De novo DDX3X variants account for 1-3% of syndromic intellectual disability (ID) in females and have been occasionally reported in males. Furthermore, somatic DDX3X variants occur in several ...aggressive cancers, including medulloblastoma. We report three unrelated females with severe ID, dysmorphic features, and a common brain malformative pattern characterized by malformations of cortical development, callosal dysgenesis, basal ganglia anomalies, and midbrain-hindbrain malformations. A pilocytic astrocytoma was incidentally diagnosed in Patient 1 and trigonocephaly was found in Patient 2. With the use of family based whole exome sequencing (WES), we identified three distinct de novo variants in DDX3X. These findings expand the phenotypic spectrum of DDX3X-related disorders, demonstrating unique neuroradiological features resembling those of the tubulinopathies, and support a role for DDX3X in neuronal development. Our observations further suggest a possible link between germline DDX3X variants and cancer development.
NAA20 is the catalytic subunit of the NatB complex, which is responsible for N‐terminal acetylation of approximately 20% of the human proteome. Recently, pathogenic biallelic variants in NAA20 were ...associated with a novel neurodevelopmental disorder in five individuals with limited clinical information. We report two sisters harboring compound heterozygous variant (c.100C>T (p.Gln34Ter) and c.11T>C p.(Leu4Pro)) in the NAA20 gene, identified by exome sequencing. In vitro studies showed that the missense variant p.Leu4Pro resulted in a reduction of NAA20 catalytic activity due to weak coupling with the NatB auxiliary subunit. In addition, unpublished data of the previous families were reported, outlining the core phenotype of the NAA20‐related disorder mostly characterized by cognitive impairment, microcephaly, ataxia, brain malformations, dysmorphism and variable occurrence of cardiac defect and epilepsy. Remarkably, our two patients featured epilepsy onset in adolescence suggesting this may be a part of syndrome evolution. Functional studies are needed to better understand the complexity of NAA20 variants pathogenesis as well as of other genes linked to N‐terminal acetylation.
Biallelic pathogenic variants in the NAA20 gene have been described in 7 individuals belonging to 3 separate families. These variants functionally results in a reduced cellular N‐acetylation, leading to a phenotypic spectrum that includes developmental delay, cognitive impairment, microcephaly, ataxia, epilepsy, brain malformations, congenital heart defects, and craniofacial dysmorphisms.
This article was published online with incorrect alignment in Table 4. Column and rows are out of order. The correct Table 4 is presented here. The original article has been corrected.
UPF3B encodes the Regulator of nonsense transcripts 3B protein, a core‐member of the nonsense‐mediated mRNA decay pathway, protecting the cells from the potentially deleterious actions of transcripts ...with premature termination codons. Hemizygous variants in the UPF3B gene cause a spectrum of neuropsychiatric issues including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia/childhood‐onset schizophrenia (COS). The number of patients reported to date is very limited, often lacking an extensive phenotypical and neuroradiological description of this ultra‐rare syndrome. Here we report three subjects harboring UPF3B variants, presenting with variable clinical pictures, including cognitive impairment, central hypotonia, and syndromic features. Patients 1 and 2 harbored novel UPF3B variants—the p.(Lys207*) and p.(Asp429Serfs*27) ones, respectively—while the p.(Arg225Lysfs*229) variant, identified in Patient 3, was already reported in the literature. Novel features in our patients are represented by microcephaly, midface hypoplasia, and brain malformations. Then, we reviewed pertinent literature and compared previously reported subjects to our cases, providing possible insights into genotype–phenotype correlations in this emerging condition. Overall, the detailed phenotypic description of three patients carrying UPF3B variants is useful not only to expand the genotypic and phenotypic spectrum of UPF3B‐related disorders, but also to ameliorate the clinical management of affected individuals.
Objectives
To describe the neurological phenotype of children with prenatal diagnosis of agenesis of corpus callosum (ACC) and interhemispheric cysts associated with malformations of cortical ...development (MCD).
Methods
We reviewed the neuroimaging, neurologic, EEG, and genetic data of 36 patients (21 males, mean age 7 years) with ACC and interhemispheric cysts. Associations were tested with Chi-squared and Fisher exact tests.
Results
According to the 2001 Barkovich classification, we found 4 type 1c (11.1%), 6 type 2a (16.6%), 18 type 2b (50%, 6/18 girls with Aicardi syndrome), and 9 type 2c cysts (22.2%). EEG showed specific epileptic activity in 27/36 patients (75%). Epilepsy was diagnosed in 16 subjects (16/36, 44.4%), including all Aicardi patients, and was associated with cognitive impairment (
p
= 0.032). Severe intellectual disability and epilepsy were associated with type 2b cysts, always due to Aicardi patients (
p
< 0.05). After excluding Aicardi patients, all subjects with type 2b cysts had mild neurological phenotype. Patients with 2a and 2c cysts more frequently had normal cognition (83.3% and 62.5% of cases, respectively). Patients with type 1c cyst mostly had mild/moderate cognitive impairment. Severe neurologic deficits were associated with 1c cysts and 2b cysts with Aicardi syndrome (
p
< 0.05). Multilobar and/or bilateral MCD were associated with severe neurological and epileptic phenotypes (
p
< 0.05).
