•RHOBTB2 gene variants cause early infantile epileptic encephalopathy type 64.•Neurological phenotype includes epileptic encephalopathy and movement disorder.•Little is known on therapeutic ...strategies for movement disorder.•Carbamazepine can be effective on RHOBTB2-related paroxysmal dyskinesia.
Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its ...rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.
In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.
All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.
Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
Background: SOX2 disorders are associated with anophthalmia-esophageal-genital syndrome or microphthalmia, syndromic 3 (MCOPS3- # 206900). Case Report: We describe a third fetal case with a de novo ...3q26.32q26.33 deletion extending for 4.31 Mb, detected in a 15-week fetus. After legal interruption of pregnancy, at autopsy, the fetus presented bilateral microphthalmia, right cleft lip and palate, bilateral cerebral ventriculomegaly and dilated third ventricle, microcystic left lung, and intestinal malrotation. Histologically, the left lung showed congenital pulmonary airway malformation (CPAM) type 2. Retinal dysplasia was found in both eyes. Discussion/Conclusion: The human SOX2 gene (OMIM #184429) is located on chromosome 3 at position q26.3-27 and encodes a transcription factor involved in the development of the central and peripheral nervous systems, retina, and lung. In our case, the combination of cerebral, retinal, and pulmonary anomalies, not previously described, are consistent with SOX2 haploinsufficiency due to chromosomal deletion.
Spondylocostal dysostosis (SCD), a condition characterized by multiple segmentation defects of the vertebrae and rib malformations, is caused by bi‐allelic variants in one of the genes involved in ...the Notch signaling pathway that tunes the “segmentation clock” of somitogenesis: DLL3, HES7, LFNG, MESP2, RIPPLY2, and TBX6. To date, seven individuals with LFNG variants have been reported in the literature. In this study we describe two newborns and one fetus with SCD, who were found by trio‐based exome sequencing (trio‐ES) to carry homozygous (c.822‐5C>T) or compound heterozygous (c.863dup;1063G>A) and (c.521G>T;890T>G) variants in LFNG. Notably, the c.822‐5C>T change, affecting the polypyrimidine tract of intron 5, is the first non‐coding variant reported in LFNG. This study further refines the clinical and molecular features of spondylocostal dysostosis 3 and adds to the numerous investigations supporting the usefulness of trio‐ES approach in prenatal and neonatal settings.
Five unpublished biallelic variants in LFNG, including one non‐exonic affecting the polypyrimidine tract, were identified by trio‐based whole exome sequencing in three subjects (two newborns and one fetus) from three independent pedigrees with definitive diagnosis of spondylocostal dysostosis (SCD; upper panel). All LFNG variants described so far in SCD patients are expected to exert a loss‐of‐function effect, being nonsense/frameshift variants or missense changes affecting the critical Fringe domain (lower panel).
Cranio‐lenticulo‐sutural dysplasia (CLSD; MIM 607812) is a rare or underdiagnosed condition, as only two families have been reported. The original family (Boyadjiev et al., Human Genetics, 2003, 113, ...1–9 and Boyadjiev et al., Nature Genetics, 2006, 38, 1192–1197) showed recessive inheritance of the condition with a biallelic SEC23A missense variant in affected individuals. In contrast, another child with sporadic CLSD had a monoallelic SEC23A variant inherited from the reportedly unaffected father (Boyadjiev et al., Clinical Genetics, 2011, 80, 169–176), raising questions on possible digenism. Here, we report a 2‐month‐old boy seen because of large fontanels with wide cranial sutures, a large forehead, hypertelorism, a thin nose, a high arched palate, and micrognathia. His mother was clinically unremarkable, while his father had a history of large fontanels in infancy who had closed only around age 10 years; he also had a large forehead, hypertelorism, a thin, beaked nose and was operated for bilateral glaucoma with exfoliation of the lens capsule. Trio genome sequencing and familial segregation revealed a monoallelic c.1795G > A transition in SEC23A that was de novo in the father and transmitted to the proband. The variant predicts a nonconservative substitution (p.E599K) in an ultra‐conserved residue that is seen in 3D models of yeast SEC23 to be involved in direct binding between SEC23 and SAR1 subunits of the coat protein complex II coat. This observation confirms the link between SEC23A variants and CLSD but suggests that in addition to the recessive inheritance described in the original family, SEC23A variants may result in dominant inheritance of CLSD, possibly by a dominant‐negative disruptive effect on the SEC23 multimer.
Activating Signal Cointegrator 1 complex (ASC-1 complex) is a ribonucleoprotein tetramer participating in transcriptional coactivation and RNA processing, consisting of four subunits: ASCC1-ASCC3 and ...ASC-1. Pathogenic variants in the TRIP4 and ASCC1 genes, encoding the ASC-1 and ASCC1 subunits, were recently described in congenital myopathic conditions without signs of motor neuron involvement, and Spinal Muscular Atrophy-like (SMA-like) phenotype with prenatal bone fractures. We present a novel pathogenic TRIP4 variant in two siblings with severe phenotype and mixed sensory-motor polyneuropathy. The reviewed phenotypic spectrum is broad, but sensory-motor polyneuropathy is so-far unreported. We thus expand ASC-1 related myopathy phenotype.
Sleep disturbances are frequently reported in Mowat-Wilson Syndrome (MWS). The current study aimed to evaluate clinical and video-polysomnographic (VPSG) characteristics of the sleep architecture and ...abnormal electroencephalogram (EEG) patterns during sleep in MWS.
Sixteen individuals with MWS (range 16 months–25 years), attending the Department of Child Neurology and Psychiatry of the University of Bologna, were included. The “Sleep Disturbances Scale for Children (SDSC)” questionnaire was administered to all parents of MWS patients, and all patients underwent a VPSG recording.
The analysis of the SDSC questionnaire revealed disturbances mainly at the sleep–wake transition and in initiating and maintaining sleep. Evaluation of sleep structure in MWS patients showed a significant reduction of total sleep time, an increase of wake after sleep onset and arousal index as compared to normal controls. An EEG pattern characterized by slowing of background activity and poverty of physiological sleep characterisitcs was observed in all patients. Moreover, in patients aged >7 years, anteriorly predominant spike and waves were observed, markedly activated by sleep configuring a sub-continuous or continuous activity.
Our data (both clinical and VPSG) documented the presence of significant and clinically relevant sleep disturbances in MWS patients. Moreover, we identified a characteristic age-dependent sleep EEG pattern that could provide a new element to assist in the management of MWS.
•This is the first study of sleep in MWS using questionnaire and video-polysomnography (VPSG).•SDSC questionnaire revealed disturbances at the sleep–wake transition and in initiating and maintaining sleep.•VPSG documented reduction of total sleep time and increase of wake time after sleep.•Slowing of EEG background and a poverty of sleep figures were observed in all patients.•After age seven, sleep-related sub-continuous EEG epileptiform activity was observed.
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