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SCY1‐like protein 2 (SCYL2) is a member of the SCY1‐like pseudokinase family which regulates secretory protein trafficking. It plays a crucial role in the nervous system by suppressing excitotoxicity in the developing brain. Scyl2 knockout mice have excess prenatal mortality and survivors show severe neurological dysfunction. Bi‐allelic loss‐of‐function (LOF) variants in SCYL2 were recently associated with arthrogryposis multiplex congenita‐4 (AMC4) following the report of 6 individuals from two consanguineous unrelated families. The AMC4 phenotype described included severe arthrogryposis, corpus callosum agenesis, epilepsy and frequently, early death. We describe here two additional similarly affected individuals with AMC4, including one diagnosed in the prenatal period, with bi‐allelic LOF variants in SCYL2, and two individuals homozygous for missense variants in the protein kinase domain of SCYL2 and presenting with developmental delay only. Our study confirms the association of SCYL2 with AMC4 and suggests a milder phenotype can occur, extending the phenotypic spectrum of autosomal recessive SCYL2‐related disorders. [ABSTRACT FROM AUTHOR]

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Human cytomegalovirus (CMV) causes a common congenital infection leading to long-term neurological impairments including brain, cochlear, and ocular pathology. Infection of newborn mice with murine (M)CMV is an established model of neuropathology caused by congenital CMV infection, with recent work suggesting that brain pathology may be driven by immune responses. In the eye, however, CMV retinitis is thought to result from virus-driven necrosis in the absence of T cell responses. We found that MCMV infection of newborn mice recapitulates human eye disease after congenital CMV infection, including focal chorioretinitis, inflamed vasculature, and disrupted blood-retinal barriers. Moreover, infection drove extensive T cell infiltration of the retina and marked gliosis. Blocking immune responses generally, or via targeting the chemokine receptor CXCR3, did not exacerbate retinal disease but instead prevented pathology despite retinal MCMV infection. Thus, our data establish this model for studies of congenital retinal disease and show that the immune system drives pathology in the neonatal eye after MCMV infection. [ABSTRACT FROM AUTHOR]

The letter published in the Journal of Clinical Immunology discusses Vici Syndrome, a rare autosomal recessive disorder caused by mutations in the EPG5 gene. The syndrome is characterized by various symptoms, including immune deficiency, cardiomyopathy, and hypopigmentation. The letter reports on three patients with Vici Syndrome who presented with inflammatory bowel disease and hemophagocytic lymphohistiocytosis, expanding the understanding of immune dysregulation in this population. The study highlights the importance of evaluating patients with Vici Syndrome for immune deficiency and hyperinflammatory states, emphasizing the need for further research on the role of EPG5 in immune regulation. [Extracted from the article]

Vici syndrome (VICIS) is a congenital disorder characterized by agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive. This study aimed to elucidate the number of patients with VICIS, its clinical characteristics and relevant genetic information in Japan. After developing diagnostic criteria for VICIS, we conducted a nationwide questionnaire-based survey of VICIS in Japan. In the initial survey, we investigated the number of VICIS patients who fulfilled definite or probable criteria. The second survey was used to obtain detailed clinical and genetic information of VICIS from institutions that responded to the initial survey. Clinical information was available for 15 patients (12 definite, three probable). As of October 2023, nine patients (60%) were alive and six (40%) had died. All patients presented with developmental delay, agenesis of the corpus callosum, elevated serum aspartate/alanine aminotransferase, hypopigmentation and hypotonia. Developmental delay was profound. Most patients developed recurrent infection, high-arched palate, epilepsy, failure to thrive, and microcephaly. Cardiomyopathy and cataracts, both initially described as principal features in VICIS, were notably uncommon in our study. Based on the information collected, all 14 patients for whom information was available received home medical care: 11 (79%) received tube feeding, three (21%) required noninvasive ventilation, four (29%) required tracheostomy, and four (29%) required home subcutaneous immunoglobulin administration. This study revealed for the first time the nationwide status of patients with VICIS in Japan. The mortality rate of patients with VICIS is as high as 40%, and almost all VICIS patients require various forms of home medical care, necessitating comprehensive management. Additionally, we identified one adult patient, underscoring the need for comprehensive medical management extending into adulthood for patients with VICIS. [ABSTRACT FROM AUTHOR]

Objective: Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X‐linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities. Methods: Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. Results: The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post‐fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability. Interpretation: Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X‐linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024;96:914–931 [ABSTRACT FROM AUTHOR]

Inhalant misuse and inhalant use disorder are global public health concern that impacts adolescents but can occur throughout life. Toluene is the most commonly misused inhalant. Toluene use leads to significant neuroanatomic, cognitive, and psychiatric deficits. The purpose of this study was to review and summarize the effects of toluene and present a case of a middle-aged patient with an inhalant use disorder. A literature review was conducted to evaluate imaging, neurocognitive, and psychiatric consequences of toluene misuse. The common imaging findings amongst those who misuse toluene were cerebral and cerebellar atrophy, ventricular dilation, loss of gray-white matter differentiation, corpus callosum thinning, and diffuse white matter changes. Concerning cognition, toluene misusers were shown to have deficits in intelligence, attention, memory, visuospatial function, and complex cognition. In addition, toluene users also commonly presented with apathy, flat affect, hallucinations, delusions, anxiety, depression, and insomnia. The neuroanatomical, neurocognitive, and psychiatric effects of toluene misuse are profound. These deficits can make inhalant use disorder difficult to treat. Therefore, evidence-based treatments that recognize and address these domain-specific neurocognitive deficits are needed. [ABSTRACT FROM AUTHOR]

The ARX mutations encompass a nearly continuous spectrum of neurodevelopmental disorders (NDDs), ranging from lissencephaly to Proud syndrome, as well as infantile spasms without brain malformations, and including both syndromic and non-syndromic intellectual disabilities (IDs). We describe worsening neuropsychiatric symptoms in the offspring of a Korean family with ID/developmental delay (DD) caused by a novel ARX p.Lys385Ter variant. Sequential genetic testing was performed to investigate the ID, DD, agenesis of the corpus callosum (ACC), and developmental epileptic encephalopathy (DEE) observed in the proband. A comprehensive trio clinical exome sequencing approach using a Celemics G-Mendeliome Clinical Exome Sequencing Panel was employed. Given the clinical manifestations observed in the proband, gene panel sequencing identified a heterozygous ARX variant, c.1153A>T/p.Lys385Ter (Reference transcript ID: NM_139058.3), as the most likely cause of ID, DD, ACC, and DEE in the proband. Sanger sequencing confirmed the segregation of the ARX variant, c.1153A>T/p.Lys385Ter, with the phenotype and established the maternally inherited dominant status of the heterozygous variant in the patient, as well as in her grandmother, mother, and aunt. Our case report adds to the understanding of the female phenotype in ARX-related disorders caused by loss-of-function variants in the ARX gene. Genetic counseling for ARX families should proceed with caution, as female carriers can exhibit a wide range of phenotypes, from normal cognitive development to ID/DD, ACC, and DEE. [ABSTRACT FROM AUTHOR]

