Protein Phosphatase 2ACα Regulates ATR-Mediated Endogenous DNA Damage Response Against Microcephaly.

Protein phosphatase 2A (PP2A) is an abundant heterotrimeric holoenzyme in eukaryotic cells coordinating with specific kinases to regulate spatial-temporal protein dephosphorylation in various biological processes. However, the function of PP2A in cortical neurogenesis remains largely unknown. Here, we report that neuronal-specific deletion of Pp2acα in mice displayed microcephaly, with significantly smaller brains and defective learning and memory ability. Mechanistically, neuronal Pp2acα deficiency resulted in elevated endogenous DNA damage and activation of ATR/CHK1 signaling. It was further induced by the loss of direct interaction between PP2AC and ATR as well as the function of PP2AC to dephosphorylate ATR. Importantly, ATR/CHK1 signaling dysregulation altered both the expression and activity of several critical downstream factors including P53, P21, Bcl2, and Bax, which led to decreased proliferation of cortical progenitor cells and increased apoptosis in developing cortical neurons. Taken together, our results indicate an essential function of PP2ACα in endogenous DNA damage response-mediated ATR signaling during neurogenesis, and defective PP2ACα in neurons contributes to microcephaly.

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease. METHODS: We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

Feeding practices and weight status of children with congenital Zika syndrome: A longitudinal study in Brazil.

OBJECTIVE: The objective of this study was to describe feeding practices and weight status in a cohort of children with congenital Zika syndrome (CZS) in northeastern Brazil. METHODS: This longitudinal study of children with CZS (N = 156) included data collection on child feeding practices and weight status at five timepoints between 2018 and 2022. The average age of the children was 32.1 months at enrollment and 76.6 months at the fifth assessment. Multilevel models, with repeated observations nested within children, were used to estimate time-related differences in each outcome. RESULTS: Use of enteral feeding, such as gastrostomy, increased from 19.2% to 33.3% over 4 years (p < .001). Among children who did not exclusively use an enteral feeding method, the percentage experiencing at least one dysphagia-associated behavior, such as coughing or gagging, increased from 73.9% to 85.3% (p = .030) while consuming liquids and from 36.2% to 73.5% (p = .001) while consuming solids. Based on weight-for-age z-scores, the percentage of children who were moderately or severely underweight increased from 42.5% to 46.1% over the 4 years but was not statistically significant. Children exclusively using an enteral feeding method had significantly decreased odds of being underweight at assessments 3, 4, and 5. CONCLUSIONS: These data highlight the ongoing and increasing challenges of feeding young children with CZS. Our findings elucidate the physiological reasons children with CZS may be underweight and point to intervention targets, such as enteral feeding, to improve their feeding practices.

Zika Virus Neuropathogenesis-Research and Understanding.

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.

Serious Concern of Congenital Zika Syndrome (CZS) in India: A Narrative Review.

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.

Pregnant women's perceptions on Information Sources on Zika Virus: a qualitative study.

The Zika virus (ZIKV) epidemic had a sanitary, psychosocial, and economic impact on individuals of reproductive age. The primary concern revolved around infection during pregnancy due to possible vertical transmission and its association with adverse fetal and infant outcomes, known as Congenital Zika Syndrome (CZS). This qualitative study employs phenomenology and grounded theory. This study includes interviews with 98 women, some pregnant during the ZIKV epidemic in Brazil, Colombia, and Puerto Rico, who had children with CZS or without diagnosed neurological impairment. Additionally, the study included a group of women who were pregnant during the COVID-19 pandemic in these same countries. In both groups, interviewees had varying levels of knowledge about ZIKV. The study found that messages conveyed through the media tended to be alarmist, in contrast to the information provided by healthcare professionals, which was considered more trustworthy. Pregnant women during the ZIKV epidemic reported receiving their ZIKV and CSZ infection diagnoses late, either during or after childbirth. The study underscores the needs of pregnant women in high-risk scenarios, the importance of health education processes, and the necessity to reinforce communication and continuing education.

