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Background: Brain anomalies (BAs) have been the focus of research, as they have a high impact on fetal health but therapeutic and diagnostic approaches are limited. Objectives: In this study, the application and efficiency of exome sequencing (ES) in detecting different cases of BAs in fetuses were evaluated and compared with chromosomal microarray analysis (CMA). Search strategy: To conduct this study, three databases including PubMed, Web of Science and Embase were utilised with the keywords 'prenatal', 'diagnoses', 'brain anomalies' and 'exome sequencing'. Selection criteria: Studies were included based on the STARD checklist, for which the ES and CMA diagnostic yields were calculated. Data collection and analysis: Meta‐analysis was performed on the included studies using a random‐effects model and subgroup analysis to define the risk difference between them. Main results: We included 11 studies representing 779 fetuses that implemented ES along with imaging techniques. The pooled ES diagnostic yield in fetuses with BAs detected through magnetic resonance imaging (MRI) and ultrasonography was 26.53%, compared with 3.46% for CMA. The risk difference between ES and CMA for complex BAs was 0.36 [95% confidence interval (CI) 0.24–0.47], which was higher than for single BAs (0.22; 95% CI 0.18–0.25]. Conclusions: ES is a useful method with a significantly higher diagnostic yield than CMA for genetic assessment of fetuses with complex BAs detected by imaging techniques. Moreover, ES could be applied to suspected fetuses with related family histories to predict congenital diseases with high efficiency. [ABSTRACT FROM AUTHOR]

Chromosome 21q deletion syndrome is a rare disorder affecting the long arm of chromosome 21 and manifesting with wide phenotypic features depending on the size and position of the deleted region. In the syndrome, three distinct deleted regions have been distinguished: region 1, from the centromere to approximately 31.2 Mb (21q11.2-q22.11); region 2, from 31.2 to 36 Mb (21q22.11-q22.12); and region 3, from 36 to 37.5 Mb to the telomere (21q22.12-q22.3). The clinical features are highly variable manifesting with mild, poorly recognizable signs or with severe symptoms including craniofacial dysmorphism, growth failure, developmental delay, behavioral/affective abnormalities, and systemic malformations. We report here the case of a young boy with speech delay, mild spastic diplegia, and brain anomalies on magnetic resonance imaging (MRI). The genetic analysis displayed a microdeletion of the long arm of chromosome 21 approximately extending up to 1.08 Mb. Clinical presentation of the patient and cases of 21q21 deletion reported by the literature are discussed.

The WWOX gene encodes a 414-amino-acid protein composed of two N-terminal WW domains and a C-terminal short-chain dehydrogenase/reductase (SDR) domain. WWOX protein is highly conserved among species and mainly expressed in the cerebellum, cerebral cortex, brain stem, thyroid, hypophysis, and reproductive organs. It plays a crucial role in the biology of the central nervous system, and it is involved in neuronal development, migration, and proliferation. Biallelic pathogenic variants in WWOX have been associated with an early infantile epileptic encephalopathy known as WOREE syndrome. Both missense and null variants have been described in affected patients, leading to a reduction in protein function and stability. The most severe WOREE phenotypes have been related to biallelic null/null variants, associated with the complete loss of function of the protein. All affected patients showed brain anomalies on magnetic resonance imaging (MRI), suggesting the pivotal role of WWOX protein in brain homeostasis and developmental processes. We provided a literature review, exploring both the clinical and radiological spectrum related to WWOX pathogenic variants, described to date. We focused on neuroradiological findings to better delineate the WOREE phenotype with diagnostic and prognostic implications.

