[Mitochondrial pyruvate carrier deficiency: 3 cases report and literature review].

Objective: To analyze the clinical and genetic features of patients with mitochondrial pyruvate carrier deficiency (MPYCD). Methods: This was a case series research. The clinical data, genetic characteristics, and glutamine treatment efficacy of 3 patients diagnosed with MPYCD at the Department of Neurology, Beijing Children's Hospital, Capital Medical University and Department of Pediatrics, Guizhou Provincial People's Hospital, from August 2019 to June 2023 were retrospectively collected. A literature search with "MPC1 gene" "MPC2 gene and" "mitochondrial pyruvate carrier deficiency" as keywords was conducted at the Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure (CNKI) and PubMed (up to June 2023). Clinical and genetic characteristics of patients with MPYCD were summarized. Results: Case 1 was a 3 years and 11 months old boy, while case 2 was a 4 years and 10 months old boy and case 3 was an 8 years and 9 months old girl. Case 2 and case 3 were siblings from one consanguineous family. All 3 patients presented with general developmental delay, growth failure and elevated serum lactate. Cranial magnetic resonance imaging (MRI) showed subtle bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus in case 1, but normal in case 2 and 3. Trio-WES revealed case 1 harboring compound heterozygous missense variants c.208G>A (p.Ala70Thr) and c.290G>A (p.Arg97Gln) in MPC1 gene, while case 2 and 3 revealed a homozygous variant c.290G>A (p.Arg97Gln) in the same gene. All 3 cases were diagnosecl as MPYCD. Clinical symptoms including motor ability, cognition and activity endurance were improved in these 3 patients after taking glutamine for 2 years. A total of 5 articles published in English were reviewed, and no Chinese literature was found. Including these 3 cases, 15 cases were enrolled for analysis. Eleven patients carried MPC1 gene variants and 4 cases carried MPC2 gene variants. Except for 3 cases died during prenatal period, 9 of 12 enrolled born cases were onset before 6 months old. The most common clinical symptoms were mental and motor general developmental delay, microcephaly, growth failure and hypotonia. All patients had elevated blood lactate and pyruvate, but the ratio of lactate/pyruvate was normal. Seven patients performed cranial MRI, 3 exhibited non-specific changes, 2 showed bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus, and 3 were normal. A total of 5 MPC1 gene missense variants and 2 MPC2 gene variants were identified in 15 cases. Conclusions: Onset age of patients with MPYCD is usually within 6 months. The main clinical characteristics are developmental delay, microcephaly and growth failure, accompanied by increased serum lactate and pyruvate. Glutamine supplement could lead to clinical improvements.

Diverse Clinical Phenotypes of CASK-Related Disorders and Multiple Functional Domains of CASK Protein.

CASK-related disorders are a form of rare X-linked neurological diseases and most of the patients are females. They are characterized by several symptoms, including microcephaly with pontine and cerebellar hypoplasia (MICPCH), epilepsy, congenital nystagmus, and neurodevelopmental disorders. Whole-genome sequencing has identified various mutations, including nonsense and missense mutations, from patients with CASK-related disorders, revealing correlations between specific mutations and clinical phenotypes. Notably, missense mutations associated with epilepsy and intellectual disability were found throughout the whole region of the CASK protein, while missense mutations related to microcephaly and MICPCH were restricted in certain domains. To investigate the pathophysiology of CASK-related disorders, research groups have employed diverse methods, including the generation of CASK knockout mice and the supplementation of CASK to rescue the phenotypes. These approaches have yielded valuable insights into the identification of functional domains of the CASK protein associated with a specific phenotype. Additionally, recent advancements in the AI-based prediction of protein structure, such as AlphaFold2, and the application of genome-editing techniques to generate CASK mutant mice carrying missense mutations from patients with CASK-related disorders, allow us to understand the pathophysiology of CASK-related disorders in more depth and to develop novel therapeutic methods for the fundamental treatment of CASK-related disorders.

Deficiency in the omega-3 lysolipid transporter Mfsd2a leads to aberrant oligodendrocyte lineage development and hypomyelination.

