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Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD's critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a, which, without NMD suppression, slow the cell cycle. Trp53KO restores the progenitor cell pool and rescues the microcephaly of Upf2KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size.

The transcription factor p53 (encoded by TP53) plays diverse roles in human development and disease. While best known for its role in tumor suppression, p53 signaling also influences mammalian development by triggering cell fate decisions in response to a wide variety of stresses. After over 4 decades of study, a new pathway that triggers p53 activation in response to mitotic delays was recently identified. Termed the mitotic surveillance or mitotic stopwatch pathway, the USP28 and 53BP1 proteins activate p53 in response to delayed mitotic progression to control cell fate and promote genomic stability. In this Minireview, I discuss its identification, potential roles in neurodevelopmental disorders and cancer, as well as explore outstanding questions about its function, regulation and potential use as a biomarker for anti-mitotic therapies. [ABSTRACT FROM AUTHOR]

• A novel case of ALG11-CDG, a very rare disease, is reported. • Novel compound heterozygous variants: c.1307G> T (p.G436V) and c.1403G> A (p.R468H) are identified in ALG11 gene. • These two variants decreased stability of the mutant protein and concurrent hypoglycosylation of GP130, a hyperglycosylated protein. Congenital disorders of glycosylation (CDG) represent a heterogeneous group of rare inherited metabolic disorders due to abnormalities in protein or lipid glycosylation pathways, affecting multiple systems, and frequently being accompanied by neurological symptoms. ALG11-CDG, also known as CDG-1p, arises from a deficiency in a specific mannosyltransferase encoded by the ALG11 gene. To date, only 17 cases have been documented, and these patients have prominent clinical phenotypes, including seizures, developmental delay, and microcephaly. We describe a novel case of a four-month-old boy from a Chinese family exhibiting developmental delay, seizures, and microcephaly. Trio whole-exome sequencing (WES) and subsequent Sanger sequencing were employed to identify the potential genetic cause, and functional study was performed to evaluate the pathogenicity of genetic variant identified. Trio WES unveiled novel compound heterozygous variants: c.1307G> T (p.G436V) and c.1403G> A (p.R468H) within exon 4 of the ALG11 gene, inherited from the father and mother, respectively. Subsequent in vitro functional analysis revealed decreased stability of the mutant protein and concurrent hypoglycosylation of GP130, a hyperglycosylated protein. Our findings not only expand the clinical and variant spectrum of ALG11-CDG, but also emphasize the importance of WES as a first-tier genetic test in determining the molecular diagnosis. [ABSTRACT FROM AUTHOR]

Background: The Coiled-Coil Domain-Containing Protein 88 A (CCDC88A) gene encodes the actin-binding protein Girdin, which plays important roles in maintaining the actin cytoskeleton and in cell migration and was recently associated with a specific form of epileptic encephalopathy. Biallelic protein-truncating variants of CCDC88A have been considered responsible for progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome. To date, only three consanguineous families with loss-of-function homozygous variants in the CCDC88A gene have been reported. The described patients share many clinical features, such as microcephaly, neonatal hypotonia, seizures, profound developmental delay, face and limb edema, and dysmorphic features, with a similar appearance of the eyes, nose, mouth, and fingers. Case presentation: We report on a child from a nonconsanguineous family who presented with profound global developmental delay, severe epilepsy, and brain malformations, including subcortical band heterotopia. The patient harbored two heterozygous pathogenic variants in the trans configuration in the CCDC88A gene, which affected the coiled-coil and C-terminal domains. Conclusions: We detail the clinical and cerebral imaging data of our patient in the context of previously reported patients with disease-causing variants in the CCDC88A gene, emphasizing the common phenotypes, including cortical malformations, that warrant screening for sequence variants in this gene. [ABSTRACT FROM AUTHOR]

Background: Silver-Russell Syndrome (SRS, MIM #180860) is a clinically and genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation; SRS is also accompanied by dysmorphic features such as triangular facial appearance, broad forehead, body asymmetry and significant feeding difficulties. The incidence is unknown but estimated at 1:30,000-100,000 live births. The diagnosis of SRS is guided by specific criteria described in the Netchine–Harbison clinical scoring system (NH-CSS). Case presentation: Hereby we describe four patients with syndromic short stature in whom, despite fitting the criteria for SRS genetic analysis (and one on them even meeting the clinical criteria for SRS), molecular analysis actually diagnosed a different syndrome. Some additional features such as hypotonia, microcephaly, developmental delay and/or intellectual disability, and family history of growth failure, were actually discordant with SRS in our cohort. Conclusions: The clinical resemblance of other short stature syndromes with SRS poses a risk of diagnostic failure, in particular when clinical SRS only criteria are met, allowing SRS diagnosis in the absence of a positive result of a genetic test. The presence of additional features atypical for SRS diagnosis becomes a red flag for a more extensive and thorough analysis. The signs relevant to the differential diagnosis should be valued as much as possible since a correct diagnosis of these patients is the only way to provide the appropriate care pathway, a thorough genetic counselling, prognosis definition, follow up setting, appropriate monitoring and care of possible medical problems. [ABSTRACT FROM AUTHOR]