Objective: The aim of this systematic review and meta-analysis was to compare the additional value of fetal neurosonography (NS) and fetal magnetic resonance imaging (MRI) in fetuses at risk for brain anomalies. Materials and Methods: This systematic review article was conducted based on PRISMA guidelines. On January 30, 2021, a systematic search was conducted using Embase, Medline, Web of Science, Scopus, and the Cochrane Library, with no language restrictions. The purpose was to identify all articles comparing NS with fetal MRI, in cases of suspected brain abnormalities. The statistical analysis was performed using STATA-15 and Meta-Disk 1.4 software. Results: Eight articles were included in this review. The overall agreement rate between NS and MRI was 81%. Data from NS changed the management of 6% of patients, and MRI data added data to the results of NS, in 9% of cases. In cases where the fetal MRI was normal, the added value of the postnatal MRI was 4%. Conclusion: When brain abnormalities are suspected, based on NS, MRI can play a significant role in the diagnostic path by clarifying the findings and significantly increasing the detection of abnormalities, especially when abnormalities are suspected in the posterior, midline, or cortical areas of the brain. [ABSTRACT FROM AUTHOR]

Congenital brain anomalies are structural abnormalities that occur during fetal development and can have a significant impact on an individual neurological function. Detecting and classifying these anomalies accurately and efficiently is crucial for early diagnosis, intervention, and treatment planning. In recent years, recurrent neural networks (RNNs) have emerged as powerful tools for analyzing sequential and time-series data in various domains, including medical imaging. This research presents an overview of RNN-based algorithms for the detection and classification of congenital brain anomalies. Specifically, Long Short-Term Memory (LSTM) networks and Convolutional LSTM networks have demonstrated great potential in this domain. LSTMs excel at capturing long-range dependencies in sequential data and mitigating the vanishing gradient problem, making them well-suited for analyzing brain scans or other medical imaging sequences. Convolutional LSTM networks combine the strengths of convolutional neural networks (CNNs) and LSTMs, enabling them to extract spatial features from brain images while preserving temporal dependencies. The application of RNN algorithms in the detection and classification of congenital brain anomalies shows promising results, enabling accurate and timely identification of these abnormalities. However, further research is needed to validate and refine these algorithms, improve their interpretability, and enhance their clinical utility in real-world scenarios. [ABSTRACT FROM AUTHOR]

Background: Brain damage in preterm infants may result from a series of eventsrather than one specific insult. Maturational characteristics with a failingadaptation capacity may predispose the brain to harmful events during bothintrauterine and extrauterine life. The study aimed to detect anomalies in the brain of neonates with neurosonography. Methods : the studywas conducted on patients with clinically suspected lesions in the brain, undergoing NSG for evaluation of brain abnormalities in Prathima Institute ofmedical sciences, Karimnagar.Neurosonographic examinations were performed through anteriorfontanelle in both the coronal and sagittal planes.The examination started in the coronal plane along the coronal suture, with a transducer angled towards the frontal region. Then brain was examined invarious coronal planes by sweeping the transducer from anterior to posterior. Results : The most common abnormality found on neurosonogram in 3 – 5 days was germinal- matrix haemorrahge comprising n=13 (31%) followed by PVL n=12 (28.6%), cyst n=5 (11.9%), flaring n=5 (11.9%), cerebral edema n=4 (9.5%), congenital lesions n=2 (4.8%) and infections n=1 (2.4%). Follow up scan was performed around 2nd week of life, n=24 (57.1%) neonates were showing normal neurosonogram findings, remaining 18 (43%) showing abnormal findings, which are PVL n=6 (14.3%), GMH n=9 (21.4%), cyst n=1(2.4%), cerebral edema n=1 (2.4%) and congenital lesions n=1 (2.4%). Conclusion: High incidence of brain injuries was detected in babies born less than 32 weeks of gestation, weighing less than 1500 gm. The commonest clinical presentation was seizures followed by absent suckling and lethargy. The abnormalities found on the neurosonogram in our study were germinal matrix hemorrhage, periventricular leukomalacia, cystic PVL, corpus callosum agenesis, and TORCH infection.The mortality rate was high in grade III and grade IV GMH.10-14 days followup scan detected new cases of cystic PVL which were not diagnosed in the initial scan.