Introduction: Canavan disease (CD) is a rare autosomal recessive neurodegenerative disorder caused by a deficiency of aspartoacylase A, an enzyme that degrades N-acetylaspartate (NAA). The disease is characterized by progressive white matter degeneration, leading to intellectual disability, seizures, and death. This retrospective study aims to describe the full spectrum of magnetic resonance imaging (MRI) findings in a large case series of CD patients. Materials and methods: MRI findings in 18 patients with confirmed CD were investigated, and the full spectrum of brain abnormalities was compared with the existing literature to provide new insights regarding the brain MRI findings in these patients. All the cases were proven based on genetic study or NAA evaluation in urine or brain. Results: Imaging analysis showed involvement of the deep and subcortical white matter as well as the globus pallidus in all cases, with sparing of the putamen, caudate, and claustrum. The study provides updates on the imaging characteristics of CD and validates some underreported findings such as the involvement of the lateral thalamus with sparing of the pulvinar, involvement of the internal capsules and corpus callosum, and cystic formation during disease progression. Conclusion: To our knowledge, this is one of the largest case series of patients with CD which includes a detailed description of the brain MRI findings. The study confirmed many of the previously reported MRI findings but also identified abnormalities that were previously rarely or not described. We speculate that areas of ongoing myelination are particularly vulnerable to changes in CD. [ABSTRACT FROM AUTHOR]

Objectives: The corpus callosum is the main pathway that connects interhemispheric communication. Agenesis of corpus callosum (ACC) have not consistently detected replicate genetic risk factors, potentially due to Etiological heterogeneity of this trait. This study aimed to retrospectively analyze the molecular basis for the ACC and the potential genotyping-phenotyping association and provide the basis for genetic counselling. Material and methods: Karyotyping and chromosomal microarray analysis were performed for copy number variants. Results: Three cases had 1p36 deletions, two cases had 2q31.2 and 2p16.3 microdeletions, one case had microdeletion of Xq26.3q27.1, five cases involved derived chromosomes due to unbalanced translocations. These cases had variable deletions and duplications with partial overlapping. Phenotypically, besides agenesis of corpus callosum and other brain morphological abnormalities as well as heart abnormalities. Conclusions: ACC may occur alone or be related to other abnormal clinical phenotypes, and its genetic mechanism is very complicated. These results revealed ACC is associated with a variety of chromosomal abnormalities. The findings of the present study expand the genotypes associated with ACC, and further delineation of the genotype-phenotype correlations for ACC. With current applications of chromosome microarray analysis, congenital submicroscopic copy-number variations in fetuses can be detected more effectively. [ABSTRACT FROM AUTHOR]

Abstract Purpose Aicardi syndrome is a rare epileptic encephalopathy, almost exclusively affecting girls. It was first described as a triad of infantile spasms, chorioretinal defects and agenesis of the corpus callosum. The etiology remains unknown and there is uncertainty on best practice therapy and outcome. We aimed at defining quantitative clinical endpoints that will inform future research and clinical trials. Methods Quantitative natural history modeling of cases with Aicardi syndrome from published clinical reports. Main outcome measures were age at disease onset, survival and diagnostic delay. Phenotypic features of affected individuals as well as neuroradiological and ophthalmological features were descriptively stated. STROBE criteria were respected. Results Two hundred forty-five cases were available for analysis. Median age at disease onset was 2.2 months. Median diagnostic delay was 1 month. Mortality was estimated with 6% at 1 and 17% at 5 years of age. 60% of children showed the classic clinical features, while 40% met the revised diagnostic criteria. We delineate possible predictors of disease severity and of seizure control. Conclusion We provide natural history data including geographical localization of 245 published patients with Aicardi syndrome. Quantitative history modeling in rare epileptic encephalopathies will help to raise disease awareness and facilitate future clinical trials as one core element of quantitative systems pharmacology.

In 1969 Joseph Bogen, a colleague of Roger Sperry and the neurosurgeon who performed commissurotomy on Sperry's "split-brain" study participants, wrote an article subtitled "The Corpus Callosum and Creativity." The article argued for the critical role of the corpus callosum and hemispheric specialization in creativity. Building on a four-stage model of creativity (learning, incubation, illumination, refinement) and Sperry's innovative studies, the Bogens posited that in the intact brain, creativity relies on two opposing functions of the corpus callosum: (a) interhemispheric inhibition to facilitate simultaneous and independent activity of uniquely-specialized processing centers during learning and incubation and (b) interhemispheric facilitation to support the increased bi-hemispheric integration and coordination which produces illumination. This article revisits the Bogens' theory considering scientific discoveries over the past 50 years. We begin by reviewing relevant findings from split-brain studies, and then briefly consider findings from studies that examine the association of creativity with callosal structure and function in neurotypical participants. Finally, we provide an in-depth discussion of creativity in persons with agenesis of the corpus callosum (ACC)--the congenital absence of the corpus callosum. These three lines of inquiry strongly support the theory suggested by Bogen and Bogen in 1969 and provide further clarification regarding the critical and unique role of the corpus callosum in creative cognition. [ABSTRACT FROM AUTHOR]

Agenesis of the corpus callosum is a rare congenital condition, present at birth, characterized by the partial or complete absence of the corpus callosum. Although the exact causes are usually unknown, the condition can be inherited either as an autosomal recessive trait or as an X-linked dominant trait [1]. Alternatively, it may result from an infection or injury during the 20th to 22nd weeks of pregnancy, which can lead to disruptions in the development of the fetal brain, or it may be caused by toxic factors, such as fetal alcohol syndrome [2]. We present the case of a 2-month-old male patient with acute surgical pathology that began at birth and rapidly progressed to severe infection, requiring sustained antibiotic treatment and assisted respiration. The presence of muscular hypotonia and tonic-clonic seizures at home, following the first hospitalization, necessitated readmission to another university clinic, where he was also diagnosed with agenesis of the corpus callosum. The management of this case required special attention to clinical manifestations, rapid identification of complications, appropriate therapeutic management, and essential collaboration among members of the medical team. [ABSTRACT FROM AUTHOR]

Imagawa-Matsumoto syndrome (IMMAS; MIM #618786) is an autosomal dominant syndrome characterized by overgrowth, dysmorphic features, musculoskeletal abnormalities, developmental delay, and intellectual disability. The first case was reported in 2017 and has subsequently been diagnosed in only another 12 patients. We also present the first IMMAS patient from Turkey. A 19-year-old female was admitted to the neurology outpatient clinic due to a behavioral disorder and intellectual disability. Her physical examination revealed macrocephaly and dysmorphic features like a round face, broad forehead, hypertelorism, and variable skeletal anomalies such as flat feet, clinodactyly, and macrocephaly. Cranial magnetic resonance imaging (MRI) showed agenesis of the corpus callosum and polymicrogyria. Chromosomal analysis results were consistent with a normal constitutional female karyotype and microarray analysis showed a de novo 1.5-MB size deletion on the long arm of chromosome 17; band q11.2 encompassing the Polycomb Repressive Complex 2 Subunit (SUZ12 gene, MIM *606245). This report will contribute to the limited information in the literature. [ABSTRACT FROM AUTHOR]