Kinesin family member 11 (KIF11)‐associated disorder, a rare condition caused by autosomal dominant mutations in the KIF11 gene, presents with microcephaly, chorioretinal dysplasia, lymphoedema, and varying degrees of intellectual disability. While intellectual disability is often described in the literature on KIF11 mutations, autism spectrum disorder (ASD) and attention‐deficit/hyperactivity disorder (ADHD) are only mentioned by a few authors but not thoroughly investigated. We present a case report of an 8‐year‐old boy with KIF11‐associated disorder alongside ADHD and ASD but without intellectual disability. Genetic testing confirmed a KIF11 mutation. Cognitive, language, and motor assessments revealed delays in fine motor skills and attention deficits. The diagnosis of ADHD was confirmed by a child neurologist through multidisciplinary investigations, while the ASD diagnosis was established by a child psychiatrist. Despite the challenges of delayed psychiatric assessment, interventions including physiotherapy and medication management were initiated with positive results. We designed a parent support group survey that showed a higher prevalence of neurodevelopmental disorders in children with KIF11 mutations compared to the general population. Therefore, low‐threshold referrals to a child psychiatrist have to be made when the potential presence of developmental problems is suspected. Collaboration between ophthalmologists, paediatricians, and child psychiatrists is crucial for early detection and intervention. Addressing developmental disorders promptly improves long‐term outcomes and enhances quality of life. Moreover, gaining a deeper understanding of the higher prevalence of ASD and ADHD in individuals with KIF11 mutations could offer valuable insights into the genetic mechanisms underlying neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/β-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/β-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants. [Display omitted] Boonsawat et al. establish germline missense variants in the tumor suppressor gene ZNRF3 as a cause of neurodevelopmental disorders (NDDs) with microcephaly or macrocephaly, depending on the functional/domain-specific effects of the variants on Wnt/β-catenin signaling. This study finds that ZNRF3 haploinsufficiency does not cause NDDs but rather other phenotypes. [ABSTRACT FROM AUTHOR]

Background: Early pregnancy Zika virus (ZIKV) infection is associated with major brain damage in fetuses, leading to microcephaly in 0.6–5.0% of cases, but the underlying mechanisms remain largely unknown. Methods: To understand the kinetics of ZIKV infection during fetal development in a nonhuman primate model, four cynomolgus macaque fetuses were exposed in utero through echo-guided intramuscular inoculation with 103 PFU of ZIKV at 70–80 days of gestation, 2 controls were mock inoculated. Clinical, immuno-virological and ultrasound imaging follow-ups of the mother/fetus pairs were performed until autopsy after cesarean section 1 or 2 months after exposure (n = 3 per group). Results: ZIKV was transmitted from the fetus to the mother and then replicate in the peripheral blood of the mother from week 1 to 4 postexposure. Infected fetal brains tended to be smaller than those of controls, but not the femur lengths. High level of viral RNA ws found after the first month in brain tissues and placenta. Thereafter, there was partial control of the virus in the fetus, resulting in a decreased number of infected tissue sections and a decreased viral load. Immune cellular and humoral responses were effectively induced. Conclusions: ZIKV infection during the second trimester of gestation induces short-term brain injury, and although viral genomes persist in tissues, most of the virus is cleared before delivery. [ABSTRACT FROM AUTHOR]

Cockayne syndrome (CS) is a rare, severe, genetic neurodegenerative disorder. To better understand the condition, this article aimed to discuss the clinical manifestations and prognosis of CS. This clinical study was a retrospective review of the medical records of patients diagnosed with CS between January 2010 and January 2020. A total of 9 patients (6 males, 66.7%; 3 females, 33.3%) from 7 families were enrolled in the study. The median age of the patients was 94 (4-186) months. Genetic confirmation of CS was obtained in 5 of the patients and ERCC8 mutations were identified in all patients who underwent genetic confirmation of the disease. On admission, 8 patients were found to have microcephaly 4 patients were admitted for psychomotor retardation, 3 for seizures, and two for walking disabilities. The diagnosis of patients with CS can be challenging due to the wide range of symptoms. In patients who are normal at birth but develop microcephaly during follow-up, physicians should consider CS in addition to metabolic diseases in the differential diagnosis. [ABSTRACT FROM AUTHOR]

Oropouche virus (OROV) is an emerging arbovirus endemic in Latin America and the Caribbean that causes Oropouche fever, a febrile illness that clinically resembles some other arboviral infections. It is currently spreading through Brazil and surrounding countries, where, from 1 January to 1 August 2024, more than 8000 cases have been identified in Bolivia, Brazil, Columbia, and Peru and for the first time in Cuba. Travelers with Oropouche fever have been identified in the United States and Europe. A significant occurrence during this epidemic has been the report of pregnant women infected with OROV who have had miscarriages and stillborn fetuses with placental, umbilical blood and fetal somatic organ samples that were RT-PCR positive for OROV and negative for other arboviruses. In addition, there have been four cases of newborn infants having microcephaly, in which the cerebrospinal fluid tested positive for IgM antibodies to OROV and negative for other arboviruses. This communication examines the biology, epidemiology, and clinical features of OROV, summarizes the 2023–2024 Oropouche virus epidemic, and describes the reported cases of vertical transmission and congenital infection, fetal death, and microcephaly in pregnant women with Oropouche fever, addresses experimental animal infections and potential placental pathology findings of OROV, and reviews other bunyavirus agents that can cause vertical transmission. Recommendations are made for pregnant women travelling to the regions affected by the epidemic. [ABSTRACT FROM AUTHOR]

Microcephaly, epilepsy and diabetes syndrome 1 (MEDS1) is a rare autosomal recessive disorder caused by defects in the immediate early response 3 interacting protein 1 (IER3IP1) gene. Only nine cases have been described in the literature. MEDS1 manifests as microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes. A simplified gyral pattern has been described in all cases reported to date. Diagnosis is made by demonstration of specific mutations in the IER3IP1 gene. In this study, we present an additional case of a patient with MEDS1 who was homozygous for the c.53C>T p.(Ala18Val) variant. This case, the first to be reported from Turkey, differs from other cases due to the absence of a typical simplified gyral pattern on early brain magnetic resonance imaging, the late onset of diabetes, and the presence of a new genetic variant. The triad of microcephaly, generalized seizures and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. [ABSTRACT FROM AUTHOR]