RHOA‐related neuroectodermal syndrome is characterised by linear skin hypopigmentation along Blaschko's lines associated with alopecia, leukoencephalopathy, facial and limb hypoplasia, and ocular, dental, and acral anomalies. Herein, we report a patient with patterned cutaneous hypopigmentation with a similar phenotype due to a novel postzygotic RHOA variant (c.210G>T; p.Arg70Ser). This illustrates that the complexity of the orchestration of morphogenesis and organogenesis can be affected by different variants in the same gene. [ABSTRACT FROM AUTHOR]

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10-26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG's abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.Conclusions: These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known • Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability • Immune dysfunction is a common finding but autoimmune diseases are rarely seen • Neurological features are common What is New • Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus) • Higher prevalence of autoimmune disorders than previously reported • Particular neurological features are present in this cohort (EEG and MRI brain abnormalities). [ABSTRACT FROM AUTHOR]

Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell‐cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders. Neuropathies, impaired higher brain functions, structural brain abnormalities and multiple congenital anomalies (i.e., renal, urogenital, and limb anomalies) can result from pathogenic variants in many KIF genes. We expand the phenotype associated with KIF4A variants from developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of phenotypic manifestations. Additional anomalies of the kidneys and urinary tract, congenital lymphedema, eye, and dental anomalies seem to be variably associated and overlap with clinical signs observed in other kinesinopathies. Caution still applies to missense variants, but hopefully, future work will further establish genotype–phenotype correlations in a larger number of patients and functional studies may give further insights into the complex function of KIF4A. [ABSTRACT FROM AUTHOR]

Background: This study aimed to delineate the clinical phenotype of patients with 9p deletions, pinpoint the chromosomal breakpoints, and identify the critical region for trigonocephaly, which is a frequent finding in 9p terminal deletion. Methods: We investigated a cohort of nine patients with chromosome 9p terminal deletions who all displayed developmental delay, intellectual disability, hypotonia, and dysmorphic features. Of them, eight had trigonocephaly, seven had brain anomalies, seven had autistic manifestations, seven had fair hair, and six had a congenital heart defect (CHD). Results: Karyotyping revealed 9p terminal deletion in all patients, and patients 8 and 9 had additional duplication of other chromosomal segments. We used six bacterial artificial chromosome (BAC) clones that could identify the breakpoints at 17–20 Mb from the 9p terminus. Array CGH identified the precise extent of the deletion in six patients; the deleted regions ranged from 16 to 18.8 Mb in four patients, patient 8 had an 11.58 Mb deletion and patient 9 had a 2.3 Mb deletion. Conclusion: The gene deletion in the 9p24 region was insufficient to cause ambiguous genitalia because six of the nine patients had normal genitalia. We suggest that the critical region for trigonocephaly lies between 11,575 and 11,587 Mb from the chromosome 9p terminus. To the best of our knowledge, this is the minimal critical region reported for trigonocephaly in 9p deletion syndrome, and it warrants further delineation. [ABSTRACT FROM AUTHOR]

Background: Unbalanced translocations between the q arm of chromosomes 5 and 13 are exceedingly rare and there is only one reported case with distal trisomy 5q/monosomy 13q. In this report, we describe a second patient with a similar rearrangement arising from a paternal balanced translocation. Methods: Karyotype analysis was performed on the proband and their parents. Microarray was also conducted on the proband. Results: Our patient was found to have global developmental delay, distinct facial features, short stature, growth hormone deficiency, delayed puberty, and brain anomalies including a small pituitary. Karyotype and microarray analysis revealed a terminal duplication of chromosome regions 5q33.3 to 5qter and a terminal deletion of chromosome regions 13q34 to 13qter that resulted from a balanced translocation in her father. The endocrine abnormalities and neuroimaging findings have not been previously described in patients with either copy number change. Conclusions: This case helps expand on the phenotype of patients with distal trisomy 5q/monosomy 13q as well as possibly providing useful information on the more common individual copy number changes. [ABSTRACT FROM AUTHOR]

