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Objective: We present prenatal diagnosis of a 15q11.2-q14 deletion of paternal origin associated with increased nuchal translucency (NT), mosaicism for de novo multiple unbalanced translocations involving 15q11-q14, 5qter, 15qter, 17pter and 3qter, and Prader-Willi syndrome (PWS)., Case Report: A 32-year-old, primigravid woman underwent amniocentesis at 18 weeks of gestation because of an increased NT thickness of 5.6 mm and abnormal maternal serum screening results in the first trimester. The pregnancy was conceived by in vitro fertilization and embryo transfer. Amniocentesis revealed a karyotype of 45,XX,der(5)t(5;15)(q35;q14),-15 [16]/45,XX,-15,der(17)t(15;17)(q14;p13)[3]/45,XX,der(15)t(15;15)(q35;q14),-15[2]. The parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from cultured amniocytes revealed the result of arr 15q11.2q14 (22,765,628-38,651,755) × 1.0 [GRCh37 (hg19)] with a 15.886-Mb 15q11.2-q14 deletion encompassing TUBGCP5, CYFIP1, NIPA2, NIPA1, SNRPN, SNURF, SNORD116-1, IPW, UBE3A, ACTC1 and MEIS2. The pregnancy was subsequently terminated, and a malformed fetus with facial dysmorphism was delivered. The cord blood had a karyotype of 45,XX,der(5)t(5;15)(q35;q14),-15[46]/45,XX,der(3)t(3;15) (q29;q14),-15[2]/45,XX,-15,der(17)t(15;17)(q14;p13)[2]. The placenta had a karyotype of 45,XX,der(5) t(5;15)(q35;q14),-15. Polymorphic DNA marker analysis confirmed a paternal origin of the proximal 15q deletion., Conclusion: Increased NT and abnormal maternal serum screening results may prenatally be associated with PWS. Chromosome 15 rearrangements in PWS include mosaicism for de novo multiple unbalanced translocations., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Objective: We present prenatal diagnosis, molecular cytogenetic characterization and genetic counseling of a chromosome 15q24 microdeletion of paternal origin., Case Report: A 34-year-old primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY. Simultaneous array comparative genomic hybridization (aCGH) analysis on amniotic fluid revealed a de novo 2.571-Mb microdeletion of 15q24.1-q24.2. Prenatal ultrasound findings were unremarkable except persistent left superior vena cava and enlarged coronary sinus. The woman requested repeat amniocentesis at 22 weeks of gestation, and aCGH analysis confirmed the result of arr 15q24.1q24.2 (72,963,970-75,535,330) × 1.0 [GRCh37 (hg19)] and a 15q24 microdeletion encompassing the genes of STRA6, CYP11A1, SEMA7A, ARID3B, CYP1A1, CYP1A2, CSK and CPLX3. The parents did not have such a deletion, and polymorphic DNA marker analysis confirmed a paternal origin of the de novo deletion. Metaphase fluorescence in situ hybridization analysis confirmed a 15q24 deletion. The parents elected to terminate the pregnancy, and a malformed fetus was delivered with characteristic facial dysmorphism., Conclusion: Simultaneous aCGH analysis of uncultured amniocytes at amniocentesis may help to detect rare de novo microdeletion disorders., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020. Published by Elsevier B.V.)

Objective: The L1 cell adhesion molecule (L1CAM) gene, encodes the L1 cell adhesion molecule, is involved in the central nervous system development. Its mutations result in L1 syndrome which is associated with brain malformation and nervous developmental delay., Case Report: We presented three fetuses with hydrocephalus and agenesis of the corpus callosum detected by ultrasound, followed by medical exome sequencing (MES) test with L1CAM mutations: two known missense mutation c.551G > A (p. R184Q) and c.1354G > A (p. G452R), and a novel frameshift mutation c.1322delG which causes the early termination of translation (p. G441Afs∗72). By utilizing multiple computational analysis, all the variants were scored to be likely pathogenic., Conclusion: Combined use of ultrasound and MES to identify the molecular etiology of fetal anomalies may contribute to expanding our knowledge of the clinical phenotype of L1 syndrome observed in the south Chinese population., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier B.V.)