Introduction: Microcephaly, characterized by abnormal head growth, can often serve as an initial indicator of congenital, genetic, or acquired disorders. In this study, we sought to evaluate the effectiveness of chromosomal microarray (CMA) testing in detecting abnormalities in both prenatal and postnatal cases of microcephaly. Materials and methods: CMA Testing: We conducted CMA testing on 87 prenatally-detected microcephaly cases and 742 postnatal cases at a single laboratory. We evaluated the CMA yield in relation to specific clinical characteristics. Results: In prenatal cases, pathogenic and likely pathogenic (LP) results were identified in 4.6% of cases, a significantly higher rate compared to low-risk pregnancies. The male-to-female ratio in this cohort was 3, and the CMA yield was not influenced by gender or other clinical parameters. For postnatal cases, the CMA yield was 15.0%, with a significantly higher detection rate associated with dysmorphism, hypotonia, epilepsy, congenital heart malformations (CHM), learning disabilities (LD), and a history of Fetal growth restriction (FGR). No specific recurrent copy number variations (CNVs) were observed, and the rate of variants of unknown significance was 3.9%. Conclusions: The yield of CMA testing in prenatal microcephaly is lower than in postnatal cases (4.6% vs. 15%). The presence of microcephaly, combined with dysmorphism, hypotonia, epilepsy, CHD, LD, and FGR, significantly increases the likelihood of an abnormal CMA result. [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. We enrolled individuals with BPTF -related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. We studied 11 individuals with a null variant in BPTF , including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. Our study provides the first characterization of BPTF -related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare. [ABSTRACT FROM AUTHOR]

Background: Neurodevelopmental disorders (NDDs) encompass a diverse group of disorders characterized by impaired cognition, behavior, and motor skills. Genetic factor is the leading cause in about 35% of NDDs patients. Mutations of UFC1, an E2 enzyme participating in the post-translational modification of proteins through attachment of ubiquitin-like proteins, were recently reported to be associated with NDDs. However, the UFC1 associated NDDs are rare and the data are scarce, thus making it difficult to identify this disease. Objective: This study reported a novel compound heterozygous mutation of UFC1 in a Chinese patient with NDD. Methods: Detailed clinical data were recorded. Whole exome sequencing (WES) was performed to determine the genetic cause of the patient. The candidate mutation was verified using Sanger sequencing. Results: WES analysis identified a novel compound heterozygous mutation of UFC1 (c.19 C > T, p.Arg7* and c.164G > A, p.Arg55Gln). The nonsense mutation c.19 C > T (p.Arg7*) led to a premature truncation of UFC1 and nonsense-mediated RNA decay. Arg55 is highly conserved among orthologues. Molecular modeling predicted that mutation c.164G > A (p.Arg55Gln) may influence the correct folding of UFC1. These two mutations were evaluated as likely pathogenic based on the ACMG guideline. Moreover, neurodevelopmental delay, microcephaly, and epilepsy were confirmed as major phenotypes of UFC1 mutation. Conclusion: This study expands the mutational spectrum of NDDs. We reported the nonsense mutation of UFC1 for the first time. We also confirmed the major phenotypes that may guide clinical identification of UFC1 mutation. Ubiquitination mechanism is highlighted in NDDs pathogenesis. [ABSTRACT FROM AUTHOR]

We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug‐resistant epilepsy. Brain magnetic resonance imaging revealed distinctive features, including a Z‐shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion. Whole‐exome sequencing uncovered a pathogenic variant in the ARF3 gene c.200A>T, p.(Asp67Val). The neurodevelopmental disorder associated with the ARF3 gene is exceptionally rare, with only two previously documented cases in the literature. This disorder is characterized by global developmental delay and brain malformations, particularly affecting the white matter, cerebellum, and brainstem. It can also manifest as acquired microcephaly and epilepsy. These phenotypic characteristics align with Golgipathies, underscoring the significance of considering this group of conditions in relevant clinical contexts. In cases where a Z‐shaped morphology of the brainstem is observed, ARF3‐associated disorder should be included in the list of differential diagnoses. [ABSTRACT FROM AUTHOR]

Background: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is a rare autosomal dominant disease caused by mutations in KIF11 which disrupt EG5 protein function, impacting the development and maintenance of retinal and lymphatic structures due to its expression in the retinal photoreceptor cilia. The primary ocular finding in MCLMR is chorioretinopathy. Additional features can include microphthalmia, angle-closure glaucoma, persistent hyperplastic primary vitreous, cataract, pseudo-coloboma, persistent hyaloid artery, and myopic or hypermetropic astigmatism. The appearance of the chorioretinal lesions as white to pinkish, round, non-elevated atrophic areas devoid of blood vessels resembles the lacunae in Aicardy syndrome. Due to the lack of systematic description of the lesions and significant phenotypical variability, there is an impending need for a detailed report of each case. Case presentation: A child with microcephaly detected in the third trimester of gestation began her following in the ophthalmology department due to a non-visually significant cataract. Shortly after, she developed nystagmus and large-angle alternating esotropia with cross-fixation. Her fundus initially showed a pallid optic disc and pigmentary changes, developing thereafter retinal lacunae and a retinal fold. Her differential diagnosis accompanied the dynamic changes in her fundus, which included congenital infections, Leber´s Congenital Amaurosis and Aicardy syndrome. At 19 months old, genetic testing identified a heterozygous mutation (c.1159 C > T, p.Arg387*) in the KIF11 gene. The patient underwent bilateral medial rectus muscle recession surgery at 2 years old for persistent esotropia, with significant improvement. Refraction revealed a hyperopic astigmatism in both eyes (+ 0.25 -2.50 × 180 OD and + 0.75 -2.00 × 170 OS). She continues to require right eye patching for 2 hours daily. Conclusions: This case report expands the phenotypic spectrum of MCLMR by demonstrating a unique combination of retinal features which sheds new light on differential diagnosis from Aicardy syndrome. Our findings emphasize the significant phenotypic variability associated with MCLMR, particularly regarding ocular involvement. This underscores the importance of detailed clinical evaluation and comprehensive reporting of cases to improve our understanding of the disease spectrum and genotype-phenotype correlations. [ABSTRACT FROM AUTHOR]

