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1.
Braz. j. biol ; 83: e246040, 2023. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1285610

RESUMO

Abstract Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a congenitally reduced head circumference (-3 to -5 SD) and non-progressive intellectual disability. The objective of the study was to evaluate pathogenic mutations in the ASPM gene to understand etiology and molecular mechanism of primary microcephaly. Blood samples were collected from various families across different remote areas of Pakistan from February 2017 to May 2019 who were identified to be affected with primary microcephaly. DNA extraction was performed using the salting-out method; the quality and quantity of DNA were evaluated using spectrophotometry and 1% agarose gel electrophoresis, respectively in University of the Punjab. Mutation analysis was performed by whole exome sequencing from the Cologne Center for Genomics, University of Cologne. Sanger sequencing was done in University of the Punjab to confirm the pathogenic nature of mutation. A novel 4-bp deletion mutation c.3877_3880delGAGA was detected in exon 17 of the ASPM gene in two primary microcephaly affected families (A and B), which resulted in a frame shift mutation in the gene followed by truncated protein synthesis (p.Glu1293Lysfs*10), as well as the loss of the calmodulin-binding IQ domain and the Armadillo-like domain in the ASPM protein. Using the in-silico tools Mutation Taster, PROVEAN, and PolyPhen, the pathogenic effect of this novel mutation was tested; it was predicted to be "disease causing," with high pathogenicity scores. One previously reported mutation in exon 24 (c.9730C>T) of the ASPM gene resulting in protein truncation (p.Arg3244*) was also observed in family C. Mutations in the ASPM gene are the most common cause of MCPH in most cases. Therefore, enrolling additional affected families from remote areas of Pakistan would help in identifying or mapping novel mutations in the ASPM gene of primary microcephaly.


Resumo Microcefalia primária autossômica recessiva (MCPH) é um distúrbio do neurodesenvolvimento caracterizado por uma redução congênita do perímetro cefálico (-3 a -5 DP) e deficiência intelectual não progressiva. O objetivo do estudo foi avaliar mutações patogênicas no gene ASPM a fim de compreender a etiologia e o mecanismo molecular da microcefalia primária. Amostras de sangue foram coletadas de várias famílias em diferentes áreas remotas do Paquistão de fevereiro de 2017 a maio de 2019, que foram identificadas como afetadas com microcefalia primária. A extração do DNA foi realizada pelo método salting-out; a qualidade e a quantidade de DNA foram avaliadas por espectrofotometria e eletroforese em gel de agarose a 1%, respectivamente, na Universidade de Punjab. A análise de mutação foi realizada por sequenciamento completo do exoma do Cologne Center for Genomics, University of Cologne. O sequenciamento de Sanger foi feito na Universidade do Punjab para confirmar a natureza patogênica da mutação. Uma nova mutação de deleção de 4 bp c.3877_3880delGAGA foi detectada no exon 17 do gene ASPM em duas famílias afetadas por microcefalia primária (A e B), que resultou em uma mutação de frame shift no gene seguida por síntese de proteína truncada (pGlu1293Lysfs * 10), bem como a perda do domínio IQ de ligação à calmodulina e o domínio do tipo Armadillo na proteína ASPM. Usando as ferramentas in-silico Mutation Taster, PROVEAN e PolyPhen, o efeito patogênico dessa nova mutação foi testado; foi previsto ser "causador de doenças", com altos escores de patogenicidade. Uma mutação relatada anteriormente no exon 24 (c.9730C > T) do gene ASPM, resultando em truncamento de proteína (p.Arg3244 *) também foi observada na família C. Mutações no gene ASPM são a causa mais comum de MCPH na maioria dos casos . Portanto, a inscrição de famílias afetadas adicionais de áreas remotas do Paquistão ajudaria a identificar ou mapear novas mutações no gene ASPM da microcefalia primária.


