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Cells Apr 2023Microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a neurodevelopmental disorder caused by the deficiency of the X-chromosomal gene CASK. However,...
Microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a neurodevelopmental disorder caused by the deficiency of the X-chromosomal gene CASK. However, the molecular mechanisms by which CASK deficiency causes cerebellar hypoplasia in this syndrome remain elusive. In this study, we used CASK knockout (KO) mice as models for MICPCH syndrome and investigated the effect of CASK mutants. Female CASK heterozygote KO mice replicate the progressive cerebellar hypoplasia observed in MICPCH syndrome. CASK KO cultured cerebellar granule (CG) cells show progressive cell death that can be rescued by co-infection with lentivirus expressing wild-type CASK. Rescue experiments with CASK deletion mutants identify that the CaMK, PDZ, and SH3, but not L27 and guanylate kinase domains of CASK are required for the survival of CG cells. We identify missense mutations in the CaMK domain of CASK derived from human patients that fail to rescue the cell death of cultured CASK KO CG cells. Machine learning-based structural analysis using AlphaFold 2.2 predicts that these mutations disrupt the structure of the binding interface with Liprin-α2. These results suggest that the interaction with Liprin-α2 via the CaMK domain of CASK may be involved in the pathophysiology of cerebellar hypoplasia in MICPCH syndrome.
Topics: Cerebellum; Mental Retardation, X-Linked; Microcephaly; Guanylate Kinases; Humans; Membrane Proteins; Adaptor Proteins, Signal Transducing; Mice, Knockout; Animals; Mice; Female; Cells, Cultured; Mutation; Protein Domains; Machine Learning; Software; Apoptosis
PubMed: 37190086
DOI: 10.3390/cells12081177 -
Einstein (Sao Paulo, Brazil) 2023• Seventy-four (33.18%) municipalities in the state of Paraíba registered live births with microcephaly. • The highest proportion of cases (23.03%) was concentrated...
OBJECTIVE
• Seventy-four (33.18%) municipalities in the state of Paraíba registered live births with microcephaly. • The highest proportion of cases (23.03%) was concentrated in the capital, João Pessoa. • Number of inhabitants, number of cases of Zika virus, water supply, and average household income were associated with a higher proportion of new cases. To analyze the relationship between microcephaly and social inequality indicators in the state of Paraíba during the biennium January 2015 and December 2016.
METHODS
Ecological study with data from newborn microcephaly records and municipal socioeconomic, environmental, and demographic indicators was conducted using two health information systems from the Brazilian Ministry of Health (SINASC and SINAN) and the Brazilian Institute of Geography and Statistics. A Poisson multiple regression model was applied with a significance level of 5%.
RESULTS
Among 223 municipalities in Paraíba, 74 registered new cases of microcephaly. The number of Zika virus cases, number of inhabitants, number of households without adequate water supply, and household income were predictor variables of the number of new cases of microcephaly in Paraíba.
CONCLUSION
Microcephaly is associated with indicators of social inequality in Paraíba. Zika virus cases, water supply, and family income are the indicators that best explain the increase in microcephaly cases. Therefore, these variables must be monitored by health professionals and authorities.
Topics: Infant, Newborn; Humans; Microcephaly; Zika Virus Infection; Brazil; Zika Virus; Socioeconomic Factors
PubMed: 37075460
DOI: 10.31744/einstein_journal/2023AO0043 -
Chromosoma Jun 2020The International University of Andalucía (UNIA) Current Trends in Biomedicine Workshop on Molecular Causes of Primary Microcephaly and Related Diseases took place in... (Review)
Review
The International University of Andalucía (UNIA) Current Trends in Biomedicine Workshop on Molecular Causes of Primary Microcephaly and Related Diseases took place in Baeza, Spain, November 18-20, 2019. This meeting brought together scientists from Europe, the USA and China to discuss recent advances in our molecular and genetic understanding of a group of rare neurodevelopmental diseases characterised by primary microcephaly, a condition in which head circumference is smaller than normal at birth. Microcephaly can be caused by inherited mutations that affect key cellular processes, or environmental exposure to radiation or other toxins. It can also result from viral infection, as exemplified by the recent Zika virus outbreak in South America. Here we summarise a number of the scientific advances presented and topics discussed at the meeting.
Topics: Centrosome; Cilia; Congresses as Topic; DNA Damage; DNA Replication; Disease Susceptibility; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Humans; Microcephaly; Neurodevelopmental Disorders; Neurogenesis; Phenotype; Spindle Apparatus
PubMed: 32424716
DOI: 10.1007/s00412-020-00737-6 -
Archives of Disease in Childhood Sep 2021To estimate the minimum incidence of congenital Zika syndrome (CZS) and severe microcephaly in Canada and describe key clinical, epidemiological, aetiological and...
PURPOSE
To estimate the minimum incidence of congenital Zika syndrome (CZS) and severe microcephaly in Canada and describe key clinical, epidemiological, aetiological and outcome features of these conditions.
METHODS
Two separate national surveillance studies were conducted on CZS and severe microcephaly using the well-established Canadian Paediatric Surveillance Program from 2016 to 2019. Over 2700 paediatricians across Canada were surveyed monthly and asked to report demographic details, pregnancy and travel history, infant anthropometry, clinical features and laboratory findings of newly identified cases. Reports were reviewed to assign an underlying aetiology of severe microcephaly. Incidence rates were estimated using monthly live birth denominators.
RESULTS
Thirty-four infants met the case definition for severe microcephaly and <5 met the case definition for CZS. The associated minimum incidence rates were 4.5 per 100 000 live births for severe microcephaly and 0.1-0.5 per 100 000 live births for CZS. Of severe microcephaly cases, 53% were attributed to genetic causes, 15% to infectious or ischaemic causes and 32% to unknown causes. The median head circumference-for-age Z-score at birth was -3.2 (IQR -3.8 to -2.6), and catch-up growth was often not achieved. Common clinical features included intracranial abnormalities (n=23), dysmorphology (n=19) and developmental delays (n=14). Mothers of infants with non-genetic aetiologies travelled during pregnancy more often (10/16) than mothers of infants with genetic aetiologies (<5/18; p<0.01).
CONCLUSION
Severe microcephaly and CZS are both rare in Canada. Minimum incidence rates can be used as a baseline against which novel or re-emergent causes of severe microcephaly or CZS can be compared.
Topics: Adult; Anthropometry; Birth Weight; Canada; Female; Gestational Age; Humans; Incidence; Infant; Infant, Newborn; Live Birth; Male; Microcephaly; Population Surveillance; Pregnancy; Pregnancy Complications, Infectious; Premature Birth; Severity of Illness Index; Surveys and Questionnaires; Zika Virus; Zika Virus Infection
PubMed: 33419730
DOI: 10.1136/archdischild-2020-320968 -
Archives of Disease in Childhood Sep 2021To describe infants aged <12 months reported with microcephaly to the Australian Paediatric Surveillance Unit (APSU) following emergence of Zika virus infection...
OBJECTIVE
To describe infants aged <12 months reported with microcephaly to the Australian Paediatric Surveillance Unit (APSU) following emergence of Zika virus infection internationally.
DESIGN, SETTING AND PATIENTS
National, active, monthly surveillance for microcephaly using the APSU. Microcephaly was defined as occipitofrontal circumference (OFC) of more than 2 SDs below the mean for age, gender and gestation.
MAIN OUTCOME MEASURES
Clinical spectrum, aetiology and birth prevalence of microcephaly reported by paediatricians.
RESULTS
Between June 2016 and July 2018, 106 notifications were received, with clinical details provided for 96 (91%). After excluding ineligible notifications, 70 cases were confirmed, giving an annual birth prevalence of 1.12 (95% CI 0.88 to 1.42) per 10 000 live births. Of the total number of cases, 47 (67%) had primary microcephaly (at birth); and 25 (36%) had severe microcephaly (OFC >3 SDs). Birth defects were reported in 42 (60%). Of 49 infants with developmental assessment details available, 25 (51%) had failed to reach all milestones. Vision impairment was reported in 14 (26%). The cause of microcephaly was unknown in 60%: 13 (19%) had been diagnosed with genetic disorders; 22 (39%) had anomalies on neuroimaging. No congenital or probable Zika infection was identified. Severe microcephaly was more often associated with hearing impairment than microcephaly of >2 SDs but ≤3 SDs below the mean (p<0.007). Indigenous children and children with socioeconomic advantage were over-represented among children with microcephaly.
CONCLUSION
Novel national data on microcephaly highlight the high proportion of idiopathic cases. This has implications for prevention and management and suggests the need for a standardised diagnostic approach and ongoing surveillance mechanism in Australia.
Topics: Adult; Australia; Congenital Abnormalities; Developmental Disabilities; Female; Genotype; Humans; Infant; Infant, Newborn; Male; Microcephaly; Neuroimaging; Pregnancy; Pregnancy Complications, Infectious; Prevalence; Public Health Surveillance; Severity of Illness Index; Vision Disorders; Zika Virus; Zika Virus Infection
PubMed: 33229416
DOI: 10.1136/archdischild-2020-320456 -
Archives of Disease in Childhood Mar 2023To determine the incidence, causes and neurodevelopmental impact of severe microcephaly (head circumference <-3SD) up to age 2 years. (Observational Study)
Observational Study
OBJECTIVE
To determine the incidence, causes and neurodevelopmental impact of severe microcephaly (head circumference <-3SD) up to age 2 years.
DESIGN
Binational active paediatric surveillance study undertaken in 2017-2018 to identify and characterise new diagnoses of severe microcephaly.
SETTING
UK and Ireland.
PARTICIPANTS
Infants aged under 12 months at diagnosis.
INTERVENTIONS
Observational study.
MAIN OUTCOME MEASURES
Incidence, aetiology and neurodevelopmental outcomes at age 2 years.
RESULTS
Fifty-nine infants met the case definition, of whom 30 (51%) were girls; 24 (41%) were born preterm (<37 weeks' gestation); and 34 (58%) were of 'white' ethnicity. Eight (14%) children died before 12 months of age. Incidence of severe microcephaly was 5.5 per 100 000 infants (95% CI 4.0 to 7.3). Higher relative risk (RR) was associated with preterm birth (RR 7.7, 95% CI 3.8 to 15.1) and British Asian ethnicity (RR 3.6, 95% CI 1.6 to 7.8). Microcephaly was mainly due to genetic causes (59%), brain ischaemia/hypoxia (10%) and congenital infection (8%), and 19% remained undetermined. Each child was referred on average to eight specialists, and 75% had abnormal brain imaging. By 2 years of age, 55 children experienced neurodevelopmental abnormalities, including feeding problems (68%), motor delay (66%), visual impairment (37%), hearing loss (24%) and epilepsy (41%).
CONCLUSIONS
Although severe microcephaly is uncommon, it is associated with high mortality, complex multimorbidity and neurodisability, thus representing a significant ongoing burden for families and healthcare services. Potentially preventable causes include preterm birth, hypoxic/ischaemic brain injury and congenital infections. Clinical guidelines are essential to standardise aetiological investigation and optimise multidisciplinary management.
Topics: Infant; Female; Infant, Newborn; Humans; Child; Child, Preschool; Middle Aged; Male; Premature Birth; Microcephaly; Incidence; Brain; Gestational Age
PubMed: 36600319
DOI: 10.1136/archdischild-2022-324311 -
European Journal of Human Genetics :... Jan 2020Stromme syndrome.Jejunal atresia with microcephaly and ocular anomalies.Apple peel syndrome with microcephaly and ocular anomalies.Ciliopathy phenotype.Primary...
Stromme syndrome.Jejunal atresia with microcephaly and ocular anomalies.Apple peel syndrome with microcephaly and ocular anomalies.Ciliopathy phenotype.Primary microcephaly and intellectual disability.OMIM# of the disease 243605.Name of the analysed genes or DNA/chromosome segments CENPF.OMIM# of the gene(s) 600236.Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in CENPF genes in diagnostic, prenatal settings, and for risk assessment in relatives.
Topics: Chromosomal Proteins, Non-Histone; Eye Abnormalities; Genetic Testing; Humans; Intestinal Atresia; Microcephaly; Microfilament Proteins; Mutation; Phenotype; Sensitivity and Specificity
PubMed: 31488893
DOI: 10.1038/s41431-019-0498-y -
Journal of Pediatric Urology Apr 2021An outbreak of Zika virus disease, a self-limiting arbovirus infection involving skin rash and fever, occurred in Brazil in 2015 and was followed by an increase in...
INTRODUCTION
An outbreak of Zika virus disease, a self-limiting arbovirus infection involving skin rash and fever, occurred in Brazil in 2015 and was followed by an increase in newborns with microcephaly and brain malformations. Although two recent studies reported neurogenic bladder in children with microcephaly and congenital Zika syndrome (CZS), urologic evaluation is not yet routine.
OBJECTIVE
To investigate the urological profile of children with microcephaly and CZS.
STUDY DESIGN
A descriptive, cross-sectional study conducted with children with microcephaly undergoing clinical, laboratory, urodynamic and ultrasonographic evaluation at a center for childhood urinary disorders in Salvador, Bahia, Brazil.
RESULTS
Thirty-three children were evaluated. Mean age was 40.3 ± 3.2 months (range 35-47 months). Twenty-one (63.6%) were female. None urinated voluntarily. Urine stream was continuous in 22 (66.7%) and intermittent in 3 (9.1%), with no information in 8 cases (24.2%). Abdominal straining during voiding was absent in 27 (81.8%) and present in 3 (9.1%), with no information in 3 cases (9.1%). Upper urinary tract dilatation was not detected in any of the 27 ultrasounds performed. Twenty-two urine cultures were performed, with no cases of bacterial growth. Renal function was normal in all cases (mean creatinine 0.41 ± 0.1 mg/dl, range 0.29-0.79 mg/dl and urea 20 ± 7 mg/dl, 6-36 mg/dl). Mean maximum bladder capacity was lower than expected for age: 46.4 ± 25.6 mL range 15-110 mL versus 135.2 ± 6.6 mL, 125.5-153 mL, respectively (p < 0.0001). Sixteen patients (59.2%) had immature and reflex bladder, 3 (11.1%) had neurogenic bladder with small bladder compliance, 5 (18.5%) had neurogenic bladder and detrusor overactivity and 1 (3.7%) had normal bladder capacity and compliance, but urinated with abdominal straining and a significant residue. Urodynamic evaluation was normal in only two children (7.4%).
DISCUSSION
Most children evaluated had immature and reflex bladder, with no repercussions on the upper urinary tract. Literature on urological complications in children with microcephaly is sparse; however, the present results differ from cases of neurogenic bladder in children with neural tube closure defects. Microcephaly in CZS involves a neurological and urodynamic pattern very similar to that found in children with cerebral palsy. Study limitations include the absence of a control group and neurological data with which to correlate these findings.
CONCLUSION
Neurogenic bladder in children with CZS-associated microcephaly was much less common than recently reported. Most patients had no kidney abnormalities, but small bladder capacity and reflex bladder, with non-significant post-void residual urine.
Topics: Adult; Aged; Brazil; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Infant, Newborn; Male; Microcephaly; Middle Aged; Urinary Bladder, Neurogenic; Urodynamics; Young Adult; Zika Virus; Zika Virus Infection
PubMed: 33531217
DOI: 10.1016/j.jpurol.2020.10.011 -
Oral Diseases Jul 2023This study aimed to assess whether microcephaly is a risk factor for alterations in the chronology and sequence of tooth eruption and for developmental defects of enamel.
OBJECTIVE
This study aimed to assess whether microcephaly is a risk factor for alterations in the chronology and sequence of tooth eruption and for developmental defects of enamel.
MATHERIALS AND METHODS
In this case-control study, 81 children aged 30-36 months, including 40 normoreactive children and 41 with microcephaly, were submitted to oral clinical examination to determine the frequency of alterations in the chronology and sequence of tooth eruption and developmental enamel defects. The sample was matched for sex and age (1:1) and allocated to the case (presence of dental alterations) and control (absence of dental alterations) groups. Gestational age, birthweight and socioeconomic characteristics were also analyzed. Chi-square test and Fisher's exact test were applied (α = 0.05).
RESULTS
Microcephaly was significantly associated with delayed tooth eruption, alterations in the sequence of tooth eruption, and defects in dental enamel (p < 0.001). Low birthweight also showed a significant association with this alterations (p < 0.005) and prematurity was associated with defects in enamel development (p < 0.005).
CONCLUSION
Microcephaly is a risk factor for alterations in the tooth eruption process and enamel formation in primary teeth.
Topics: Child; Humans; Dental Enamel Hypoplasia; Birth Weight; Microcephaly; Case-Control Studies; Tooth Abnormalities; Risk Factors; Tooth, Deciduous
PubMed: 35332642
DOI: 10.1111/odi.14199 -
Molecular Genetics and Metabolism Jun 2022Phenylketonuria (PKU) is a common genetic metabolic disorder that causes phenylalanine accumulation in the blood. The most serious symptoms are related to the brain, as...
Phenylketonuria (PKU) is a common genetic metabolic disorder that causes phenylalanine accumulation in the blood. The most serious symptoms are related to the brain, as intellectual disability, seizure, and microcephaly are commonly found in poorly treated PKU patients and the babies of maternal PKU. However, the mechanism of hyperphenylalaninemia on human neurodevelopment is still unclear. Here we utilized human induced pluripotent stem cell (iPSC)-derived cerebral organoids to investigate the neurotoxicity of hyperphenylalaninemia. Cerebral organoids at days 40 or 100 were treated with different concentrations of phenylalanine for 5 days. After phenylalanine treatments, the cerebral organoids displayed alterations in organoid size, induction of apoptosis, and depletion of neural progenitor cells. However, phenylalanine did not have an impact on neurons and glia, including astrocytes, immature oligodendrocytes, and mature oligodendrocytes. Remarkably, a reduction in the thickness of the cortical rosettes and a decrease in myelination at the intermediate zone were inspected with the elevated phenylalanine concentrations. RNA-seq of phenylalanine-treated organoids revealed that gene sets related to apoptosis, p53 signaling pathway, and TNF signaling pathway via NF-kB were enriched in upregulated genes, while those related to cell cycle and amino acid metabolism were enriched in downregulated genes. In addition, there were several microcephaly disease genes, such as ASPM, LMNB1, and CENPE, ranked at the top of the downregulated genes. These findings indicate that phenylalanine exposure may contribute to microcephaly, abnormal cortical expansion, and myelination lesions in the developing human brain.
Topics: Female; Humans; Induced Pluripotent Stem Cells; Microcephaly; Organoids; Phenylalanine; Phenylketonuria, Maternal; Phenylketonurias; Pregnancy
PubMed: 35562278
DOI: 10.1016/j.ymgme.2022.04.005