Mutations in the IER3IP1 (Immediate Early Response-3 Interacting Protein 1) gene can give rise to MEDS1 (Microcephaly with Simplified Gyral Pattern, Epilepsy, and Permanent Neonatal Diabetes Syndrome-1), a severe condition leading to early childhood mortality. The small endoplasmic reticulum (ER)-membrane protein IER3IP1 plays a non-essential role in ER-Golgi transport. Here, we employed secretome and cell-surface proteomics to demonstrate that the absence of IER3IP1 results in the mistrafficking of proteins crucial for neuronal development and survival, including FGFR3, UNC5B and SEMA4D. This phenomenon correlates with the distension of ER membranes and increased lysosomal activity. Notably, the trafficking of cargo receptor ERGIC53 and KDEL-receptor 2 are compromised, with the latter leading to the anomalous secretion of ER-localized chaperones. Our investigation extended to in-utero knock-down of Ier3ip1 in mouse embryo brains, revealing a morphological phenotype in newborn neurons. In summary, our findings provide insights into how the loss or mutation of a 10 kDa small ER-membrane protein can cause a fatal syndrome. [ABSTRACT FROM AUTHOR]

Entosis, a form of cell cannibalism, is a newly discovered pathogenic mechanism leading to the development of small brains, termed microcephaly, in which P53 activation was found to play a major role. Microcephaly with entosis, found in Pals1 mutant mice, displays P53 activation that promotes entosis and apoptotic cell death. This previously unappreciated pathogenic mechanism represents a novel cellular dynamic in dividing cortical progenitors which is responsible for cell loss. To date, various recent models of microcephaly have bolstered the importance of P53 activation in cell death leading to microcephaly. P53 activation caused by mitotic delay or DNA damage manifests apoptotic cell death which can be suppressed by P53 removal in these animal models. Such genetic studies attest P53 activation as quality control meant to eliminate genomically unfit cells with minimal involvement in the actual function of microcephaly associated genes. In this review, we summarize the known role of P53 activation in a variety of microcephaly models and introduce a novel mechanism wherein entotic cell cannibalism in neural progenitors is triggered by P53 activation. [ABSTRACT FROM AUTHOR]

Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing. We investigated the genetic basis of syndromic microcephaly accompanied by NDD in a Brazilian cohort of 45 individuals and characterized associated clinical features, as well as evaluated the effectiveness of whole-exome sequencing (WES) as a diagnostic tool for this condition. Patients previously negative for pathogenic copy number variants underwent WES, which was performed using a trio approach for isolated index cases (n = 31), only the index in isolated cases with parental consanguinity (n = 8) or affected siblings in familial cases (n = 3). Pathogenic/likely pathogenic variants were identified in 19 families (18 genes) with a diagnostic yield of approximately 45%. Nearly 86% of the individuals had global developmental delay/intellectual disability and 51% presented with behavioral disturbances. Additional frequent clinical features included facial dysmorphisms (80%), brain malformations (67%), musculoskeletal (71%) or cardiovascular (47%) defects, and short stature (54%). Our findings unraveled the underlying genetic basis of microcephaly in half of the patients, demonstrating a high diagnostic yield of WES for microcephaly and reinforcing its genetic heterogeneity. We expanded the phenotypic spectrum associated with the condition and identified a potentially novel gene (CCDC17) for congenital microcephaly. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic variants in ZNF335 are one of the genetic causes of microcephaly, reported only in the past decade. It regulates neural progenitor proliferation and neurogenesis by interacting with a H3K4 methyltransferase complex. Biallelic pathogenic ZNF335 variants predispose to neuronal cell death and aberrant differentiation, thus causing secondary microcephaly. These neurodevelopmental anomalies lead to imaging findings in the cortex, posterior fossa, and basal ganglia. We report an individual of Nepalese ancestry with a novel homozygous ZNF335 variant (c.3591 + 2dup) (p.?) (NM_022095.3) which on further RNA analysis confirmed a splice site variant in intron 23. The patient presented with primary microcephaly with atrophic cerebral hemispheres, oversimplification of gyri, basal ganglia, and corpus callosal atrophy. Literature review on the topic revealed a spectrum of brain abnormalities, which can present either with a primary or secondary microcephaly depending upon the underlying genetic variant. [ABSTRACT FROM AUTHOR]

Cockayne syndrome (CS) is a rare, severe, genetic neurodegenerative disorder. To better understand the condition, this article aimed to discuss the clinical manifestations and prognosis of CS. This clinical study was a retrospective review of the medical records of patients diagnosed with CS between January 2010 and January 2020. A total of 9 patients (6 males, 66.7%; 3 females, 33.3%) from 7 families were enrolled in the study. The median age of the patients was 94 (4-186) months. Genetic confirmation of CS was obtained in 5 of the patients and ERCC8 mutations were identified in all patients who underwent genetic confirmation of the disease. On admission, 8 patients were found to have microcephaly 4 patients were admitted for psychomotor retardation, 3 for seizures, and two for walking disabilities. The diagnosis of patients with CS can be challenging due to the wide range of symptoms. In patients who are normal at birth but develop microcephaly during follow-up, physicians should consider CS in addition to metabolic diseases in the differential diagnosis.

Abstract Background Early pregnancy Zika virus (ZIKV) infection is associated with major brain damage in fetuses, leading to microcephaly in 0.6–5.0% of cases, but the underlying mechanisms remain largely unknown. Methods To understand the kinetics of ZIKV infection during fetal development in a nonhuman primate model, four cynomolgus macaque fetuses were exposed in utero through echo-guided intramuscular inoculation with 103 PFU of ZIKV at 70–80 days of gestation, 2 controls were mock inoculated. Clinical, immuno-virological and ultrasound imaging follow-ups of the mother/fetus pairs were performed until autopsy after cesarean section 1 or 2 months after exposure (n = 3 per group). Results ZIKV was transmitted from the fetus to the mother and then replicate in the peripheral blood of the mother from week 1 to 4 postexposure. Infected fetal brains tended to be smaller than those of controls, but not the femur lengths. High level of viral RNA ws found after the first month in brain tissues and placenta. Thereafter, there was partial control of the virus in the fetus, resulting in a decreased number of infected tissue sections and a decreased viral load. Immune cellular and humoral responses were effectively induced. Conclusions ZIKV infection during the second trimester of gestation induces short-term brain injury, and although viral genomes persist in tissues, most of the virus is cleared before delivery.