A epidemia do vírus Zika (ZIKV) teve impacto sanitário, psicossocial e econômico sobre pessoas em idade reprodutiva. A principal preocupação foi a infecção durante a gravidez devido a possível transmissão vertical e sua associação com resultados fetais e infantis adversos, conhecida como síndrome congênita associada à infecção pelo Vírus Zika (SCZ). Este estudo qualitativo utiliza a fenomenologia e a teoria fundamentada. O estudo inclui entrevistas com 98 mulheres, parte grávida durante a epidemia de ZIKV no Brasil, Colômbia e Porto Rico e que tiveram filhos com SCZ ou sem comprometimento neurológico diagnosticado. Além disso, o estudo inclui um grupo de mulheres grávidas durante a pandemia de COVID-19 nos mesmos países. Em ambos os grupos, as entrevistadas tinham diferentes níveis de conhecimento sobre ZIKV. O estudo constatou que as mensagens veiculadas por meio da mídia eram alarmistas; em contraste com as informações fornecidas por profissionais de saúde, consideradas mais confiáveis. Mulheres gestantes durante a epidemia do ZIKV relataram ter recebido seu diagnóstico de infecção por ZIKV e SCZ tardiamente ou após o parto. O estudo destaca as necessidades das mulheres grávidas em cenários de alto risco, a importância de processos de educação em saúde e a necessidade de reforçar a comunicação e a educação continuada.

Expanding the clinical phenotype and variant spectrum associated with RFX7.

RFX7 encodes a transcription factor that is ubiquitously expressed and important for neural development. Haploinsufficiency of RFX7 is associated with intellectual disability, developmental delay, and diverse malformations of brain structures. Currently, there are only 16 clinically described individuals who have variants in RFX7. A recognizable pattern of malformation associated with mutation in RFX7 has not yet been uncovered. Here we describe the phenotypic presentation of two additional individuals who have novel de novo variants in RFX7. One of the individuals we describe is from an under-represented Afro-Caribbean population.

Argentine and World Health Organization head circumference standards: A comparison study. / Estándares de perímetro cefálico argentinos y de la Organización Mundial de la Salud: estudio comparativo.

Introduction. Several studies have shown population differences in head circumference (HC) that question the universal validity of the World Health Organization (WHO) standard to assess head growth. Objectives. To compare the Argentine reference charts for HC from 0 to 5 years of age with the WHO standards. Population and methods. The 3rd and 97th percentiles for HC based on the Argentine reference charts were compared with the corresponding WHO standard and the percentage of children classified as having microcephaly (HC < 3rd percentile of the WHO) and macrocephaly (HC > 97th percentile of the WHO) at specific ages between 0 and 5 years were estimated. Results. The comparison of the Argentine reference charts with the WHO standards shows that, in both males and females, at the 3rd percentile, the Argentine reference charts are below the WHO standards from 1 to 6 months of age, similar from 9 to 18 months of age, and then above until 60 months old. In relation to the 97th percentile, the Argentine reference charts are above the WHO standards from birth to 60 months in both boys and girls. Conclusions. The head size of Argentine children is different from that established by the WHO standards. The adoption of the WHO standards for our population increases the percentage of macrocephaly diagnosis at all ages.