We performed RNA sequencing on 40,000 cells to create a high-resolution single-cell gene expression atlas of developing human cortex, providing the first single-cell characterization of previously uncharacterized cell types, including human subplate neurons, comparisons with bulk tissue, and systematic analyses of technical factors. These data permit deconvolution of regulatory networks connecting regulatory elements and transcriptional drivers to single-cell gene expression programs, significantly extending our understanding of human neurogenesis, cortical evolution, and the cellular basis of neuropsychiatric disease. We tie cell-cycle progression with early cell fate decisions during neurogenesis, demonstrating that differentiation occurs on a transcriptomic continuum; rather than only expressing a few transcription factors that drive cell fates, differentiating cells express broad, mixed cell-type transcriptomes before telophase. By mapping neuropsychiatric disease genes to cell types, we implicate dysregulation of specific cell types in ASD, ID, and epilepsy. We developed CoDEx, an online portal to facilitate data access and browsing., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Research shows that a high majority of parents receiving prenatal diagnosis of intellectual disability terminate pregnancy. They have reasons for rejecting a child with intellectual disabilities-these reasons are, most commonly, beliefs about quality of life for it or them. Without a negative evaluation of intellectual disability, their choice makes no sense. Disability-based abortion has been critiqued through virtue ethics for being inconsistent with admirable moral character. Parental selectivity conflicts with the virtue of acceptingness (the commitment to welcome whatever child comes naturally) and exhibits the vice of wilfulness (the project of picking and choosing what children one will take). In this paper I claim that, beyond failures of moral virtue, disability abortion often involves failures of epistemic virtue on the part of parents. I argue two things: parents believe something false, or at least contested, about life with intellectual disability-and they do so because they are not epistemically conscientious. I first explain why a central motivation for disability abortion-that it prevents harm to the child-is mistaken. I next give a brief account of intellectual virtue and culpable ignorance. I then indicate why many parents fail to be intellectually virtuous when choosing to terminate pregnancy. I focus on elimination of intellectual disability and have little to say about physical and sensory impairments.

Objective: We present detection of de novo del(18)(q22.2) and a familial 15q13.2-q13.3 microduplication in a fetus with congenital heart defects (CHD)., Case Report: A 27-year-old, primigravid woman was referred for genetic counseling because of fetal CHD. Prenatal ultrasound at 17 weeks of gestation revealed pericardial effusion, cardiomegaly and a large ventricular septal defect. The pregnancy was subsequently terminated at 18 weeks of gestation, and a 192-g female fetus was delivered with facial dysmorphism. Cytogenetic analysis of the umbilical cord revealed a karyotype of 46,XX,del(18)(q22.2). The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) of the placental tissue revealed a 2.08-Mb 15q13.2-q13.3 microduplication encompassing KLF13 and CHRNA7, and a 10.74-Mb 18q22.2-q23 deletion encompassing NFATC1. The phenotypically normal father carried the same 2.08-Mb 15q13.2-q13.3 microduplication. Polymorphic DNA marker analysis confirmed a paternal origin of the distal 18q deletion., Conclusion: Prenatal diagnosis of CHD should include a complete genetic study of the embryonic tissues, and the acquired information is useful for genetic counseling., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Congenital diaphragmatic hernia (CDH) is associated with Simpson-Golabi-Behmel syndrome (SGBS), but few cases diagnosed prenatally have been reported. The aim of this series is to highlight the association of nonisolated CDH with SGBS type I on prenatal ultrasound and emphasize the importance of genetic testing, fetal autopsy, and family history in confirming this diagnosis., Method: Retrospective review of 3 cases of SGBS type I in a single tertiary care centre. Family history, fetal ultrasound, autopsy findings, and genetic testing for GPC3 was performed for each case., Results: Fetal ultrasound findings in the second trimester were CDH, omphalocele, increased nuchal fold, renal anomaly, and cleft lip and palate. Fetal autopsy confirmed the prenatal ultrasound findings and also showed dysmorphic facial features and premalignant lesions on renal and gonadal histology. Microarray and DNA analysis of the GPC3 gene confirmed the diagnosis of SGBS type I in each case., Conclusion: Nonisolated CDH in a male fetus suggests a diagnosis of SGBS type I. Fetal autopsy, pedigree analysis, and genetic testing for GPC3 are all essential to confirming the diagnosis. The histological findings of ovotestes and nephroblastomatosis indicate that cancer predisposition is established early in fetal life., (© 2017 John Wiley & Sons, Ltd.)