Abstract Background Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is a rare autosomal dominant disease caused by mutations in KIF11 which disrupt EG5 protein function, impacting the development and maintenance of retinal and lymphatic structures due to its expression in the retinal photoreceptor cilia. The primary ocular finding in MCLMR is chorioretinopathy. Additional features can include microphthalmia, angle-closure glaucoma, persistent hyperplastic primary vitreous, cataract, pseudo-coloboma, persistent hyaloid artery, and myopic or hypermetropic astigmatism. The appearance of the chorioretinal lesions as white to pinkish, round, non-elevated atrophic areas devoid of blood vessels resembles the lacunae in Aicardy syndrome. Due to the lack of systematic description of the lesions and significant phenotypical variability, there is an impending need for a detailed report of each case. Case presentation A child with microcephaly detected in the third trimester of gestation began her following in the ophthalmology department due to a non-visually significant cataract. Shortly after, she developed nystagmus and large-angle alternating esotropia with cross-fixation. Her fundus initially showed a pallid optic disc and pigmentary changes, developing thereafter retinal lacunae and a retinal fold. Her differential diagnosis accompanied the dynamic changes in her fundus, which included congenital infections, Leber´s Congenital Amaurosis and Aicardy syndrome. At 19 months old, genetic testing identified a heterozygous mutation (c.1159 C > T, p.Arg387*) in the KIF11 gene. The patient underwent bilateral medial rectus muscle recession surgery at 2 years old for persistent esotropia, with significant improvement. Refraction revealed a hyperopic astigmatism in both eyes (+ 0.25 -2.50 × 180 OD and + 0.75 -2.00 × 170 OS). She continues to require right eye patching for 2 hours daily. Conclusions This case report expands the phenotypic spectrum of MCLMR by demonstrating a unique combination of retinal features which sheds new light on differential diagnosis from Aicardy syndrome. Our findings emphasize the significant phenotypic variability associated with MCLMR, particularly regarding ocular involvement. This underscores the importance of detailed clinical evaluation and comprehensive reporting of cases to improve our understanding of the disease spectrum and genotype-phenotype correlations.

INTRODUCTION: Microcephaly (MC) is a clinical finding mostly reflecting deficiency of brain growth. The aim of this retrospective cohort study was to assess risk factors and follow-up features of children with MC. METHODS: Children’s personal health records (n=7580) followed between 2002 and 2020 in the Unit of a Well Child Clinic were assessed retrospectively. The case group comprised children with MC. MC was defined as head circumference (HC) standard deviation score (SDS) value ≤-2 SDS. Age and sex-matched children with normal HC were selected as the control group. RESULTS: Children with MC (n=49) had more disadvantaged sociodemographic characteristics, such as young maternal and paternal age and low maternal and paternal education. Breastfeeding was more common among controls (n=98). Resolution of MC was observed in 26 (53.1%) children with MC, whether it was mild (HC SDS between -2 and -2.9) or severe (HC SDS ≤3). Children with persistent MC had poorer developmental milestones than controls and cases with resolution. Sociodemographic features or developmental milestones in mild and severe MC did not differ. DISCUSSION AND CONCLUSION: These results suggest that the use of a definition of MC of ≤-2 SDS would be appropriate in order not to miss cases on follow-up. Greater sociodemographic equality may prevent some cases of MC. Further studies are needed evaluating socioeconomic factors on MC.

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses. neuron navigator-3 (NAV3) is involved in neuronal morphogenesis, vision, and neuromuscular responses, and the biallelic/mono-allelic variants of NAV3 are causative of a spectrum of neurodevelopmental disorders [ABSTRACT FROM AUTHOR]

Primary microcephaly is a rare neurogenic and genetically heterogeneous disorder characterized by significant brain size reduction that results in numerous neurodevelopmental disorders (NDD) problems, including mild to severe intellectual disability (ID), global developmental delay (GDD), seizures and other congenital malformations. This disorder can arise from a mutation in genes involved in various biological pathways, including those within the brain. We characterized a recessive neurological disorder observed in nine young adults from five independent consanguineous Pakistani families. The disorder is characterized by microcephaly, ID, developmental delay (DD), early-onset epilepsy, recurrent infection, hearing loss, growth retardation, skeletal and limb defects. Through exome sequencing, we identified novel homozygous variants in five genes that were previously associated with brain diseases, namely CENPJ (NM_018451.5: c.1856A > G; p.Lys619Arg), STIL (NM_001048166.1: c.1235C > A; p.(Pro412Gln), CDK5RAP2 (NM_018249.6 c.3935 T > G; p.Leu1312Trp), RBBP8 (NM_203291.2 c.1843C > T; p.Gln615*) and CEP135 (NM_025009.5 c.1469A > G; p.Glu490Gly). These variants were validated by Sanger sequencing across all family members, and in silico structural analysis. Protein 3D homology modeling of wild-type and mutated proteins revealed substantial changes in the structure, suggesting a potential impact on function. Importantly, all identified genes play crucial roles in maintaining genomic integrity during cell division, with CENPJ, STIL, CDK5RAP2, and CEP135 being involved in centrosomal function. Collectively, our findings underscore the link between erroneous cell division, particularly centrosomal function, primary microcephaly and ID. [ABSTRACT FROM AUTHOR]