Abstract Background Unbalanced translocations between the q arm of chromosomes 5 and 13 are exceedingly rare and there is only one reported case with distal trisomy 5q/monosomy 13q. In this report, we describe a second patient with a similar rearrangement arising from a paternal balanced translocation. Methods Karyotype analysis was performed on the proband and their parents. Microarray was also conducted on the proband. Results Our patient was found to have global developmental delay, distinct facial features, short stature, growth hormone deficiency, delayed puberty, and brain anomalies including a small pituitary. Karyotype and microarray analysis revealed a terminal duplication of chromosome regions 5q33.3 to 5qter and a terminal deletion of chromosome regions 13q34 to 13qter that resulted from a balanced translocation in her father. The endocrine abnormalities and neuroimaging findings have not been previously described in patients with either copy number change. Conclusions This case helps expand on the phenotype of patients with distal trisomy 5q/monosomy 13q as well as possibly providing useful information on the more common individual copy number changes.

Abstract Background This study aimed to delineate the clinical phenotype of patients with 9p deletions, pinpoint the chromosomal breakpoints, and identify the critical region for trigonocephaly, which is a frequent finding in 9p terminal deletion. Methods We investigated a cohort of nine patients with chromosome 9p terminal deletions who all displayed developmental delay, intellectual disability, hypotonia, and dysmorphic features. Of them, eight had trigonocephaly, seven had brain anomalies, seven had autistic manifestations, seven had fair hair, and six had a congenital heart defect (CHD). Results Karyotyping revealed 9p terminal deletion in all patients, and patients 8 and 9 had additional duplication of other chromosomal segments. We used six bacterial artificial chromosome (BAC) clones that could identify the breakpoints at 17–20 Mb from the 9p terminus. Array CGH identified the precise extent of the deletion in six patients; the deleted regions ranged from 16 to 18.8 Mb in four patients, patient 8 had an 11.58 Mb deletion and patient 9 had a 2.3 Mb deletion. Conclusion The gene deletion in the 9p24 region was insufficient to cause ambiguous genitalia because six of the nine patients had normal genitalia. We suggest that the critical region for trigonocephaly lies between 11,575 and 11,587 Mb from the chromosome 9p terminus. To the best of our knowledge, this is the minimal critical region reported for trigonocephaly in 9p deletion syndrome, and it warrants further delineation.

Prenatal ultrasound (US) is the first prenatal imaging tool for screening and evaluation of posterior fossa malformations since it is noninvasive, widely available, and safe for both mother and child. Fetal MRI is a widely used secondary technique to confirm, correct, or complement questionable US findings and plays an essential role in evaluating fetuses with suspected US findings and /or positive family history. The main sequences of fetal MRI consist of T2‐weighted (T2w) ultrafast, single‐shot sequences. Axial, coronal, and sagittal images are typically acquired allowing for a detailed evaluation of the posterior fossa contents. Also, various complimentary sequences, such as T1w, T2*w gradient sequences, or advanced techniques, including diffusion‐weighted imaging, diffusion tensor imaging, and magnetic resonance spectroscopy, may provide additional information based on the studied malformation. Inclusion of these techniques should be done with careful risk–benefit analysis. The use of fetal MRI also aims to evaluate for associated anomalies. In addition, prenatal diagnosis of posterior fossa malformations is still a challenge but advances in knowledge in human developmental anatomy, genetic, and imaging recognition patterns have enabled us to shed some light on prognostic information that will help with the counseling of families. Finally, high‐resolution late third trimester fetal MRI offers a safe alternative to early postnatal MR imaging, basically taking advantage of the uterine environment as a kind of "maternal incubator." Our goal is to discuss the spectrum of prenatal posterior fossa pathologies that can be studied by fetal MRI and their key neuroimaging features. [ABSTRACT FROM AUTHOR]

