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Background: The ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease characterized by cerebral anomalies. These patients have congenital microcephaly, progressive encephalopathy, severe intellectual disability, and intractable seizures. Method: Clinical characteristics of the patient were collected. Exome sequencing was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. The structure of the protein was checked using the DynaMut2 web server. Results: The proband is an 11‐year‐old Iranian‐Azeri girl with primary microcephaly and severe intellectual disability in a family with a consanguineous marriage. Symptoms emerged around the 10–20th days of life, when refractory epileptic gaze and unilateral tonic–clonic seizures initiated without any provoking factor such as fever. A brain MRI revealed no abnormalities except for brain atrophy. The karyotype was normal. Using exome sequencing, we identified a novel homozygous variant of thymine to adenine (NM_001673.5:c.538T>A) in the ASNS gene. Both parents had a heterozygous variant in this location. Subsequently, Sanger sequencing confirmed this variant. We also reviewed the clinical manifestations and MRI findings of the previously reported patients. Conclusion: In the present study, a novel homozygous variant was recognized in the ASNS gene in an Iranian‐Azeri girl manifesting typical ASNSD symptoms, particularly intellectual disability and microcephaly. This study expands the mutation spectrum of ASNSD and reviews previously reported patients. [ABSTRACT FROM AUTHOR]

Background: Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain containing 2 gene (EFTUD2, OMIM* 603892). It is characterized by mandibulofacial dysplasia, microcephaly, malformed ears, cleft palate, growth and intellectual disability. MFDM can be easily misdiagnosed due to its phenotypic overlap with other craniofacial dysostosis syndromes. The clinical presentation of MFDM is highly variable among patients. Methods: A patient with craniofacial anomalies was enrolled and evaluated by a multidisciplinary team. To make a definitive diagnosis, whole‐exome sequencing was performed, followed by validation by Sanger sequencing. Results: The patient presented with extensive facial bone dysostosis, upward slanting palpebral fissures, outer and middle ear malformation, a previously unreported orbit anomaly, and spina bifida occulta. A novel, pathogenic insertion mutation (c.215_216insT: p.Tyr73Valfs*4) in EFTUD2 was identified as the likely cause of the disease. Conclusions: We diagnosed this atypical case of MFDM by the detection of a novel pathogenetic mutation in EFTUD2. We also observed previously unreported features. These findings enrich both the genotypic and phenotypic spectrum of MFDM. [ABSTRACT FROM AUTHOR]

Background: Phosphoserine aminotransferase deficiency (PSATD) is an autosomal recessive disorder associated with hypertonia, psychomotor retardation, and acquired microcephaly. Patients with PSATD have low concentrations of serine in plasma and cerebrospinal fluid. Methods: We reported a 2‐year‐old female child with developmental delay, dyskinesia, and microcephaly. LC–MS/MS was used to detect amino acid concentration in the blood and whole‐exome sequencing (WES) was used to identify the variants. PolyPhen‐2 web server and PyMol were used to predict the pathogenicity and changes in the 3D model molecular structure of protein caused by variants. Results: WES demonstrated compound heterozygous variants in PSAT1, which is associated with PSATD, with a paternal likely pathogenic variant (c.235G>A, Gly79Arg) and a maternal likely pathogenic variant (c.43G>C, Ala15Pro). Reduced serine concentration in LC–MS/MS further confirmed the diagnosis of PSATD in this patient. Conclusions: Our findings demonstrate the importance of WES combined with LC–MS/MS reanalysis in the diagnosis of genetic diseases and expand the PSAT1 variant spectrum in PSATD. Moreover, we summarize all the cases caused by PSAT1 variants in the literature. This case provides a vital reference for the diagnosis of future cases. [ABSTRACT FROM AUTHOR]

Background: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized primarily by congenital microcephaly and intellectual disability but without extra-central nervous system malformations. This investigation aimed to elucidate the genetic underpinnings of microcephaly in a patient from a Chinese consanguineous family. Methods: A comprehensive clinical assessment, including brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic analyses, was conducted to evaluate the patient's condition. Whole-exome sequencing (WES) was employed to identify the causative gene, followed by Sanger sequencing, to confirm the mutation and its segregation within the family. Reverse transcript polymerase chain reaction (RT-PCR) was utilized to detect changes in splicing. Western blot was employed to reveal the difference of protein expression level between the wild-type and mutant WDR62 in vitro. Results: The patient exhibited classic MCPH symptoms, including microcephaly, recurrent epilepsy, delayed psychomotor development, and intellectual disability. Additionally, asymmetrical limb length was noted as a prominent feature. MRI findings indicated reduced brain volume with cortical malformations, while EEG demonstrated heightened sharp wave activity. A molecular analysis uncovered a novel homozygous variant c.4154-6 C > G in the WDR62 intron, and a functional analysis confirmed the pathogenicity of this mutation, resulting in the formation of an abnormal transcript with premature termination codons. Conclusion: This study enhances our understanding of the genetic heterogeneity associated with MCPH and highlights the pivotal role of genetic testing in the diagnosing and managing of rare neurodevelopmental disorders. Furthermore, it highlights the potential of emerging genetic therapies in treating conditions such as MCPH2. [ABSTRACT FROM AUTHOR]

Feeding disorders of infancy are common in paediatric practice. Among rare causes of this disturbance is diabetes insipidus (DI), which is a clinical syndrome characterized by polyuria, polydypsia and dehydration with hypernatraemia. Central diabetes insipidus (CDI, vasopressin deficiency) is more common in children than nephrogenic diabetes insipidus (NDI, an inability to respond adequately to vasopressin). Regardless of the type of DI, the main goal of treatment is to decrease thirst and urine output and achieve proper ion and fluid balance. We present three cases of infants with feeding difficulties. The first two cases concerned patients with semilobar holoprosencephaly (HPE). Their stories show the importance of knowing the most common abnormalities associated with HPE, such as CDI. The third child had similar problems with feeding which resembled a defect of the central nervous system, but was finally diagnosed as NDI. The diagnostic and therapeutic approach is demonstrated in the paper with special regards to safe management of hypernatraemic dehydration. [ABSTRACT FROM AUTHOR]

Objective: Genetic variants in EFTUD2 were proven to influence variable phenotypic expressivity in mandibulofacial dysostosis Guion-Almeida type (MFDGA) or mandibulofacial dysostosis with microcephaly (MFDM). Yet, the association between the severity of clinical findings with variants within the EFTUD2 gene has not been established. Thus, we aim to elucidate a possible genotype–phenotype correlation in MFDM. Methods: Forty articles comprising 156 patients were evaluated. The genotype–phenotype correlation was analyzed using a chi-square or Fisher's exact test. Results: The proportion of patients with MFDM was higher in Caucasian relative to Asian populations. Although, in general, there was no apparent genotype–phenotype correlation in patients with MFDM, Asians tended to have more severe clinical manifestations than Caucasians. In addition, cardiac abnormality presented in patients with intronic variants located in canonical splice sites was a predisposing factor in affecting MFDM severity. Conclusion: Altogether, this article provides the pathogenic variants observed in EFTUD2 and possible genotype–phenotype relationships in this disease. [ABSTRACT FROM AUTHOR]