Assuntos
Humanos , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Paquistão , Consanguinidade , Mutação/genética
2.
Cleft Palate Craniofac J ; : 10556656221136177, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36317361

RESUMO

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

3.
Artigo em Inglês | MEDLINE | ID: mdl-36326785

RESUMO

BACKGROUND: Northeast Brazil has the world's highest rate of Zika-related microcephaly. However, Zika case counts cannot accurately describe burden because mandatory reporting was only established when the epidemic was declining in the region. METHODS: To advance the study of the Zika epidemic, we identified hotspots of Zika in Pernambuco state, Northeast Brazil, using Aedes-borne diseases (dengue, chikungunya and Zika) and microcephaly data. We used Kulldorff's Poisson purely spatial scan statistic to detect low- and high-risk clusters for Aedes-borne diseases (2014-2017) and for microcephaly (2015-2017), separately. Municipalities were classified according to a proposed gradient of Zika burden during the epidemic, based on the combination of cluster status in each analysis and considering the strength of the evidence. RESULTS: We identified 26 Aedes-borne diseases clusters (11 high-risk) and 5 microcephaly clusters (3 high-risk) in Pernambuco. According to the proposed Zika burden gradient, our results indicate that the northeast of Pernambuco and the Sertão region were hit hardest by the Zika epidemic. The first is the most populous area of Pernambuco, while the second has one of the highest rates of social and economic inequality in Brazil. CONCLUSION: We successfully identified possible hidden Zika hotspots using a simple methodology combining Aedes-borne diseases and microcephaly information.

4.
Osong Public Health Res Perspect ; 13(5): 341-351, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36328238

RESUMO

Zika virus (ZIKV) was identified in 1947 in a rhesus monkey during an investigation of the yellow fever virus in the Zika Forest of Uganda; it was also isolated later from humans in Nigeria. The main distribution areas of ZIKV were the African mainland and South-East Asia in the 1980s, Micronesia in 2007, and more recently the Americas in 2014. ZIKV belongs to the Flaviviridae family and Flavivirus genus. ZIKV infection, which is transmitted by Aedes mosquitoes, is an emerging arbovirus disease. The clinical symptoms of ZIKV infection are fever, headache, rashes, arthralgia, and conjunctivitis, which clinically resemble dengue fever syndrome. Sometimes, ZIKV infection has been associated with Guillain-Barré syndrome and microcephaly. At the end of 2015, following an increase in cases of ZIKV infection associated with Guillain-Barré syndrome and microcephaly in newborns in Brazil, the World Health Organization declared a global emergency. Therefore, considering the global distribution and pathogenic nature of this virus, the current study aimed at reviewing the virologic features, transmission patterns, clinical manifestations, diagnosis, treatment, and prevention of ZIKV infection.

5.
Genes Genomics ; 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371492

RESUMO

BACKGROUND: Syndromic intellectual disability (ID) with accompanying primary microcephaly is a group of rare neurodevelopmental disorders exhibiting extreme genetic and clinical heterogeneity. This layered heterogeneity can partially be resolved by unbiased genetic approaches targeting the genome with next generation sequencing (NGS) technologies, including exome sequencing (ES). OBJECTIVE: This study was performed to dissect the clinical and genetic features in five distinct IDM cases. METHODS: Singleton or trio ES approach followed by in-depth variant analysis using alternative inheritance models was performed. RESULTS: We have identified biallelic loss of function variants in genes WDR62 and AP4M1 in three families, together with de novo missense variants in genes SOX11 and TRIO in two families. ES based haplotype analysis in two cases upon identification of an identical WDR62 variant in the homozygous state in two cases was suggestive of a small shared haplotype of 0.1 Mb. Additionally, we have shown a paternal origin for the de novo variant in TRIO via a polymorphic tag SNP, which enlightens the mutational mechanism for this variant. CONCLUSION: In populations with high parental consanguinity, an autosomal recessive inheritance pattern for data analysis is usually the most obvious choice. Therefore, heterozygous variants may be overlooked in standard NGS analyses in consanguineous families. Our findings underlie the importance of using multiple inheritance models in NGS data analysis.