Introducción. Diversos estudios han evidenciado diferencias poblacionales en el tamaño cefálico que cuestionan la validez universal del estándar de la Organización Mundial de la Salud (OMS) para evaluar el crecimiento cefálico. Objetivos. Comparar las referencias argentinas de perímetro cefálico (PC) de 0 a 5 años con los estándares de la OMS. Población y métodos. Se compararon los percentiles 3 y 97 de PC de las referencias argentinas con los correspondientes del estándar de la OMS y se calcularon los porcentajes de niños clasificados como microcefálicos (PC < percentil 3 de la OMS) y macrocefálicos (PC > percentil 97 de la OMS) a edades específicas entre el nacimiento y los 5 años de edad. Resultados. La comparación de las referencias argentinas con los estándares de la OMS, muestra que ­en ambos sexos­ en el percentil 3, desde el primer mes y hasta los 6 meses, las referencias argentinas se encuentran por debajo de los estándares de la OMS, son similares entre los 9 y 18 meses, y luego se ubican por encima hasta los 60 meses. En relación con el percentil 97, las referencias argentinas se ubican por encima de los estándares de la OMS desde el nacimiento hasta los 60 meses en ambos sexos. Conclusiones. El tamaño cefálico de los niños y niñas argentinos difiere del de los estándares de la OMS. La adopción de los estándares de la OMS en nuestra población incrementa el porcentaje de diagnóstico de macrocefalia a todas las edades.

Pontocerebellar Hypoplasia Type 9: A Case Study Highlighting Distinctive Magnetic Resonance Imaging Features.

Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it presents distinctive clinical and neuroradiological features. Diagnosing it is challenging yet crucial for appropriate management. We describe a 21-month-old boy with clinical and neuroradiological manifestations of the diagnosis, including characteristic signs such as an eight-configured midbrain and hypoplasia of the brainstem and cerebellar structures. Genetic evaluation confirmed homozygous missense mutations in the AMPD2 gene. This case highlights the pathognomonic neuroradiological features of pontocerebellar hypoplasia type 9 that point toward diagnosis.

Gamma-Tubulin 1 (TUBG1) Mutation-Associated Lissencephaly and Microcephaly in an Indian Child: A Rare Case.

Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in psychomotor development and epilepsy in children. Lissencephaly (smooth brain) forms a major group of brain malformations. Microtubules help in the migration of neuronal cells. Defect in tubulin gene alpha-tubulin (TUBA), beta-tubulin (TUBB), and gamma-tubulin (TUBG) leads to defective neuronal migration. This group of disorders is termed as "tubulinopathies." The important genes implicated in causing lissencephaly are LIS1, XLIS, and TUBA1A gene. Recently, a mutation in the TUBG1 gene is associated with it. Here, we report a one-and-a-half-year-old girl with global developmental delay, microcephaly, infantile-onset epilepsy, epileptic spasms, dysmorphism, and motor signs. There was no significant birth history. Neuroimaging (MRI) showed a broad thick gyri and a decreased number of sulci suggestive of lissencephaly/pachygyria spectrum. There was dilatation of the ventricles, and no grey matter heterotopia was noted. Sleep EEG showed multifocal epileptiform discharges. The child was treated with multiple anti-seizure medicines (ASMs). A genetic test, whole exome sequencing, was done to determine the etiology of MCD. A heterozygous missense variation in exon 6 of the TUBG1 gene was identified and reported as a "variant of unknown significance." Still, because the genotype matched with the clinical phenotype of the patient, it was considered clinically significant. Therefore, a complete diagnosis of TUBG1 mutation-associated cortical malformation (lissencephaly/pachygyria) with microcephaly and early-onset epilepsy was established. TUBG1 mutation is de novo in most cases, but parental testing is recommended. The parents of such patients need to be counseled about the need for prenatal testing and the risk of the disease to siblings. The overall prognosis in such cases is poor because of refractory seizures, physical limitations, and intellectual disability.

Craniosynostosis Associated With Novel TUBG1 Mutation (NM_001070.4:c.821C>T) (p.Thr274Ile).

TUBG1, a tubulin gene, plays an important role in neurodevelopment. Here we describe a case of a novel TUGB1 mutation (NM_001070.4:c.821C>T) (p.Thr274Ile). This patient presented similarly to previous cases with features including microcephaly, epilepsy, and speech and motor delay. Unique characteristics were also present such as trigonocephaly, tethered frenulum, scoliosis, nystagmus, and a concurrent FBXW7 mutation. This case expands our breadth of knowledge on TUBG1 genotypic and phenotypic variation. However, further work is needed to fully understand this rare mutation and the associations between TUBG1 and FBXW7 mutations.