Microcephaly, a form of cortical cortex malformation, results from abnormal cellular production and proliferation, identified when the occipital frontal head circumference (OFC) falls two or more standard deviations (SDs) below the expected average for age, gender, and population. Severity is classified based on SD: mild (OFC < 2 SD) or severe (OFC < 3 SD). While microcephaly can lead to developmental delay, intellectual disability, epilepsy, and cerebral palsy, not all cases exhibit these issues. Classified as primary/congenital or secondary/postnatal, microcephaly can stem from genetic or acquired factors in both types. Congenital microcephaly origins vary, while secondary microcephaly is characterized by normal OFC at birth, followed by a decrease within the first year, often associated with progressive cognitive and motor impairments. Primary hereditary microcephaly (MCPH), or microcephaly vera, is genetically diverse, with 28 related genes (MCPH1 to MCPH28) encoding proteins linked to centrosomes and progenitor cell mitosis in the brain ventricle's neuroepithelium. Defects in deoxyribonucleic acid (DNA) repair pathways (e.g., NBN , FANCA , ATR , ATM genes) can lead to microcephaly by impairing DNA repair. Enzyme deficiencies in metabolic pathways may also contribute, causing toxic metabolite accumulation or essential metabolite loss (microcephaly of metabolic origin). Acquired congenital microcephaly may result from ischemic or infectious processes, drugs, radiation, maternal diseases during pregnancy, with damage influenced by fetal genetics, environmental interactions, developmental stage, and exposure intensity/duration. Diagnostic workup includes electroencephalogram, ophthalmological, auditory, magnetic resonance imaging, metabolic, echocardiogram, and infection screening tests, alongside genetic evaluations like cytogenetic studies, fluorescence in situ hybridization, comparative genomic microarray-hybridization, single-nucleotide microarray-polymorphism, and exome sequencing. Symptomatic treatment is available, and genetic counseling is crucial for affected families. [ABSTRACT FROM AUTHOR]

Microcephaly, in addition to craniofacial disproportion, can lead to skeletal muscle dysfunctions in the foetus, hearing and visual alterations, as well as seizures and epilepsy. It is additionally important to note that the oral health of these children can be compromised due to the difficulty in controlling mouth movements and chewing. Children have been taking anticonvulsant drugs to control seizures and epilepsy since the first year of life. But will children with microcephaly who take these drugs long term have oral manifestations from these substances? Could the delay in dental development be related to a possible excess of gingival growth, preventing tooth eruption? Based on these questions, five clinical cases of children with severe microcephaly, aged between seven and eight years in the mixed dentition stage, are presented, focusing on gingival health and dental development. [ABSTRACT FROM AUTHOR]

The past decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders, including Mendelian, de novo, and somatic factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions to support novel therapies. Stem cell-based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror disease-relevant aspects of cellular complexity and developmental timing. These models have brought key insights into neurodevelopmental disorders as diverse as microcephaly, autism, and focal epilepsy. However, intrinsic organoid-to-organoid variability, low levels of certain brain-resident cell types, and long culture times required to reach maturity can impede progress. Several recent advances incorporate specific morphogen gradients, mixtures of diverse brain cell types, and organoid engraftment into animal models. Together with nonhuman primate organoid comparisons, mechanisms of human neurodevelopmental disorders are emerging.

BackgroundLittle research has been conducted on the impact of the coronavirus disease 2019 (COVID-19) pandemic on either birth outcomes or the ability of archival medical records to accurately capture these outcomes. Our study objective is thus to compare the prevalence of preterm birth, stillbirth, low birth weight (LBW), small for gestational age (SGA), congenital microcephaly, and neonatal bloodstream infection (NBSI) before and during the first wave of the COVID-19 pandemic in Kinshasa, Democratic Republic of Congo (DRC).MethodsWe conducted a facility-based retrospective cohort study in which identified cases of birth outcomes were tabulated at initial screening and subcategorized according to level of diagnostic certainty using Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) definitions. Documentation of any birth complications, delivery type, and maternal vaccination history were also evaluated. The prevalence of each birth outcome was compared in the pre-COVID-19 (i.e., July 2019 to February 2020) and intra-COVID-19 (i.e., March to August 2020) periods via two-sample z-test for equality of proportions.ResultsIn total, 14,300 birth records were abstracted. Adverse birth outcomes were identified among 22.0% and 14.3% of pregnancies in the pre-COVID-19 and intra-COVID-19 periods, respectively. For stillbirth, LBW, SGA, microcephaly, and NBSI, prevalence estimates were similar across study periods. However, the prevalence of preterm birth in the intra-COVID-19 period was significantly lower than that reported during the pre-COVID-19 period (8.6% vs. 11.5%, p

Abstract Background The hallmarks of Emanuel syndrome are pre- and postnatal growth retardation, microcephaly, global developmental delay, ear anomalies, and in males, heart, kidney, and genital abnormalities. Results This study describes the atypical features of Emanuel syndrome, a rare chromosomal disorder. The patient had several physical features that are common in Emanuel syndrome, such as microcephaly, hypotonia, and ear anomalies. However, he exhibited certain unusual characteristics, including the lack of a prominent forehead, epicanthic folds, and a downward slanting palpebral fissure. There was infratentorial brain involution with a minor infarction in the left cerebral hemisphere and cerebellar hypoplasia on the magnetic resonance imaging (MRI) scan of the brain. Additionally, the patient had bilateral mild hearing loss and an aberrant epileptogenic pattern on the electroencephalogram (EEG). Orodental examination showed a long philtrum, everted fissured thick lower lip, highly attached labial frenum, and prominent median palatine raphe. The karyotype revealed 45XY t(11;22)(p15.5;q11.22), which is different from the typical karyotype of Emanuel syndrome. Conclusions This case sheds light on the possibility of alternative genetic mechanisms, beyond chromosomal abnormalities, in patients presenting with multiple congenital anomalies and facial dysmorphism.