Objective: To conduct genetic testing and prenatal diagnosis for a pregnant women with growth retardation, severe mental retardation, and a history of adverse pregnancies., Methods: G-banded chromosome analysis, fluorescence in situ hybridization (FISH), and whole genome DNA microarray were used to analyze the patient and her fetus., Results: The women was found to be a chimera containing two cell lines with 47 and 46 chromosomes, respectively. Both have involved deletion of 18q21.2q23. FISH analysis suggested that the cell line containing 47 chromosomes has harbored a chromosome marker derived from chromosome 15. The marker has contained chromosome 15p involving the SNRPN locus and part of 15q, which gave rise to a karyotype of 47,XX,del18q21.3,+ish mar D15Z1+ SNRPN+[82]/46,XX,del18q21.3[18]. Whole genome DNA microarray confirmed that a 3.044 Mb fragment from 15q11.2q12 was duplicated, which involved NIPA1, SNRPN and other 17 OMIM genes. Duplication of this region has been characterized by low mental retardation, autism, developmental delay. Meanwhile, there was a 17.992 Mb deletion at 18q21.33q23, which contained 39 OMIM genes including TNFRSF11A and PHLPP1. This fragment was characterized by mental retardation, developmental delay, short stature, and cleft palate. Whole genome microarray analysis confirmed that there was a 17.9 Mb deletion at 18q21.33q23, which has been implemented with mental retardation, general growth retardation, short stature, and cleft palate. After genetic counseling, the family decided to terminate the pregnancy at 21st week., Conclusion: Combined chromosome karyotyping, FISH, and whole genome DNA microarray can determine the origin of marker chromosomes and facilitate delineation of its correlation with the clinical phenotype.

Objective: To analyze the correlation between atypical neurofibromatosis type 1(NF1) microdeletion and fetal phenotype., Methods: Fetal blood sampling was carried out for a woman bearing a fetus with talipes equinovarus. G-banded karyotyping and single nucleotide polymorphism array (SNP-array) were performed on the fetal blood sample. Fluorescence in situ hybridization (FISH) was used to confirm the result of SNP array analysis. FISH assay was also carried out on peripheral blood specimens from the parents to ascertain the origin of mutation., Results: The karyotype of fetus was found to be 46, XY by G-banding analysis. However, a 3.132 Mb microdeletion was detected in chromosome region 17q11.2 by SNP array, which overlaped with the region of NF1 microdeletion syndrome. Analyzing of the specimens from the fetus and its parents with FISH has confirmed it to be a de novo deletion., Conclusion: Talipes equinovarus may be an abnormal sonographic feature of fetus with atypical NF1 microdeletion which can be accurately diagnosed with SNP array.

Objective: Neurodevelopmental disorders presumably involve events that occur during brain development. The authors hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e., differentially expressed)., Method: The authors investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with six neuropsychiatric disorders in the microarray-based "BrainCloud" dorsolateral prefrontal cortex transcriptome., Results: Using a fetal/postnatal log2-fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10-3), intellectual disability (N=88 genes, p=5.53×10-3), and autism spectrum disorder (N=242 genes, p=3.45×10-4) were relatively enriched in prenatal transcript abundance, compared with the overall transcriptome. Genes associated with schizophrenia by genome-wide association studies were not preferentially fetally expressed (N=106 genes, p=0.46), nor were genes associated with schizophrenia by exome sequencing (N=212 genes, p=0.21), but specific genes within copy-number variant regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (N=46 genes, p=1.67×10-3)., Conclusions: The authors found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorder. Future transcriptome-level association studies should evaluate regions other than the dorsolateral prefrontal cortex, at other time points, and incorporate further RNA sequencing analyses.

Mental retardation is seen in all individuals with Down syndrome (DS) and different brain abnormalities are reported. The aim of this study was to investigate if mental retardation at least in part is a result of a lower cell number in the neocortical part of the human fetal forebrain. We therefore compared brains of DS fetuses aged 19 weeks of gestation with normal control brains. The cell numbers were estimated using the optical fractionator method. The total cell number in the neocortical part of four DS human fetal forebrain was found to be substantially smaller in DS compared to the normal fetus. The average total cell number of 6.85 billion was equal to a reduction by 34% compared to the 10.4 billion cells in a normal fetal brain of that age. This study indicates that the mental retardation found in DS is based on a structural deficit in the human fetal brain already present in the second trimester.

Objectives: To evaluate the role of plasma volume expansion on 1-year infant outcome after severe hypertensive disorders of pregnancy and to determine prognostic factors for adverse neurodevelopmental infant outcome., Design: Randomised controlled trial, observational prognostic study., Setting: Two university hospitals in Amsterdam, The Netherlands., Population: One hundred and seventy-two infants alive of 216 mothers with severe hypertensive disorders of pregnancy who were randomised for a temporising management strategy with or without plasma volume expansion., Methods: At 1 year of corrected age, a neurological examination according to Bayley (mental development index [MDI] and psychomotor development index [PDI]) and Touwen was performed., Main Outcome Measures: Adverse neurodevelopmental infant outcome was defined as a MDI/PDI score below 70 and/or an abnormal Touwen. Risk factors for adverse neurodevelopmental outcome were explored by univariate and multivariate analyses., Results: Adverse neurodevelopmental infant outcome was observed in 31 infants (18%). There were no differences between the randomisation groups. In multivariate analysis, an association with abnormal umbilical artery/middle cerebral artery Doppler ratio higher than the median, major neonatal morbidity, higher education of the parents, multiparity and Caucasian ethnicity was observed., Conclusion: Nearly 70% of the infants were alive at 1 year without adverse neurodevelopmental outcome. Maternal plasma volume expansion during pregnancy has no effect on 1-year infant outcome. The prediction of adverse outcome at 1 year by perinatal parameters is limited.

Background: Broken chromosomes must acquire new telomeric "caps" to be structurally stable. Chromosome healing can be mediated either by telomerase through neo-telomere synthesis or by telomere capture., Aim: To unravel the mechanism(s) generating complex chromosomal mosaicisms and healing broken chromosomes., Methods: G banding, array comparative genomic hybridization (aCGH), fluorescence in-situ hybridisation (FISH) and short tandem repeat analysis (STR) was performed on a girl presenting with mental retardation, facial dysmorphism, urogenital malformations and limb anomalies carrying a complex chromosomal mosaicism., Results & Discussion: The karyotype showed a de novo chromosome rearrangement with two cell lines: one cell line with a deletion 9pter and one cell line carrying an inverted duplication 9p and a non-reciprocal translocation 5pter fragment. aCGH, FISH and STR analysis enabled the deduction of the most likely sequence of events generating this complex mosaic. During embryogenesis, a double-strand break occurred on the paternal chromosome 9. Following mitotic separation of both broken sister chromatids, one acquired a telomere vianeo-telomere formation, while the other generated a dicentric chromosome which underwent breakage during anaphase, giving rise to the del inv dup(9) that was subsequently healed by chromosome 5 telomere capture., Conclusion: Broken chromosomes can coincidently be rescued by both telomere capture and neo-telomere synthesis.

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder. It is characterized by two principal features, microcephaly present at birth and nonprogressive mental retardation. The microcephaly is the consequence of a small but architecturally normal brain, and it is the cerebral cortex that shows the greatest size reduction. There are at least seven MCPH loci, and four of the genes have been identified: MCPH1, encoding Microcephalin; MCPH3, encoding CDK5RAP2; MCPH5, encoding ASPM; and MCPH6, encoding CENPJ. These findings are starting to have an impact on the clinical management of families affected with MCPH. Present data suggest that MCPH is the consequence of deficient neurogenesis within the neurogenic epithelium. Evolutionary interest in MCPH has been sparked by the suggestion that changes in the MCPH genes might also be responsible for the increase in brain size during human evolution. Indeed, evolutionary analyses of Microcephalin and ASPM reveal evidence for positive selection during human and great ape evolution. So an understanding of this rare genetic disorder may offer us significant insights into neurogenic mitosis and the evolution of the most striking differences between us and our closest living relatives: brain size and cognitive ability.

Preterm newborns represent a high-risk population for brain damage, primarily affecting the white matter, and for related neurodevelopmental disabilities. Determinants of brain damage have been extensively investigated, but there are still many controversies on how these factors can influence the developing brain and provoke damage. The concept of etiological pathway, instead of a single determinant, appears to better explain pathogenetic mechanisms: the brain damage may represent the final outcome of exposure to several combinations of risk factors in the same pathway or in different pathways and can change according to the gestational age. The aim of this article is to review the current knowledge on the pathogenesis of brain damage in preterm infants, within the frame of two main theoretical models, the ischemic and the inflammatory pathway. The relationship between the two pathways and the contribution of genetic susceptibility to ischemic and/or inflammatory insult, in modulating the extent and severity of brain damage, is also discussed.

The carbonic anhydrase II (CA II) deficiency syndrome is an autosomal recessive disorder that produces osteopetrosis, renal tubular acidosis, and cerebral calcification. Other features include developmental delay, short stature, cognitive defects, and a history of multiple fractures by adolescence. With one exception, all patients with osteopetrosis and renal tubular acidosis examined have proven to have CA II deficiency. All CA II-deficient patients analyzed have been found to have mutations in the CA2 gene. Previously, we used single strand conformational (SSCP) analysis to identify exons to be sequenced from CA II-deficient patients. In this report, we amplified all seven exons by PCR from genomic DNA and directly sequenced the amplified products. Application of this method allowed identification of eleven new mutations in 21 patients referred for confirmation of the diagnosis of CA II deficiency. These mutations were scattered over the genome from exon 2 to 7. In two opportunities for prenatal diagnosis, one from cultured amniocytes and one from chorionic villus biopsy, we demonstrated the general utility of the direct sequencing method for prenatal DNA diagnosis. These studies expand our knowledge of the heterogeneity in mutations underlying the CA II deficiency syndrome., (Copyright 2004 Wiley-Liss, Inc.)

Recent reports have emphasized the role of cholesterol in vertebrate embryonic development. The RSH or so-called Smith-Lemli-Opitz syndrome (SLOS) was the first multiple congenital anomalies/mental retardation syndrome related to a cholesterol synthesis disturbance. Familial hypobetalipoproteinemia is a well-known dominantly inherited entity in which affected individuals usually are free of symptoms. We report on the unusual association of a malformation syndrome with mental retardation resembling SLOS and profound hypocholesterolemia related to familial hypobetalipoproteinemia. We discuss the possible causal relationship between the two conditions and the current understanding of the role of cholesterol in normal embryogenesis., (Copyright 2003 Wiley-Liss, Inc.)