Patients with autosomal recessive microcephaly 15 caused by deficiency in the sodium-dependent lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain-containing 2a (Mfsd2a) present with both microcephaly and hypomyelination, suggesting an important role for LPC uptake by oligodendrocytes in the process of myelination. Here we demonstrate that Mfsd2a is specifically expressed in oligodendrocyte precursor cells (OPCs) and is critical for oligodendrocyte development. Single-cell sequencing of the oligodendrocyte lineage revealed that OPCs from OPC-specific Mfsd2a-KO mice (2aOKO mice) underwent precocious differentiation into immature oligodendrocytes and impaired maturation into myelinating oligodendrocytes, correlating with postnatal brain hypomyelination. 2aOKO mice did not exhibit microcephaly, a finding consistent with the notion that microcephaly is the consequence of an absence of LPC uptake at the blood-brain barrier rather than a deficiency in OPCs. Lipidomic analysis showed that OPCs and iOLs from 2aOKO mice had significantly decreased levels of phospholipids containing omega-3 fatty acids, with a corresponding increase in unsaturated fatty acids, the latter being products of de novo synthesis governed by Srebp-1. RNA-Seq indicated activation of the Srebp-1 pathway and defective expression of regulators of oligodendrocyte development. Taken together, these findings indicate that the transport of LPCs by Mfsd2a in OPCs is important for maintaining OPC state to regulate postnatal brain myelination.

Development of a nutritional risk screening tool for preterm children in outpatient settings during a complementary feeding period: a pilot study.

BACKGROUND: A complementary feeding (CF) period is necessary for nutritional and developmental reasons. Preterm children encounter more feeding problems than their term counterparts in the CF period. The goal of this study was to develop a nutritional risk screening tool specific to preterm children (the NRSP) in outpatient settings in the CF period, with the expectation of providing a standardised process to determine feeding problems and subsequently offering targeted nutritional advice. METHODS: This study was a 2-phase study consisting of the development and evaluation phases. In the development phase, the items of the NRSP were initially developed based on references and the Delphi expert consultation method. Second, 329 preterm individuals with corrected ages from 5 to 36 months were enrolled. The participating preterm children were interviewed with the NRSP and anthropometric measurements, and underwent intellectual developmental tests and biochemistry detection (haemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, serum iron, vitamin D). Third, preterm children's anthropometric parameters were remeasured 1 month (for infants whose corrected age was 5-11 months) or 3 months (for children whose corrected age was 12-36 months) after the interview. Data in the development phase were analysed via univariate and binary logistic regression analysis sequentially to assign scores for items of the NRSP and to generate the models to predict underweight, stunting, and microcephaly of the NRSP. In the evaluation phase, another 605 preterm individuals were recruited to undergo the interview, anthropometric measurements, intellectual developmental tests, and biochemistry detection as in the development phase. Interrater reliability, test-retest reliability, area under the curve (AUC), accuracy, sensitivity, specificity, the positive/negative predictive value (P/NPV), the positive/negative likelihood ratio (LR+/-), and the correlation coefficient by Spearman's correlation analysis (rs) were used to assess the reliability and validity of the NRSP. Finally, anthropometric parameters, biochemistry levels, and intellectual development quotients (DQs) from the development and evaluation phases between the high- and low-risk groups classified by the NRSP were compared using a t-test. RESULTS: The κ coefficients of the interrater and test-retest reliability of the NRSP were all above 0.600, which meant that the reliability of the NRSP was moderate to substantial. The NRSP exhibited relatively higher efficiency in predicting underweight and stunting, with AUCs, accuracies, specificities, and NPVs near to or greater than 0.900, sensitivities above 0.600, PPVs above 0.400, LR + s near to or greater than 10, and rss above 0.400. On the other hand, the NRSP manifested a weaker ability in predicting microcephaly, with most of the values of validity indicators lower than those of underweight and stunting prediction. Z scores of body weight, body length and head circumference, as well as DQs, were all higher in the low-risk groups than in the high-risk groups. There were no significant differences with respect to biochemistry levels between the high- and low-risk groups. CONCLUSION: The NRSP shows moderate to substantial reliability and validity in predicting underweight, stunting, and microcephaly. Health care staff should shed light on improving the feeding practices of preterm children with high nutritional risk classified by the NRSP to facilitate their physical growth and intellectual development. More research is expected to promote the NRSP models.

Mismatch Negativity is associated with affective social behavior in microcephaly.

Some children with severe microcephaly related to Zika virus infection show affective social-like behavior, such as smiling and rejection to a stranger's lap. Our objective was to check the association between this behavior and the occurrence of Mismatch Response (MMR) in event-related potentials. Twenty eight microcephalic children, aged 1-3 years, were divided in Affect(+) and Affect(-) groups, according to either the presence or absence of affective social-like behavior, respectively, and underwent the OddBall paradigm with vowels as auditory stimuli. MMR was statistically estimated comparing MMR sample means between both groups. The Affect(+) group significantly differed from the Affect(-) group and, as opposed to the latter, showed MMR as Mismatch Negativity (MMN) in the left occipital, left and right posterior temporal, and (especially) the right and median parietal leads. The relationship observed between MMN and affective social-like behavior suggests that these children may have cognitive mechanisms capable of providing some social interaction, despite their profound neurological dysfunction. MMN diagnostic techniques seem to be promising for the triage of microcephalic subjects regarding cognitive functions and for choosing a strategy for some social adaptation.

Itinerários Terapêuticos de familiares de crianças com Síndrome Congênita pelo Zika Vírus de uma cidade da região metropolitana de Salvador/Bahia / Therapeutic Journeys of family members of children with Congenital Zika Syndrome in the metropolitan region of Salvador/Bahia / Rutas terapéuticas de familiares de niños con síndrome congénito por el virus Zika en una ciudad de la zona metropolitana de Salvador/Bahia

Introdução: As condições de vida e saúde de crianças com Síndrome Congênita pelo Zika vírus (SCZV) constituem importante questão de Saúde Pública. As alterações no neurodesenvolvimento impactam na vida familiar e implicam cuidados multi e interdisciplinares. São necessários estudos de itinerários terapêuticos dos familiares em busca de assistência à saúde e educação. Objetivo: Conhecer os itinerários terapêuticos de familiares de crianças com SCZV de uma cidade da região metropolitana de Salvador/Bahia. Método: Estudo descritivo e transversal de abordagem qualitativa. Foram gravados, transcritos e analisados vídeos de entrevistas com oito familiares. Estabeleceram-se eixos temáticos: conhecimento e impacto do diagnóstico, busca e suporte no cuidado em saúde e inclusão educacional. Resultados: O conhecimento do diagnóstico da SCZV ocorreu depois do parto, para maioria dos familiares. Todos receberam orientação e encaminhamentos, principalmente, de profissionais da rede pública de saúde. As crianças foram encaminhadas para diferentes especialidades. Receberam prioridade em atendimento emergencial. Algumas participantes referiram angústia ao receber o diagnóstico, mudanças na dinâmica e vida familiar, longa espera para cadeira de rodas, dificuldades de acesso às instituições especializadas pela distância e falta de transporte e problemas na inclusão educacional por falta de auxiliares de sala. A maioria apontou o apoio de parentes e amigos. Conclusão: Os achados evidenciam os impactos dos itinerários terapêuticos na vida dessas famílias e as dificuldades enfrentadas pelas repercussões no neurodesenvolvimento das crianças na busca pela assistência. Os resultados contribuem para formulações de políticas públicas consonantes às necessidades dessas crianças.

Introduction: The living and health conditions of children with Congenital Zika Syndrome (CZS) are an important public health issue. Neurodevelopment changes impact family life and imply multi and interdisciplinary care.  Therefore, studies on the therapeutic journeys of family members in search for health care and education are needed. Objective: To investigate the therapeutic journeys of family members of children with SCZV in the metropolitan region of Salvador/Bahia. Methods: Descriptive and cross-sectional study with a qualitative approach, including recording, transcribing and analyzing videos of interviews with eight family members. The following thematic axes were defined: knowledge and impact of diagnosis, search and support in healthcare and educational inclusion. Results: Most family members became aware of the diagnosis of CZS only after the birth. All received guidance and referrals, mainly from public health professionals. The children were referred to different specializations and received priority assistance. Some participants reported anguish receiving the diagnosis, changes in dynamics and family life, long waiting for a wheelchair, difficulties to access specialized institutions due to distance and lack of transportation, and problems in educational inclusion due to the lack of classroom assistants. Most family members reported having support from relatives and friends. Conclusion: The findings show the impacts of therapeutic journeys on the lives of these families and the difficulties faced due to the effects on the neurodevelopment of children in search for assistance. The results suggest the need to formulate public policies in line with the needs of these children.

Introducción: Las condiciones de vida y de salud de los niños con síndrome congénito por el virus Zika congénito (SCZV) son un importante problema de salud pública. Los cambios del neurodesarrollo impactan la vida familiar y implican cuidados multidisciplinarios y interdisciplinarios. Son necesarios estudios sobre rutas terapéuticas de los familiares en busca de atención sanitaria y educación. Objetivo: Conocer las rutas terapéuticas de familiares de niños con SCZV en una ciudad de la zona metropolitana de Salvador/Bahia. Métodos: Estudio descriptivo y transversal con abordaje cualitativo. Las entrevistas de ocho familiares fueron videograbadas, transcritas y analizadas. Se establecieron ejes temáticos: conocimiento y impacto del diagnóstico, búsqueda y apoyo en salud y educación inclusiva. Resultados: El conocimiento del diagnóstico de SCZV ocurrió después del parto para la mayoría de los familiares. Todos recibieron orientación y derivaciones, principalmente de profesionales de salud pública. Los niños referidos a diferentes especialidades. Recibieron prioridad en la atención. Algunos participantes refirieron angustia al recibir el diagnóstico, cambios en la dinámica y la vida familiar, larga espera por silla de ruedas, dificultades para acceder a instituciones especializadas por la distancia y falta de transporte y educación inclusiva por falta del maestro asistente. La mayoría señaló el apoyo de familiares y amigos. Conclusión: Hallazgos muestran lo impacto en las rutas terapéuticas en la vida de estas familias y las dificultades frente las repercusiones del neurodesarrollo infantil en la búsqueda de cuidados. Los resultados contribuyen a la formulación de políticas públicas para atender las necesidades de estos niños.

Associations between Gestational Weight Gain Adequacy and Neonatal Outcomes in Tanzania.

INTRODUCTION: Gestational weight gain (GWG) is associated with fetal and newborn health; however, data from sub-Saharan Africa are limited. METHODS: We used data from a prenatal micronutrient supplementation trial among a cohort of human immunodeficiency virus-negative pregnant women in Dar es Salaam, Tanzania to estimate the relationships between GWG and neonatal 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-specific guidelines. Neonatal 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. RESULTS: Of 7,561 women included in this study, 51% had severely inadequate (<70%) or inadequate GWG (70 to <90%), 31% had adequate GWG (90 to <125%), and 18% had excessive GWG (≥125%). Compared to adequate GWG, severely inadequate GWG was associated with a higher risk of low birthweight, SGA, stunting at birth, and microcephaly, whereas excessive GWG was associated with a higher risk of LGA and macrosomia. CONCLUSION: Interventions to support optimal GWG are needed and may contribute to preventing adverse neonatal outcomes.

Transient Receptor Potential Vanilloid 1 (TRPV1) as a plausible novel therapeutic target for treating neurological complications in ZikaVirus.

Zika virus was declared a national emergency by WHO (World Health Organization) in 2016 when its widespread outbreaks and life-threatening complications were reported, especially in newborns and adults. Numerous studies reported that neuroinflammation is one of the significant root-causes behind its major neurological complications like microcephaly and Guillain-Barré syndrome (GBS). In this hypothesis, we propose Transient Receptor Potential Vanilloid 1 channel (TRPV1) as a major culprit in triggering positive inflammatory loop, ultimately leading to sustained neuroinflammation, one of the key clinical findings in Zika induced microcephalic and GBS patients. Opening of TRPV1 channel also leads to calcium influx and oxidative stress that ultimately results in cellular apoptosis (like Schwann cell in GBS and developing fetal nerve cells in microcephaly), ultimately leading to these complications. Currently, no specific cure exists for these complications. Most of the antiviral candidates are under clinical trials. Though there is no direct research on TRPV1 as a cause of Zika virus's neurological complications, but similarity in mechanisms is undeniable. Thus, exploring pathobiological involvement of TRPV1 channels and various TRPV1 modulators in these complications can possibly prove to be an effective futuristic therapeutic strategy for treatment and management of these life-threatening complications.

Excessive Laughter-like Vocalizations, Microcephaly, and Translational Outcomes in the Ube3a Deletion Rat Model of Angelman Syndrome.

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor and balance deficits, impaired communication, and a happy, excitable demeanor with frequent laughter. We sought to elucidate a preclinical outcome measure in male and female rats that addressed communication abnormalities of AS and other neurodevelopmental disorders in which communication is atypical and/or lack of speech is a core feature. We discovered, and herein report for the first time, excessive laughter-like 50 kHz ultrasonic emissions in the Ube3amat-/pat+ rat model of AS, which suggests an excitable, playful demeanor and elevated positive affect, similar to the demeanor of individuals with AS. Also in line with the AS phenotype, Ube3amat-/pat+ rats demonstrated aberrant social interactions with a novel partner, distinctive gait abnormalities, impaired cognition, an underlying LTP deficit, and profound reductions in brain volume. These unique, robust phenotypes provide advantages compared with currently available mouse models and will be highly valuable as outcome measures in the evaluation of therapies for AS.SIGNIFICANCE STATEMENT Angelman syndrome (AS) is a severe neurogenetic disorder for which there is no cure, despite decades of research using mouse models. This study used a recently developed rat model of AS to delineate disease-relevant outcome measures to facilitate therapeutic development. We found the rat to be a strong model of AS, offering several advantages over mouse models by exhibiting numerous AS-relevant phenotypes, including overabundant laughter-like vocalizations, reduced hippocampal LTP, and volumetric anomalies across the brain. These findings are unconfounded by detrimental motor abilities and background strain, issues plaguing mouse models. This rat model represents an important advancement in the field of AS, and the outcome metrics reported herein will be central to the therapeutic pipeline.

Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.

Articulações de mães para o cuidado integral à criança com microcefalia associada ao zika vírus / Articulaciones de madres para el cuidado integral de niños con microcefalia asociada al virus zika / Articulations of mothers for the comprehensive care of children with microcephaly associated with zika virus

RESUMO Objetivo: evidenciar as articulações realizadas por mães em busca do cuidado integral à criança com microcefalia associada ao Zika vírus. Método: pesquisa qualitativa, realizada com 10 mães de crianças com microcefalia associada ao Zika vírus acompanhadas em dois serviços especializados de referência em uma capital do Nordeste brasileiro. As entrevistas ocorreram no período de julho a setembro de 2018 e foram interpretadas pela análise temática à luz do conceito de gestão do cuidado. Resultados: as mães assumem o cuidado ao filho com microcefalia e constroem suas redes de apoio para se readaptar à nova rotina. Na rede social, mobilizam familiares, comunidade e grupo de mães para apoiá-las. A falta de resolutividade do cuidado à criança com microcefalia associada ao Zika vírus e sua família faz com que as próprias mães realizem as articulações necessárias no contexto comunitário e nas redes de atenção à saúde, buscando prover as especificidades de cuidado de seu filho. Nos serviços de saúde, deparam-se com dificuldades na operacionalização da integralidade do cuidado. Considerações finais: torna-se imprescindível o engajamento direto de gestores e profissionais de saúde acenando para ações que superem a fragmentação habitual dos serviços e levem à efetivação da gestão do cuidado para uma reestruturação da rede a fim de torná-la forte o suficiente para suprir as demandas dessa população.

RESUMEN Objetivo: mostrar las articulaciones que realizan las madres en busca de una atención integral a los niños con microcefalia asociada al virus Zika. Método: investigación cualitativa, realizada con 10 madres de niños con microcefalia asociada al virus Zika seguidos en dos servicios de referencia especializados en una capital del nordeste de Brasil. Las entrevistas tuvieron lugar de julio a septiembre de 2018 y fueron interpretadas mediante análisis temático a la luz del concepto de gestión del cuidado. Resultados: las madres cuidan al niño con microcefalia y construyen sus redes de apoyo para readaptarse a la nueva rutina. En la red social, movilizan a familiares, comunidad y un grupo de madres para apoyarlos. La falta de determinación en el cuidado de los niños con microcefalia asociada al virus Zika y su familia hace que las propias madres realicen las articulaciones necesarias en el contexto comunitario y en las redes de atención de salud, buscando brindar la especificidad de la atención a su hijo. En los servicios de salud, enfrentan dificultades para operacionalizar la atención integral. Consideraciones finales: el involucramiento directo de los gerentes y profesionales de la salud es fundamental, apuntando a acciones que superen la habitual fragmentación de los servicios y conduzcan a la efectividad de la gestión asistencial para una reestructuración de la red con el fin de fortalecerla para atender las demandas de esta población.