6.
Birth Defects Res ; 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36345841

RESUMO

BACKGROUND: Severe microcephaly is a brain reduction defect where the delivery head circumference is <3rd percentile for gestational age and sex with subsequent lifelong morbidities. Our objective was to evaluate survival among 2,704 Texas infants with severe microcephaly delivered 1999-2015. METHODS: Infants with severe microcephaly from the Texas Birth Defects Registry were linked to death certificates and the national death index. Survival estimates, hazard ratios (HR) and confidence intervals (CI) were calculated using the Kaplan-Meier method and Cox proportional hazards models stratified by presence versus absence of co-occurring defects. RESULTS: We identified 496 deaths by age 4 years; most (42.9%) occurred in the neonatal period, and another 39.9% died by 1 year of age. Overall infant survival was 84.8%. Lowest infant survival subgroups included those with chromosomal/syndromic conditions (66.1%), very preterm deliveries (63.9%), or co-occurring critical congenital heart defects (44.0%). Among infants with severe microcephaly and a chromosomal/syndromic co-occurring defect, the risk of death was nearly three-fold higher among those with: proportionate microcephaly (i.e., small baby overall), relative to non-proportionate (HR = 2.84, 95% CI = 2.17-3.71); low-birthweight relative to normal (HR = 2.72, 95% CI = 1.92-3.85); critical congenital heart defects (CCHD) relative to no CCHD (HR = 2.90, 95% CI = 2.20-3.80). Trisomies were a leading underlying cause of death (27.5%). CONCLUSIONS: Overall, infants with severe microcephaly had high 4-year survival rates which varied by the presence of co-occurring defects. Infants with co-occurring chromosomal/syndromic anomalies have a higher risk of death by age one than those without any co-occurring birth defects.

7.
Front Genet ; 13: 955732, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386804

RESUMO

Background: Recently, the hemizygous variation of SSR4 gene has been reported to be associated with congenital disorder of glycosylation type Iy. To date, only 13 patients have been diagnosed with SSR4-CDG in the worldwide, but it has not been reported in the Chinese population. Methods: Whole-exome sequencing and gene copy number variation analysis were used to genetic analysis. The mRNA expression of SSR4 gene in blood was detected by Real-time Quantitative PCR. The clinical manifestations of all patients reported in the literature were reviewed. Results: WES analysis identified a de novo hemizygous variant c.269G>A (p.Trp90*) of SSR4 gene in the proband with psychomotor retardation, microcephaly, abnormal facial features, and nystagmus. This variant has not been reported in previous studies. The in vivo mRNA expression of SSR4 gene in patient was significantly decreased. Literature review showed that all 14 patients, including our patient, presented with hypotonia, intellectual disability, developmental delay, microcephaly, and abnormal facial features, while most patients had feeding difficulties, growth retardation, and ocular abnormalities, and epilepsy and skeletal abnormalities are less common. Conclusion: We reported the first case of SSR4-CDG caused by SSR4 variant in Chinese population, expanded the clinical and mutation spectra of the disorder, clarified the genetic etiology of the patient, and offered support for the prenatal diagnosis of the index family.

8.
Seizure ; 103: 92-98, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36368189

RESUMO

OBJECTIVES: To verify characteristics associated with drug resistant epilepsy in children up to 36 months of age with Congenital Zika Syndrome (CZS). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

9.
BMC Public Health ; 22(1): 2069, 2022 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371150

RESUMO

BACKGROUND: Congenital anomalies are associated with several clinical and epidemiological complications. Following the Zika epidemic onset in Latin America, the incidence of congenital anomalies increased in Brazil. This study aimed to determine the frequency of congenital anomalies in one Brazilian state and assess potential factors associated with them. METHODS: This cross-sectional descriptive study was based on data concerning congenital anomalies recorded in the Brazilian Live-Born Information System during the Zika epidemic in Mato Grosso do Sul state from 2015 to 2018. Congenital anomalies were stratified according to year of birth and classified using ICD-10 categories. RESULTS: In total, 1,473 (0.85%) anomalies were registered. Within the number of cases recorded, microcephaly showed the greatest frequency and variations, with a 420% increase observed in the number of cases from 2015 to 2016. We identified an increase in the incidence of central nervous system anomalies, with the highest peak observed in 2016 followed by a subsequent decrease. Musculoskeletal, nervous, and cardiovascular system anomalies, and eye, ear, face, and neck anomalies represented 73.9% of all recorded anomalies. There was an increased chance of congenital anomalies in uneducated (odds ratio [OR] 5.56, 95% confidence interval [CI] 2.61-11.84) and Indigenous (OR 1.32, 95% CI 1.03-1.69) women, as well as among premature births (OR 2.74, 95% CI 2.39-3.13). CONCLUSIONS: We estimated the incidence of congenital anomalies during the Zika epidemic. Our findings could help to support future research and intervention strategies in health facilities to better identify and assist children born with congenital anomalies.


Assuntos
Microcefalia , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Gravidez , Criança , Feminino , Humanos , Estudos Transversais , Complicações Infecciosas na Gravidez/epidemiologia , Microcefalia/epidemiologia , Brasil/epidemiologia
10.
Eur J Med Genet ; 66(1): 104652, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36374791

RESUMO

The diagnosis of prenatal microcephaly, as well as the possibility of underlining a genetic cause, is becoming more frequent thanks to advances in prenatal imaging and parallel massive sequencing. One case of primary microcephaly in three sibs demonstrates how complementary diagnostic exams can help to diagnose and establish the etiology.

11.
Front Neurol ; 13: 1017654, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341116

RESUMO

RhoGTPase regulators play a key role in the development of the nervous system, and their dysfunction can result in brain malformation and associated disorders. Several guanine nucleotide exchange factors (GEF) have been linked to neurodevelopmental disorders. In line with this, ARHGEF17 has been recently linked as a risk gene to intracranial aneurysms. Here we report siblings of a consanguineous Pakistani family with biallelic variants in the ARHGEF17 gene associated with a neurodevelopmental disorder with intellectual disability, speech delay and motor dysfunction but not aneurysms. Cranial MRI performed in one patient revealed generalized brain atrophy with an enlarged ventricular system, thin corpus callosum and microcephaly. Whole exome sequencing followed by Sanger sequencing in two of the affected individuals revealed a homozygous missense variant (g.11:73021307, c.1624C>T (NM_014786.4), p.R542W) in the ARHGEF17 gene. This variant is in a highly conserved DCLK1 phosphorylation consensus site (I/L/V/F/M]RRXX[pS/pT][I/L/M/V/F) of the protein. Our report expands the phenotypic spectrum of ARHGEF17 variants from increased intracranial aneurysm risk to neurodevelopmental disease and thereby add ARHGEF17 to the list of GEF genes involved in neurodevelopmental disorders.

12.
Front Cardiovasc Med ; 9: 917507, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36277771

RESUMO

Objectives: This study aims to evaluate the school careers of patients with congenital heart disease (CHD) and microcephaly. Methods: An exploratory online survey was conducted on patients from a previous study on somatic development in children with CHD in 2018 (n = 2818). A total of 750 patients participated in the online survey (26.6%). This publication focuses on 91 patients (12.1%) diagnosed with CHD and microcephaly who participated in the new online survey. Results: Microcephaly was significantly associated with CHD severity (p < 0.001). Microcephalic patients suffered from psychiatric comorbidity two times as often (67.0%) as non-microcephalic patients (29.8%). In particular, the percentage of patients with developmental delay, intellectual debility, social disability, learning disorder, or language disorder was significantly increased in microcephalic CHD patients (p < 0.001). A total of 85.7% of microcephalic patients and 47.6% of non-microcephalic patients received early interventions to foster their development. The school enrollment of both groups was similar at approximately six years of age. However, 89.9% of non-microcephalic but only 51.6% of microcephalic patients were enrolled in a regular elementary school. Regarding secondary school, only half as many microcephalic patients (14.3%) went to grammar school, while the proportion of pupils at special schools was eight times higher. Supportive interventions, e.g., for specific learning disabilities, were used by 52.7% of microcephalic patients and 21.6% of non-microcephalic patients. Conclusion: Patients with CHD and microcephaly are at high risk for impaired educational development. Early identification should alert clinicians to provide targeted interventions to optimize the developmental potential.