CT and MR tools are commonly used to diagnose lumbar fractures (LF). However, numerous limitations have been found in practice. The aims of this study were to innovate and develop a spinal disease-specific neural network and to evaluate whether synthetic MRI of the LF affected clinical diagnosis and treatment strategies. A total of 675 LF patients who met the inclusion and exclusion criteria were included in the study. For each participant, two mid-sagittal CT and T2-weighted MR images were selected; 1350 pairs of LF images were also included. A new Self-pix based on Pix2pix and Self-Attention was constructed. A total of 1350 pairs of CT and MR images, which were randomly divided into a training group (1147 pairs) and a test group (203 pairs), were fed into Pix2pix and Self-pix. The quantitative evaluation included PSNR and SSIM (PSNR1 and SSIM1: real MR images and Pix2pix-generated MR images; PSNR2 and SSIM2: real MR images and Self-pix-generated MR images). The qualitative evaluation, including accurate diagnosis of acute fractures and accurate selection of treatment strategies based on Self-pix-generated MRI, was performed by three spine surgeons. In the LF group, PSNR1 and PSNR2 were 10.884 and 11.021 (p < 0.001), and SSIM1 and SSIM2 were 0.766 and 0.771 (p < 0.001), respectively. In the ROI group, PSNR1 and PSNR2 were 12.350 and 12.670 (p = 0.004), and SSIM1 and SSIM2 were 0.816 and 0.832 (p = 0.005), respectively. According to the qualitative evaluation, Self-pix-generated MRI showed no significant difference from real MRI in identifying acute fractures (p = 0.689), with a good sensitivity of 84.36% and specificity of 96.65%. No difference in treatment strategy was found between the Self-pix-generated MRI group and the real MRI group (p = 0.135). In this study, a disease-specific GAN named Self-pix was developed, which demonstrated better image generation performance compared to traditional GAN. The spine surgeon could accurately diagnose LF and select treatment strategies based on Self-pix-generated T2 MR images. [ABSTRACT FROM AUTHOR]

Central diabetes insipidus (CDI) is a disorder in the pediatric population resulting from antidiuretic hormone deficiency. The excessive production of dilute urine characterizes it and manifests with polyuria, nocturia, and polydipsia. The diagnostics of CDI is often challenging, especially concerning the underlying condition of the disease. This article highlights the diverse clinical presentation of children with CDI and diagnostic difficulties among patients with polyuria and polydipsia. The article also reviews the etiology, symptoms, diagnostic workup, and management of CDI. We present 4 pediatric patients (aged 3-13.5 years) diagnosed with CDI of different etiology: 1 due to septo-optic dysplasia/optic nerve hypoplasia and 3 due to acquired processes such as Langerhans cell histiocytosis and germ cell tumor in 2 patients. Central diabetes insipidus was the first manifestation of a tumor or granuloma in all presented patients with acquired pathology. The patients sometimes need long-term follow-up to establish the proper final diagnosis. [ABSTRACT FROM AUTHOR]

Objective: Investigate factors influencing autism spectrum disorder (ASD) diagnosis in children under and over 36 months, and determine the average age for ASD diagnosis at Charoenkrung Pracharak Hospital, Bangkok, Thailand, after implementing ASD screening. Materials and Methods: A retrospective cross-sectional study of 252 children with ASD aged 1-15 years from 2014 to 2023, classified into ≤36 months (n=104) and >36 months (n=148) at diagnosis. Demographic, clinical data and child/family factors were analyzed using multivariate regression analysis. Results: Mean age at ASD diagnosis was 44.77 ± 19.91 months. Attending well-baby clinics (aOR 2.64, p=0.038), higher family income ≥ 814 US dollars per month (aOR 2.33, p=0.020), and higher parental education (aOR 3.43, p=0.011) were significantly associated with diagnosis before 36 months. Hyperactivity as the main complaint (aOR 0.07, p=0.001) and global developmental delay/intellectual disability (aOR 0.45, p=0.023) predicted later diagnosis. Child's gender, being an only child, sibling order, and parental age had no significant impact. Conclusion: Over half of all ASD diagnoses occurred after age 3, with an average age around 44 months. Regular attendance in well-child clinics allowing ASD screening, and higher socioeconomic status and parental education facilitated earlier diagnosis. In contrast, concerns about hyperactivity and global developmental delay often lead to delayed ASD assessment. Enhancing awareness of ASD among families with limited resources can promote timely diagnosis and access to intervention. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have found deficits in imaginative elaboration and social inference to be associated with agenesis of the corpus callosum (ACC; Renteria-Vasquez et al., 2022; Turk et al., 2009). In the current study, Thematic Apperception Test (TAT) responses from a neurotypical control group and a group of individuals with ACC were used to further study the capacity for imaginative elaboration and story coherence. Method: Topic modeling was employed utilizing Latent Diritchlet Allocation to characterize the narrative responses to the pictures used in the TAT. A measure of the difference between models (perplexity) was used to compare the topics of the responses of individual participants to the common core model derived from the responses of the control group. Story coherence was tested using sentence-to-sentence Latent Semantic Analysis. Results: Group differences in perplexity were statistically significant overall, and for each card individually (p <.001). There were no differences between the groups in story coherence. Conclusions: TAT narratives from persons with ACC were normally coherent, but more conventional (i.e., more similar to the core text) compared to those of neurotypical controls. Individuals with ACC can make conventional social inferences about socially ambiguous stimuli, but are restricted in their imaginative elaborations, resulting in less topical variability (lower perplexity values) compared to neurotypical controls. [ABSTRACT FROM AUTHOR]

Caudal regression syndrome (CRS), also known as caudal agenesis, results from abnormal development of the caudal aspect of the spinal cord and vertebral column due to an earlier abnormality of gastrulation. This report showcases a unique scenario where three siblings, devoid of any prior family history or identifiable risk factors, exhibit symptoms of CRS and receive care at a government-run tertiary facility dedicated to children's health. In establishing a concrete diagnosis, we relied on skeletal surveys, comprehensive symptom evaluation, and medical history assessment. Additionally, we recommended further investigation through magnetic resonance imaging and genetic testing to attain a more in-depth understanding and confirmation of the condition. Unfortunately, the financial constraints faced by the parents led to the unfeasibility of pursuing these advanced diagnostic options. Given the rarity of this syndrome and the limited existing literature, our report is a significant contribution. It marks the first comprehensive exploration of CRS from the genetic and familial predisposition perspective, shedding new light on this rare condition. This case series pioneers our understanding of the familial and genetic connections between CRS and sacral agenesis. Strikingly, each subsequent generation has experienced more severe manifestations earlier, furnishing compelling evidence that underpins the genetic predisposition to CRS. [ABSTRACT FROM AUTHOR]

This article discusses three cases of post-surgical spontaneous paroxysmal hypothermia (SPH), a condition characterized by recurrent episodes of hypothermia and mental confusion related to a hypothalamic lesion. The cases involve patients who underwent surgery for various hypothalamus disorders and experienced episodes of hypothermia, bradycardia, and other symptoms. The article highlights the importance of prompt diagnosis and appropriate interventions for effective treatment of SPH. It also suggests that changes in sympatho-vagal balance may play a role in the cardiac consequences of SPH. [Extracted from the article]

This article explores the development and prenatal imaging of the corpus callosum (CC), a crucial structure in the brain that facilitates communication between the two hemispheres. Prenatal imaging techniques like ultrasound and MRI have made it possible to study the CC's development earlier than before. The article also discusses the various abnormalities that can be observed in the CC during prenatal imaging and the challenges in accurately describing and classifying these abnormalities. The authors propose a simplified classification system based on well-defined criteria to improve the diagnosis and prognosis of CC anomalies. [Extracted from the article]