Pfeiffer syndrome (PS) is a rare autosomal dominant craniofacial disorder characterized by primary craniosynostosis, midface hypoplasia, and extremities' abnormalities including syndactyly. The purpose of this article was to review the current knowledge regarding how PS affects the nervous system. Methodologically, we conducted a systematic review of the existing literature concerning involvement of the nervous system in PS. Multiple-suture synostosis is common, and it is the premature fusion and abnormal growth of the facial skeleton's bones that cause the characteristic facial features of these patients. Brain abnormalities in PS can be primary or secondary. Primary anomalies are specific developmental brain defects including disorders of the white matter. Secondary anomalies are the result of skull deformity and include intracranial hypertension, hydrocephalus, and Chiari type I malformation. Spinal anomalies in PS patients include fusion of vertebrae, "butterfly" vertebra, and sacrococcygeal extension. Different features have been observed in different types of this syndrome. Cloverleaf skull deformity characterizes PS type II. The main neurological abnormalities are mental retardation, learning difficulties, and seizures. The tricky neurological examination in severely affected patients makes difficult the early diagnosis of neurological and neurosurgical complications. Prenatal diagnosis of PS is possible either molecularly or by sonography, and the differential diagnosis includes other craniosynostosis syndromes. Knowing how PS affects the nervous system is important, not only for understanding its pathogenesis and determining its prognosis but also for the guidance of decision-making in the various critical steps of its management. The latter necessitates an experienced multidisciplinary team. [ABSTRACT FROM AUTHOR]

Abstract Background WNT1 mutations cause bone fragility as well as brain anomalies. There are some reported cases of WNT1 mutations with normal cognition. Genotype and phenotype correlation of WNT1 mutations has not been established. Case presentation Here we present two female siblings with osteogenesis imperfecta (OI) born to a consanguineous couple. Both sustained severe bone deformities. However, only the younger had severe brain anomalies resulting in an early death from pneumonia, while the older had normal intellectual development. Next generation sequencing showed a homozygous mutation, c.6delG, p.Leu3Serfs*36 in WNT1. To our knowledge, it is the most 5′ truncating mutation to date. Conclusion This report emphasizes the intrafamilial variability of brain anomalies found in this OI type and suggests that WNT1 may not be necessary for normal human cognitive development.

Objective: We present prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II (TD2) and a review of prenatal diagnosis of brain anomalies associated with TD. Case report: A 33-year-old woman was referred for genetic counseling at 25 weeks of gestation because of fetal ultrasound abnormalities. Prenatal ultrasound at 14 weeks of gestation revealed an increased nuchal translucency (NT) and hydrocephalus. Level II ultrasound examination at 25 weeks of gestation revealed hydrancephaly, macrocephaly, a cloverleaf skull, frontal bossing, enlarged cerebellum and cisterna magna, a narrow chest, small ribs, short straight limbs. Amniocentesis revealed a karyotype of 46,XX. FGFR3 mutation analysis using the DNA extracted from uncultured amniocytes revealed a genotype of WT/c.1948A>G (p.Lys650Glu). The result was consistent with a K650E mutation in FGFR3 and TD2. The pregnancy was subsequently terminated. Conclusion: Fetuses with TD2 may present increased NT, early onset hydrocephalus, enlarged cerebellum and cisterna magna, and hydrancephaly on prenatal ultrasound.

The WWOX gene encodes a 414-amino-acid protein composed of two N-terminal WW domains and a C-terminal short-chain dehydrogenase/reductase (SDR) domain. WWOX protein is highly conserved among species and mainly expressed in the cerebellum, cerebral cortex, brain stem, thyroid, hypophysis, and reproductive organs. It plays a crucial role in the biology of the central nervous system, and it is involved in neuronal development, migration, and proliferation. Biallelic pathogenic variants in WWOX have been associated with an early infantile epileptic encephalopathy known as WOREE syndrome. Both missense and null variants have been described in affected patients, leading to a reduction in protein function and stability. The most severe WOREE phenotypes have been related to biallelic null/null variants, associated with the complete loss of function of the protein. All affected patients showed brain anomalies on magnetic resonance imaging (MRI), suggesting the pivotal role of WWOX protein in brain homeostasis and developmental processes. We provided a literature review, exploring both the clinical and radiological spectrum related to WWOX pathogenic variants, described to date. We focused on neuroradiological findings to better delineate the WOREE phenotype with diagnostic and prognostic implications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Battaglia, Scorrano, Spiaggia, Basile, Palmucci, Foti, Spatola, Iacomino, Marinangeli, Francia, Comisi, Corsello, Salpietro, Vittori and David.)