Abstract Introduction Adverse birth outcomes particularly preterm births and congenital anomalies, are the leading causes of infant mortality globally, and the burden is highest in developing countries. We set out to determine the frequency of adverse birth outcomes and the risk factors associated with such outcomes in a cohort of pregnant women in Kenya. Methods From October 2017 to July 2019, pregnant women

Aim: A Zika virus outbreak that began in Brazil, developed into an international public health emergency that extended from February 2015 until November 2016. Zika-infected pregnant women gave birth to a cohort of infants with congenital Zika syndrome (CZS) originally defined by severe microcephaly, retinal scarring, joint deformities, and hypertonia. This study examines the nature, extent, and severity of all CZS clinicopathologic findings described to date, compiled and analyzed by system. It reviews studies monitoring disease progression and proposing classification schemes for CZS stages. The teratogenic cellular and molecular mechanisms implicated in CZS pathogenesis are also discussed. Methods: A systematic review was conducted by literature search through WorldCat.org and ProQuest Central databases to identify studies on case series from the 2015–2016 CZS outbreak. Results: Twenty-six reports were included describing radiologic, ophthalmologic, audiologic, orthopedic, and laboratory test results in CZS cases including stillborns between 2016 and 2023. CZS neuropathology included prenatal and postnatal microcephaly, cerebral calcifications, quadriparesis, epilepsy, ventriculomegaly, reduced cerebral parenchyma, malformation of cortical development, and sleep electroencephalogram disturbances. Visual deficits were due to retinal and optic nerve lesions. Conductive and sensorineural hearing deficits were stable. Hypertonia, hypotonia, and spasticity with foot, hip, knee, and shoulder deformities resulted in arthrogryposis and restricted joint mobility. There was enlargement of immune organs, increased leukocyte counts, and cytokine dysregulation. Oro-craniofacial deformities affected the midface and caused dental eruption delay. Additional studies proposed that these systemic teratogenic effects could be attributable to transplacental Zika virus infection of multiple fetal progenitor cell lineages. Conclusions: The CZS-associated impairments in brain, eye, musculoskeletal, and immunologic functions caused disabilities that varied from moderate to severe, and significantly increased age-specific mortality rates. Further research is warranted to assess progression, classify stages, elucidate the precise molecular mechanisms mediating Zika teratogenicity, develop suitable therapeutic strategies, and design supportive social policies.

Microcephaly is a sign, not a diagnosis. Its incidence varies widely due to the differences in the definition and the population being studied. It is strongly related to neurodevelopmental disorders. Differences in definitions and measurement techniques between fetuses and newborns pose a great challenge for the diagnosis and prognostication of fetal microcephaly. A false positive diagnosis can result (in countries where it is legal) in erroneous termination of pregnancy, where a false negative diagnosis might lead to the birth of a microcephalic newborn. Microcephaly in growth restricted fetuses deserves special attention and separate evaluation as it is an important prognostic factor, and not necessarily part of the general growth retardation. Several genetic syndromes incorporating microcephaly and intrauterine growth retardation (IUGR) are discussed. Deceleration of the head circumference (HC) growth rate even when the HC is still within normal limits might be the only clue for developing microcephaly and should be considered during fetal head growth follow up. Combining additional parameters such as a positive family history, associated anomalies, and new measurement parameters can improve prediction in about 50% of cases, and thus should be part of the prenatal workup. Advances in imaging modalities and in prenatal genetic investigation along with the emergence of new growth charts can also improve diagnostic accuracy. In this article, we review the different definitions and etiologies of fetal microcephaly, discuss difficulties in diagnosis, investigate the reasons for the low yield of prenatal diagnosis, and provide improvement suggestions. Finally, we suggest an updated algorithm that will aid in the diagnosis and management of fetal microcephaly. [ABSTRACT FROM AUTHOR]

Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, microcephaly, nonspecific brain malformations, hypotonia and seizures. Four individuals carry missense variants (three of them detected de novo) and three individuals carry null variants (two of them maternally inherited). Molecular modeling of the heterozygous missense variants suggests that the majority of them affect the globular structure of DOCK4. In vitro functional expression studies in transfected Neuro-2A cells showed that all missense variants impaired neurite outgrowth. Furthermore, Dock4 knockout Neuro-2A cells also exhibited defects in promoting neurite outgrowth. Our results, including clinical, molecular and functional data, suggest that loss-of-function variants in DOCK4 probable cause a variable spectrum of a novel neurodevelopmental disorder with microcephaly. [ABSTRACT FROM AUTHOR]

Microcephaly presents heterogeneous genetic etiology linked to several neurodevelopmental disorders (NDD). Copy number variants (CNVs) are a causal mechanism of microcephaly whose investigation is a crucial step for unraveling its molecular basis. Our purpose was to investigate the burden of rare CNVs in microcephalic individuals and to review genes and CNV syndromes associated with microcephaly. We performed chromosomal microarray analysis (CMA) in 185 Brazilian patients with microcephaly and evaluated microcephalic patients carrying < 200 kb CNVs documented in the DECIPHER database. Additionally, we reviewed known genes and CNV syndromes causally linked to microcephaly through the PubMed, OMIM, DECIPHER, and ClinGen databases. Rare clinically relevant CNVs were detected in 39 out of the 185 Brazilian patients investigated by CMA (21%). In 31 among the 60 DECIPHER patients carrying < 200 kb CNVs, at least one known microcephaly gene was observed. Overall, four gene sets implicated in microcephaly were disclosed: known microcephaly genes; genes with supporting evidence of association with microcephaly; known macrocephaly genes; and novel candidates, including OTUD7A, BBC3, CNTN6, and NAA15. In the review, we compiled 957 known microcephaly genes and 58 genomic CNV loci, comprising 13 duplications and 50 deletions, which have already been associated with clinical findings including microcephaly. We reviewed genes and CNV syndromes previously associated with microcephaly, reinforced the high CMA diagnostic yield for this condition, pinpointed novel candidate loci linked to microcephaly deserving further evaluation, and provided a useful resource for future research on the field of neurodevelopment. [ABSTRACT FROM AUTHOR]

Introduction: Miller-Dieker syndrome has an autosomal dominant pattern of inheritance and belongs to the group of neuronal migration disorders. It is characterized by the presence of type 1 lissencephaly, global development delay, microcephaly, epilepsy and facial dysmorphisms caused by mutations in chromosome 17p13. Miller-Dieker syndrome is an extremely rare disease with a prevalence of 1 case per 100,000 live births. Case presentation: We present two cases of Miller-Dieker syndrome in which data from the physical examination and questioning were clues that allowed a strong diagnostic suspicion and that, in turn, the definitive diagnosis by means of FISH allowed us to provide adequate management in order to improve the long-term prognosis. Conclusion: A high diagnostic suspicion must be achieved through physical examination aimed at identifying alterations in patients with difficult-to-control epilepsy, since it allows guiding the etiological diagnosis and thereby providing adequate treatment. [ABSTRACT FROM AUTHOR]

Aicardi-Goutières syndrome is a rare genetic disorder that affects the brain, spinal cord, and immune system. It is a type of leukodystrophy, a group of conditions that affect the white matter of the brain. These diseases affect the myelin sheath, which surrounds and protects the nerve cells in the brain and spinal cord and speeds up the transmission of messages between cells. Affected individuals present with congenital brain malformations, microcephaly, global developmental delays with epilepsy, spastic tetraparesis or tetraplegia, often leading to the loss of independent mobility. In this article, we report the case of a 2-year-old boy diagnosed with Aicardi-Goutières syndrome, who presented with craniofacial dysmorphism, cognitive-verbal delay, microcephaly, spastic tetraparesis, dystonia, and immune deficits. The child exhibited mutations in the TREX1, SAMHD1, and ADAR1 genes, suggestive of Aicardi-Goutières syndrome. [ABSTRACT FROM AUTHOR]

This report presents a case of ring chromosome 7 syndrome with bilateral cleft lip and palate. A four-year-old boy presented with bilateral cleft lip and palate, microcephaly, clenched toes, cafe-au-lait spots, a history of epilepsy, and severe intellectual disability. Genetic karyotyping revealed 46 XY r(7) (p22q36). His cheiloplasty and delayed palatoplasty were successful. A review of 22 previous r(7) patients revealed that 22.7% had cleft lip and/or palate. This case demonstrates the importance of a multidisciplinary evaluation for cleft patients, particularly those with syndromic features and global developmental delay. [ABSTRACT FROM AUTHOR]

Primary microcephaly (MCPH) is an autosomal recessive disorder characterized by head circumference of at least two standard deviations below the mean. Biallelic variants in the kinetochore gene KNL1 is a known cause of MCPH4. KNL1 is the central component of the KNL1–MIS12–NSL1 (KMN) network, which acts as the signaling hub of the kinetochore and is required for correct chromosomal segregation during mitosis. We identified biallelic KNL1 variants in two siblings from a non‐consanguineous family with microcephaly and intellectual disability. The two siblings carry a frameshift variant predicted to prematurely truncate the transcript and undergo nonsense mediated decay, and an intronic single nucleotide variant (SNV) predicted to disrupt splicing. An in vitro splicing assay and qPCR from blood‐derived RNA confirmed that the intronic variant skips exon 23, significantly reducing levels of the canonical transcript. Protein modeling confirmed that absence of exon 23, an inframe exon, would disrupt a key interaction within the KMN network and likely destabilize the kinetochore signaling hub, disrupting mitosis. Therefore, this splicing variant is pathogenic and, in trans with a frameshift variant, causes the MCPH phenotype associated with KLN1. This finding furthers the association of splicing variants as a common pathogenic variant class for KNL1. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) can cause neurological issues in infants. To provide protection, neutralizing antibodies should be transferred from the mother to the infant. We conducted a study at the Hospital General de Pochutla, Oaxaca, Mexico. Samples were collected from mothers (blood and breast milk) and infants (saliva and dried blood spots) within the first 12 postnatal hours (December 2017 to February 2018) and tested for ZIKV total and neutralizing antibodies as well as ZIKV-PCR. Microcephaly was evaluated according to INTERGROWTH-21st standards. Maternal IgG seroprevalence was 28.4% with 10.4% active infection, while infant IgG seroprevalence was 5.5% with 2.4% active infection. There were two cases of virolactia, and 6.3% of the infant saliva samples tested positive for ZIKV. Additionally, 18.3% of the infants were in a cephalic perimeter percentile lower than 10 and had an association between microcephaly and serology or a PCR between 8.6 and 60.9%. The infant blood samples had neutralizing antibodies, indicating intrauterine protection. Microcephaly was correlated with serology or PCR, but in our study population, non-ZIKV factors may be involved as well. Low ZIKV infection values in breast milk mean that breastfeeding is safe in most of the mothers and infants of the endemic area studied. [ABSTRACT FROM AUTHOR]

Background: We present two genetic causes of polyhydramnios that were challenging to diagnose due to their rarity and complexity. In view of the severe implications, we wish to highlight these rare genetic conditions when obstetricians consider differential diagnoses of polyhydramnios in the third trimester. Case presentation: Patient 1 is a 34-year-old Asian woman who was diagnosed with polyhydramnios at 28 weeks' gestation. First trimester testing, fetal anomaly scan, and intrauterine infection screen were normal. Subsequent antenatal ultrasound scans revealed macroglossia, raising the suspicion for Beckwith–Wiedemann syndrome. Chromosomal microarray analysis revealed a female profile with no pathological copy number variants. The patient underwent amnioreduction twice in the pregnancy. The patient presented in preterm labor at 34 weeks' gestation but elected for an emergency caesarean section. Postnatally, the baby was noted to have a bell-shaped thorax, coat hanger ribs, hypotonia, abdominal distension, and facial dysmorphisms suggestive of Kagami–Ogata syndrome. Patient 2 is a 30-year-old Asian woman who was diagnosed with polyhydramnios at 30 weeks' gestation. She had a high-risk first trimester screen but declined invasive testing; non-invasive prenatal testing was low risk. Ultrasound examination revealed a macrosomic fetus with grade 1 echogenic bowels but no other abnormalities. Intrauterine infection screen was negative, and there was no sonographic evidence of fetal anemia. She had spontaneous rupture of membranes at 37 + 3 weeks but subsequently delivered by caesarean section in view of pathological cardiotocography. The baby was noted to have inspiratory stridor, hypotonia, low-set ears, and bilateral toe polysyndactyly. Further genetic testing revealed a female profile with a pathogenic variant of the GLI3 gene, confirming a diagnosis of Greig cephalopolysyndactyly syndrome. Conclusion: These cases illustrate the importance of considering rare genetic causes of polyhydramnios in the differential diagnosis, particularly when fetal anomalies are not apparent at the 20-week structural scan. We would like to raise awareness for these rare conditions, as a high index of suspicion enables appropriate counseling, prenatal testing, and timely referral to pediatricians and geneticists. Early identification and diagnosis allow planning of perinatal care and birth in a tertiary center managed by a multidisciplinary team. [ABSTRACT FROM AUTHOR]

Zika virus has been circulating in Thailand since 2002 through continuous but likely low-level circulation. Here, we describe an infection in a pregnant woman who traveled to Thailand and South America during her pregnancy. By combining phylogenetic analysis with the patient's travel history and her pregnancy timeline, we confirmed that she likely got infected in Thailand at the end of 2021. This imported case of microcephaly highlights that Zika virus circulation in the country still constitutes a health risk, even in a year of lower incidence. Main points Here we trace the origin of travel-acquired microcephaly to Thailand, providing additional evidence that pre-American lineages of Zika virus can harm the fetus and highlighting that Zika virus constitutes a health threat even in a year of lower incidence. [ABSTRACT FROM AUTHOR]

Background: The hallmarks of Emanuel syndrome are pre- and postnatal growth retardation, microcephaly, global developmental delay, ear anomalies, and in males, heart, kidney, and genital abnormalities. Results: This study describes the atypical features of Emanuel syndrome, a rare chromosomal disorder. The patient had several physical features that are common in Emanuel syndrome, such as microcephaly, hypotonia, and ear anomalies. However, he exhibited certain unusual characteristics, including the lack of a prominent forehead, epicanthic folds, and a downward slanting palpebral fissure. There was infratentorial brain involution with a minor infarction in the left cerebral hemisphere and cerebellar hypoplasia on the magnetic resonance imaging (MRI) scan of the brain. Additionally, the patient had bilateral mild hearing loss and an aberrant epileptogenic pattern on the electroencephalogram (EEG). Orodental examination showed a long philtrum, everted fissured thick lower lip, highly attached labial frenum, and prominent median palatine raphe. The karyotype revealed 45XY t(11;22)(p15.5;q11.22), which is different from the typical karyotype of Emanuel syndrome. Conclusions: This case sheds light on the possibility of alternative genetic mechanisms, beyond chromosomal abnormalities, in patients presenting with multiple congenital anomalies and facial dysmorphism. [ABSTRACT FROM AUTHOR]

Introduction: Adverse birth outcomes particularly preterm births and congenital anomalies, are the leading causes of infant mortality globally, and the burden is highest in developing countries. We set out to determine the frequency of adverse birth outcomes and the risk factors associated with such outcomes in a cohort of pregnant women in Kenya. Methods: From October 2017 to July 2019, pregnant women < 28 weeks gestation were enrolled and followed up until delivery in three hospitals in coastal Kenya. Newborns were examined at delivery. Among women with birth outcome data, we assessed the frequency of congenital anomalies defined as gastroschisis, umbilical hernia, limb abnormalities and Trisomy 21, and adverse birth outcomes, defined as either stillbirth, miscarriage, preterm birth, small for gestational age, or microcephaly. We used log-binomial regression to identify maternal characteristics associated with the presence of at least one adverse outcome. Results: Among the 2312 women enrolled, 1916 (82.9%) had birth outcome data. Overall, 402/1916 (20.9%; 95% confidence interval (CI): 19.1–22.8) pregnancies had adverse birth outcomes. Specifically, 66/1916 (3.4%; 95% CI: 2.7–4.4) were stillbirths, 34/1916 (1.8%; 95% CI: 1.2–2.4) were miscarriages and 23/1816 (1.2%; 95% CI: 0.8–1.9) had congenital anomalies. Among the participants with anthropometric measurements data, 142/1200 (11.8%; 95% CI: 10.1 − 13.8) were small for gestational age and among the participants with ultrasound records, 143/1711 (8.4%; 95% CI: 7.1–9.8) were preterm. Febrile illnesses in current pregnancy (adjusted risk ratio (aRR): 1.7; 95% CI: 1.1–2.8), a history of poor birth outcomes in prior pregnancy (aRR: 1.8; 95% CI: 1.3–2.4) and high blood pressure in pregnancy (aRR: 3.9, 95% CI: (1.7–9.2) were independently associated with adverse birth outcomes in a model that included age, education, human immunodeficiency virus status and high blood pressure at enrolment. Conclusion: We found similar rates of overall adverse birth outcomes, congenital anomalies, and small for gestational age but higher rates of stillbirths and lower rates of prematurity compared to the rates that have been reported in the sub-Saharan Africa region. However, the rates of adverse birth outcomes in this study were comparable to other studies conducted in Kenya. Febrile illnesses during the current pregnancy, previous history of poor birth outcomes and high blood pressure in pregnancy are predictive of an increased risk of adverse birth outcomes. [ABSTRACT FROM AUTHOR]

ObjectiveMethodsResultsConclusionProtocol registrationTo assess fetal and neonatal eyes abnormalities and their progression during the last ZIKV outbreak and summarize learned lessons.A systematic review and meta-analysis was conducted by a team of obstetricians and ophthalmologists.Studies reporting ocular abnormalities during the prenatal (n = 5) and postnatal (n = 24) periods were included in the analysis. In the prenatal period, the most common ocular findings were intraocular calcification cases (4/6, 66.6%) and microphthalmia (3/6, 50%). Postnatal ocular abnormalities of congenital ZIKV infection were described after birth in 479 cases. Among them microphthalmia was reported in 13 cases (13/479, 2.7%). Posterior segment (retina and optic nerve) was the most affected structure, consisting of pigmentary changes (229/479, 47.8%), macular chorioretinal atrophy (216/479, 45%), optic nerve atrophy (181/479, 37.8%), increased cup-to-disk ratio (190/479, 39.6.%), optic nerve hypoplasia (93/479,19.4%), vascular changes (26/479, 5.4%), and retinal coloboma (20/479, 4.1%). The anterior segment was involved in 4.6% (22/479) of cases, including cataract (9/479, 1.8%), lens subluxation (1/479, 0.2%), iris coloboma (5/479, 1%), and congenital glaucoma (7/479, 1.4%). These ocular anomalies were isolated in one case (1/479, 0.2%) and multiple anomalies were found in the other cases. Long-term visual disorders have been described, with no possible improvement and even a worsening of some of the ocular anomalies previously observed. No reactivation of ocular lesions was observed.This review highlights the severe ocular abnormalities associated with congenital ZIKV infections. The importance of multidisciplinary communication between the obstetrician, the maternal-fetal medicine specialist, and the ophthalmologist is emphasized.This systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration440 188. [ABSTRACT FROM AUTHOR]