Background: Lamb-Shaffer syndrome (LAMSHF, OMIM: 616803) is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, which is attributed to haploinsufficiency by heterozygous variants of SOX5 gene (SRY-Box Transcription Factor 5, HGNC: 11201) on chromosome 12p12. A total of 113 cases have been reported in the world, however, only 3 cases have been reported.in China. Here, we aimed to report novel variants of SOX5 gene and provide examples for clinical diagnosis by reporting the clinical phenotype of a series of Chinese patients with LAMSHF. Methods: This study retrospectively collected the information of families of LAMSHF patients in China. Whole Exome Sequencing (WES) were performed to confirm the diagnosis of 4 children with unexplained developmental delay or epilepsy. A minigene splicing assay was used to verify whether the splice variant affected splicing. Meanwhile, a literature review was conducted to analyze the clinical and genetic characteristics of patients with LAMSHF. Results: Three of the LAMSHF patients had a de novo heterozygous mutation in the SOX5 gene respectively, c.290delC (p.Pro97fs*30), chr12:23686019_24048958del, c.1772-1C > A, and the remaining one had a mutation inherited from his father, c.1411C > T (p.Arg471*). The main clinical manifestations of these children were presented with global developmental delays, and one of them also had seizures. And the results of the minigene experiment indicated that the splice variant, c.1772-1C > A, transcribed a novel mRNA product which leaded to the formation of a truncated protein. Conclusions: Through a comprehensive review and analysis of existing literature and this study showed intellectual disability, speech delay and facial dysmorphisms were common clinical manifestation, while the seizures and EEG abnormalities were rare (21/95, 22.16%). Notably, we represent the largest sample size of LAMSHF in Asia that encompasses previously unreported SOX5 gene mutation, and a minigene testing have been conducted to validate the pathogenicity of the c.1772-1C > A splice variant. The research further expands the phenotype and genotype of LAMSHF while offers novel insights for potential pathogenicity of genes locus. [ABSTRACT FROM AUTHOR]

Introduction: myo7aa, the homolog of the human Usher 1B syndrome pathogenic gene, myo7A, plays an important role in stereociliary development and maintenance, therefore, is critical for hearing and balance. However, the molecular mechanisms that myo7aa regulate hearing and balance still need to be studied. Methods: In this study, we generated two independent zebrafish myo7aa knockout lines using CRISPR/Cas9 technology. To investigate the effects of myo7aa on hearing, YO-PRO-1 staining and startle response assay were used. To gain insight into the specific molecular mechanisms by which myo7aa affects hearing, transcriptome sequencing and bioinformatics analysis were employed. Results: Our study showed that hair cells of myo7aa-/-zebrafish can not take up YO-PRO-1 fluorescent dye and are insensitive to acoustic stimulation in myo7aa-/- zebrafish compared to wild type. Genes related to the Rho GTPase signaling pathway, such as arhgap33, dab2ip, and arghef40, are significantly down-regulated in myo7aa-/- zebrafish embryos at 3 dpf. GTP and ATP compensation can partially rescue the hair cell defects in myo7aa knockout zebrafish. Discussion: Our findings suggest that zebrafish myo7aa affects congenital hearing by regulating Rho GTPase signaling, and loss of myo7aa leads to abnormal Rho GTPase signaling and impairs hair cell function. myo7aa, myo7A, arhgap33, dab2ip, arghef40 and myo7aa-/-fonts in the abstract are italicized. -/- is a superscript format. [ABSTRACT FROM AUTHOR]

Introduction: Estimates for cause-specific mortality for neonates are generally available for all countries for neonates overall (0 to 28 days). However, cause-specific mortality is generally not being estimated at higher age resolution for neonates, despite evidence of heterogeneity in the causes of deaths during this period. We aimed to use the adapted log quadratic model in a setting where verbal autopsy was the primary means of determining cause of death. Methods: We examined the timing and causes of death among a cohort of neonates in rural Nepal followed as part of the Nepal Oil Massage Study (NOMS). We adapted methods defined by Wilmoth et al (2012) and Guillot et al. (2022) to estimate age and cause-specific mortality among neonates. We used cross validation to estimate the accuracy of this model, holding out each three month period. We took the average cross validation across hold out as our measure of model performance and compared to a standard approach which did not account for the heterogeneity in cause-specific mortality rate within this age group. Results: There were 957 neonates in the NOMS cohort with known age and cause of death. We estimated an average cross-validation error of 0.9 per 1000 live births for mortality due to prematurity in the first week, and 1.1 for mortality due to birth asphyxia, compared to the standard approach, having error 7.4 and 7.8 per 1000 live births, respectively. Generally mortality rates for less common causes such as congenital malformations and pneumonia were estimated with higher cross-validation error. Conclusions: The stability and precision of these estimates compare favorably with similar estimates developed with higher quality cause-specific mortality surveillance from China, demonstrating that reliably estimating causes of mortality at high resolution is possible for neonates in low resources areas. [ABSTRACT FROM AUTHOR]

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2 -related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders. [Display omitted] MSL2 encodes a member of the MSL complex, an epigenetic regulator acetylating histone H4. We identify MSL2 variants leading to a neurodevelopmental disorder with intellectual disability, developmental delay, motor issues, seizures, dysmorphisms, and a specific blood methylation episignature. Patient-derived reprogrammed cells reveal developmental gene dysregulation without altered global H4 acetylation. [ABSTRACT FROM AUTHOR]

Background: Mesomelia-Synostoses Syndrome (MSS)(OMIM 600,383) is a rare autosomal dominant disorder characterized by mesomelic limb shortening, acral synostoses and multiple congenital malformations which is described as a contiguous deletion syndrome involving the two genes SULF1 and SLCO5A1. The study of apparently balanced chromosomal rearrangements (BCRs) is a cytogenetic strategy used to identify candidate genes associated with Mendelian diseases or abnormal phenotypes. With the improved development of genomic technologies, new methods refine this search, allowing better delineation of breakpoints as well as more accurate genotype-phenotype correlation. Case presentation: We present a boy with a global development deficit, delayed speech development and an ASD (Asperger) family history, with an apparently balanced "de novo" reciprocal translocation [t(1;8)(p32.2;q13)dn]. The cytogenetic molecular study identified a likely pathogenic deletion of 21 kb in the 15q12 region, while mate pair sequencing identified gene-truncations at both the 1p32.2 and 8q13 translocation breakpoints. Conclusions: The identification of a pathogenic alteration on 15q12 involving GABRA5 was likely the main cause of the ASD-phenotype. Importantly, the chr8 translocation breakpoint truncating SLCO5A1 exclude SLCO5A1 as a candidate for MSS, leaving SULF1 as the primary candidate. However, the deletions observed in MSS remove a topological associated domain (TAD) boundary separating SULF1 and SLCO5A1. Hence, Mesomelia-Synostoses syndrome is either caused by haploinsufficiency of SULF1 or ectopic enhancer effects where skeletal/chrondrogenic SULF1 enhancers drive excopic expression of developmental genes in adjacent TADs including PRDM14, NCOA2 and/or EYA1. [ABSTRACT FROM AUTHOR]

Introduction: Corpus callosum injury is a rare type of injury that occurs after a stroke and can cause lower limb dysfunction and a decrease in activities of daily living ability. Furthermore, there are no studies that focus on the progress in rehabilitation of the lower limb dysfunction caused by infarction in the corpus callosum and the effective treatment plans for this condition. We aimed to present a report of two patients with lower limb dysfunction caused by corpus callosum infarction after a stroke and a walking training method. Methods: We implemented a walking training method that prioritizes bilateral symmetry and increases lateral swaying before the patients established sitting/standing balance. The plan is a rapid and effective method for improving walking dysfunction caused by corpus callosum infarction. Case characteristics: Following sudden corpus callosum infarction, both patients experienced a significant reduction in lower limb motor function scores and exhibited evident gait disorders. Scale evaluations confirmed that walking training based on symmetrical and increased lateral sway for patients with lower limb motor dysfunction after corpus callosum infarction led to significant symptom improvement. Conclusion: We report two cases of sudden motor dysfunction in patients with corpus callosum infarction. Symmetrical and increased lateral sway-based walking training resulted in substantial symptom improvement, as confirmed by scale assessments. [ABSTRACT FROM AUTHOR]

The canonical visual cycle employing RPE65 as the retinoid isomerase regenerates 11-cis-retinal to support both rod- and conemediated vision. Mutations of RPE65 are associated with Leber congenital amaurosis that results in rod and cone photoreceptor degeneration and vision loss of affected patients at an early age. Dark-reared Rpe65-/- mouse has been known to form isorhodopsin that employs 9-cis-retinal as the photosensitive chromophore. The mechanism regulating 9-cis-retinal synthesis and the role of the endogenous 9-cis-retinal in cone survival and function remain largely unknown. In this study, we found that ablation of fatty acid transport protein-4 (FATP4), a negative regulator of 11-cis-retinol synthesis catalyzed by RPE65, increased the formation of 9-cis-retinal, but not 11-cis-retinal, in a light-independent mechanism in both sexes of RPE65-null rd12 mice. Both rd12 and rd12; Fatp4-/- mice contained a massive amount of all-trans-retinyl esters in the eyes, exhibiting comparable scotopic vision and rod degeneration. However, expression levels of M- and S-opsins as well as numbers of M- and S-cones surviving in the superior retinas of rd12;Fatp4-/- mice were at least twofold greater than those in age-matched rd12 mice. Moreover, FATP4 deficiency significantly shortened photopic b-wave implicit time, improved M-cone visual function, and substantially deaccelerated the progression of cone degeneration in rd12 mice, whereas FATP4 deficiency in mice with wild-type Rpe65 alleles neither induced 9-cis-retinal formation nor influenced cone survival and function. These results identify FATP4 as a new regulator of synthesis of 9-cis-retinal, which is a "cone-tropic" chromophore supporting cone survival and function in the retinas with defective RPE65. [ABSTRACT FROM AUTHOR]

Purpose: The identification and prognosis of the agenesis of the corpus callosum (ACC) for prenatal consultation are complex and currently unclear. This study aims to explore the correlated genetic mutations of prenatal ACC. Methods: We retrospectively analyzed 114 prenatal cases of ACC. All cases (n = 114) were subjected to chromosomal microarray analysis (CMA), and 66 CMA-negative cases underwent prenatal exome sequencing (pES) for further analysis. Results: CMA was diagnosed positively in 15/114 (13.2%) cases and pES was diagnosed positively in 24/66 (36.4%) CMA-negative cases. The detection rate of genetic causes between complete and partial ACCs was not significantly different (P > 0.05). Between isolated and non-isolated (other anomalies present) ACCs, the diagnostic rate of pES in non-isolated cases was significantly higher (P < 0.001), while CMA results did not differ (P > 0.05). The diagnostic rate of CMA was significantly increased in cases combined with intracranial and extracranial malformations (P = 0.014), while no CMA positivity was detected in cases combined with only intracranial malformations. Conclusion: For fetuses with prenatal ACC, further pES analysis should be recommended after negative CMA results. Chromosome abnormalities are less likely to occur when ACC with only intracranial malformations combined. [ABSTRACT FROM AUTHOR]

• Neuroinflammation-related PET signal was measured in long COVID patients with diverse symptoms. • PET neuroimaging found neuroinflammation across multiple brain regions in long COVID vs. controls. • Some neuroinflammation signal was found in brain areas known to have reduced blood-brain barrier. • Neuroinflammation in Long COVID correlated with blood levels of factors related to vascular damage. The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction. In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls. We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction. These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC. [ABSTRACT FROM AUTHOR]

Introduction: Meckel-Gruber Syndrome (MKS) is an autosomal recessive genetic disorder, notable for its triad of occipital encephalocele, polycystic renal dysplasia, and postaxial polydactyly. Identified by Johann Friederich Meckel in 1822, MKS is categorized as a ciliopathy due to gene mutations. Diagnosis is confirmed by the presence of at least two key features. The condition is incompatible with life, leading to death in the womb or shortly after birth. Recent studies have largely focused on the genetic aspects of MKS, with limited information regarding the impact of neurosurgical approaches, particularly in treating encephaloceles. Methods: A systematic review was performed according to the PRISMA statement. The PubMed, Embase, and Web of Science databases were consulted for data screening and extraction, which was conducted by two independent reviewers. The search strategy aimed to encompass studies documenting cases of MKS with published reports of encephalocele excisions, and the search strings for all databases were: Meckel-Gruber syndrome OR Meckel Gruber syndrome OR Meckel-gruber OR Meckel Gruber. Results: The study included 10 newborns with MKS associated with occipital encephalocele or meningocele, all of whom underwent surgical repair of the occipital sac. The mean gestational age at birth was 36 (± 2) weeks. The mean of birth weight was 3.14 (± 0.85) kilograms. The average head circumference at birth was 33.82 cm (± 2.17). The mean diameter of the encephalocele/meningocele was 5.91 (± 1.02) cm. Other common central nervous system abnormalities included hydrocephalus, Dandy-Walker malformation, and agenesis of the corpus callosum. 40% required shunting for hydrocephalus. Surgery to remove the occipital sac occurred at a median age of 2.5 days (1.5–6.5). The most common post-surgical complication was the need for mechanical ventilation. The most common cause of death was pneumonia and the median age at death was 6.66 (0.03–18) months. Conclusion: Our findings suggest that neurosurgical intervention, especially for managing encephaloceles, may offer some improvement in survival, albeit within a context of generally poor prognosis. However, these results should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6, or PMS2. This syndrome is characterized by a broad spectrum of early-onset malignancies, including hematologic malignancies, colorectal malignancies, brain tumors, and other malignancies. It is common to have more than one malignancy in an individual diagnosed with CMMRD. In addition to malignancies, primary immunodeficiency in the form of low or absent immunoglobulin levels can also be seen in CMMRD. Congenital abnormalities such as agenesis of the corpus callosum (ACC), cavernous hemangioma, and other non-neoplastic diseases can also be linked to it. In this case report, we discussed the case of a girl born out of consanguineous marriage initially identified as having T-cell acute lymphoblastic lymphoma and later found to have selective immunoglobulin A (IgA) deficiency. Her younger sibling with a pontine cavernous hemangioma was also diagnosed with lymphoma. The girl exhibited brain lesions on magnetic resonance imaging (MRI), which were initially diagnosed as posterior reversible encephalopathy syndrome (PRES) related changes; however, one of the lesions persisted and remained stable over a period of 2 years and more in favor of diffuse glioma. The younger sibling also showed a solitary lesion in the brain. Based on the clinical and radiological findings, a diagnosis of CMMRD was suspected. Next-generation sequence (NGS) analysis of her blood sample was done. The results showed a homozygous mutation in the MSH6 gene was diagnostic of CMMRD. [ABSTRACT FROM AUTHOR]