Intranasal Immunization for Zika in a Pre-Clinical Model.

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.

Long-Term Disease Course of Pontocerebellar Hypoplasia Type 10.

BACKGROUND: Pontocerebellar hypoplasia type 10 (PCH10) due to CLP1 gene mutations is characterized by structural brain anomalies, progressive microcephaly, severe intellectual and physical disabilities, and spasticity. In this follow-up study, evolution of phenotypic and neurological characteristics of patients with PCH10 is discussed. METHODS: Phenotype, growth parameters, motor functions, developmental tests, spasticity assessments, functional independence assessments, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) of 10 patients with PCH10 were monitored on separate examinations. Alterations were recorded. RESULTS: Patients were followed-up for an average of 2.83 years. The tone of the upper extremities was significantly higher than that of the lower extremities, according to Modified Ashworth Scale (MAS) values. Sixty percent of patients could sit unsupported; 20% achieved supported sitting initially but lost the ability during follow-up. Absence of grabbing or sitting was observed in 20% of patients. During follow-up, one person achieved supported sitting and one person achieved head holding. Only one patient was able to speak a few words. Cerebellar atrophy (two of 10), pons hypoplasia (four of 10), cortical atrophy (seven of 10), enlarged ventricles (10 of 10), thinning of the corpus callosum (10 of 10), hypomyelination (six of 10), and increased white matter signal intensity (six of 10) were the observed MRI findings. CONCLUSIONS: Progressive cerebral and cerebellar atrophy was demonstrated radiologically for the first time in a PCH10 cohort. It is of crucial importance to identify these patients promptly with the help of dysmorphic findings and spasticity being pronounced in the upper extremities. Furthermore, we note that phenotypic and neurological examination findings tend to change slightly over time.

Epilepsy as a Novel Phenotype of BPTF-Related Disorders.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Novel Mutation in the HSD17B10 Gene Accompanied by Dysmorphic Findings in Female Patients.

Introduction: Hydroxysteroid 17-beta dehydrogenase type 10 (HSD10) protein is a mitochondrial enzyme. Multisystemic involvement occurs in HSD10 deficiency as in other mitochondrial diseases. HSD10 deficiency (disease) is rare. Less than 40 index cases have been reported so far. A female patient is even rarer because of X-linked transmission. Five index female cases have been reported. Case Presentation: We report a three-year-old female patient who was investigated due to microcephaly and global developmental delay. She had significant dysmorphic findings. The tiglylglycine peak was detected in urinary organic acid analysis. Other metabolic investigations and laboratory tests were unremarkable. Mild cerebral atrophy, mild ventricular dilation, thin corpus callosum, and an increase in T2 signal in the globus pallidus were revealed at brain magnetic resonance imaging. Heterozygous novel mutation in the HSD17B10 gene was found by whole-exome sequencing (WES) analysis. We started isoleucine-restricted diet and a "cocktail" of the mitochondrial vitamin. Discussion/Conclusion: We will see HSD10 disease patients more frequently with the increasing use of WES and genetic panels. Thus, different findings and phenotypes of the HSD10 disease will be revealed.

Clinical Presentation and Molecular Characterization of 3 Patients with Vici Syndrome: Two Novel Variants in the EPG5 Gene.

Introduction: Vici syndrome is an ultra-rare, congenital disorder of autophagy characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Patients usually present in the neonatal period or infancy with profound hypotonia, based on information available from the nearly 100 cases reported to date. Case Presentation: We present 3 new cases of Vici syndrome confirmed by genetic analysis of EPG5 gene. The 3 male patients had neonatal hypotonia, progressive microcephaly, psychomotor retardation, recurrent respiratory tract infections, optic atrophy, and failure to thrive, but no cataracts or hepatomegaly. Three disease-causing variants in homozygous state were detected in the EPG5 gene: two novel c.1652C>T and c.7557+2T>C forms; and one previously reported c.7447C>T. The patient, who was homozygous for the c.1652C>T mutation, presented with neonatal onset seizures that had not been reported previously. Discussion/Conclusion: The present study provides data for the evaluation of the natural history and genotype-phenotype correlations for treatment options that are expected to be available in the future.

