Primary Scale of Intelligence-Revised and the NEPSY-Second Edition. At age 12 years the same children were re-assessed with tasks from the Motor-Free Visual Perception Test, Third Edition, during functional magnetic resonance imaging., Results: Test performance at age five years was significantly poorer in the very preterm group than the control subjects, but at age 12 years performance was similar in both groups. In the very preterm group, better nonverbal skills at age five years were significantly associated with stronger neural activation during the visual perception task at age 12 years. No associations between nonverbal skills at age five years and brain activation at age 12 years appeared in the control group., Conclusions: The associations between better nonverbal skills and stronger neural activation during visual perception task only observed in the very preterm group may reflect delayed development of the visual perception network and/or prematurity-related neural plasticity. The developmental follow-up of very preterm children should include psychological assessment of nonverbal skills at least until age five years., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mitochondrial complex I deficiency is caused by pathogenic variants in mitochondrial and nuclear genes associated with complex I structure and assembly. We report the case of a patient with　NDUFA8-related mitochondrial disease. The patient presented with developmental delay, microcephaly, and epilepsy. His fibroblasts showed apparent biochemical defects in mitochondrial complex I. Whole-exome sequencing revealed that the patient carried a homozygous variant in NDUFA8. His fibroblasts showed a reduction in the protein expression level of not only NDUFA8, but also the other complex I subunits, consistent with assembly defects. The enzyme activity of complex I and oxygen consumption rate were restored by reintroducing wild-typeNDUFA8 cDNA into patient fibroblasts. The functional properties of the variant in NDUFA8 were also investigated using NDUFA8 knockout cells expressing wild-type or mutated NDUFA8 cDNA. These experiments further supported the pathogenicity of the variant in complex I assembly. This is the first report describing that the loss of NDUFA8, which has not previously been associated with mitochondrial disease, causes severe defect in the assembly of mitochondrial complex I, leading to progressive neurological and developmental abnormalities., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We analyzed our two new cases of infantile-onset epilepsy with developmental delay with de novo variant in TUBB2A and review the related literatures. Our two probands were both girls with infantile-onset epilepsy and global developmental delay. Case 1 had a novel de novo heterozygous missense variant: c.728C>T [p.Pro243Leu] (NM&#95;001069.2). Her brain magnetic resonance imaging (MRI) showed nonspecific white matter myelination delay and slightly enlarged anterior horn of lateral ventricle. Her epilepsy had been controlled by TPM monotherapy. Case 2 had a reported de novo variant c.743C>T [p.Ala248Val] (NM&#95;001069.2). Her brain MRI showed bilateral microgyria and corpus callosum dysplasia. A total of seven TUBB2A mutations cases had been published previously in five papers, therefore, until now, there were nine patients with TUBB2A mutations. All patients had developmental delay, among them seven cases also with infantile-onset epilepsy, one case with abnormal EEG but without clinical seizures. There are six cases that have different degree of cortical dysplasia, one case with cerebellar vermis atrophy and brainstem sacsinopathy, the rest two cases have no obvious brain structural abnormalities. There was one case with variant c.1249G>A (p.D417N) that had atypical clinical presentation, including prominent progressive spastic ataxia, sensory motor axonal neuropathy, and bilateral optic macular dystrophy, but relatively mild intellectual disability, his MRI showed cerebellar atrophy, thinning of the corpus callosum and pons sacsinopathy, but no cortical malformation. The p.A248V mutation was the most common mutation occurred in three patients (3/9). The clinical phenotypes of these three patients were similar, all of them had global developmental delay with no language and corpus callosum dysplasia, two cases with epilepsy and the other one only have EEG epileptic discharges without clinical seizure, two cases with cortical dysplasia and the other one without obvious brain malformation. In brief, global developmental delay was the most common phenotype of TUBB2A mutation-related disease, most cases also had infantile-onset epilepsy and cortical dysplasia and corpus callosum dysplasia. The region between seventh and eighth alpha-helix of TUBB2A may be a "hot spot" mutation domain.

Objective: The purpose of this study is to describe the imaging findings in a group of fetuses with suspected agenesis of the septum pellucidum (ASP) and to evaluate their clinical outcome., Methods: This is a retrospective multicenter study on a cohort of fetuses diagnosed with suspected ASP, between 2008 and 2017. The records of each patient, including ultrasound (US) and magnetic resonance studies, were reviewed and compared with the postnatal findings., Results: Forty-seven patients were included in the study at a mean gestational age of 26.6 weeks. In 17 patients, the ASP was considered isolated. Fourteen patients delivered live-born, and all 14 are developing normally. Three were lost to follow-up. Twenty-four patients had associated malformations involving the central nervous system (CNS); 13 were delivered (normal development [5], abnormal [6] and no follow-up [2]). Nine patients opted for termination, and two pregnancies were lost to follow-up. Six patients had non-CNS associated findings, two were delivered with normal neurological development and four had a termination., Conclusions: Isolated ASP is usually associated with a favorable outcome; but in the presence of associated malformations, there is at least a 50% risk of abnormal development. Current imaging techniques can provide an accurate prognosis in cases when ASP appears isolated., (© 2020 John Wiley & Sons, Ltd.)