ABSTRACT Objective: to show the articulations performed by mothers in search of comprehensive care for children with microcephaly associated with the Zika virus. Method: qualitative research, carried out with 10 mothers of children with microcephaly associated with Zika virus followed up in two specialized reference services in the capital of Northeastern Brazil. The interviews took place from July to September 2018 and were interpreted by thematic analysis based on the concept of care management. Results: mothers take care of the child with microcephaly and build their support networks to readjust to the new routine. In the social network, they mobilize family members, the community, and a group of mothers to support them. The lack of resoluteness in the care of children with microcephaly associated with the Zika virus and their families makes the mothers carry out the necessary articulations in the community context and health care networks, seeking to provide the specifics of care for their child. In health services, they face difficulties in the operationalization of comprehensive care. Final considerations: the direct engagement of managers and health professionals is essential, pointing to actions that overcome the usual fragmentation of services and lead to the effectiveness of care management for a restructuring of the network to make it strong enough to supply the demands of this population.

Seguimento de crianças com microcefalia associada ao zika na atenção primária à saúde: o olhar materno / Follow-up of children with zika-associated microcephaly in primary health care: the maternal look / Seguimiento de niños con microcefalia asociada al zika en atención primaria de salud: mirada materna

Objetivo: Analisar o seguimento de crianças com microcefalia na Atenção Primária à Saúde, segundo relato de mães. Método: Pesquisa qualitativa, realizada com nove mães de crianças com microcefalia de um município de grande porte da Paraíba, por meio de entrevista semiestruturada. A interpretação dos dados seguiu os princípios da análise temática. Resultados: As mães relataram receber assistência pouco resolutiva devido à inexistência de uma rede articulada de cuidado em saúde; não valorizam o acompanhamento da Atenção Primária à Saúde para as crianças com microcefalia, preferindo consultar seus filhos com especialistas, comprometendo a oferta da atenção contínua e integral para a promoção da saúde infantil. Conclusão: É indispensável o fortalecimento da Rede de Atenção à Saúde, com construção de vínculo, tendo a Atenção Primária à Saúde como coordenadora e ordenadora do cuidado à criança com microcefalia

Objective: To analyse the follow-up of children with microcephaly in Primary Health Care, according to mothers report. Method: Qualitative research, conducted with nine mothers of children with microcephaly from a large city of Paraíba, through semi-structured interview. Data interpretation followed the principles of thematic analysis. Results: Mothers reported receiving poor care because of the lack of an articulated health care network; do not value the monitoring of Primary Health Care for children with microcephaly, choosing to consult their children with specialists, compromising the provision of continuous and comprehensive care for the promotion of child health. Conclusion: It is essential to strengthen the Health Care Network, with the construction of a bond, having Primary Health Care as coordinator and orderer of care for children with microcephaly

Objetivo: Comprender el seguimiento de los niños con microcefalia en atención primaria de salud, según el informe de las madres. Método: Investigación cualitativa, realizada con nueve madres de niños con microcefalia de una gran ciudad de Paraíba, por medio de una entrevista semiestructurada. La interpretación de los datos siguió los principios del análisis temático. Resultados: Las madres informaron que recibieron poca atención debido a la falta de una red articulada de atención médica; No valoramos el monitoreo de la Atención Primaria de Salud para niños con microcefalia, prefiriendo consultar a sus hijos con especialistas, comprometiendo la provisión de atención continua e integral para la promoción de la salud infantil. Conclusión: Es esencial fortalecer la Red de Atención Médica, con la construcción de un vínculo, teniendo la Atención Primaria de Salud como coordinador y encargado de la atención de niños con microcefalia

Avaliação de incapacidade em crianças com síndrome congênita pelo zika vírus com idade acima de três anos / Evaluation of disability in children with congenital zika virus syndrome over the age of three