Molecular genetics, neuroimaging outcomes, and structural analyses of novel and recurrent variants of WDR62 gene in two consanguineous Pakistani families with autosomal recessive primary microcephaly.

BACKGROUND: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental and genetically heterogeneous disorder, characterized by small cranium size (> - 3 SD below mean) and often results in varying degree of intellectual disability. Thirty genes have been identified for the etiology of this disorder due to its clinical and genetic heterogeneity. METHODS AND RESULTS: Here, we report two consanguineous Pakistani families affected with MCPH exhibiting mutation in WDR62 gene. The investigation approach involved Next Generation Sequencing (NGS) gene panel sequencing coupled with linkage analysis followed by validation of identified variants through automated Sanger sequencing and Barcode-Tagged (BT) sequencing. The molecular genetic analysis revealed one novel splice site variant (NM_001083961.2(WDR62):c.1372-1del) in Family A and one known exonic variant NM_001083961.2(WDR62):c.3936dup (p.Val1313Argfs*18) in Family B. Magnetic Resonance Imaging (MRI) scans were also employed to gain insights into the structural architecture of affected individuals. Neurological assessments showed the reduced gyral and sulcal patterns along with normal corpus callosum in affected individuals harboring novel variant. In silico assessments of the identified variants were conducted using different tools to confirm the pathogenicity of these variants. Through In silico analyses, both variants were identified as disease causing and protein modeling of exonic variant indicates subtle conformational alterations in prophesied protein structure. CONCLUSION: This study identifies a novel variant (c.1372-1del) and a recurrent pathogenic variant c.3936dup (p.Val1313Argfs*18) in the WDR62 gene among the Pakistani population, expanding the mutation spectrum for MCPH. These findings emphasize the importance of genetic counseling and awareness to reduce consanguinity and address the burden of this disorder.

TNF-α blockage prevents late neurological consequences of Zika virus infection in mice.

Zika virus (ZIKV) is a neurotropic Orthoflavivirus that causes a myriad of neurological manifestations in newborns exposed in uterus. Despite the devastating consequences of ZIKV on the developing brain, strategies to prevent or treat the consequences of viral infection are not yet available. We previously showed that short-term treatment with the TNF-α neutralizing monoclonal antibody. Infliximab could prevent seizures at acute and chronic stages of ZIKV infection, but had no impact on long-term cognitive and motor dysfunction. Due to the central role of inflammation in ZIKV-neuropathology, we hypothesized that prolonged treatment with the anti-TNF-α monoclonal antibody Infliximab could provide complete rescue of long-term behavioral deficits associated with neonatal ZIKV infection in mice. Here, neonatal (post-natal day 3) Swiss mice were submitted to subcutaneous (s.c.) injection of 106 PFU of ZIKV or mock medium and were then treated with Infliximab (20 µg/day) or sterile saline intraperitoneally (i.p.), for 40 days starting on the day of infection, and behavioral assessment started at 60 days post-infection (dpi). Infliximab prevented ZIKV-induced cognitive and motor impairments in mice. In addition, microgliosis and cell death found in mice following ZIKV infection were partially reversed by TNF-α blockage. Altogether, these results suggest that TNF-α-mediated inflammation is central for late ZIKV-induced behavioral deficits and cell death and strategies targeting this cytokine may be promising approaches to treat subjects exposed to the virus during development.

Genetic Microcephaly in a Saudi Population: Unique Spectrum of Affected Genes Including a Novel One.

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.

Low-intensity ultrasound ameliorates brain organoid integration and rescues microcephaly deficits.

Human brain organoids represent a remarkable platform for modeling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses reveal that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays reveal that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage.