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A female infant, who was diagnosed antenatally with complex heart disease, confirmed to be Shone’s complex postnatally, underwent bilateral pulmonary artery banding, patent ductus arteriosus stent insertion and balloon aortic valvuloplasty soon after birth. She was found to have bilateral megaureters, left hydronephrosis and asplenia. She was on lifelong prophylactic antibiotics and extra vaccines. She had two episodes of pseudo-obstruction of the small bowel, but barium follow-through was normal. She also had a large bowel obstruction and work-up for Hirschsprung disease confirmed the diagnosis. It was noticed that she had developmental delay and hypotonia, together with subtle dysmorphism. She also had failure to thrive and difficulty feeding. Exome sequencing revealed a diagnosis of Mowat-Wilson syndrome (MWS). This case shows a previously undescribed association of Shone’s complex, a complex left-sided obstructive heart defect, and MWS. It also highlights the usefulness of trio-exome sequencing in detecting such rare mutations.

The tRNA methyltransferase 10 homologue A (TRMT10A) gene encodes a tRNA methyl transferase, and biallelic loss of function mutations cause a recessive syndrome of intellectual disability, microcephaly, short stature and diabetes. A case with intellectual disability and distinctive features including microcephaly was admitted. She was diagnosed with epilepsy at 2.5 years old. At 3.6 years of age, severe short stature related to growth hormone deficiency was detected. She had an incidental diagnosis of diabetes at age 11.4 years that was negative for diabetes antibodies with persistent C-peptide level and treated with metformin. Spontaneous puberty did not begin until 15.7 years of age and she was found to have primary ovarian failure. A homozygous p.Arg127* mutation in TRMT10A was detected. In addition to the typical clinical features that characterize TRMT10A syndrome we observed in our patient an unusual form of impaired glucose metabolism that was presented in early childhood with hypoglycemia followed by diabetes in late childhood. Growth hormone deficiency and primary ovarian failure may also be additional findings of this syndrome. Patients with slow onset diabetes that are negative for auto-antibodies and have extra-pancreatic features should be tested for all known subtypes monogenic diabetes.

To verify characteristics associated with drug resistant epilepsy in children up to 36 months of age with Congenital Zika Syndrome (CZS).This is a prospective cohort study with children aged up to 36 months diagnosed with CZS. Obstetric, demographic, phenotype and other clinical signs, cranial tomography, growth and motor development of the children were collected.Of a total of 109 children diagnosed with CZS, 100 (91.7%) had epilepsy and 68 (68%) with drug resistant seizures. The types of seizures associated with drug resistant epilepsy were focal seizures from the occipital lobe, generalized tonic and generalized tonic-clonic seizures. There was an association between drug resistant epilepsy and microcephaly at birth, severe microcephaly at birth, excess nuchal skin, ventriculomegaly, reduced brain parenchyma volume, and hypoplasia or malformation of the cerebellum. Difficulty sleeping, irritability, continuous crying, dysphagia and gross motor function were clinical signs associated with drug resistant epilepsy, as were the presence of ocular abnormalities, low head circumference in the first year of life and low weight in the first six months.The prevalence of drug resistant epilepsy in children up to 36 months with CZS was 62.4% and was associated with the severity of the child's neurological damage, with emphasis on the reduction of brain parenchyma volume and damage to the cerebellum.

Northeast Brazil has the world’s highest rate of Zika-related microcephaly. Yet, in this hard-hit region, traditional case counts of Zika cannot accurately describe Zika risk. Reporting of Zika cases only became mandatory after its association with microcephaly in neonates, when the Zika epidemic was already declining in the region. To advance the study of the Brazilian Zika epidemic and its impacts, we identified hotspots of Zika in Pernambuco state, Northeast Brazil, using Aedes-borne diseases (dengue, chikungunya and Zika) and microcephaly data. We used the Kulldorff’s Poisson purely spatial scan statistic to detect low- and high-risk clusters and combined the results to identify the municipalities most affected by the Zika epidemic. Municipalities were classified as hotspots if they were part of any high-risk cluster, and classified according to a gradient of Zika burden during the epidemic, considering the strength of the evidence. In Pernambuco, officials confirmed 123,934 dengue cases, 167 Zika cases, and 32,983 chikungunya cases between 2014-2017, and 800 microcephaly cases between 2015-2017. We identified 26 Aedes-borne diseases clusters (11 high-risk), and 5 microcephaly cases clusters (3 high-risk). Combining the results, sixty-three out of 184 municipalities were identified as hotspots for Zika. The northeast of Pernambuco and the Sertão region were hit hardest by the Zika epidemic. The first is the most populous area, while the second has one of the highest rates of social and economic inequality in Brazil. The identification of Sertão as a Zika hotspot was only possible because the clusters results were combined. The under-reporting of acute infectious diseases is expected to be higher in poor areas. Therefore, using only Aedes-borne data does not correctly identify the high-risk areas. We successfully identified hidden Zika hotspots using a simple methodology combining Aedes-borne diseases and microcephaly information.

MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending. MTSS2 is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants in MTSS2 have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygous de novo variant in MTSS2 (GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support that mim is important for appropriate neural function, and that the MTSS2 c.2011C>T variant causes a syndromic form of intellectual disability.

Galloway-Mowat syndrome (GAMOS) is a very rare condition characterized by early-onset nephrotic syndrome and microcephaly with variable neurologic features. While considerable genetic heterogeneity of GAMOS has been identified, the majority of cases are caused by pathogenic variants in genes encoding the four components of the Kinase, endopeptidase, and other proteins of small size (KEOPS) complex, one of which is TP53RK. Here we describe a 3-year-old male with progressive microcephaly, neurodevelopmental deficits, and glomerular proteinuria. He was found to carry a novel homozygous TP53RK missense variant, c.163CG (p.Arg55Gly), which was considered as potentially disease-causing. We generated a morpholino tp53rk knockdown model in Xenopus laevis showing that the depletion of endogenous Tp53rk caused abnormal eye and head development. This phenotype could be rescued by the expression of human wildtype TP53RK but not by the c.163CG mutant nor by another previously described GAMOS-associated mutant c.125GA (p.Gly42Asp). These findings support the pathogenic role of the novel TP53RK variant.

In a patient with severe microcephaly, congenital bone marrow failure, growth retardation, and renal hypoplasia, we identified a likely pathogenic variant in NUF2 that impairs the cell's ability to properly complete mitosis. Interestingly, these clinical features as well as the observed cellular alterations are highly reminiscent of what is reported in Fanconi Anaemia supporting a unifying causal role of the variant in the disease. This case provides the first evidence that a kinetochore defect, previously associated with microcephaly, can be responsible for an inherited bone marrow failure syndrome, highlighting the unique pathological link between neurogenesis and haematopoiesis.

To verify whether access to information about oral hygiene influenced the practices of caregivers of children with microcephaly caused by Zika virus (ZIKV).A case series study was developed at the Mens Sana Rehabilitation Center, in the municipality of Arcoverde, Pernambuco, Brazil. The study universe included the mothers of 32 children with microcephaly caused by Zika virus. Data collection took place in June 2018 and was carried out through a structured questionnaire. The variables studied comprised socioeconomic issues, habits, diet, and knowledge about oral hygiene. Fisher's Exact and Pearson's Chi-square tests were used with a significance level of 5%.Out of 32 individuals eligible to participate in the study, only 27 were selected. Most mothers reported receiving information about oral hygiene from their infants (63.0%). Fisher's Exact and Pearson's Chi-square tests showed that access to oral hygiene information was associated with mother's education, family income, regular visits to the dentist, frequency of tooth brushing, age at which the infant started brushing, and brushing time (p 0.05).Access to information about oral hygiene positively influenced the oral health care of mothers with their children with microcephaly caused by ZIKV.

Verheij syndrome (VRJS) is a rare craniofacial spliceosomopathy presenting with craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay. It is caused by single nucleotide variants (SNVs) in PUF60 or interstitial deletions of the 8q24.3 region. PUF60 encodes a splicing factor which forms part of the spliceosome. To date, 36 patients with a sole diagnosis of VRJS due to disease-causing PUF60 SNVs have been reported in peer-reviewed publications. Although the depth of their phenotyping has varied greatly, they exhibit marked phenotypic heterogeneity. We report 10 additional unrelated patients, including the first described patients of Khmer, Indian, and Vietnamese ethnicities, and the eldest patient to date, with 10 heterozygous PUF60 variants identified through exome sequencing, 8 previously unreported. All patients underwent deep phenotyping identifying variable dysmorphism, growth delay, neurodevelopmental delay, and multiple congenital anomalies, including several unique features. The eldest patient is the only reported individual with a germline variant and neither neurodevelopmental delay nor intellectual disability. In combining these detailed phenotypic data with that of previously reported patients (n = 46), we further refine the known frequencies of features associated with VRJS. These include neurodevelopmental delay/intellectual disability (98%), axial skeletal anomalies (74%), appendicular skeletal anomalies (73%), oral anomalies (68%), short stature (66%), cardiac anomalies (63%), brain malformations (48%), hearing loss (46%), microcephaly (41%), colobomata (38%), and other ocular anomalies (65%). This case series, incorporating three patients from previously unreported ethnic backgrounds, further delineates the broad pleiotropy and mutational spectrum of PUF60 pathogenic variants.

As a member of vector-borne viruses, Zika virus (ZIKV) can cause microcephaly and various neurological symptoms in newborns. Previously, we found that ZIKV could infect hypothalamus, causing a decrease in growth hormone (GH) secretion, growth delay and deficits in learning and memory in suckling mice. Early administration of GH can improve the cognitive function of the mice. Therefore, in this study we further investigated the mechanism underlying the protective role of GH in ZIKV infection in suckling mice. Our results showed that GH could effectively reduce brain damage caused by ZIKV infection via reducing cell apoptosis and inflammatory response rather than inhibiting viral replication. Our results provide important evidences not only for understanding the mechanism underlying ZIKV-associated neurological symptoms but also for the treatment of ZIKV infection.

Deoxyhypusine hydroxylase (DOHH) is the enzyme catalyzing the second step in the post-translational synthesis of hypusine [N(ε)-(4-amino-2-hydroxybutyl)lysine] in the eukaryotic initiation factor 5A (eIF5A). Hypusine is formed exclusively in eIF5A by two sequential enzymatic steps catalyzed by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Hypusinated eIF5A is essential for translation and cell proliferation in eukaryotes, and all three genes encoding eIF5A, DHPS, and DOHH are highly conserved throughout eukaryotes. Pathogenic variants affecting either DHPS or EIF5A have been previously associated with neurodevelopmental disorders. Using trio exome sequencing, we identified rare bi-allelic pathogenic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. The DOHH variants are associated with a neurodevelopmental phenotype that is similar to phenotypes caused by DHPS or EIF5A variants and includes global developmental delay, intellectual disability, facial dysmorphism, and microcephaly. A two-dimensional gel analyses revealed the accumulation of deoxyhypusine-containing eIF5A [eIF5A(Dhp)] and a reduction in the hypusinated eIF5A in fibroblasts derived from affected individuals, providing biochemical evidence for deficiency of DOHH activity in cells carrying the bi-allelic DOHH variants. Our data suggest that rare bi-allelic variants in DOHH result in reduced enzyme activity, limit the hypusination of eIF5A, and thereby lead to a neurodevelopmental disorder.

Brazil is one of the countries that experienced an epidemic of microcephaly and other congenital manifestations related to maternal Zika virus infection which can result in Congenital Zika Syndrome (CZS). Since the Zika virus can modulate the immune system, studying mothers’ and children’s immune profiles become essential to better understanding CZS development. Therefore, we investigated the lymphocyte population profile of children who developed CZS and their mothers’ immune response in this study. The study groups were formed from the Plaque Reduction Neutralization Test (PRNT) (CZS+ group) result. To evaluate the lymphocyte population profile, we performed phenotyping of peripheral lymphocytes and quantification of serum cytokine levels. The immunophenotyping and cytokine profile was correlated between CSZ+ children and their mothers. Both groups exhibited increased interleukin-17 levels and a reduction in the subpopulation of CD4+ T lymphocytes. In contrast, the maternal group showed a reduction in the population of B lymphocytes. Thus, the development of CZS is related to the presence of an inflammatory immune profile in children and their mothers characterized by Th17 activation.

Purpose: to describe feeding characteristics of children with microcephaly, encompassing the feeding route, food consistencies, and utensils used to feed them. Methods: a descriptive study approved by the Research Ethics Committee, including 34 caregivers of children diagnosed with microcephaly. They answered a structured interview on the children’s feeding route, breastfeeding, utensils used to feed them, and the food consistencies, besides sociodemographic and overall development data. Descriptive statistical analyses were performed, presenting absolute and percentage frequencies and measures of central tendency and dispersion. Results: the 34 caregivers in the sample were responsible for 34 children born between 2015 and 2018, diagnosed with microcephaly, due to various causes. Of these, 33 (97.02%) were on oral feeding in their first year of life - 26 (76.44%) on breastfeeding, nine of which (26.46%) exclusively so until 6 months old. The children were served food in baby bottles, cups, spoons, and syringes. Pureed food was the consistency most accepted by the children. Conclusions: there was a low prevalence of exclusive breastfeeding until they were 6 months old, delayed progress of consistencies, use of utensils inadequate to their age, and necessary adaptations to feed children, orally. RESUMO Objetivo: descrever características relacionadas à alimentação de crianças com microcefalia, considerando via de alimentação, consistência e utensílios utilizados. Métodos: estudo descritivo, aprovado pelo Comitê de Ética em Pesquisa. Participaram 34 cuidadores de crianças com diagnóstico de microcefalia. Foi realizada entrevista estruturada com os cuidadores quanto à via de alimentação, amamentação, utensílios para oferta e consistência do alimento, além de aspectos sociodemográficos e de desenvolvimento global. Foi realizada análise estatística descritiva, apresentada por meio de frequências absoluta e percentual, e medidas de posição e dispersão. Resultados: os 34 cuidadores que compuseram a amostra eram responsáveis por 34 crianças nascidas entre os anos de 2015 e 2018 com diagnóstico de microcefalia de causas diversas. Dessas, 33 (97,02%) alimentaram-se por via oral durante o primeiro ano de vida, sendo que 26 (76,44%) foram amamentadas, nove delas (26,46%) de forma exclusiva até o sexto mês. Para oferta do alimento foram utilizados mamadeira, copo, colher e seringa. A consistência alimentar mais aceita pelas crianças foi a pastosa. Conclusões: observa-se baixa prevalência de aleitamento materno exclusivo até o sexto mês, atraso na progressão de consistências, uso de utensílios inadequados para a idade e necessidade de adaptações para as crianças que se mantiveram em alimentação por via oral.

Microcephalic children due congenital Zika virus syndrome (CZS) present neurological symptoms already well described. However, several other alterations can also be observed. Here, we aimed to evaluate the immune system of microcephaly CZS children. We showed that these patients have enlarged thymus, spleen and cervical lymph nodes, analysed by ultrasound and compared to the reference values for healthy children. In the periphery, they have an increase in eosinophil count and morphological alterations as hypersegmented neutrophils and atypical lymphocytes, even in the absence of urinary tract infections, parasitological infections or other current symptomatic infections. Microcephalic children due CZS also have high levels of IFN-γ, IL-2, IL-4, IL-5 and type I IFNs, compared to healthy controls. In addition, this population showed a deficient cellular immune memory as demonstrated by the low reactivity to the tuberculin skin test even though they had been vaccinated with BCG less than 2 years before the challenge with the PPD. Together, our data demonstrate for the first time that CZS can cause alterations in primary and secondary lymphoid organs and also alters the morphology and functionality of the immune system cells, which broadens the spectrum of CZS symptoms. This knowledge may assist the development of specific therapeutic and more efficient vaccination schemes for this population of patients.

Neurodevelopmental disorder with microcephaly, ataxia, and seizures (NEDMAS) syndrome is a rare neurodevelopmental disorder characterized by moderate intellectual disability (ID), thin body habitus, microcephaly, seizures, ataxia, muscle weakness, and speech impairment. So far, only two families with NEDMAS have been reported. We report the clinical and molecular characteristics of three unrelated Turkish families with four NEDMAS patients. Whole-exome sequencing was used to search for the disease-causing variant. The main manifestations of the probands are severe developmental delay and ID, thin body habitus, and severe hypotonia. Brain imaging revealed bilateral cerebral and cerebellar diffuse atrophy. Sequencing results showed that both patients carried a novel missense variant c.1196C>T (p.Thr399Met) in the seryl-tRNA synthetase gene. Our findings help expand the variant spectrum of NEDMAS and provide additional information for diagnosing cases with atypical features. © 2022 Lippincott Williams and Wilkins. All rights reserved.

To describe the differences in clinical presentation and relative disease burden of congenital Zika syndrome (CZS)-associated microcephaly at 2 large hospitals in Salvador, Brazil that serve patients of different socioeconomic status (SES).Clinical and serologic data were collected prospectively from pregnant women and their infants, who delivered at 2 study centers during the 2015-2016 Zika virus (ZIKV) epidemic in Salvador, Brazil.Pregnant women from Salvador, Brazil delivering in a low SES hospital had 3 times higher ZIKV exposure rate than women at a high SES hospital. However, different SES hospitals had similar prevalence of infants with CZS-associated microcephaly (10% vs 6%, p = 0.16) after controlling for ZIKV exposure in their mothers.Our study supports the positive association between low SES, high maternal ZIKV exposure, and high rates of CZS-associated microcephaly.

TAF8 is part of the transcription factor II D complex, composed of the TATA-binding protein and 13 TATA-binding protein–associated factors (TAFs). Transcription factor II D is the first general transcription factor recruited at promoters to assemble the RNA polymerase II preinitiation complex. So far disorders related to variants in 5 of the 13 subunits of human transcription factor II D have been described. Recently, a child with a homozygous c.781-1G>A mutation in TAF8 has been reported. Here we describe seven further patients with mutations in TAF8 and thereby confirm the TAF8 related disorder.In two sibling patients, we identified two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8. In five further patients, the previously described c.781-1G > A mutation was present on both alleles. The clinical phenotype associated with the different TAF8 mutations is characterized by severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Cerebral imaging showed hypomyelination, a thin corpus callosum and brain atrophy. Moreover, repeated imaging in the sibling pair demonstrated progressive cerebral and cerebellar atrophy. Consistently, reduced N-acetylaspartate, a marker of neuronal viability, was observed on magnetic resonance spectroscopy.Further review of the literature shows that mutations causing a reduced expression of transcription factor II D subunits have an overlapping phenotype of microcephaly, developmental delay and intellectual disability. Although transcription factor II D plays an important role in RNA polymerase II transcription in all cells and tissues, the symptoms associated with such defects are almost exclusively neurological. This might indicate a specific vulnerability of neuronal tissue to widespread deregulation of gene expression as also seen in Rett syndrome or Cornelia de Lange syndrome.

A new syndrome of diabetes, short stature, microcephaly and intellectual disability has been described in association with mutations in the tRNA methyltransferase 10 homologue A (TRMT10A) gene. We report a patient who presented with fasting hyperglycemia, a raised HbA1C and positive islet cell autoantibodies. Additional clinical features included intellectual disability, hypoplastic kidneys and short stature. In view of syndromic features alongside diabetes, genetic evaluation was carried out revealing a homozygous mutation in the TRMT10A gene (c.616G>A, p.G206R). The case highlights the importance of genetic evaluation of patients with diabetes with atypical features that can further progress our understanding of the pathophysiology of the rarer subtypes of diabetes.

Pathogenic variants in CASK, an X-linked gene that plays a role in brain development and synaptic function, are the cause of both microcephaly with pontine and cerebellar hypoplasia (MICPCH), and X-linked intellectual disability (XLID) with or without nystagmus. MICPCH is caused by loss of function variants in CASK, typically affects females, and is associated with moderate-to-severe intellectual disability (ID). Additional findings, present in about one-third of individuals, include feeding difficulties, ophthalmologic issues, hypertonicity, epilepsy, and sensorineural hearing loss. Only a few affected males with MICPCH phenotype have been reported and most have had profound developmental disability and intractable epilepsy. The XLID phenotype is typically caused by missense variants and most often manifests in males; carrier females are mildly affected or unaffected. Nystagmus is often present. In total, over 175 patients have been reported in the literature. We now report an additional 11 patients with pathogenic variants in CASK that expand these phenotypes and reported genotype-phenotype correlations.

Impaired replication has been previously linked to growth retardation and microcephaly; however, why the brain is critically affected compared with other organs remains elusive. Here, we report the differential response between early neural progenitors (neuroepithelial cells [NECs]) and fate-committed neural progenitors (NPs) to replication licensing defects. Our results show that, while NPs can tolerate altered expression of licensing factors, NECs undergo excessive replication stress, identified by impaired replication, increased DNA damage, and defective cell-cycle progression, leading eventually to NEC attrition and microcephaly. NECs that possess a short G1 phase license and activate more origins than NPs, by acquiring higher levels of DNA-bound MCMs. In vivo G1 shortening in NPs induces DNA damage upon impaired licensing, suggesting that G1 length correlates with replication stress hypersensitivity. Our findings propose that NECs possess distinct cell-cycle characteristics to ensure fast proliferation, although these inherent features render them susceptible to genotoxic stress.

To describe the urological outcomes in children with congenital Zika syndrome (CZS) and investigate the relationship between clinical and urological findings in this population.This cross-sectional study involved children with CZS followed up by a referral centre for children with microcephaly in the state of Paraiba in northeast Brazil. The urological evaluation included clinical history, urine culture results, ultrasonography of the urinary tract, and urodynamic evaluation, following the protocol proposed by Costa Monteiro et al. (2017). Descriptive statistical analysis was performed in addition to association and correlation tests, considering clinical and urodynamic variables.Among the 88 children with CZS (35.5 ± 5.5 months), 97.7% had microcephaly, and 51% presented urinary tract infection (UTI) confirmed with clinical history and lab tests. The number of confirmed UTI episodes varied from one to 14 per child. The urodynamic evaluation confirmed the presence of an overactive bladder in 78 children and incomplete voiding in 50. Urodynamic findings were associated with the number of confirmed UTI episodes, child's sex, and actual weight, in addition to the use of anticonvulsant and myorelaxant drugs.UTIs were confirmed in most children. Other urological outcomes observed were overactive bladder and low bladder capacity, which were associated with the number of confirmed UTI episodes, use of anticonvulsants and myorelaxants, and the child's sex and weight. These are treatable conditions, and it is paramount that paediatricians, neonatologists, and infectious disease specialists are aware of them to make clinical decisions and help reduce the risk of renal damage and other morbidities.

To describe ocular findings in infants with signs of congenital Zika virus syndrome (CZS) in Paraíba, Brazil, as well as to conduct a literature review and report correlations with published clinical cases.In the Paraíba sample, infants with microcephaly suggestive of CZS were classified as Z (confirmed), PZ (probable), or SZ (suspected) according to serological testing and/or clinical findings of CZS. The patients underwent a clinical eye examination, and the results were correlated with published clinical cases.Ocular findings were present in 24 (42.9%) of 56 patients, consisting of gross retinal pigmentation in 11 (45.8%), macular chorioretinal atrophy in 11 (45.8%), optic nerve hypoplasia in 1 (4.2%), optic nerve pallor in 14 (58.3%), and increased cup-to-disk ratio in 2 (8.3%). The study revealed retina and optic nerve findings consistent with previous reports of ophthalmic involvement in CZS. However, external ocular changes observed in other studies were not detected.Ocular findings similar and consistent with the literature on CZS were observed with considerable frequency and severity, regardless of the patients' serological confirmation or classification. Infants with signs of CZS should undergo ocular examination.

Pontocerebellar hypoplasia (PCH) type 12 is a rare, perinatal lethal neurodegenerative genetic disorder caused by biallelic mutations in the COASY gene. Herein, we describe the clinical and neuroradiological profile of nine affected fetuses/neonates from five families identified with a common COASY: c.1486-3CG biallelic variant. Four of the five families were identified after data reanalysis of unresolved, severe PCH like phenotype and the fifth family through collaboration. The common antenatal phenotype was cerebellar hypoplasia. Microcephaly, arthrogryposis, and intrauterine growth restriction were the shared postnatal findings. The neurological manifestations included seizures, poor sucking, and spasticity. Novel findings of corpus callosum agenesis, simplified gyral pattern, normal sized pons, optic neuropathy, and a small thorax are reported in this series. The allele frequency of the COASY: c.1486-3CG variant was 0.62% in the available Asian Indian database. We describe this as a possible common Indian origin variant. To the best of our knowledge, this is the largest PCH12 series reported.

We describe a proband evaluated through the Undiagnosed Diseases Network (UDN) who presented with microcephaly, developmental delay, and refractory epilepsy with a de novo p.Ala47Thr missense variant in the protein phosphatase gene, PPP5C. This gene has not previously been associated with a Mendelian disease, and based on the population database, gnomAD, the gene has a low tolerance for loss-of-function variants (pLI = 1, o/e = 0.07). We functionally evaluated the PPP5C variant in C. elegans by knocking the variant into the orthologous gene, pph-5, at the corresponding residue, Ala48Thr. We employed assays in three different biological processes where pph-5 was known to function through opposing the activity of genes, mec-15 and sep-1. We demonstrated that, in contrast to control animals, the pph-5 Ala48Thr variant suppresses the neurite growth phenotype and the GABA signaling defects of mec-15 mutants, and the embryonic lethality of sep-1 mutants. The Ala48Thr variant did not display dominance and behaved similarly to the reference pph-5 null, indicating that the variant is likely a strong hypomorph or complete loss-of-function. We conclude that pph-5 Ala48Thr is damaging in C. elegans. By extension in the proband, PPP5C p.Ala47Thr is likely damaging, the de novo dominant presentation is consistent with haplo-insufficiency, and the PPP5C variant is likely responsible for one or more of the proband's phenotypes.

Zika virus (ZIKV), a flavivirus associated with neurological disorders, constitutes a global health threat. During pregnancy, ZIKV traverses the placenta and causes congenital disease such as microcephaly and Guillain-Barre syndrome in newborns. To develop a specific antiviral therapy against ZIKV-induced microcephaly that could cross placental and blood-brain barriers, we designed targeted small extracellular vesicles (sEVs) encapsulating antiviral siRNA (small interfering RNA) to inhibit ZIKV. The neuro-specific targeting was achieved by engineering EVs membrane protein lamp2b fused with a neuron-specific rabies virus glycoprotein derived peptide (RVG). Intravenous administration of the RVG-engineered sEVs loaded with siRNA (ZIKV-specific siRNA) protected pregnant AG6 mice against vertical transmission of ZIKV. Particularly, sEVsRVG-siRNA traversed placental and blood-brain barriers and suppressed ZIKV infection in fetal brains. Moreover, sEVsRVG-siRNA alleviated the neuroinflammation and neurological damage caused by ZIKV in the fetal mouse model. In general, we developed a sEVs-based targeted system of antiviral therapy for brain and fetal brain infections.

Purpose: to investigate the profile of speech-language-hearing therapists from Northeastern Brazil assisting children presented with congenital Zika syndrome and their perception of these children’s orofacial myofunctional aspects and speech-language-hearing intervention procedures. Methods: a cross-sectional observational study with quantitative/qualitative analysis. The data collection instrument was an online questionnaire with 34 items on the speech-language-hearing therapists’ sociodemographic information and perception of the study topic. The sample comprised 23 speech-language-hearing therapists from the nine Northeastern states. Results: altogether, 96% of the sample were females. Most professionals had more than 3 years of experience with congenital Zika syndrome. Concerning stomatognathic system characterization, the professionals described a greater degree of change in aspects of orofacial muscle posture and mobility. Regarding oral functions, they perceived greater changes in speech and swallowing liquids and solid foods. There was a greater degree of change in masticating solids than in swallowing liquids. Conclusion: most speech-language-hearing therapists in the research had a specialization degree, especially in dysphagia and oral-motor control. Most of them had more than 3 years of experience following up with children with congenital Zika syndrome, which indicates a satisfactory time working with this population to help identify orofacial myofunctional changes in them. The professionals stated that orofacial muscle posture and mobility, speech, and swallowing liquids and solid foods were the most changed aspects. RESUMO Objetivo: investigar o perfil e a percepção de fonoaudiólogos do Nordeste do Brasil, que atuam com crianças com Síndrome Congênita pelo Zika vírus, quanto aos aspectos miofuncionais orofaciais e aos procedimentos de intervenção fonoaudiológica. Métodos: trata-se de estudo transversal, observacional, com análise quanti-qualitativa. O instrumento de coleta de dados tratou-se de um questionárioon-line, que continha 34 questões abrangendo: dados sociodemográficos e questões voltadas para a percepção de fonoaudiólogos no que se refere ao assunto estudado. A amostra foi composta por 23 fonoaudiólogos dos nove estados do Nordeste. Resultados: da amostra, 96% foram mulheres. A maioria dos profissionais apresentava mais de 3 anos de experiência com a Síndrome Congênita pelo Zika Vírus. Na caracterização do sistema estomatognático, os profissionais descreveram maior grau de alteração nos aspectos de postura e mobilidade da musculatura orofacial. Em relação às funções, observou-se maior percepção de alteração na fala e deglutição para líquido e sólido. Conclusão: a maioria dos fonoaudiólogos da pesquisa possuem especialização, com destaque nas áreas de Disfagia e Motricidade Orofacial. Os profissionais afirmaram que a postura e mobilidade da musculatura orofacial são os aspectos mais alterados, assim como as funções de fala e deglutição de sólido e líquido.

International adoption has declined in recent years, although international adoption of children with special needs arises. We aim to describe our experience in international adoption of children with special needs and to analyze the concordance between the pathologies included in pre-adoption reports and the diagnosis made upon arrival. We conducted a retrospective descriptive study including internationally adopted children with special needs evaluated at the reference unit of La Paz University Hospital (Madrid) between 2016-2019. Epidemiological and clinical variables were collected from medical records, and pre-adoption reports were compared to established diagnoses following their evaluation and complementary tests. Fifty-seven children were included: 36.8% females, median of age: 27 months [IQR: 17-39], mostly coming from China (63.2%) and Vietnam (31.6%). The main pathologies described in the pre-adoption reports were hematological (22.6%) and neurological (24.6%). The initial diagnosis that motivated the international adoption via special needs was confirmed in 79.0% of the children. After evaluation, 17.5% were diagnosed with weight and growth delay and 27.4% with microcephaly, not previously reported. Infectious diseases were also prevalent (29.8%). Only 7% provided a complete immunization schedule. Conclusion: According to this series, the pre-adoption reports appear accurate, with a very low rate of new diagnosis. Pre-existing conditions were confirmed in over 75% of cases. Complete evaluation upon arrival, including infectious diseases screening and close follow-up, ideally by experienced multidisciplinary teams in specialized units, is recommended to provide comprehensive care.

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.

TRIO gene; Macrocephaly; Phenotype Gen TRIO; Macrocefàlia; Fenotip Gen TRIO; Macrocefalia; Fenotipo The TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype-to-phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A > G (N1465S) and c.6244-2A > G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype-to-phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues. This work was supported by grants from the Agence Nationale de la Recherche to Anne Debant (ANR-2019 TRIOTISM). Diana Baralle is supported by National Institute for Health Research (NIHR) (RP-2016-07-011) research professorship.

The Drosophila abnormal spindle (asp) gene was discovered about 40 years ago and shown to be required for both mitotic and meiotic cell division. Subsequent studies showed that asp is highly conserved and that mutations in its human ortholog ASPM (Abnormal Spindle-like Microcephaly-associated; or MCPH5) are the most common cause of autosomal recessive primary microcephaly. This finding greatly stimulated research on ASPM and its fly and mouse (Aspm) orthologs. The three Asp orthologous proteins bind the microtubules (MTs) minus ends during cell division and also function in interphase nuclei. Investigations on different cell types showed that Asp/Aspm/ASPM depletion disrupts one or more of the following mitotic processes: aster formation, spindle pole focusing, centrosome-spindle coupling, spindle orientation, metaphase-to-anaphase progression, chromosome segregation, and cytokinesis. In addition, ASPM physically interacts with components of the DNA repair and replication machineries and is required for the maintenance of chromosomal DNA stability. We propose the working hypothesis that the asp/Aspm/ASPM genes play the same conserved functions in Drosophila, mouse, and human cells. Human microcephaly is a genetically heterogeneous disorder caused by mutations in 30 different genes that play a variety of functions required for cell division and chromosomal DNA integrity. Our hypothesis postulates that ASPM recapitulates the functions of most human microcephaly genes and provides a justification for why ASPM is the most frequently mutated gene in autosomal recessive primary microcephaly.

Phelan–McDermid syndrome (PMS) is a multisystem disorder that is associated with deletions of the 22q13 genomic region or pathogenic variants in the SHANK3 gene. Notable features include developmental issues, absent or delayed speech, neonatal hypotonia, seizures, autism or autistic traits, gastrointestinal problems, renal abnormalities, dolichocephaly, and both macro- and microcephaly. Assessment of the genetic factors that are responsible for abnormal head size in PMS has been hampered by small sample sizes as well as a lack of attention to these features. Therefore, this study was conducted to investigate the relationship between head size and genes on chromosome 22q13. A review of the literature was conducted to identify published cases of 22q13 deletions with information on head size to conduct a pooled association analysis. Across 56 studies, we identified 198 cases of PMS with defined deletion sizes and head size information. A total of 33 subjects (17%) had macrocephaly, 26 (13%) had microcephaly, and 139 (70%) were normocephalic. Individuals with macrocephaly had significantly larger genomic deletions than those with microcephaly or normocephaly (p < 0.0001). A genomic region on 22q13.31 was found to be significantly associated with macrocephaly with CELSR1, GRAMD4, and TBCD122 suggested as candidate genes. Investigation of these genes will aid the understanding of head and brain development.

Primary microcephaly and Seckel syndrome are rare genetically and clinically heterogenous brain development disorders. Several exonic/splicing mutations are reported for these disorders to date, but ∼40% of all cases remain unexplained. We aimed to uncover the genetic correlate(s) in a family of multiple siblings with microcephaly. A novel homozygous intronic variant (NC_000013.10:g.25459823TC) in CENPJ (13q12) segregating with all four affected male siblings was identified by exome sequencing and validated by targeted linkage approach (logarithm of the odds score 1.8 at θ 0.0). RT-PCR of CENPJ in affected siblings using their EBV derived cell lines showed aberrant transcripts suggestive of exon skipping confirmed by Sanger sequencing. Significantly reduced wild type transcript/protein in the affected siblings having the splice variant indicates a leaky gene expression of pathological relevance. Based on known CENPJ function, assessing for mitotic alterations revealed defect in centrosome duplication causing mono/multicentrosome(s) at prophase, delayed metaphase, and unequal chromosomal segregation in patient cells. Clinical features witnessed in this study expand the spectrum of CENPJ-associated primary microcephaly and Seckel syndrome. Furthermore, besides the importance of regulatory variants in classical monogenic disorders these findings provide new insights into splice site biology with possible implications for ASO-based therapies.

TRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities.Exome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients' blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics.All 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites.We identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.

Improper expansion of neural stem and progenitor cells during brain development manifests in primary microcephaly. This disease is characterized by a reduced head circumference, which correlates with a reduction in brain size. This often corresponds to a general underdevelopment of the brain and entails cognitive, behavioral and motoric retardation. In the past decade significant research efforts have been undertaken to identify genes and the molecular mechanisms underlying microcephaly. One such gene set encompasses factors required for DNA replication. Intriguingly, a growing body of evidence indicates that a substantial number of these genes mediate faithful centrosome and cilium function in addition to their canonical function in genome duplication. Here, we summarize, which DNA replication factors are associated with microcephaly syndromes and to which extent they impact on centrosomes and cilia.

The US Zika Pregnancy and Infant Registry (USZPIR) monitors infants born to mothers with confirmed or possible Zika virus infection during pregnancy. The surveillance case definition for Zika-associated birth defects includes microcephaly based on head circumference (HC).We assessed birth and follow-up data from infants with birth HC measurements3rd percentile and birthweight ≥10th percentile to determine possible misclassification of microcephaly. We developed a schema informed by literature review and expert opinion to identify possible HC measurement inaccuracy using HC growth velocity and longitudinal HC measurements between 2 and 12 months of age. Two or more HC measurements were required for assessment. Inaccuracy in birth HC measurement was suspected if growth velocity was3 cm/month in the first 3 months or HC was consistently25th percentile during follow-up.Of 6,799 liveborn infants in USZPIR, 351 (5.2%) had Zika-associated birth defects, of which 111 had birth HC measurements3rd percentile and birthweight ≥10th percentile. Of 84/111 infants with sufficient follow-up, 38/84 (45%) were classified as having possible inaccuracy of birth HC measurement, 19/84 (23%) had HC ≥3rd percentile on follow-up without meeting criteria for possible inaccuracy, and 27/84 (32%) had continued HC3rd percentile. After excluding possible inaccuracies, the proportion of infants with Zika-associated birth defects including microcephaly decreased from 5.2% to 4.6%.About one-third of infants in USZPIR with Zika-associated birth defects had only microcephaly, but indications of possible measurement inaccuracy were common. Implementation of this schema in longitudinal studies can reduce misclassification of microcephaly.

Regulator of telomere elongation helicase 1 (RTEL1) is an Fe-S cluster containing DNA helicase that plays important roles in telomere DNA maintenance, DNA repair, and genomic stability. It is a modular protein comprising an N-terminal helicase domain, two tandem harmonin homology domains 12 (HHD1 and HHD2), and a C-terminal C4C4 type RING domain. The N-terminal helicase domain disassembles the telomere t/D-loop and unwinds the G-quadruplex via its helicase activity. The C-terminal RING domain interacts with telomere DNA binding protein TRF2 and helps RTEL1 recruitment to the telomere. The tandem HHD1 and HHD2 are characterized as a putative protein-protein interaction domain and have recently been shown to interact with a DNA repair protein SLX4. Several mutations associated with Hoyeraal-Hreidarsson syndrome and pulmonary fibrosis have been found in HHD1 and HHD2 of RTEL1. However, these domains have not been characterized for their structures. We have expressed and purified HHD1 and HHD2 of human RTEL1 for their characterization using solution NMR spectroscopy. Here, we report near complete backbone and sidechain

DYRK1A haploinsufficiency syndrome is a well-established neurodevelopmental disorder, but detailed information on the range of cognitive and behavioral issues associated with the condition is limited. We studied 24 participants with likely pathogenic or pathogenic variants in DYRK1A through the Simons Searchlight study and systematically assessed their medical history and development using standardized instruments: Vineland Adaptive Behavior Scale II (VABS-II) and Child Behavior Checklists/1.5-5 and 6-18 (CBCL/1.5-5, CBCL/6-18). All of the individuals in the cohort had neurological manifestations including intellectual disability or developmental delay, microcephaly, autism spectrum disorder, and/or seizures. The severity of the neurodevelopmental disorder was variable with a few children scoring in the moderately low range on the adaptive behavior composite score on the VABS-II. This study confirms the association of DYRK1A haploinsufficiency with neurodevelopmental disabilities, microcephaly, autism spectrum disorder, and epilepsy and quantifies the range of adaptive behaviors.

The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus because four of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A) and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders and microcephaly. Using structural molecular modelling and functional testing of the variants in a cell-based Saccharomyces cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway. In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.

Resumo Objetivo: Compreender as expectativas de mães de crianças com síndrome congênita do vírus zika sobre as atribuições dos gestores direcionadas à assistência integral à criança. Materiais e métodos: Estudo qualitativo realizado a partir das entrevistas em profundidade e do desenho estória-tema com 10 mães em Feira de Santana, Bahia, Brasil, entre setembro e novembro de 2017. Resultados: As expectativas das mães residem em elevar o número de sessões de estimulação precoce e reabilitação; incluir novos métodos de tratamento, como a ecoterapia, a hidroginástica e a fisioterapia avançada; construir centros de reabilitação; qualificar os profissionais da rede de atenção à saúde; inserir, minimamente, os serviços de terapia ocupacional, fisioterapia e fonoaudiologia na rede de saúde do município de residência; assegurar o acesso a órteses, próteses, cadeira de rodas e de banho, além de outros aparelhos de reabilitação, bem como fraldas e medicamentos; desburocratizar o percurso para a concessão do benefício de prestação continuada; definir um modelo de ensino-aprendizagem específico para as crianças. Conclusões: Desconsiderar as expectativas das mães significa sobrecarregá-las de serviços que seriam de responsabilidade legal do Estado, o que repercute no seu adoecimento, além de restringir o desenvolvimento da criança e elevar os casos de judicialização da saúde. Resumen Objetivo: Comprender las expectativas de las madres de niños con síndrome de virus del zika congénito acerca de las atribuciones de los gestores encaminadas al cuidado infantil integral. Materiales y métodos: Estudio cualitativo basado en entrevistas en profundidad y dibujo historia-tema con 10 madres en Feira de Santana, Bahia, Brasil, entre septiembre y noviembre de 2017. Resultados: Las expectativas de las madres son aumentar el número de sesiones de estimulación precoz y rehabilitación; incluir nuevos métodos de tratamiento como ecoterapia, hidrogimnasia y fisioterapia avanzada; construir centros de rehabilitación; calificar los profesionales de la red de atención de salud; integrar, de forma básica, los servicios de terapia ocupacional, fisioterapia y fonoaudiología en la red de salud del municipio de residencia; garantizar el acceso a las ortesis, prótesis, sillas de ruedas y de baño, además de otros dispositivos de rehabilitación, así como pañales y medicamentos; reducir la burocracia para otorgar el beneficio de servicio continuo; definir un modelo de enseñanza-aprendizaje específico para niños. Conclusiones: ignorar las expectativas de las madres significa sobrecargarlas de servicios que serían responsabilidad legal del Estado, afectando su enfermedad, además de restringir el desarrollo del niño y aumentar los casos de judicialización de la salud. Abstract Objective: Understand the expectations of the mothers of children with Congenital Zika virus Syndrome on the attributions of the managers directed to integral care to the child. Materials and method: Qualitative study based on in-depth interviews and Story-Theme Design with 10 mothers in Feira de Santana, Bahia, Brazil, between September and November 2017. Results: The expectations of the mothers reside in increasing the number of sessions of early stimulation and rehabilitation; include new treatment methods such as eco-therapy, hydrogymnastics and advanced physiotherapy; building rehabilitation centers; qualify the professionals of the health care network; insert, minimally, the services of Occupational Therapy, Physiotherapy and Speech Therapy in the health network of the municipality of residence; ensure access to orthosis, prosthesis, wheelchairs and bath chairs, and other rehabilitation appliances, as well as materials such as diapers and medicines; to debureaucratize the course for the granting of the continuous benefit; to define a specific teaching-learning model for children. Conclusions: Disregarding the expectations of mothers means overloading them with services that would be the legal responsibility of the State, affecting their illness, in addition to restricting the child's development and increasing cases of judicialization of health.

Intellectual disability is a form of neurodevelopmental disorders that begin in childhood and is characterized by substantial intellectual difficulties as well as difficulties in conceptual, social, and practical areas of living. Several genetic and nongenetic factors contribute to its development; however, its most severe forms are generally attributed to single-gene defects. High-throughput technologies and data sharing contributed to the diagnosis of hundreds of single-gene intellectual disability subtypes.We applied exome sequencing to identify potential variants causing syndromic intellectual disability in six Sudanese patients from four unrelated families. Data sharing through the Varsome portal corroborated the diagnosis of one of these patients and a Tunisian patient investigated through exome sequencing. Sanger sequencing validated the identified variants and their segregation with the phenotypes in the five studied families.We identified three pathogenic/likely pathogenic variants in CCDC82, ADAT3, and HUWE1 and variants of uncertain significance in HERC2 and ATP2B3. The patients with the CCDC82 variants had microcephaly and spasticity, two signs absent in the two previously reported families with CCDC82-related intellectual disability.In conclusion, we report new patients with pathogenic mutations in the genes CCDC82, ADAT3, and HUWE1. We also highlight the possibility of extending the CCDC82-linked phenotype to include spastic paraplegia and microcephaly.

Transplacental transmission of Zika virus has been reported during all trimesters of pregnancy and might lead to central nervous system anomalies, including microcephaly. We report 3 cases of perinatal Zika infection identified during the epidemic in Colombia and provide detailed descriptions of clinical features, diagnosis, and neurodevelopmental outcome at 18 months of age (corrected).

In recent years, exome sequencing (ES) has shown great utility in the diagnoses of Mendelian disorders. However, after rigorous filtering, a typical ES analysis still involves the interpretation of hundreds of variants, which greatly hinders the rapid identification of causative genes. Since the interpretations of ES data require comprehensive clinical analyses, taking clinical expertise into consideration can speed the molecular diagnoses of Mendelian disorders. To leverage clinical expertise to prioritize candidate genes, we developed PhenoApt, a phenotype-driven gene prioritization tool that allows users to assign a customized weight to each phenotype, via a machine-learning algorithm. Using the ability to rank causative genes in top-10 lists as an evaluation metric, baseline analysis demonstrated that PhenoApt outperformed previous phenotype-driven gene prioritization tools by a relative increase of 22.7%-140.0% in three independent, real-world, multi-center cohorts (cohort 1, n = 185; cohort 2, n = 784; and cohort 3, n = 208). Additional trials showed that, by adding weights to clinical indications, which should be explained by the causative gene, PhenoApt performance was improved by a relative increase of 37.3% in cohort 2 (n = 471) and 21.4% in cohort 3 (n = 208). Moreover, PhenoApt could assign an intrinsic weight to each phenotype based on the likelihood of its being a Mendelian trait using term frequency-inverse document frequency techniques. When clinical indications were assigned with intrinsic weights, PhenoApt performance was improved by a relative increase of 23.7% in cohort 2 and 15.5% in cohort 3. For the integration of PhenoApt into clinical practice, we developed a user-friendly website and a command-line tool.

Neocortex development comprises of a complex series of time- and space-specific processes to generate the typical interconnected six-layered architecture of adult mammals. Axon growth is required for the proper establishment of cortical circuits. Malformations in axonal growth and pathfinding might lead to severe neuropathologies, such as corpus callosum dysgenesis. Cenpj, a microcephaly gene, encodes a scaffold protein that regulates centrosome biogenesis and microtubule stabilization. During corticogenesis, Cenpj regulates progenitor division and neuronal migration. Since microtubule stabilization is crucial for axon extension, we investigated the role of Cenpj in axon growth during cortical development in a mouse model. Through loss- and gain-of-function assays ex vivo and in utero, we quantified callosal axonal length, branching, and growth cone size compared to controls. We observed that silencing Cenpj results in an increased axonal length. Ex vivo, we assessed the number of branches, the area of growth cones and the stability of microtubules. In silenced Cenpj axons, there were more branches, larger growth cone area, and more stable microtubules. Rescue experiments confirmed that neurons present axonal length comparable to controls. Here we propose that Cenpj regulates axon growth by destabilizing microtubules during cortical development. Finally, our findings suggest that Cenpj might be a novel target for axonal regeneration.