Introdução: Crianças com Síndrome Congênita pelo Zika vírus (SCZV) necessitam de apoio coordenado de saúde, educação e assistência social, com avaliações amplas sobre sua condição de saúde. Contudo, poucos estudos têm por objeto a descrição das experiências relacionadas à incapacidade destas crianças, principalmente nas repercussões em longo prazo. Objetivo: Descrever a incapacidade em crianças com SCZV acompanhadas em um hospital de referência do Estado do Rio de Janeiro. Métodos: Estudo transversal e descritivo, composto por crianças com SCZV em acompanhamento num hospital de referência do Rio de Janeiro com idade acima de três anos. A caracterização da incapacidade foi baseada nos desfechos relacionados aos componentes do sistema da Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF), utilizando os instrumentos das avaliações clínicas e do desenvolvimento motor. Análise dos dados realizada de forma descritiva. Resultados: Amostra de 50 crianças, com mediana da idade de 40 meses, sendo 47 (94%) crianças graves e 46 (92%) com microcefalia. Encontrados prejuízos na estrutura de cabeça e pescoço e em área da pele da maioria dos pacientes, e toda a amostra apresentou alteração em imagem do sistema nervoso central. As funções do corpo mais evidentes que apresentaram prejuízos foram: funções de consciência, tônus muscular e da fala. Limitações de atividade em todas as categorias, porém mais evidente, entre 80% e 94% da amostra, nas transferências posturais e deslocamentos. Sem dados referentes à participação. Os fatores ambientais identificados na maioria da amostra foram o uso de produtos ou substâncias para consumo pessoal e acesso aos serviços de saúde. Conclusão: A distribuição de frequência de incapacidades, especialmente no domínio de atividade motora, em crianças com SCZV permanece elevada após três anos do início da epidemia no Brasil. A apropriação do modelo biopsicossocial de assistência sustentado pela CIF pode ampliar a avaliação e auxiliar o planejamento de das ações de cuidado integral.

Introduction: Children with Congenital Zika Virus Syndrome (CZVS) require coordinated support for health, education, and social assistance, with a comprehensive evaluation of their health condition. Nonetheless, few studies have described, as objective, the experiences related to the disability of these children, especially within the long-term consequences. Objective: To measure the prevalence of disability in children with CZVS followed up at a reference hospital in the State of Rio de Janeiro. Methods: Cross-sectional and descriptive study, composed of children with CZVS being followed up at a reference hospital in Rio de Janeiro over three years of age. The characterization of disability was based on outcomes related to the components of the International Classification of Functioning, Disability, and Health (ICF) framework, using the instruments of clinical and motor development assessments. Data performed under descriptive analysis. Results: Sample of 50 children, with an average age of 40 months, 47 (94%) of whom were children under severe condition and 46 (92%) with microcephaly. Losses were found in the head and neck structure and the skin area of most patients, and the entire sample showed alterations in the image of the central nervous system. The most evident body functions were: functions of consciousness, muscle tone, and speech. Activity limitations in all categories, but more evident, between 80% to 94% of the sample, in postural transfers and displacements. No data regarding participation. The environmental factors identified in most parts of the sample were the use of products or substances for personal consumption and access to health services. Conclusion: The prevalence of disabilities, especially in the motor activity domain, in children with CZVS remained high three years after the beginning of the epidemic in Brazil. The appropriation of the biopsychosocial care model supported by the ICF can expand the evaluation and help in the planning of comprehensive care actions.

Preventive effects of folic acid on Zika virus-associated poor pregnancy outcomes in immunocompromised mice.

Zika virus (ZIKV) infection may lead to congenital microcephaly and pregnancy loss in pregnant women. In the context of pregnancy, folic acid (FA) supplementation may reduce the risk of abnormal pregnancy outcomes. Intriguingly, FA may have a beneficial effect on the adverse pregnancy outcomes associated with ZIKV infection. Here, we show that FA inhibits ZIKV replication in human umbilical vein endothelial cells (HUVECs) and a cell culture model of blood-placental barrier (BPB). The inhibitory effect of FA against ZIKV infection is associated with FRα-AMPK signaling. Furthermore, treatment with FA reduces pathological features in the placenta, number of fetal resorptions, and stillbirths in two mouse models of in utero ZIKV transmission. Mice with FA treatment showed lower viral burden and better prognostic profiles in the placenta including reduced inflammatory response, and enhanced integrity of BPB. Overall, our findings suggest the preventive role of FA supplementation in ZIKV-associated abnormal pregnancy and warrant nutritional surveillance to evaluate maternal FA status in areas with active ZIKV transmission.