This study aimed to explore the genetic causes of agenesis of the corpus callosum (ACC) and assess the utility of karyotype analysis, copy number variation sequencing (CNV-seq), and whole-exome sequencing (WES) to genetically diagnose fetal ACC. We retrospectively examined 40 fetuses diagnosed with ACC who underwent prenatal ultrasonography or magnetic resonance imaging between January 2019 and October 2023. Genetic tests were conducted on the fetuses using karyotype analysis or CNV-seq as the first-line diagnosis. WES was performed if aneuploid and pathogenic CNVs were excluded. Among the 40 fetuses, 29 (72 %) had non-isolated ACC and 11 (28 %) had isolated ACC. Cerebellar dysplasia and hydrocephalus were the most common abnormal developments in the central nervous system. Twenty-eight patients underwent karyotype analysis, with a detection rate of 14 % (4/28). Twenty-six patients underwent CNV-seq; three patients were found to have pathogenic CNVs, with a detection rate of 12 % (3/26). Thirty-three fetuses with no findings of karyotype analysis or CNV-seq were subsequently tested using WES, with a detection rate of 36 % (12/33). Overall, the total diagnostic yield was 48 % (19/40), and monogenic etiology accounted for 30 % (12/40). The genetic detection rate of fetal non-isolated ACC (62 %, 18/29) was higher than that of isolated ACC (9 %, 1/11). Prenatal genetic analysis of fetuses with ACC is clinically significant, with monogenic disorders being the main cause. WES may enhance the detection rate of fetuses with ACC with negative karyotype analysis or CNV-seq results. [ABSTRACT FROM AUTHOR]

Introduction: Children with intellectual disability (ID) often face challenges in maintaining proper oral hygiene due to their motor, sensory, and intellectual impairments, which can lead to compromised oral health; therefore, there is a need to enhance the oral health status of these populations and establish an effective system for administering preventive interventions. Here, we aimed to evaluate the prevalence of Entamoeba gingivalis and Trichomonas tenax among children with ID in Lorestan province, in Western Iran through parasitological and molecular methods. Methods: The current descriptive investigation involved 215 in children with ID and 215 healthy children (non-ID) who were referred to health facilities in Lorestan province, Iran between October 2022 and March 2024. The prevalence of protozoa in the oral cavity was found through the utilization of both microscopic analysis and conventional polymerase chain reaction (PCR) techniques. Results: The total prevalence of the E. gingivalis and T. tenax in children with ID was found to be 87 (40.5%) and 92 (42.8%) through microscopic and PCR methods, respectively. Among the positive samples, 57 (61.9%) and 35 (38.1%) children tested positive for E. gingivalis and T. tenax, respectively. In contrast, among the 215 non-ID children in the control group, 39 (18.1%) and 42 (19.5%) tested positive by microscopic and PCR methods, respectively. Among positive samples in non-ID children, 23 (54.7%) and 19 (45.3%) children were positive for E. gingivalis and T. tenax, respectively. Multiple logistic regression analysis indicated that residing in urban areas, parental education, monthly family income, and tooth brushing p<0.001) were identified as independent risk factors for oral cavity parasites. Conclusion: This study identified a notable prevalence of oral cavity parasites in children with ID in Lorestan province, Western Iran. It is imperative to recognize the primary risk factors associated with these parasites, particularly inadequate teeth brushing, in order to enhance public and oral health strategies for children with ID. Therefore, pediatric dental professionals should remain vigilant regarding these risk factors to effectively recognize and address oral health issues in this population, thereby mitigating the occurrence of oral diseases and infections. [ABSTRACT FROM AUTHOR]

Diprosopus is a congenital anomaly in which partial or complete duplication of craniofacial structures occurs. Because it is rare, the mortality rate is high, and information concerning this anomaly is scarce. This study describes a case of human diprosopus in a 9‐year‐old male individual, who has severe complications associated with the central nervous, cardiovascular, respiratory, and digestive systems. Since birth, he has been monitored in a specialized hospital environment, where he has undergone several surgeries and multidisciplinary treatments. Regarding the craniofacial aspects, he had agenesis of the corpus callosum, floor of the nasal cavity, and floor of the anterior cranial fossa, in addition to the presence of bone dysplasia, ocular hypertelorism and cleft palate with nasal and oral teratoma. Regarding dental characteristics, the patient has duplication of the maxilla, mandible, tongue, and some teeth. After complementary imaging exams, several supernumerary teeth were found, with some being impacted and in complex regions, with an indication for extraction due to the risks of impaction, irruptive deviation, root resorption, and associated cystic or tumoral lesions. Because of the numerous complications, knowledge, and preparation of the entire team is necessary for the correct management of the case. [ABSTRACT FROM AUTHOR]

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Introduction: The corpus callosum is one of the five main cerebral commissures. It is key to combining sensory and motor functions. Its structure can be pathological (dysgenesis) or completely absent (agenesis). The corpus callosum dys- or agenesis is a rare disease (1:4000 live births), but it can have serious mental effects. Methods: In our study, we processed the data of 64 pregnant women. They attended a prenatal diagnostic center and genetic counseling from 2005 to 2019 at the Department of Obstetrics and Gynecology at Semmelweis University. Results: The pregnancies had the following outcomes: 52 ended in delivery, 1 in spontaneous abortion, and 11 in termination of pregnancy (TOP) cases (n = 64). The average time of detection with imaging tests was 25.24 gestational weeks. In 16 cases, prenatal magnetic resonance imaging (MRI) was performed. If the abnormality was detected before the 20th week, a genetic test was performed on an amniotic fluid sample obtained from a genetic amniocentesis. Karyotyping and cytogenetic tests were performed in 15 of the investigated cases. Karyotyping gave normal results in three cases (46,XX or XY). In one of these cases, postnatally chromosomal microarray (CMA) was later performed, which confirmed Aicardi syndrome (3q21.3–21.1 microdeletion). In one case, postnatally, the test found Wiedemann–Rautenstrauch syndrome. In other cases, it found X ring, Di George syndrome, 46,XY,del(13q)(q13q22) and 46,XX,del(5p)(p13) (Cri-du-chat syndrome). Edwards syndrome was diagnosed in six cases, and Patau syndrome in one case. Conclusions: We found that corpus callosum abnormalities are often linked to chromosomal problems. We recommend that a cytogenetic test be performed in all cases to rule out inherited diseases. Also, the long-term outcome does not just depend on the disease's severity and the associated other conditions, and hence proper follow-up and early development are also key. For this reason, close teamwork between neonatology, developmental neurology, and pediatric surgery is vital. [ABSTRACT FROM AUTHOR]