IntroductionGestational weight gain (GWG) is associated with fetal and newborn health; however, data from sub-Saharan Africa are limited.MethodsWe used data from a prenatal micronutrient supplementation trial among a cohort of HIV-negative pregnant women in Dar es Salaam, Tanzania to estimate the relationships between GWG and newborn outcomes. GWG adequacy was defined as the ratio of the total observed weight gain over the recommended weight gain based on the Institute of Medicine body mass index (BMI)-specific guidelines. Newborn outcomes assessed were: stillbirth, perinatal death, preterm birth, low birthweight, macrosomia, small-for-gestational age (SGA), large-for-gestational age (LGA), stunting at birth, and microcephaly. Modified Poisson regressions with robust standard error were used to estimate the relative risk of newborn outcomes as a function of GWG adequacy.ResultsOf 7561 women included in this study, 51% had severely inadequate (ConclusionInterventions to support optimal gestational weight gain are needed and are likely to improve newborn outcomes.

Centrosomal protein 152 (Cep152) regulates centriole duplication as a molecular scaffold during the cell cycle. Its gene abnormalities are responsible for autosomal recessive primary microcephaly 9 and Seckel syndrome. In this study, we prepared an antibody against mouse Cep152, anti-Cep152, and performed expression analyses focusing on mouse brain development. Western blotting analyses revealed that Cep152 with a molecular mass of ∼150 kDa was expressed strongly at embryonic day (E)13 and then gradually decreased during the brain development process. Instead, protein bands of ∼80 kDa and ∼60 kDa came to be recognized after postnatal day (P)15 and P30, respectively. In immunohistochemical analyses, Cep152 was enriched in the centrosome of neuronal progenitors in the ventricular zone at E14, whereas it was diffusely distributed mainly in the cytoplasm of cortical neurons at P18. In developing cerebellum at P7, Cep152 was localized at the centrosome in the external granular layer, where neurogenesis takes place. Notably, biochemical analysis revealed that Cep152 was also present in the postsynaptic density fraction. Subsequent immunofluorescent analyses showed co-localization of Cep152 with excitatory synaptic markers, PSD95 and synaptophysin, but not with an inhibitory synaptic marker gephyrin in differentiated primary cultured hippocampal neurons. The obtained results suggest that Cep152 takes part not only in neurogenesis during corticogenesis but also in the regulation of synaptic function in differentiated neurons.

We report the case of the third patient with Tsukahara-Azuno-Kaiji syndrome. It is characterized by brachydactyly A1, dwarfism, microcephaly, scoliosis, intellectual disability, ptosis, and hearing loss. The first patient was reported in 1989, and the second in 2010. The present patient had many features in common with the previous 2 patients, with a few minor differences. Although this combination of symptoms is very characteristic, the clinicians should know about this syndrome to diagnose it. The syndrome in this patient appeared sporadically, and chromosome G-banding revealed a normal female karyotype of 46XX. However, further genetic research could not be performed. Steady accumulation of information will enable us to discover the true clinical and genetic nature of the disease and to make the diagnosis more easily.

Introduction: Premature infants are exceptionally vulnerable to nutrition-related diseases, and the utilization of standardized feeding guidelines may reduce nutritional practice variation, which can promote growth. Nutritional risk screening is the first step for standardized nutrition advice. However, risk screening tools specific for following up preterm infants are scarce. Hence, our study aimed to develop and evaluate a standardized Nutritional Risk Screening Tool for Preterm Infants (NRSP subscale 1) from birth to corrected age four months old . Methods: This study was a two-phase (the development phase and evaluation phase) study. Initially, we used the Delphi expert consultation method to create NRSP subscale 1. Then, a professional panel interviewed the participated preterm infants using the screening tool, measured anthropometric parameters, and conducted an intellectual development test on the interview day and remeasured anthropometric parameters 2 weeks or 1 month after the first interview. In the development phase, we cross-tabulated the responses to the screening tool with the classifications of z-scores of the body weight, length, or head circumference to identify significant predictors of underweight, stunting, or microcephaly. We then combined significant predictors to produce models for predicting underweight, stunting, or microcephaly by multivariate logistic regression analysis. In the evaluation phase, the area under the curve (AUC), sensitivity, specificity, and correlation coefficient by Spearman’s correlation analysis (rs) between the risk classifications by NRSP subscale 1 and the classifications of the z-scores of the body weight, length, or head circumference were calculated to assess the validity of the screening tool. Intellectual development levels between high and low nutritional risk infants were statistically compared. Results: A total of 219 and 244 preterm infants were included to two phases, respectively. AUC was 0.936 (95% CI: 0.860–1.000, p < 0.001), sensitivity was 0.667, specificity was 0.941, rs = 0.407 (p < 0.001); AUC was 0.794 (95% CI: 0.638–0.951, p = 0.002), sensitivity was 0.500, specificity was 0.953, rs = 0.339 (p < 0.001); AUC was 0.831 (95% CI: 0.737–0.925, p = 0.001), sensitivity was 0.889, specificity was 0.643, rs = 0.215 (p = 0.001) in predicting underweight, stunting, and microcephaly on the interview day, respectively. AUC was 0.905 (95% CI: 0.826–0.984, p = 0.006), sensitivity was 0.500, specificity was 0.905, rs = 0.504 (p < 0.001); AUC was 0.738 (95% CI: 0.515–0.960, p = 0.034), sensitivity was 0.429, specificity was 0.848, rs = 0.382 (p < 0.001); AUC was 0.664 (95% CI: 0.472–0.856, p = 0.071), sensitivity was 0.455, specificity was 0.809, rs = 0.169 (p = 0.037) in predicting underweight, stunting, and microcephaly 2 weeks or 1 month after the first interview, respectively. Gross motor development quotients (DQs) (95.85 [32.87] vs. 86.29 [17.19], p = 0.022), fine motor DQs (115.77 [46.03] vs. 102.12 [20.27], p = 0.010), and verbal DQs (110.73 [35.27] vs. 100.63 [21.28], p = 0.042) were higher in low nutritional risk infants than high-risk ones. Conclusion: NRSP subscale 1 was acceptable and reliable in predicting underweight, but the validity in predicting stunting or microcephaly was slightly mild. Further investigations are required to authenticate NRSP subscale 1’s effectiveness.

Ribosome RNA (rRNA) accounts for more than 80% of the cell's total RNA, while the physiological functions of rRNA modifications are poorly understood. Mutations of 18S rRNA m6A methyltransferase METTL5 cause intellectual disability, microcephaly, and facial dysmorphisms in patients, however, little is known about the underlying mechanisms. In this study, we identified METTL5 protein complex and revealed that METTL5 mainly interacts with RNA binding proteins and ribosome proteins. Functionally, we found that Mettl5 knockout in mESCs leads to the abnormal craniofacial and nervous development. Moreover, using Mettl5 knockout mouse model, we further demonstrated that Mettl5 knockout mice exhibit intellectual disability, recapitulating the human phenotype. Mechanistically, we found that Mettl5 maintains brain function and intelligence by regulating the myelination process. Our study uncovered the causal correlation between mis-regulated 18S rRNA m6A modification and neural function defects, supporting the important physiological functions of rRNA modifications in human diseases.