A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age.

Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis.

The stem cells of neurogenesis and carcinogenesis share many properties, including proliferative rate, an extensive replicative potential, the potential to generate different cell types of a given tissue, and an ability to independently migrate to a damaged area. This is also evidenced by the common molecular principles regulating key processes associated with cell division and apoptosis. Autosomal recessive primary microcephaly (MCPH) is a neurogenic mitotic disorder that is characterized by decreased brain size and mental retardation. Until now, a total of 25 genes have been identified that are known to be associated with MCPH. The inactivation (yin) of most MCPH genes leads to neurogenesis defects, while the upregulation (yang) of some MCPH genes is associated with different kinds of carcinogenesis. Here, we try to summarize the roles of MCPH genes in these two diseases and explore the underlying mechanisms, which will help us to explore new, attractive approaches to targeting tumor cells that are resistant to the current therapies.

CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.

BACKGROUND: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. METHODS: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. RESULTS: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. CONCLUSION: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. TRIAL REGISTRATION NUMBER: NCT01565005.

Caracterização do potencial evocado auditivo de tronco encefálico em recém-nascidos infectados pelo Zika vírus / Characterization of auditory brainstem response in newborns infected by Zika virus

RESUMO Objetivo Caracterizar as avaliações seqüenciais do potencial evocado auditivo de tronco encefálico em recém-nascidos infectados pelo Zika vírus, correlacionando com a presença de microcefalia e com os sintomas de Zika nas mães durante a gestação. Métodos Estudo descritivo, longitudinal e quantitativo, do qual participaram 20 recém-nascidos, filhos de mães infectadas pelo Zika vírus no período gestacional. Foram analisados os prontuários desses bebês, que passaram por duas avaliações eletrofisiológicas, uma no primeiro mês de vida e outra, após 6 meses. Os dados comparativos foram tabulados e analisados por meio de estatística descritiva e inferencial. Resultados Setenta por cento dos bebês apresentaram microcefalia e 55% das mães tiveram os sintomas da infecção pelo Zika no primeiro trimestre de gestação. Não houve alteração significativa dos limiares eletrofisiológicos em nenhum dos momentos. Houve mudança estatisticamente significativa, principalmente das latências das ondas III e V, entre os exames, caracterizando maturação da via auditiva nos bebês. Não foi encontrada correlação entre a microcefalia e alterações nas latências do PEATE. Conclusão Bebês portadores de Zika apresentaram limiares eletrofisiológicos dentro da normalidade e diminuição das latências absolutas das ondas III e V e interpicos, confirmando a ação citotóxica do Zika. Houve dois casos de piora significativa do limiar eletrofisiológico. Não foi observada correlação entre resultados do PEATE e época de aparecimento dos sintomas durante a gestação, ou a presença de microcefalia.

ABSTRACT Purpose To characterize sequential assessments of auditory brainstem responses in newborns infected by zika virus, correlating with presence of microcephaly and with Zika virus symptoms in mothers during pregnancy. Methods A descriptive, longitudinal and quantitative study, in which 20 newborns, children of mothers infected by Zika virus during pregnancy, participated. Medical records of these babies were analyzed, and they underwent two electrophysiological assessments, one in the first month of life and the other, after 6 months. Comparative data were tabulated and analyzed using descriptive and inferential statistics. Results Seventy percent of babies had microcephaly and 55% of mothers had symptoms of Zika infection in the first trimester of pregnancy. There was no significant alteration in electrophysiological thresholds at any moments. There was a statistically significant change, mainly in the latencies of waves III and V, between the tests, characterizing maturation of the auditory pathway in babies. No correlation was found between microcephaly and changes in ABR latencies. Conclusion Babies with Zika had normal electrophysiological thresholds and decreased absolute latencies of waves III and V and interpeaks, confirming the cytotoxic action of Zika. There were two cases of significant worsening of the electrophysiological threshold. There was no correlation between ABR results and time of onset of the symptoms during pregnancy, or presence of microcephaly.