Introduction: The congenital vaginal obstructions, which may be associated with labial synechia, imperforate hymen, complete vaginal transverse septum, partial vaginal agenesis or atresia are extremely rare reproductive system anomalies in children and a dolescents. A complete consensus has not been achieved in the diagnosis and management of uterovaginal canal obstructions in children and a dolescents. In this study, our uterovaginal canal obstruction experiences were evaluated with the literature. Materials and Methods: Data of patients with uterovaginal obstruction were evaluated, between 2015 and 2018. Values were expressed as counts and percentages. The files containing age, symptoms, diagnosis, radiological modalities and surgical management of the pa tients diagnosed with reproductive tract obstruction, between 1st April 2015 and 1st August 2018 were evaluated retrospectively. In addition to the general physical examination, a careful urogenital system examination was performed in the initial evaluation of the patients Results: Twenty-one female patients with uterovaginal obstruction were detected. The mean age was. The most common anomalies detected were labial synechia and imperforate hymen. Moreover, the labial synechia was determined in 9 patients, the imperforate hymen in 7 patients, the distal vaginal atresia in 2 patients, the OHVIRA in 2 patients. Conclusion: Most of the uterovaginal obstructions can be treated with simple surgical intervention when differential diagnosis is kept in mind. However, complex cases require a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Jean François Marie Aicardi, a renowned pediatric neurologist and epileptologist, was born in France in 1926. He made significant contributions to the field of pediatric neurology, including the discovery of Aicardi syndrome and Aicardi-Goutières syndrome. Aicardi's research also led to advancements in understanding conditions like Rett syndrome and epilepsy. Throughout his career, he received numerous awards and published extensively, leaving a lasting impact on the field of neurology. Aicardi passed away in 2015, leaving behind a legacy of groundbreaking discoveries and dedication to his work. [Extracted from the article]

The article discusses the prenatal diagnosis of Walker-Warburg syndrome (WWS), a rare autosomal recessive disorder affecting the brain, eyes, and muscles. The case study presented involves a child with WWS who exhibited generalized hypotonia, cataracts, and progressive muscular dystrophy leading to death within the second year after birth. The syndrome is associated with defective glycosylation of α-dystroglycan, resulting in neuronal overmigration and impaired muscle cell communication, with similarities to other severe forms of congenital muscular dystrophy. Various prenatal ultrasound and magnetic resonance imaging features are described, including brainstem abnormalities, cerebellar hypoplasia, and lissencephaly. Other malformations associated with WWS, such as corpus callosum agenesis and facial dysmorphism, are also mentioned. [Extracted from the article]

The article discusses a case of a female neonate with multiple congenital anomalies due to in-utero exposure to mycophenolate mofetil (MMF). The neonate exhibited craniofacial and cervicothoracic anomalies consistent with MMF-induced embryopathy, but also had genitourinary anomalies not commonly reported with MMF exposure. Molecular analyses did not reveal any monogenic mutations responsible for the anomalies, suggesting that the patient's condition may be linked to drug exposure. The study suggests that MMF exposure may lead to a novel clinical consequence resembling Müllerian duct aplasia–renal agenesis–cervicothoracic somite dysplasia (MURCS) association, which warrants further investigation. [Extracted from the article]

Background. Proud syndrome is rare inherited disease with X-linked inheritance associated with mutations in the homeobox gene ARX. Typical clinical signs of this syndrome are severe mental retardation, intractable epilepsy, agenesis (dysgenesis) of corpus callosum. Less common features are genital abnormalities, microcephaly, facial dysmorphia, and skeletal malformations. Clinical case description. The article describes the clinical findings of Proud syndrome in girl A., admitted to Children’s City Clinical Hospital No. 1 in Nizhny Novgorod. The girl was born without asphyxia at term through natural vaginal delivery after the first uneventful pregnancy. Body weight at birth was 2600 g. The genealogical history is burdened by the presence of epilepsy in girl’s father relatives. There were no deviations in psychomotor skills development before disease onset. Hemi-convulsive seizures (switching sides) have appeared at the age of 6 months. These attacks had status course and were resistant to anticonvulsant therapy. Neuroimaging has revealed agenesis of corpus callosum. Regression of psychomotor development, new behavioral disorders (stereotypes and auto-aggression), hyperexcitability, and sleep disorders were observed in dynamics. The diagnosis of Proud syndrome was confirmed by identification of probably pathogenic mutation in the ARX gene (c.1111C>T, p. Arg 371*64). The features of anticonvulsant management were demonstrated in the patient. Conclusion. This clinical case presents typical clinical picture of Proud syndrome. The disease is non-curable. Such patients should be administered with syndromic therapy: constant anticonvulsant therapy, correction of behavioral disorders (classes with specialist on mental defects), neurologist, epileptologist, psychiatrist observations. Parental examination is crucial ARX mutation search in order to determine the prognosis for further child-bearing (parents refused to perform genetic study at the time of article writing).

Free water fraction (FWF) represents the amount of water per unit volume of brain parenchyma, which is not bound to macromolecules. Its excess in multiple sclerosis (MS) is related to increased tissue loss. The use of mcDESPOT (multicomponent driven single pulse observation of T1 and T2), a 3D imaging method which exploits both the T1 and T2 contrasts, allows FWF to be derived in clinically feasible times. However, this method has not been used to quantify changes of FWF and their potential clinical impact in MS. The aim of this study is to investigate the changes in FWF in MS patients and their relationship with tissue damage and cognition, under the hypothesis that FWF is a proxy of clinically meaningful tissue loss. To this aim, we tested the relationship between FWF, MS lesion burden and information processing speed, evaluated via the Symbol Digit Modalities Test (SDMT). In addition to standard sequences, used for T1‐ and T2‐weighted lesion delineation, the mcDESPOT sequence with 1.7 mm isotropic resolution and a diffusion weighted imaging protocol (b = 0, 1200 s/mm2, 40 diffusion directions) were employed at 3 T. The fractional anisotropy map derived from diffusion data was used to define a subject‐specific white matter (WM) atlas. Brain parenchyma segmentation returned masks of gray matter (GM) and WM, and normal‐appearing WM (NAWM), in addition to the T1 and T2 lesion masks (T1L and T2L, respectively). Ninety‐nine relapsing–remitting MS patients (age = 43.3 ± 9.9 years, disease duration 12.3 ± 7.7 years) were studied, together with twenty‐five healthy controls (HC, age = 38.8 ± 11.0 years). FWF was higher in GM and NAWM of MS patients, compared to GM and WM of HC (both p <.001). In MS patients, FWF was the highest in the T1L and GM, followed by T2L and NAWM, respectively. FWF increased significantly with T1L and T2L volume (ρ ranging from 0.40 to 0.58, p <.001). FWF in T2L was strongly related to both T1L volume and the volume ratio T1L/T2L (ρ = 0.73, p <.001). MS patients performed worse than HC in the processing speed test (mean ± SD: 54.1 ± 10.3 for MS, 63.8 ± 10.8 for HC). FWF in GM, T2L, perilesional tissue and NAWM increased with SDMT score reduction (ρ = −0.30, −0.29, −0.33 respectively and r = −.30 for T2L, all with p <.005). A regional analysis, conducted to determine which NAWM regions were of particular importance to explain the relationship between FWF and cognitive impairment, revealed that FWF spatial variance was negatively related to SDMT score in the corpus callosum and the superior longitudinal fasciculus, WM structures known to be associated with cognitive impairment, in addition to the left corticospinal tract, the sagittal stratum, the right anterior limb of internal capsule. In conclusion, we found excess free water in brain parenchyma of MS patients, an alteration that involved not only MS lesions, but also the GM and NAWM, impinging on brain function and negatively associated with cognitive processing speed. We suggest that the FWF metric, derived from noninvasive, rapid MRI acquisitions and bearing good biological interpretability, may prove valuable as an MRI biomarker of tissue damage and associated cognitive impairment in MS. [ABSTRACT FROM AUTHOR]