Background: Hypoxic-ischemic encephalopathy (HIE), caused due to reduced oxygenation and brain blood flow, occurs in 1-8 per 1000 live full-term births in developed countries and up to 26 per 1000 live in the developing world. The growth status of survivors of birth HIE has not been evaluated sufficiently. Objective: This study evaluated, the growth parameters (weight, height, and head circumference) of neonates with Sarnat stage.2 of HIE at 6, 10, and 12 months and its relationship with findings of neonatal brain diffusion-weighted imaging (DWI) sequence. Materials and Methods: Medical records and growth parameters of 35 neonates with gestational age > 34 wk who were admitted with stage.2 of HIE in Neonatal Intensive Care Unit of Shahid Sadoughi hospital, Yazd, Iran from March 2021-March 2022, and its relationship with neonatal brain DWI sequence finding was evaluated. Results: 15 girls and 20 boys with a mean birth weight of 2880.3 ± 221.8 gr were evaluated. Conventional magnetic resonance imaging and DWI were found to be abnormal in 6 (17.1%) and 18 neonates (51.4%). The most abnormal finding of DWI was high signal in basal ganglia/thalamus in 9 neonates (25.7%). Abnormal DWI is more frequent in neonates with seizures and low birth weight. Hospital stay days were more prolonged in neonates with abnormal DWI. Microcephaly at 12 months was more frequent in children with abnormal DWI. Conclusion: In survivors of moderate neonatal HIE, abnormal brain DWI sequence might predict inappropriate head growth, and need close medical and nutritional interventions for growth improvement. [ABSTRACT FROM AUTHOR]

Microcephaly is a rare neurodevelopmental disorder characterized by reduced skull circumference and brain volume that occurs sporadically in farm animals. We investigated an early‐onset neurodegenerative disorder observed in seven lambs of purebred Kerry Hill sheep. Clinical signs included inability to stand or severe ataxia, convulsions, and early death. Diagnostic imaging and brain necropsy confirmed microcephaly. The pedigree of the lambs suggested monogenic autosomal recessive inheritance. We sequenced the genome of one affected lamb, and comparison with 115 control genomes revealed a single private protein‐changing variant. This frameshift variant, MFSD2A: c.285dupA, p.(Asp96fs*9), represents a 1‐bp duplication predicted to truncate 80% of the open reading frame. MFSD2A is a transmembrane protein that is essential for maintaining blood–brain barrier homeostasis and plays a key role in regulating brain lipogenesis. Human MFSD2A pathogenic variants are associated with a neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities (NEDMISBA, OMIM 616486). Here we present evidence for the occurrence of a recessively inherited form of microcephaly in sheep due to a loss‐of‐function variant in MFSD2A (OMIA 002371‐9940). To the best of our knowledge, this is the first report of a spontaneous MFSD2A variant in domestic animals. [ABSTRACT FROM AUTHOR]

Microcephaly with simplified gyral pattern (MSG) is an intrinsic genetic central nervous system disorder, characterized by microcephaly (a reduction of brain volume) and a simplified gyral pattern (a reduced number of gyri and shallow sulci associated with normal cortical thickness and neuroanatomical architecture), related to a reduced number of neuronal progenitors in the germinal matrix. We report the first prenatal series of MSG and define the prenatal imaging pattern, which should inform diagnosis and guide prenatal counseling in cases of fetal microcephaly. In this single‐center retrospective study of fetuses with MSG, we assessed features on ultrasound and magnetic resonance imaging (MRI), as well as genetic and neuropathological/postnatal data. We included eight patients who had been referred following observation of microcephaly. Ultrasound examination confirmed microcephaly, with a mean growth delay in head circumference of 3.4 weeks, associated with both a lack of gyration and a lack of opercularization of the Sylvian fissure and without any extracephalic anomaly. Fetal brain MRI confirmed lack of gyration with normal cortical thickness and normal intensity of the white matter in all cases. These MRI features led to exclusion of migration/corticogenesis disorders (lissencephaly/polymicrogyria), instead suggesting MSG. The posterior fossa was normal in seven of the eight cases. The corpus callosum was thin in four cases, hypoplastic in two and dysgenetic in two. In four cases, the pregnancy was terminated. The diagnosis of MSG was confirmed from neuropathological and postnatal MRI data. MSG was associated with a genetic diagnosis of RTTN (n = 1) and ASPM (n = 2) biallelic variants in three of the six cases in which genetic work‐up was performed. Mild or moderate intellectual deficit with speech delay was present in the three surviving children who were at least 5 years of age at their last examination, without seizures. In conclusion, in the presence of isolated fetal microcephaly with lack of gyration on ultrasound, fetal cerebral MRI is key to diagnosing MSG, which, in the majority of cases, affects the supratentorial space exclusively, and to ruling out other cortical malformations that show a similar sonographic pattern. In addition to imaging, genetic assessment may guide prenatal counseling, since the prenatal prognosis of MSG is different from that of both diffuse polymicrogyria and lissencephaly. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and PEHO‐like syndromes are very rare infantile disorders characterized by profound intellectual disability, hypotonia, convulsions, optic, and progressive brain atrophy. Many causative genes for PEHO and PEHO‐like syndromes have been identified including CCDC88A. So far, only five patients from two unrelated families with biallelic CCDC88A variants have been reported in the literature. Herein, we describe a new family from Egypt with a lethal epileptic encephalopathy. Our patient was the youngest child born to a highly consanguineous couple and had a family history of five deceased sibs with the same condition. She presented with postnatal microcephaly, poor visual responsiveness, and epilepsy. Her brain MRI showed abnormal cortical gyration with failure of opercularization of the insula, hypogenesis of corpus callosum, colpocephaly, reduced white matter, hypoplastic vermis, and brain stem. Whole exome sequencing identified a new homozygous frameshift variant in CCDC88A gene (c.1795_1798delACAA, p.Thr599ValfsTer4). Our study presents the third reported family with this extremely rare disorder. We also reviewed all described cases to better refine the phenotypic spectrum associated with biallelic loss of function variants in the CCDC88A gene. [ABSTRACT FROM AUTHOR]

Background: ABCC8 variants can cause hyperinsulinemia by activating or deactivating gene expression. This study used targeted exon sequencing to investigate genetic variants of ABCC8 and the associated phenotypic features in Chinese patients with hyperinsulinemic hypoglycemia (HH). Methods: We enrolled eight Chinese children with HH and analyzed their clinical characteristics, laboratory results, and genetic variations. Results: The age at presentation among the patients ranged from neonates to 0.6 years old, and the age at diagnosis ranged from 1 month to 5 years, with an average of 1.3 ± 0.7 years. Among these patients, three presented with seizures, and five with hypoglycemia. One patient (Patient 7) also had microcephaly. All eight patients exhibited ABCC8 abnormalities, including six missense mutations (c. 2521 C > G, c. 3784G > A, c. 4478G > A, c. 4532T > C, c. 2669T > C, and c. 331G > A), two deletion-insertion mutations (c. 3126_3129delinsTC and c. 3124_3126delins13), and one splicing mutation (c. 1332 + 2T > C). Two of these mutations (c. 3126_3129delinsTC and c. 4532T > C) are novel. Six variations were paternal, two were maternal, and one was de novo. Three patients responded to diazoxide and one patient responded to octreotide treatment. All there patients had diazoxide withdrawal with age. Two patients (patients 3 and 7) were unresponsive to both diazoxide and octreotide and had mental retardation. Conclusions: Gene analysis can aid in the classification, treatment, and prognosis of children with HH. In this study, the identification of seven known and two novel variants in the ABCC8 gene further enriched the variation spectrum of the gene. [ABSTRACT FROM AUTHOR]