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans , we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies. [ABSTRACT FROM AUTHOR]

Prenatal exposure to Zika virus (ZIKV) is associated with congenital anomalies of the brain and the eye and neurodevelopmental sequelae. The spectrum of disease outcomes may relate to timing of infection as well as genetic and environmental factors. Congenital infections occurring in twin pregnancies can inform the clinical spectrum of these conditions and provide unique information regarding timing of infection and in utero environment with disease pathophysiology. Herein, we report a monozygotic dichorionic-diamniotic twin pregnancy with probable prenatal ZIKV exposure identified through the Colombian ZIKV disease surveillance system. Multidisciplinary clinical evaluations were provided to the twins during their first three years of life through a national program for children with in utero ZIKV exposure. Laboratory evidence of congenital infection as well as microcephaly, brain, eye, and neurodevelopmental compromise related to prenatal ZIKV infection were identified in only one infant of the twin pregnancy. This is the first report of monozygotic twins discordant for Zika-associated birth defects. The evaluation of the pathophysiology of discordance in disease outcome for congenital infections in twin pregnancies may lead to a better understanding of potential complex environmental and genetic interactions between the mother, her offspring, and an infectious exposure.

Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease-gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created 'matching' platforms. We describe four individuals from three unrelated families 'matched' by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease-causing gene and interprets the variants as 'pathogenic.' TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder. [ABSTRACT FROM AUTHOR]

Encephalocraniocutaneous lipomatosis (ECCL) is a rare sporadic neurocutaneous syndrome characterized by presence of central nervous system, ocular and cutaneous anomalies. The exact pathogenesis is still not known. We present the third case from the Indian subcontinent, who is a five year old girl with history of right sided seizures. Dermatological examination showed alopecia on right side of the scalp and ipsilateral limbal dermoid and nodular skin tags over the upper eyelid. The computerized tomography scan of the brain revealed porencephalic cyst, cerebral calcifications and atrophy of right brain. The histopathology of the skin lesions showed lipomatous hamartoma and features of non scarring alopecia. The constellation of these findings and in adherence to the diagnostic criteria of ECCL proposed in 2009, we consider this report as a definite case of ECCL.

Walker–Warburg syndrome (WWS) is a rare form of autosomal recessive, congenital muscular dystrophy that is associated with brain and eye anomalies. Several genes encoding proteins involved in abnormal α-dystroglycan glycosylation have been implicated in the aetiology of WWS, most recently the ISPD gene. Typical WWS brain anomalies, such as cobblestone lissencephaly, hydrocephalus and cerebellar malformations, can be prenatally detected through routine ultrasound examinations. Here, we report two karyotypically normal foetuses with multiple brain anomalies that corresponded to WWS symptoms. Using a SNP-array examination on the amniotic fluid DNA, a homozygous microdeletion was identified at 7p21.2p21.1 within the ISPD gene. Published data and our findings led us to the conclusion that a homozygous segmental intragenic deletion of the ISPD gene causes the most severe phenotype of Walker–Warburg syndrome. Our results also clearly supports the use of chromosomal microarray analysis as a first-line diagnostic test in patients with a foetus with one or more major structural abnormalities identified on ultrasonographic examination. [ABSTRACT FROM AUTHOR]

ABSTRACT Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis. [ABSTRACT FROM AUTHOR]