Biallelic variants in the OTUD6B gene have been reported in the literature in association with an intellectual developmental disorder featuring dysmorphic facies, seizures, and distal limb abnormalities. Physical differences described for affected individuals suggest that the disorder may be clinically recognizable, but previous publications have reported an initial clinical suspicion for Kabuki syndrome (KS) in some affected individuals. Here, we report on three siblings with biallelic variants in OTUD6B co‐segregating with neurodevelopmental delay, shared physical differences, and other clinical findings similar to those of previously reported individuals. However, clinical manifestations such as long palpebral fissures, prominent and cupped ears, developmental delay, growth deficiency, persistent fetal fingertip pads, vertebral anomaly, and seizures in the proband were initially suggestive of KS. In addition, previously unreported clinical manifestations such as delayed eruption of primary dentition, soft doughy skin with reduced sweating, and mirror movements present in our patients suggest an expansion of the phenotype, and we perform a literature review to update on current information related to OTUD6B and human gene‐disease association. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV), a mosquito-borne flavivirus, is prominently associated with microcephaly in babies born to infected mothers as well as Guillain-Barré Syndrome in adults. Each cell type infected by ZIKV—neuronal cells (radial glial cells, neuronal progenitor cells, astrocytes, microglia cells, and glioblastoma stem cells) and non-neuronal cells (primary fibroblasts, epidermal keratinocytes, dendritic cells, monocytes, macrophages, and Sertoli cells)—displays its own characteristic changes to their cell physiology and has various impacts on disease. Here, we provide an in-depth review of the ZIKV life cycle and its cellular targets, and discuss the current knowledge of how infections cause neuropathologies, as well as what approaches researchers are currently taking to further advance such knowledge. A key aspect of ZIKV neuropathogenesis is virus-induced neuronal apoptosis via numerous mechanisms including cell cycle dysregulation, mitochondrial fragmentation, ER stress, and the unfolded protein response. These, in turn, result in the activation of p53-mediated intrinsic cell death pathways. A full spectrum of infection models including stem cells and co-cultures, transwells to simulate blood–tissue barriers, brain-region-specific organoids, and animal models have been developed for ZIKV research. [ABSTRACT FROM AUTHOR]

The article focuses on a 3-year-old girl with microcephaly and developmental delay presenting symptoms of waddling gait, refusal to walk, and feeding difficulties. Topics include her medical history, anthropometric measurements, and initial clinical findings indicating hyponatremia, acute kidney injury, and lactic acidosis.

Congenital Zika syndrome (CZS) is a major concern in India and highlights the multifaceted challenges posed by the Zika virus (ZIKV). The alarming increase in CZS cases in India, a condition that has serious effects on both public health and newborns, has raised concerns. This review highlights the importance of raising concern and awareness and taking preventive measures by studying the epidemiology, clinical symptoms, and potential long‐term consequences of CZS. The review also contributes to worldwide research and information sharing to improve the understanding and prevention of CZS. As India deals with the changing nature of CZS, this thorough review is an important tool for policymakers, health workers, and researchers to understand what is happening now, plan for what to do in the future, and work together as a team, using medical knowledge, community involvement, and study projects to protect newborns' health and reduce the public health impact of these syndromes. [ABSTRACT FROM AUTHOR]

The biallelic variants of the POP1 gene are associated with the anauxetic dysplasia (AAD OMIM 607095), a rare skeletal dysplasia, characterized by prenatal rhizomelic shortening of limbs and generalized joint hypermobility. Affected individuals usually have normal neurodevelopmental milestones. Here we present three cases from the same family with likely pathogenic homozygous POP1 variant and a completely novel phenotype: a girl with global developmental delay and autism, microcephaly, peculiar dysmorphic features and multiple congenital anomalies. Two subsequent pregnancies were terminated due to multiple congenital malformations. Fetal DNA samples revealed the same homozygous variant in the POP1 gene. Expression of the RMRP was reduced in the proband compared with control and slightly reduced in both heterozygous parents, carriers for this variant. To our knowledge, this is the first report of this new phenotype, associated with a novel likely pathogenic variant in POP1. Our findings expand the phenotypic spectrum of POP1‐related disorders. [ABSTRACT FROM AUTHOR]

Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved treatment poses further challenges for healthcare providers. In this study, we developed a microparticulate Zika vaccine using an inactivated whole Zika virus as the antigen that can be administered pain-free via intranasal (IN) immunization. These microparticles (MP) were formulated using a double emulsion method developed by our lab. We explored a prime dose and two-booster-dose vaccination strategy using MPL-A® and Alhydrogel® as adjuvants to further stimulate the immune response. MPL-A® induces a Th1-mediated immune response and Alhydrogel® (alum) induces a Th2-mediated immune response. There was a high recovery yield of MPs, less than 5 µm in size, and particle charge of −19.42 ± 0.66 mV. IN immunization of Zika MP vaccine and the adjuvanted Zika MP vaccine showed a robust humoral response as indicated by several antibodies (IgA, IgM, and IgG) and several IgG subtypes (IgG1, IgG2a, and IgG3). Vaccine MP elicited a balance Th1- and Th2-mediated immune response. Immune organs, such as the spleen and lymph nodes, exhibited a significant increase in CD4+ helper and CD8+ cytotoxic T-cell cellular response in both vaccine groups. Zika MP vaccine and adjuvanted Zika MP vaccine displayed a robust memory response (CD27 and CD45R) in the spleen and lymph nodes. Adjuvanted vaccine-induced higher Zika-specific intracellular cytokines than the unadjuvanted vaccine. Our results suggest that more than one dose or multiple doses may be necessary to achieve necessary immunological responses. Compared to unvaccinated mice, the Zika vaccine MP and adjuvanted MP vaccine when administered via intranasal route demonstrated robust humoral, cellular, and memory responses. In this pre-clinical study, we established a pain-free microparticulate Zika vaccine that produced a significant immune response when administered intranasally. [ABSTRACT FROM AUTHOR]

Objective: Microcephaly (MC) is a clinical finding mostly reflecting deficiency of brain growth. The aim of this retrospective cohort study was to assess risk factors and follow-up features of children with MC. Methods: Children’s personal health records (n=7580) followed between 2002 and 2020 in the Unit of a Well Child Clinic were assessed retrospectively. The case group comprised children with MC. MC was defined as head circumference (HC) standard deviation score (SDS) value ≤-2 SDS. Age and sex-matched children with normal HC were selected as the control group. Results: Children with MC (n=49) had more disadvantaged sociodemographic characteristics, such as young maternal and paternal age and low maternal and paternal education. Breastfeeding was more common among controls (n=98). Resolution of MC was observed in 26 (53.1%) children with MC, whether it was mild (HC SDS between -2 and -2.9) or severe (HC SDS ≤3). Children with persistent MC had poorer developmental milestones than controls and cases with resolution. Sociodemographic features or developmental milestones in mild and severe MC did not differ. Conclusion: These results suggest that the use of a definition of MC of ≤-2 SDS would be appropriate in order not to miss cases on follow-up. Greater sociodemographic equality may prevent some cases of MC. Further studies are needed evaluating socioeconomic factors on MC. [ABSTRACT FROM AUTHOR]