The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus–centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis. [ABSTRACT FROM AUTHOR]

Pathogenic variants in PNPLA8 have been described either with congenital onset displaying congenital microcephaly, early onset epileptic encephalopathy and early lethality or childhood neurodegeneration with progressive microcephaly. Moreover, a phenotype comprising adulthood onset cerebellar ataxia and peripheral neuropathy was also reported. To our knowledge, only six patients with biallelic variants in PNPLA8 have been reported so far. Here, we report the clinical and molecular characterizations of three additional patients in whom exome sequencing identified a loss of function variant (c.1231C>T, p.Arg411Ter) in Family I and a missense variant (c.1559T>A, p.Val520Asp) in Family II in PNPLA8. Patient 1 presented with the congenital form of the disease while Patients 2 and 3 showed progressive microcephaly, infantile onset seizures, progressive cortical atrophy, white matter loss, bilateral degeneration of basal ganglia, and cystic encephalomalacia. Therefore, our results add the infantile onset as a new distinct phenotype of the disease and suggest that the site of the variant rather than its type is strongly correlated with the disease onset. In addition, these conditions demonstrate some overlapping features representing a spectrum with clinical features always aligning with different age of onset. [ABSTRACT FROM AUTHOR]

Temporarily distant from the declaration of the Public Health Emergency of International Importance (ESPII) and Public Health Emergency of National Importance (ESPIN) caused by the Zika epidemic, in 2015, we enunciate the legacy of the humanitarian emergency. Based on qualitative research, through focus groups with health professionals and families of children affected by the Zika epidemic in Natal and Feira de Santana, we seek to discuss this public health phenomenon through the lens of State Anthropology. We conclude that the non-recognition of the State as an instance embodied in the daily practices of its local agents leads to the reproduction of discriminatory practices emptied of political sense and the recognition of moralities that permeate the absences in health promotion actions and recognition strategies, and search for methods to guarantee the right to health. [ABSTRACT FROM AUTHOR]

Objective: To carry out a descriptive analysis of direct private household health expenditures and socioeconomic vulnerability associated with the condition of Microcephaly, one of the most evidence manifestations of Congenital Zika Syndrome (CZS). The outbreak of microcephaly and other neurological disorders in children under one year of age was linked to Zika virus infection during the 2015-2016 epidemic in Brazil. Method: Ninety-six interviews were carried out in two specialized care centers for children with microcephaly in the cities of Rio de Janeiro and Fortaleza, Brazil. The structured questionnaire covered sociodemographic characteristics, out-of-pocket expenditures associated with the disease, and strategies adopted by families to deal with the financial challenges imposed by the congenital anomaly. Results: The households were mostly headed by non-whites and belonged to classes C and D-E. Expenditures on medicines accounted for 78% of medical expenses, while transportation represented 46% of private non-medical expenses. Most households faced debt and reduced domestic consumption, including food, to meet the expenses incurred by the disease. Conclusion: Microcephaly appears to reinforce the socioeconomic vulnerability of families, reinforcing the vicious circle characteristic of the health-poverty trap conceptual approach. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ATRX mutations are commonly associated with alpha-thalassaemia mental retardation syndrome (ATR-X syndrome) with a notable variable expressivity. This X-linked disorder is characterized by intellectual disability (ID) in a higher or lesser degree, in which the alpha-thalassaemia feature is not always present. Other phenotypic manifestations like facial dimorphism, hypotonia, microcephaly, skeletal abnormalities or urogenital malformations have been frequently observed in ATR-X syndrome. Herein, we report a missense ATRX mutation (Thr1621Met) in a patient with an autism spectrum disorder (ASD) diagnosis. Except for ID, no typical signs of ATR-X syndrome were found in the patient. These results confirm the extensive phenotypic variability associated to ATRX mutations and show the involvement of this gene in the ASD. [ABSTRACT FROM AUTHOR]

The progressive reappearance of Zika virus (ZIKV) infections since October 2013 and its circulation in >70 countries and territories (from French Polynesia to Brazil and other countries in the Americas, with sporadic spread in Europe and the East) has long been reported as a global public health emergency. ZIKV is a virus transmitted by arthropods (arboviruses), mainly by Aedes mosquitoes. ZIKV can also be transmitted to humans through mechanisms other than vector infection such as sexual intercourse, blood transfusions, and mother-to-child transmission. The latter mode of transmission can give rise to a severe clinical form called congenital Zika syndrome (CZS), which can result in spontaneous abortion or serious pathological alterations in the fetus such as microcephaly or neurological and orofacial anomalies. In this study, beside a succinct overview of the etiological, microbiological, and epidemiological aspects and modes of transmission of Zika virus infections, we have focused our attention on the pathogenetic and histopathological aspects in pregnancy and the pathogenetic and molecular mechanisms that can determine microcephaly, and consequently the clinical alterations, typical of the fetus and newborns, in a subject affected by CZS. [ABSTRACT FROM AUTHOR]

Background: Bi‐allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss. We report on a 6 1/2‐year‐old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly. Methods: We performed trio exome sequencing on the patient and her parents. Results: Trio exome sequencing revealed likely pathogenic compound heterozygous missense variants in AFG2B [c.527G>T, p.(Gly176Val) and c.1313T>C, p.(Leu438Pro)] in the patient. Conclusion: Of note, the change c.1313T>C, p.(Leu438Pro) has been observed in a previously published patient as part of a complex disease allele along with a second homozygous missense change, so the exact contribution of the two alterations to this patient's disease had initially remained unclear. Our results support the pathogenic relevance of the c.1313T>C, p.(Leu438Pro) allele while providing detailed insights into the disease manifestation of a further patient. [ABSTRACT FROM AUTHOR]

Background: Microcephaly with early‐onset seizures (MCSZ) is a neurodevelopmental disorder caused by pathogenic variants in the DNA strand break repair protein, polynucleotide kinase 3′‐phosphatase (PNKP). Methods: We have used whole genome sequencing and Sanger sequencing to identify disease‐causing variants, followed by a minigene assay, Western blotting, alkaline comet assay, γH2AX, and ADP‐ribose immunofluorescence. Results: Here, we describe a patient with compound heterozygous variants in PNKP, including a missense variant in the DNA phosphatase domain (T323M) and a novel splice acceptor site variant within the DNA kinase domain that we show leads to exon skipping. We show that primary fibroblasts derived from the patient exhibit greatly reduced levels of PNKP protein and reduced rates of DNA single‐strand break repair, confirming that the mutated PNKP alleles are dysfunctional. Conclusion: The data presented show that the detected compound heterozygous variants result in reduced levels of PNKP protein, which affect the repair of both oxidative and TOP1‐induced single‐strand breaks, and most likely causes MCSZ in this patient. [ABSTRACT FROM AUTHOR]

Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B -deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function. [ABSTRACT FROM AUTHOR]

Maintaining genomic stability is a prerequisite for proliferating NPCs to ensure genetic fidelity. Though histone arginine methylation has been shown to play important roles in safeguarding genomic stability, the underlying mechanism during brain development is not fully understood. Protein arginine N-methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that plays a role in transcriptional regulation. Here, we identify PRMT5 as a key regulator of DNA repair in response to double-strand breaks (DSBs) during NPC proliferation. Prmt5F/F; Emx1-Cre (cKO-Emx1) mice show a distinctive microcephaly phenotype, with partial loss of the dorsal medial cerebral cortex and complete loss of the corpus callosum and hippocampus. This phenotype is resulted from DSBs accumulation in the medial dorsal cortex followed by cell apoptosis. Both RNA sequencing and in vitro DNA repair analyses reveal that PRMT5 is required for DNA homologous recombination (HR) repair. PRMT5 specifically catalyzes H3R2me2s in proliferating NPCs in the developing mouse brain to enhance HR-related gene expression during DNA repair. Finally, overexpression of BRCA1 significantly rescues DSBs accumulation and cell apoptosis in PRMT5-deficient NSCs. Taken together, our results show that PRMT5 maintains genomic stability by regulating histone arginine methylation in proliferating NPCs. [ABSTRACT FROM AUTHOR]

Chromosomal deletion and duplication syndromes can lead to intellectual disability, autism, microcephaly, and poor growth. Usually manifestations of duplication syndromes are milder than that of the deletion syndromes. With the availability of tests for analysis of copy number variants, it is possible to identify the deletion and duplication syndromes with greater ease. We report 32 cases of chromosomal duplication syndromes, identified in children presenting with developmental delay, intellectual disability, or microcephaly and/or additional features, at a tertiary care center on karyotyping or microarray analysis. Seven were isolated duplications, and one child had an additional smaller pathogenic deletion. Thus, duplication syndromes can have milder presentations with spectrum of dysmorphism, behavioral problems, and intellectual disability, but it is possible to diagnose easily with latest emerging high-throughput technologies. [ABSTRACT FROM AUTHOR]

Objective: To systematically review studies on the effects of early stimulation on the neuropsychomotor development of children with microcephaly. Data source: A systematic review was conducted in PubMed/ MEDLINE, Virtual Health Library, and Cochrane Library databases. Studies that addressed the use of early stimulation in playful and interactive environments in children with microcephaly were included. There were no restrictions on the publication date or language of the studies. The outcomes assessed were muscle tone, social interaction, fine and gross motor skills, intelligence quotient, socioemotional and adaptive behavior of the child. The methodological quality and the scientific evidence level were assessed using the Risk of Bias in Non-randomized Studies of Interventions, the Revised Cochrane risk of bias tool for randomized trials and the Grading of Recommendations Assessment, Development and Evaluation. Data synthesis: 264 articles were identified, but only 7 met the eligibility criteria. The included studies had a total population of 125 individuals, with sample sizes ranging from 1 to 71 participants. Conclusions: The studies showed low evidence of an effect of early intervention on the outcomes muscle tone, social interaction, fine and gross motor skills, intelligence quotient, and socioemotional and adaptive behavior in children with microcephaly. However, further randomized clinical trials are needed. [ABSTRACT FROM AUTHOR]

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Sphingomyelin phosphodiesterase 4 (SMPD4) encodes a member of the Mg2+-dependent, neutral sphingomyelinase family that catalyzes the hydrolysis of the phosphodiester bond of sphingomyelin to form phosphorylcholine and ceramide. Recent studies have revealed that biallelic loss-of-function variants of SMPD4 cause syndromic neurodevelopmental disorders characterized by microcephaly, congenital arthrogryposis, and structural brain anomalies. In this study, three novel loss-of-function SMPD4 variants were identified using exome sequencing (ES) in two independent patients with developmental delays, microcephaly, seizures, and brain structural abnormalities. Patient 1 had a homozygous c.740_741del, p.(Val247Glufs*21) variant and showed profound intellectual disability, hepatomegaly, a simplified gyral pattern, and a thin corpus callosum without congenital dysmorphic features. Patient 2 had a compound heterozygous nonsense c.2124_2125del, p.(Phe709*) variant and splice site c.1188+2dup variant. RNA analysis revealed that the c.1188+2dup variant caused exon 13 skipping, leading to a frameshift (p.Ala406Ser*6). In vitro transcription analysis using minigene system suggested that mRNA transcribed from mutant allele may be degraded by nonsense-mediated mRNA decay system. He exhibited diverse manifestations, including growth defects, muscle hypotonia, respiratory distress, arthrogryposis, insulin-dependent diabetes mellitus, sensorineural hearing loss, facial dysmorphism, and various brain abnormalities, including cerebral atrophy, hypomyelination, and cerebellar hypoplasia. Here, we review previous literatures and discuss the phenotypic diversity of SMPD4-related disorders. [ABSTRACT FROM AUTHOR]

Autosomal Recurrent Primary Microscopic (MCPH, OMIM: 251200) is a neurodevelopmental disorder that is characterized by a noticeable decrease in brain size, particularly in the cerebral cortex, but with a normal brain structure and a non-progressive intellectual disability. MCPH1 has been identified as the gene that triggers primary microcephaly (MCPH1，OMIM: 607117). Here we report a case of autosomal recessive primary microcephaly as caused by a novel variant in the MCPH1 gene. Head circumference was measured by Magnetic Resonance Imaging (MRI), while the Wechsler Intelligence Scale was used to evaluate the intelligence of the individual being tested. B-ultrasound was used to assess gonadal development, and semen routine was used to assess sperm status. The whole-exome sequencing (WES) was performed on the proband. Sanger sequencing was conducted on the parents of the proband to determine if the novel variant in the MCPH1 gene was present. The effect of the mutation on the splicing of MCPH1 was verified by minigene approach. It was observed that the proband had autosomal recessive primary microcephaly and azoospermatism. A novel splice-site homozygous mutation (c.233+2T > G) of the MCPH1 gene was identified, which inherited from his parents. Minigene approach confirmed that c.233+2T > G could affect the splicing of MCPH1. Therefore, our findings contributed to the mutation spectrum of the MCPH1 gene and may be useful in the diagnosis and gene therapy of MCPH.