As some critics have stated, the term "developmental dyslexia" refers to a strictly human disorder, relating to a strictly human capacity - reading - so it cannot be modeled in experimental animals, much less so in lowly rodents. However, two endophenotypes associated with developmental dyslexia are eminently suitable for animal modeling: Cerebral Lateralization, as illustrated by the association between dyslexia and non-righthandedness, and Cerebrocortical Dysfunction, as illustrated by the described abnormal structural anatomy and/or physiology and functional imaging of the dyslexic cerebral cortex. This paper will provide a brief review of these two endophenotypes in human beings with developmental dyslexia and will describe the animal work done in my laboratory and that of others to try to shed light on the etiology of and neural mechanisms underlying developmental dyslexia. Some thought will also be given to future directions of the research., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Galaburda.)

Background: For the followers of criminal anthropology, during the second half of the 19th and the beginning of the 20th century, the association "anatomical anomaly - psyche anomaly" represented an immediate diagnostic tool to identify mental illness and consequently the tendency to become a criminal. In this article, we analyse a clinical report published in 1900 in which the author, Dr. Saporito, described five brains of alienated criminals from the Aversa asylum., Methods: Through the observations of Dr. Saporito's autoptic evaluations and the literature of the times, the beliefs of the positivist science of that time are highlighted., Results: The identification of multiple physical anomalies focused on the brains, with particular attention to the alteration at the level of some fissures, could lead to identify psychiatric disorders and criminal tendency., Conclusions: From the observations presented here, the author reiterated that several anomalies recorded in these five brains reproduced atavistic characteristics, which disappeared in the ontogenetic and phylogenetic evolution of the human brain., (Published by Elsevier Masson SAS.)

Brain anomalies are frequently found in early psychoses. Although they may remain undetected for many years, their interpretation is critical for differential diagnosis. In secondary psychoses, their identification may allow specific management. They may also shed light on various pathophysiological aspects of primary psychoses. Here we reviewed cases of secondary psychoses associated with brain anomalies, reported over a 20-year period in adolescents and young adults aged 13-30 years old. We considered age at first psychotic symptoms, relevant medical history, the nature of psychiatric symptoms, clinical red flags, the nature of the brain anomaly reported, and the underlying disease. We discuss the relevance of each brain area in light of normal brain function, recent case-control studies, and postulated pathophysiology. We show that anomalies in all regions, whether diffuse, multifocal, or highly localized, may lead to psychosis, without necessarily being associated with non-psychiatric symptoms. This underlines the interest of neuroimaging in the initial workup, and supports the hypothesis of psychosis as a global network dysfunction that involves many different regions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Anterior encephaloceles are rare conditions. Except for a few places from South East Asia, no large series has been published in the World literature. Materials and Methods: At AIIMS, we have managed 133 cases over a 40-year-period from 1971 to 2010. Frontoethmoidal type was the most frequent, noticed in 104 patients, followed by nasopharyngeal nasal in 12 and orbital encephaloceles in 6 patients. Observation: Ten patients were adults over the age of 18 years and 15 patients were between 5 and 18 years of age. Swelling over the nose was reported in all 104 patients with frontoethmoid type. In nasopharyngeal type, patients presented with respiratory problem. Patients with orbital mass had proptosis, on the side of encephalocele. Computed tomography (CT)/Magnetic resonance imaging (MRI) was performed in 127 patients, which was able to delineate the bone defect and associated brain anomalies. All the patients were subjected to repair of encephalocele. Patients with hypertelorism required orbital osteotomies and correction of deformity. Outcome: There were four deaths, all prior to 2000. No death was encountered in the last 10 years. CSF leak was the commonest postoperative complication, noticed in 24 patients. Overall cosmetic outcome was good. [ABSTRACT FROM AUTHOR]