Infections in the first trimester of pregnancy can be teratogenic, but the possibility that Covid-19 could lead to birth defects is unclear. We examined whether SARS-CoV-2 infection during pregnancy or exposure to pandemic conditions were associated with the risk of congenital anomalies. We carried out a retrospective study of 420,222 neonates born in Quebec, Canada in two time periods: prepandemic (January 1, 2017 to March 12, 2020) vs. pandemic (March 13, 2020 to March 31, 2022). We classified pandemic births as early (first trimester completed before the pandemic) or late (first trimester during the pandemic), and identified patients with SARS-CoV-2 infections during pregnancy. We applied (1) adjusted log-binomial regression models to assess the association between SARS-CoV-2 infection and congenital anomalies, and (2) autoregressive interrupted time series regression to analyze temporal trends in the monthly number of defects in all patients regardless of infection. In total, 29,263 newborns (7.0%) had a congenital anomaly. First trimester SARS-CoV-2 infections were not associated with a greater risk of birth defects compared with no infection (RR 1.07, 95% CI 0.59–1.95). However, births during the late pandemic period were more likely to be diagnosed with congenital microcephaly compared with prepandemic births (RR 1.44, 95% CI 1.21–1.71). Interrupted time series analysis confirmed that the frequency of microcephaly increased during the late pandemic period, whereas other anomalies did not. We conclude that Covid-19 is likely not teratogenic, but enhanced surveillance of anomalies among late pandemic births may have heightened the detection of infants with microcephaly. [ABSTRACT FROM AUTHOR]

UPF3B encodes the Regulator of nonsense transcripts 3B protein, a core‐member of the nonsense‐mediated mRNA decay pathway, protecting the cells from the potentially deleterious actions of transcripts with premature termination codons. Hemizygous variants in the UPF3B gene cause a spectrum of neuropsychiatric issues including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia/childhood‐onset schizophrenia (COS). The number of patients reported to date is very limited, often lacking an extensive phenotypical and neuroradiological description of this ultra‐rare syndrome. Here we report three subjects harboring UPF3B variants, presenting with variable clinical pictures, including cognitive impairment, central hypotonia, and syndromic features. Patients 1 and 2 harbored novel UPF3B variants—the p.(Lys207*) and p.(Asp429Serfs*27) ones, respectively—while the p.(Arg225Lysfs*229) variant, identified in Patient 3, was already reported in the literature. Novel features in our patients are represented by microcephaly, midface hypoplasia, and brain malformations. Then, we reviewed pertinent literature and compared previously reported subjects to our cases, providing possible insights into genotype–phenotype correlations in this emerging condition. Overall, the detailed phenotypic description of three patients carrying UPF3B variants is useful not only to expand the genotypic and phenotypic spectrum of UPF3B‐related disorders, but also to ameliorate the clinical management of affected individuals. [ABSTRACT FROM AUTHOR]

Brain organoids represent a useful tool for modeling of neurodevelopmental disorders and can recapitulate brain volume alterations such as microcephaly. To monitor organoid growth, brightfield microscopy images are frequently used and evaluated manually which is time-consuming and prone to observer-bias. Recent software applications for organoid evaluation address this issue using classical or AI-based methods. These pipelines have distinct strengths and weaknesses that are not evident to external observers. We provide a dataset of more than 1,400 images of 64 trackable brain organoids from four clones differentiated from healthy and diseased patients. This dataset is especially powerful to test and compare organoid analysis pipelines because of (1) trackable organoids (2) frequent imaging during development (3) clone diversity (4) distinct clone development (5) cross sample imaging by two different labs (6) common imaging distractors, and (6) pixel-level ground truth organoid annotations. Therefore, this dataset allows to perform differentiated analyses to delineate strengths, weaknesses, and generalizability of automated organoid analysis pipelines as well as analysis of clone diversity and similarity. [ABSTRACT FROM AUTHOR]

Pathogenic heterozygous loss of function variants in CTNNB1 are associated with CTNNB1 neurodevelopmental disorder. We report the clinical phenotype of individuals with CTNNB1 neurodevelopmental disorder using both caregiver‐reported data (medical history, adaptive function, quality of life, and behavior issues) and in‐person clinical assessments (neurological, motor, and cognitive function) in 32 individuals with likely pathogenic or pathogenic CTNNB1 variants. Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord. Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy. Half of individuals walked without an assistive device. The mean Gross Motor Functional Measure‐66 score was 56.6 (SD = 14.8). Average time to complete Nine‐Hole Peg Test was slower than norms. Mean general conceptual ability composite scores from Differential Ability Scales Second Edition were very low (M = 58.3, SD = 11.3). Fifty‐five percent of individuals had low adaptive functioning based on the Vineland Adaptive Behavioral Scales. Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges. The mean overall Quality of Life Inventory‐Disability score was 81.7 (SD = 11.9). These data provide a detailed characterization of clinical features in individuals with CTNNB1 neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