Conclusion
Once excluded Aicardi syndrome, most patients with ACC and interhemispheric cysts have a mild clinical phenotype characterized by borderline/normal cognition and minor neurological signs. Despite the high prevalence of EEG epileptic abnormalities, epilepsy in these cases is infrequent and usually responsive to antiepileptic drugs.
The mammillary bodies (MBs) have repeatedly been shown to be critical for memory, yet little is known about their involvement in numerous neurological conditions linked to memory impairments, ...including neonatal encephalopathy.
We implemented a multicentre retrospective study, assessing magnetic resonance scans of 219 infants with neonatal encephalopathy who had undergone hypothermia treatment in neonatal intensive care units located in the Netherlands and Italy.
Abnormal MB signal was observed in ~40% of infants scanned; in half of these cases, the brain appeared otherwise normal. MB involvement was not related to the severity of encephalopathy or the pattern/severity of hypoxic-ischaemic brain injury. Follow-up scans were available for 18 cases with abnormal MB signal; in eight of these cases, the MBs appeared severely atrophic.
This study highlights the importance of assessing the status of the MBs in neonatal encephalopathy; this may require changes to scanning protocols to ensure that the slices are sufficiently thin to capture the MBs. Furthermore, long-term follow-up of infants with abnormal MB signal is needed to determine the effects on cognition, which may enable the use of early intervention strategies. Further research is needed to assess the role of therapeutic hypothermia in MB involvement in neonatal encephalopathy.
The MBs are particularly sensitive to hypoxia in neonates. Current hypothermia treatment provides incomplete protection against MB injury. MB involvement is likely overlooked as it can often occur when the rest of the brain appears normal. Given the importance of the MBs for memory, it is necessary that this region is properly assessed in neonatal encephalopathy. This may require improvements in scanning protocols.
Mutations in AarF domain‐containing kinase 3 (ADCK3) are responsible for the most frequent form of hereditary coenzyme Q10 (CoQ10) deficiency (Q10 deficiency‐4), which is mainly associated with ...autosomal recessive cerebellar ataxia type 2 (ARCA2). Clinical presentation is characterized by a variable degree of cerebellar atrophy and a broad spectrum of associated symptoms, including muscular involvement, movement disorders, neurosensory loss, cognitive impairment, psychiatric symptoms and epilepsy. In this report, we describe, for the first time, a case of photoparoxysmal response in a female patient with a mutation in ADCK3. Disease onset occurred in early childhood with gait ataxia, and mild‐to‐moderate degeneration. Seizures appeared at eight years and six months, occurring only during sleep. Photoparoxysmal response was observed at 14 years, almost concomitant with the genetic diagnosis (c.901C>T;c.589‐3C>G) and the start of CoQ10 oral supplementation. A year later, disease progression slowed down, and photosensitivity was attenuated. A review of the literature is provided focusing on epileptic features of ADCK3‐related disease as well as the physiopathology of photoparoxysmal response and supposed cerebellar involvement in photosensitivity. Moreover, the potential role of CoQ10 oral supplementation is discussed. Prospective studies on larger populations are needed to further understand these data.
Early exposure to nociceptive events may cause brain structural alterations in preterm neonates, with long-lasting consequences on neurodevelopmental outcome. Little is known on the extent to which ...early pain may affect brain connectivity. We aim to evaluate brain functional connectivity changes in preterm neonate that underwent multiple invasive procedures during the postnatal period, and to correlate them with the neurodevelopmental outcome at 24 months.
In this prospective case-control study, we collected information about exposure to painful events during the early postnatal period and resting-state BOLD-fMRI data at term equivalent age from two groups of preterm neonate: 33 subjected to painful procedures during the neonatal intensive care (mean gestational age 27.9 ± 1.8 weeks) and 13 who did not require invasive procedures (average gestational age 31.2 ± 2.1 weeks). A data-driven principal-component-based multivariate pattern analysis (MVPA) was used to investigate the effect of early pain exposure on brain functional connectivity, and the relationship between connectivity changes and neurodevelopmental outcome at 24 months, assessed with Griffiths, Developmental Scale-Revised: 0-2.
Early pain was associated with decreased functional connectivity between thalami and bilateral somatosensory cortex, and between the right insular cortex and ipsilateral amygdala and hippocampal regions, with a more evident effect in preterm neonate undergoing more invasive procedures. Functional connectivity of the right thalamocortical pathway was related to neuromotor outcome at 24 months (
= 0.003).
Early exposure to pain is associated with abnormal functional connectivity of developing networks involved in the modulation of noxious stimuli in preterm neonate, contributing to the neurodevelopmental consequence of preterm birth.
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