Molecular karyotyping is being increasingly applied to delineate novel disease causing microaberrations and related syndromes in patients with mental retardation of unknown aetiology. We report on three unrelated patients with overlapping de novo interstitial microdeletions involving 5q14.3-q15. All three patients presented with severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies. Molecular karyotyping revealed three overlapping microdeletions measuring 5.7, 3.9 and 3.6 Mb, respectively. The microdeletions were identified using single nucleotide polymorphism (SNP) arrays (Affymetrix 100K and Illumina 550K) and array comparative genomic hybridization (1 Mb Sanger array-CGH). Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative PCR. All three aberrations were confirmed and proven to have occurred de novo. The boundaries and sizes of the deletions in the three patients were different, but an overlapping region of around 1.6 Mb in 5q14.3 was defined. It included five genes: CETN3, AC093510.2, POLR3G, LYSMD3 and the proximal part of GPR98/MASS1, a known epilepsy gene. Haploinsufficiency of GPR98/MASS1 is probably responsible for the seizure phenotype in our patients. At least one other gene contained in the commonly deleted region, LYSMD3, shows a high level of central nervous expression during embryogenesis and is also, therefore, a good candidate gene for other central nervous system (CNS) symptoms, such as psychomotor retardation, brain anomalies and muscular hypotonia of the 5q14.3 microdeletion syndrome. [ABSTRACT FROM AUTHOR]

During the last decade, increasing interest in magnetic resonance imaging has emerged for the evaluation of fetal abnormalities detected on ultrasound. The advent of single-shot rapid acquisition sequences has greatly facilitated our ability to obtain detailed imaging information of the fetal brain. To date, fetal magnetic resonance imaging has shown to have an important role in the investigation of cerebral abnormalities suspected by sonography, and in the detection of subtle brain anomalies associated with high-risk pregnancies. Magnetic resonance imaging has proved to be a useful adjunct to sonography during the prenatal period of development, especially for the detection of acquired disorders. [Copyright &y& Elsevier]

Galloway–Mowat syndrome (GMS) is a rare autosomal recessive disorder characterized by early onset nephrotic syndrome and microcephaly with various anomalies of the central nervous system. GMS likely represents a heterogeneous group of disorders with hitherto unknown genetic etiology. The clinical phenotype to some extent overlaps that of Pierson syndrome (PS), which comprises congenital nephrotic syndrome and distinct ocular abnormalities but which may also include neurodevelopmental deficits and microcephaly. PS is caused by mutations of LAMB2, the gene encoding laminin β2. We hypothesized that GMS might be allelic to PS or be caused by defects in proteins that interact with laminin β2. In a cohort of 18 patients with GMS or a GMS-like phenotype we therefore analyzed the genes encoding laminin β2 ( LAMB2), laminin α5 ( LAMA5), α3-integrin ( ITGA3), β1-integrin ( ITGB1) and α-actinin-4 ( ACTN4), but we failed to find causative mutations in these genes. We inferred that LAMA5, ITGA3, ITGB1, and ACTN4 are not directly involved in the pathogenesis of GMS. We excluded LAMB2 as a candidate gene for GMS. Further studies are required, including linkage analysis in families with GMS to identify genes underlying this disease. [ABSTRACT FROM AUTHOR]

Abstract: The multiplanar neurosonographic examination of the fetus enables superb visualization of brain anatomy during pregnancy. The examination may be performed using a transvaginal or a transfundal approach and it is indicated in patients at high risk for CNS anomalies or in those with a suspicious finding during a routine examination. The purpose of this paper is to present a description of the normal brain and of abnormal findings usually diagnosed late in pregnancy, including malformations of cortical development, infratentorial anomalies, and prenatal insults. [Copyright &y& Elsevier]

Unilateral megalencephaly is a rare anomaly of the brain which causes enlargement of a lobe or an nentire hemisphere. The radiological features of the disease are a poorly defined unusual mass effect on PEG, angiography and CT scan. Pathologically, the disease is thought to be due to abnormal cell migration in the 3rd month in utero. [ABSTRACT FROM AUTHOR]