Simple Summary: Congenital malformations of the equine caudal cervical vertebrae (C6 and C7) were first reported in the 1800s. However, by the 21st century these findings were no longer incidental, especially with studies reporting breed percentages as high as 38%. Therefore, this study examined the association between C6 osseous specimens (n = 85) demonstrating the congenital malformation of either a partial unilateral or bilateral absent ventral process and the transposition on the ventral surface of sequential C7s (44/85). The aim was to determine if the absent morphology on C6 corresponded to the transposition on C7 and in some cases replication of a transverse foramen (33/44). Findings revealed the larger morphological absence on C6 generated a stronger dependency for transposition on C7 that included the replication of a transverse foramen. The transposition on C7 was characterized by either a complete or incomplete likeness of the C6 ventral process. Complete transpositions on C7 appeared as a normal C6 ventral process, while incomplete transpositions appeared in most as a cranial ventral tubercle (CrVT). When complete bilateral transpositions were demonstrated, the morphology of C7 resembled C6. These findings are relevant to the reading of radiographic images and potential clinical findings. In recent years, equine complex vertebral malformation (ECVM) has been of concern in the equine community, with studies identifying numerous associative morphological variations. Here, we examine the morphological association between C6 and C7 for dependency in ECVM cases, where the partially absent ventral process of C6 transposes on the ventral surface of C7. A C6 ventral process presents two tubercles, one cranial (CrVT) and one caudal (CVT). In this study, the C6 osseous specimens (n = 85) demonstrated a partial or completely absent CVT (aCVT) graded 1–4 that often extended cranially creating a partially absent cranial ventral tubercle (aCrVT) graded 1–3. In the 85 C6 osseous specimens examined, the corresponding C7s demonstrated either a complete or incomplete transposition of the ventral process from C6 in 44/85, with 30/44 replicating a transverse foramen. A strong statistical dependency existed between C6 grade 4 aCVTs and grades 1–3 aCrVTs and C7 transpositions with replicated transverse foramen. Sidedness was also demonstrated, where a left sided absent C6 associated with transposition on the left ventral surface of C7. This likewise applied to right sidedness and most bilateral cases. These findings might benefit practitioners when radiographing the extent of the ECVM configuration in patients presenting caudal cervical pain. [ABSTRACT FROM AUTHOR]

Background: The low prevalence of rare diseases poses a significant challenge in advancing their understanding. This study aims to delineate the clinical and genetic characteristics of patients with rare eye diseases (RED) enrolled in the Spanish Rare Diseases Patient Registry. Methods: A total of 864 patients from the registry database were included. Diseases were categorized into inherited retinal dystrophies (n=688); anterior segment diseases (n=48); congenital malformations (n=27); and syndromic diseases with ocular involvement including muscular (n=46), neurological (n=34), or metabolic (n=13); inflammatory diseases (n=4); and tumors (n=4). Data on visual acuity (VA) and/or visual field (VF), symptoms and signs, concurrent diseases in syndromic cases, age of onset and at diagnosis, affected genes, disability rating, inability to work and dependency grade recognition were collected. Results: A mean diagnostic delay of 7 years from symptom onset was observed. Commonly reported symptoms included photophobia, night blindness, and progressive vision loss (≥57% of patients). Cataract was the most prevalent secondary disease (46%), with pseudophakia being the most common ocular surgery (26%). Hearing loss and cardiovascular diseases were the most prevalent concurrent systemic diseases (≥13%). Certificates of disability, incapacity for work, and dependency were held by 87%, 42%, and 19% of patients, respectively. Among the 719 patients with available VA data, 193 (27%) were blind, and 188 (26%) had moderate to severe visual impairment. Over half of the patients (54%) exhibited VF defects, and 216 (25%) had concentric contraction ≤5° or abolished VF. Most had genetic diseases with autosomal recessive (55%), autosomal dominant (30%), X-linked (9%), and mitochondrial (6%) patterns. One patient had mutations in both recessive USH2A and dominant RHO genes simultaneously. Of the 656 patients (75.7%) who underwent genetic testing, only 461 (70.3%) received a positive result (pathogenic or likely pathogenic mutations explaining the phenotype). We found 62 new gene variants related to RED not previously reported in databases of genetic variants related to specific phenotypes. Conclusions: This study delineates the clinical and genotypic profiles of RED in Spain. Genetic diseases, particularly retinal disorders, predominate, but a significant proportion of affected patients remain genetically undiagnosed, hindering potential gene therapy endeavors. Despite notable improvements in reducing diagnosis delays, it is still remarkable. RED frequently lead to disability and blindness among young populations. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the molecular etiology of congenital insensitivity to pain in two Thai patients. Clinical, radiographic, histopathologic, immunohistochemical, and molecular studies were performed. Patients were found to have congenital insensitivity to pain, self-mutilation, acro-osteolysis, cornea scars, reduced temperature sensation, tooth agenesis, root maldevelopment, and underdeveloped maxilla and mandible. The skin biopsies revealed fewer axons, decreased vimentin expression, and absent neurofilament expression, indicating lack of dermal nerves. Whole exome and Sanger sequencing identified a rare homozygous variant c.4039C>T; p.Arg1347Cys in the plakin domain of Plec, a cytolinker protein. This p.Arg1347Cys variant is in the spectrin repeat 9 region of the plakin domain, a region not previously found to harbor pathogenic missense variants in other plectinopathies. The substitution with a cysteine is expected to decrease the stability of the spectrin repeat 9 unit of the plakin domain. Whole mount in situ hybridization and an immunohistochemical study suggested that Plec is important for the development of maxilla and mandible, cornea, and distal phalanges. Additionally, the presence of dental anomalies in these patients further supports the potential involvement of Plec in tooth development. This is the first report showing the association between the Plec variant and congenital insensitivity to pain in humans. [ABSTRACT FROM AUTHOR]

Facultative parthenogenesis (FP) has historically been regarded as rare in vertebrates, but in recent years incidences have been reported in a growing list of fish, reptile, and bird species. Despite the increasing interest in the phenomenon, the underlying mechanism and evolutionary implications have remained unclear. A common finding across many incidences of FP is either a high degree of homozygosity at microsatellite loci or low levels of heterozygosity detected in next-generation sequencing data. This has led to the proposal that second polar body fusion following the meiotic divisions restores diploidy and thereby mimics fertilization. Here, we show that FP occurring in the gonochoristic Aspidoscelis species A. marmoratus and A. arizonae results in genome-wide homozygosity, an observation inconsistent with polar body fusion as the underlying mechanism of restoration. Instead, a high-quality reference genome for A. marmoratus and analysis of whole-genome sequencing from multiple FP and control animals reveals that a post-meiotic mechanism gives rise to homozygous animals from haploid, unfertilized oocytes. Contrary to the widely held belief that females need to be isolated from males to undergo FP, females housed with conspecific and heterospecific males produced unfertilized eggs that underwent spontaneous development. In addition, offspring arising from both fertilized eggs and parthenogenetic development were observed to arise from a single clutch. Strikingly, our data support a mechanism for facultative parthenogenesis that removes all heterozygosity in a single generation. Complete homozygosity exposes the genetic load and explains the high rate of congenital malformations and embryonic mortality associated with FP in many species. Conversely, for animals that develop normally, FP could potentially exert strong purifying selection as all lethal recessive alleles are purged in a single generation. [ABSTRACT FROM AUTHOR]