• The P2X7 receptor is upregulated in the brain of Zika virus-infected newborn mice. • ATP-P2X7 signaling triggers neuroinflammation and neuronal loss in Zika. • P2X7 receptor induces caspase-3 activation in the brain of Zika virus-infected newborn mice. • P2X7 receptor inhibits AKT/mTOR in the brain of Zika virus-infected newborn mice. • P2X7 receptor stimulates IFN-β signaling and viral control in Zika. Zika virus (ZIKV), the causative agent of Zika fever, is a flavivirus transmitted by mosquitoes of the Aedes genus. Zika virus infection has become an international concern due to its association with severe neurological complications such as fetal microcephaly. Viral infection can induce the release of ATP in the extracellular environment, activating receptors sensitized by extracellular nucleotides, such as the P2X7 receptor. This receptor is the primary purinergic receptor involved in neuroinflammation, neurodegeneration, and immunity. In this work, we investigated the role of ATP-P2X7 receptor signaling in Zika-related brain abnormalities. Wild-type mice (WT) and P2X7 receptor-deficient (P2X7-/-) C57BL/6 newborn mice were subcutaneously inoculated with 5 × 106 plaque-forming units of ZIKV or mock solution. P2X7 receptor expression increased in the brain of Zika virus-infected mice compared to the mock group. Comparative analyses of the hippocampi from WT and P2X7-/- mice revealed that the P2X7 receptor increased hippocampal damage in CA1/CA2 and CA3 regions. Doublecortin expression decreased significantly in the brains of ZIKV-infected mice. WT ZIKV-infected mice showed impaired motor performance compared to P2X7-/- infected mice. WT ZIKV-infected animals showed increased expression of glial markers GFAP (astrocytes) and IBA-1 (microglia) compared to P2X7-/- infected mice. Although the P2X7 receptor contributes to neuronal loss and neuroinflammation, WT mice were more efficient in controlling the viral load in the brain than P2X7 receptor-deficient mice. This result was associated with higher induction of TNF-α, IFN-β, and increased interferon-stimulated gene expression in WT mice than P2X7-/- ZIKV-infected. Finally, we found that the P2X7 receptor contributes to inhibiting the neuroprotective signaling pathway AKT/mTOR while stimulating the caspase-3 activation, possibly two distinct pathways contributing to neurodegeneration. These findings suggest that ATP-P2X7 receptor signaling contributes to the antiviral response in the brain of ZIKV-infected mice while increasing neuronal loss, neuroinflammation, and related brain abnormalities. [ABSTRACT FROM AUTHOR]

Loss-of-function mutation of ABCC9 , the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9 -related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction. [ABSTRACT FROM AUTHOR]

MCPH1 has been identified as the causal gene for primary microcephaly type 1, a neurodevelopmental disorder characterized by reduced brain size and delayed growth. As a multifunction protein, MCPH1 has been reported to repress the expression of TERT and interact with transcriptional regulator E2F1. However, it remains unclear whether MCPH1 regulates brain development through its transcriptional regulation function. This study showed that the knockout of Mcph1 in mice leads to delayed growth as early as the embryo stage E11.5. Transcriptome analysis (RNA-seq) revealed that the deletion of Mcph1 resulted in changes in the expression levels of a limited number of genes. Although the expression of some of E2F1 targets, such as Satb2 and Cdkn1c, was affected, the differentially expressed genes (DEGs) were not significantly enriched as E2F1 target genes. Further investigations showed that primary and immortalized Mcph1 knockout mouse embryonic fibroblasts (MEFs) exhibited cell cycle arrest and cellular senescence phenotype. Interestingly, the upregulation of p19ARF was detected in Mcph1 knockout MEFs, and silencing p19Arf restored the cell cycle and growth arrest to wild-type levels. Our findings suggested it is unlikely that MCPH1 regulates neurodevelopment through E2F1-mediated transcriptional regulation, and p19ARF-dependent cell cycle arrest and cellular senescence may contribute to the developmental abnormalities observed in primary microcephaly. [ABSTRACT FROM AUTHOR]

Background: Genetic microcephaly is linked to an increased risk of developmental disabilities, epilepsy, and motor impairment. The aim of this study is to describe the spectrum of identifiable genetic etiologies, clinical characteristics, and radiologic features of genetic microcephaly in patients referred to a tertiary center in Saudi Arabia. Method: This is a retrospective chart review study of all patients with identifiable genetic microcephaly presenting to a tertiary center in Saudi Arabia. The patients' demographics, clinical, laboratory, radiologic, and molecular findings were collected. Results: Of the total 128 cases referred, 52 cases (40%) had identifiable genetic causes. Monogenic disorders were found in 48 cases (92%), whereas chromosomal disorders were found in only 4 cases (8%). Developmental disability was observed in 40 cases (84%), whereas only 8 cases (16%) had borderline IQ or mild developmental delay. Epilepsy was seen in 29 cases (56%), and motor impairment was seen in 26 cases (50%). Brain magnetic resonance imaging (MRI) revealed abnormalities in 26 (50%) of the cohort. Hereditary neurometabolic disorders were seen in 7 (15%) of the 48 cases with monogenic disorders. The most common gene defect was ASPM, which is responsible for primary microcephaly type 5 and was seen in 10 cases (19%). A novel PLK1 gene pathogenic mutation was seen in 3 cases (6%). Conclusion: Single gene defect is common in this Saudi population, with the ASPM gene being the most common. Hereditary neurometabolic disorders are a common cause of genetic microcephaly. Furthermore, we propose the PKL1 gene mutation as a possible novel cause of genetic microcephaly. [ABSTRACT FROM AUTHOR]

Aim: Nijmegen breakage syndrome (NBS) is an autosomal recessive DNA repair disorder which is characterized by immunodeficiency and increased risk of lymphoproliferative malignancy. Case: We observed an increase in the rate of chromosomal rearrangements in the cultured cells following an incidental radiograph for craniosynostosis in a newborn who was followed up due to microcephaly. We identified a homozygous deletion of c.657_661delACAAA/p.Lys219fs (rs587776650) in the NBN gene through whole exome sequencing. Conclusion: It is crucial to thoroughly examine the clinical features of newborns with microcephaly and consider chromosomal instability syndromes just like Nijmegen breakage syndrome. Not overlooking radiosensitivity, which is a characteristic feature of this syndrome, is a vital condition to the patient's survival time. [ABSTRACT FROM AUTHOR]

DYRK1A, a ubiquitously expressed kinase, is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of DYRK1A in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the Drosophila neuromuscular junction as a model, we show that the mnb, the fly homologs of DYRK1A, is rescued by RHEB overexpression, suggesting a conserved role of DYRK1A in TORC1 regulation.