13.
Trop Med Infect Dis ; 7(10)2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36288003

RESUMO

Congenital microcephaly is caused by a multitude of drivers affecting maternal-fetal health during pregnancy. It is a rare outcome in high-income industrial countries where microcephaly rates are in the range of 0.3-0.9 per 1000 newborns. Prevalence of microcephaly varies considerably across developing countries and can go as high as 58 cases per 1000 live births in pregnancies exposed to infection by Zika virus (ZIKV). Not only ZIKV-infected pregnancies, but other drivers can modulate the occurrence and severity of this outcome. Here, we sought to test the ZIKV-microcephaly association vs. competing hypotheses using a meta-analysis with 8341 microcephaly cases pooled from 10,250,994 newborns in the Americas, Africa, and Asia. Analysis of risk ratios (RR) showed teratogens the most likely microcephaly-associated risk factor (RR = 3.43; 95%-CI 2.69-4.38; p-value < 0.0001), while the statistical significance of the ZIKV-microcephaly association was marginal (RR = 2.12; 95%-CI 1.01-4.48; p-value = 0.048). Other congenital infections showed strong but variable associations with microcephaly (RR = 15.24; 95%-CI 1.74-133.70; p-value = 0.014). Microcephaly cases were associated with impoverished socioeconomic settings, but this association was statistically non-significant (RR = 2.75; 95%-CI 0.55-13.78; p-value = 0.22). The marginal ZIKV-microcephaly association and statistical significance of the competing hypotheses suggest maternal ZIKV infection might not be a cause of microcephaly alone.

14.
Viruses ; 14(10)2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36298663

RESUMO

Understanding functioning and disabilities in children with Congenital Zika Syndrome (CZS) is essential for health planning. We describe disabilities present in children with CZS followed in a reference hospital in Rio de Janeiro, Brazil, based on the biopsychosocial model of the International Classification of Functioning, Disability and Health (ICF). This was a cohort study of children >3 years of age with CZS. Disability was characterized through outcomes related to ICF components assessed via clinical and motor development evaluations. Among 50 children, with a median age of 40 months, 47 (94%) presented with severe impairment and 46 (92%) had microcephaly. Damage to the head and neck was found in most children, with abnormal central nervous system imaging universally present. Most children had cognitive impairment (92%), muscle tone problems (90%), and speech deficits (94%). We found movement limitations in all categories but more pervasively (80-94%), in postural transfers and displacements. The main environmental factors identified in the ICF model were the use of products or substances for personal consumption and access to health services. Children with CZS have extremely high rates of disability beyond aged 3 years, particularly regarding motor activity. ICF-based models can contribute to the assessment of health domains.


Assuntos
Microcefalia , Infecção por Zika virus , Zika virus , Criança , Pré-Escolar , Humanos , Lactente , Infecção por Zika virus/congênito , Estudos de Coortes , Brasil/epidemiologia
15.
Eur J Neurosci ; 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36300719

RESUMO

To compare cell adhesion molecules levels in cerebrospinal fluid (CSF) between Zika virus (ZIKV)-exposed neonates with/without microcephaly (cases) and controls, 16 neonates (cases), 8 (50%) with and 8 (50%) without microcephaly, who underwent lumbar puncture (LP) during the ZIKV epidemic (2015-2016) were included. All mothers reported ZIKV clinical symptoms during gestation, all neonates presented with congenital infection findings, and other congenital infections were ruled out. Fourteen control neonates underwent LP in the same laboratory (2017-2018). Five cell adhesion proteins were measured in the CSF using mass spectrometry. Neurexin-1 (3.50 [2.00-4.00] vs. 7.5 [5.00-10.25], P = 0.001), neurexin-3 (0.00 [0.00-0.00] vs. 3.00 [1.50-4.00], P = 0.001) and neural cell adhesion molecule 2 (NCAM2) (0.00 [0.00-0.75] vs. 1.00 [1.00-2.00], P = 0.001) were significantly lower in microcephalic and non-microcephalic cases than in controls. When these two sub-groups of prenatally ZIKA-exposed children were compared to controls separately, the same results were found. When cases with and without microcephaly were compared, no difference was found. Neurexin-3 (18.8% vs. 78.6%, P = 0.001) and NCAM2 (25.0% vs. 85.7%, P = 0.001) were less frequently found among the cases. A positive correlation was found between cephalic perimeter and levels of these two proteins. Neurexin-2 and neurexin-2b presented no significant differences. Levels of three cell adhesion proteins were significantly lower in CSF of neonates exposed to ZIKV before birth than in controls, irrespective of presence of congenital microcephaly. Moreover, the smaller the cephalic perimeter, the lower CSF cell adhesion protein levels. These findings suggest that low CSF levels of neurexin-1, neurexin-3 and NCAM2 may reflect the effects of ZIKV on foetal brain development.

16.
Int J Mol Sci ; 23(20)2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36293418

RESUMO

The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech. The aim of the present study is to systematically review the available data on the prevalence of clinical manifestations and to evaluate the correlation between phenotype and genotype in published cases of patients with CTNNB1 Syndrome. Studies were identified by systematic searches of four major databases. Information was collected on patients' genetic mutations, prenatal and neonatal problems, head circumference, muscle tone, EEG and MRI results, dysmorphic features, eye abnormalities, early development, language and comprehension, behavioral characteristics, and additional clinical problems. In addition, the mutations were classified into five groups according to the severity of symptoms. The study showed wide genotypic and phenotypic variability in patients with CTNNB1 Syndrome. The most common moderate-severe phenotype manifested in facial dysmorphisms, microcephaly, various motor disabilities, language and cognitive impairments, and behavioral abnormalities (e.g., autistic-like or aggressive behavior). Nonsense and missense mutations occurring in exons 14 and 15 were classified in the normal clinical outcome category/group because they had presented an otherwise normal phenotype, except for eye abnormalities. A milder phenotype was also observed with missense and nonsense mutations in exon 13. The autosomal dominant CTNNB1 Syndrome encompasses a wide spectrum of clinical features, ranging from normal to severe. While mutations cannot be more generally categorized by location, it is generally observed that the C-terminal protein region (exons 13, 14, 15) correlates with a milder phenotype.


Assuntos
Anormalidades do Olho , Deficiência Intelectual , Gravidez , Feminino , Humanos , Códon sem Sentido , Fenótipo , Deficiência Intelectual/complicações , Síndrome , Genótipo , Mutação , Anormalidades do Olho/genética , beta Catenina/genética
17.
Front Med (Lausanne) ; 9: 962765, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36250095

RESUMO

Objective: The aim of this study was to assess the accuracy of prenatal imaging for the diagnosis of congenital Zika syndrome. Data sources: Medline (via Pubmed), PubMed, Scopus, Web of Science, and Google Scholar from inception to March 2022. Two researchers independently screened study titles and abstracts for eligibility. Study eligibility criteria: Observational studies with Zika virus-infected pregnant women were included. The index tests included ultrasound and/or magnetic resonance imaging. The reference standard included (1) Zika infection-related perinatal death, stillbirth, and neonatal death within the first 48 h of birth, (2) neonatal intensive care unit admission, and (3) clinically defined adverse perinatal outcomes. Synthesis methods: We extracted 2 × 2 contingency tables. Pooled sensitivity and specificity were estimated using the random-effects bivariate model and assessed the summary receiver operating characteristic (ROC) curve. Risk of bias was assessed using QUADAS 2 tool. The certainty of the evidence was evaluated with grading of recommendations. Results: We screened 1,459 references and included 18 studies (2359 pregnant women, 347 fetuses with confirmed Zika virus infection). Twelve studies (67%) were prospective cohorts/case series, and six (37%) were retrospective cohort/case series investigations. Fourteen studies (78%) were performed in endemic regions. Ten studies (56%) used prenatal ultrasound only, six (33%) employed ultrasound and fetal MRI, and two studies (11%) used prenatal ultrasound and postnatal fetal MRI. A total of six studies (ultrasound only) encompassing 780 pregnant women (122 fetuses with confirmed Zika virus infection) reported relevant data for meta-analysis (gestation age at which ultrasound imagining was captured ranged from 16 to 34 weeks). There was large heterogeneity across studies regarding sensitivity (range: 12 to 100%) and specificity (range: 50 to 100%). Under a random-effects model, the summary sensitivity of ultrasound was 82% (95% CI, 19 to 99%), and the summary specificity was 97% (71 to 100%). The area under the ROC curve was 97% (95% CI, 72 to 100%), and the summary diagnostic odds ratio was 140 (95% CI, 3 to 7564, P < 0.001). The overall certainty of the evidence was "very low". Conclusion: Ultrasound may be useful in improving the diagnostic accuracy of Zika virus infection in pregnancy. However, the evidence is still substantially uncertain due to the methodological limitations of the available studies. Larger, properly conducted diagnostic accuracy studies of prenatal imaging for the diagnosis of congenital Zika syndrome are warranted. Systematic review registration: Identifier [CRD42020162914].

18.
Am J Med Genet A ; 2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36271814

RESUMO

Hedgehog acyltransferase gene (HHAT)-associated Nivelon-Nivelon-Mabile syndrome (NNMS) is a rare genetic disorder of multiple system involvement with microcephaly, central nervous system malformations, skeletal dysplasia, and 46,XY sex reversal. Other variable and inconsistent features reported in this disorder are muscle spasms, facial dysmorphism, prenatal onset growth restriction, microphthalmia, and holoprosencephaly. This is the sixth postnatal reported patient with biallelic variants in HHAT gene, who presented with microcephaly, short stature, muscle hypertrophy, muscle spasms, and facial dysmorphism. The most prominent and presenting finding in this patient were muscle hypertrophy and muscle spasms which had a clinical response to phenytoin and acetazolamide treatment. Our report emphasizes the phenotypic variability of NNMS and further reiterates muscle spasms as an important clinical manifestation of this extremely rare condition.

19.
Int J Dev Neurosci ; 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36308023

RESUMO

Phosphoglycerate dehydrogenase (PHGDH) deficiency is a rare autosomal recessive genetic disease of serine biosynthesis. Its typical features are congenital microcephaly, epileptic seizures, and psychomotor developmental delay. Here, we reported the first Chinese familial cases with genetically confirmed PHGDH deficiency and reviewed several previous reports. Two siblings in this family presented with microcephaly, psychomotor retardation, and epilepsy in early juvenile. Brain magnetic resonance imaging (MRI) showed only a slight change of enlarged ventricle. Biochemical investigations revealed low serum serine and glycine concentrations. The whole-exome sequencing (WES) results identified a missense variant in the PHGDH gene (NM_006623.4: exon11: c.1211T>A, p. Val404Asp). Although two patients in this Chinese family carried the same pathogenic mutation in the PHGDH, their symptoms and responses to treatment were not exactly the same. We found a novel variant in the PHGDH gene and expanded the genotypic and phenotypic spectrum of serine biosynthesis disorders.

20.
Metab Brain Dis ; 37(8): 3027-3032, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36308585

RESUMO

Seizures in newborn infants may be the first finding of hereditary metabolic diseases. Pyridoxine-dependent epilepsy (PDE) is a treatable disorder associated with defects in the one of ALDH7A1, PNPO, or PLPBP genes and it is uncommon but progresses with persistent seizures in the neonatal and infancy period. The seizures are generally resistant to traditional antiepileptic drugs and show a dramatic response to high-dose pyridoxine. In 2016, mutations were reported in PLPBP (previously known as PROSC) gene, which encodes pyridoxal phosphate homeostatic protein (PLPHP).When early-onset antiepileptic resistant seizures are not treated, clinical findings emerge including the development of encephalopathy, congenital microcephaly, and subsequent retardation of psychomotor development. The present case is a 33-month-old female infant with seizures starting from postnatal day 1, who did not respond to traditional anti-epileptic drugs but responded to pyridoxine treatment. In the genetic tests, homozygote c.695 C > T (p.Ala232Val) mutation was determined in the PLPBP gene, which has not been previously identified. Since a specific treatment was found, this case is reported with the aim of emphasizing the need to consider pyridoxine dependence, which is one of the vitamin-dependent metabolic encephalopathies, in the differential diagnosis of epilepsy patients.


Assuntos
Epilepsia , Piridoxina , Lactente , Recém-Nascido , Humanos , Feminino , Pré-Escolar , Piridoxina/uso terapêutico , Homozigoto , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/diagnóstico , Convulsões/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Mutação/genética , Aldeído Desidrogenase/genética
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