We report on the incidental prenatal detection of an interstitial X-chromosomal deletion in a male fetus and his mother by fetal sexing with a primer pair recognizing an X-Y homologous locus (DXYS19), formerly unassigned on the X chromosome. The proband asked for prenatal diagnosis because of her elevated age and risk of Duchenne muscular dystrophy (DMD). Prior to molecular genetic testing for DMD, fetal sexing was carried out on DNA prepared from cultured amniocytes. PCR analysis revealed the expected Y-chromosomal product, but did not show the constitutive X-chromosomal fragment. The absence of the X-chromosomal fragment in the fetus and on one X chromosome of the mother was confirmed by Southern hybridization of HindIII restricted DNA with probe pJA1165 (DXYS19). DXYS19X was mapped to Xp22.3 by combining several approaches, including: (1) analysis of somatic cell hybrid lines containing different fragments of the human X chromosome; (2) Southern hybridization of a yeast artificial chromosome (YAC)-filter panel provided by the Resource Center/Primary Database (RZPD); (3) FISH analysis; and (4) re-evaluation of two patients with interstitial deletions in Xp22.3. The extent of the deletion in the fetus was estimated by further markers from Xp22.3 and found to include the STS gene. Mental retardation could not be excluded since some mentally retarded patients exhibit overlapping deletions., (Copyright 2000 John Wiley & Sons, Ltd.)

A 5-day-old Japanese female with Neu-Laxova syndrome was presented. The patient had severe edema throughout the body, desquamation, and erosion of the skin. She also exhibited microcephaly, exophthalmos, and rocker-bottom feet. Histologic examinations of a cutaneous specimen showed atrophy of the dermis and absence of the sebaceous glands. These represent embryonic abnormalities. Even though there was no hypoplasia of the cerebellum and lungs or hydramnios, we evaluated this patient as the first Japanese case of this sporadic disease. With intensive care, including dermatological treatment, the patient survived for 134 days.

Cerebral cortical development occurs in precisely-timed stages that can be divided into neurogenesis, neuronal migration and neuronal differentiation. These events occur during discrete time windows that span the late prenatal and early postnatal periods in both rodents and primates, including humans. Insults at particular developmental stages can lead to distinctive cortical abnormalities including cortical hypoplasia (reduced cell number), cortical ectopias (abnormalities in migration) and cortical dysplasias (abnormalities in the shapes or numbers of dendrites). In this review, we examine some of the most extensively-studied animal models of disrupted stages of cortical development and we compare long-term anatomical, neurochemical, and behavior abnormalities in these models. The behavioral abnormalities in these models range from alterations in simple motor behaviors to food hoarding and maternal behaviors as well as cognitive behaviors. Although we examine concisely animal models of cortical hypoplasia and cortical ectopias, we focus here on developmental manipulations that affect cortical differentiation, particularly, those that interrupt the normal ontogeny of the neurotransmitter-defined cortical afferent systems: norepinephrine, serotonin, dopamine and acetylcholine. All of these afferents presumably play a critical role in the maturation of their cortical targets; the timing of the afferents' entry into the cortex and their effects on their cortical targets, however, are different. We, therefore, compare the specific anatomical, neurochemical and behavioral effects of manipulations of the different cortical afferents. Because of the considerable evidence that cortical development proceeds differently in the two sexes, when data are available, we address whether perinatal insults differentially affect the sexes. Finally, we discuss how these developmental studies provide insights into cellular and neurochemical correlates of behavioral functional abnormalities and the relevance of these data to understanding developmental disabilities in humans.

Low birthweight is costly to sufferers and to society. Primary prevention gives benefits exceeding costs, but many plans to prevent low birthweight, for example improvement in antenatal care, have failed because the intervention is too late. Preconception care is generally necessary. Poor maternal nutrition and infection are the major causes of low birthweight.

The nature and the origin of de novo small marker chromosome found at prenatal diagnosis were determined by fluorescence in situ hybridization (FISH) using chromosome centromere-specific probes and by chromosome in situ suppression (CISS) using chromosome specific libraries. The small marker was characterized as being derived from chromosome 22. The fetus which exhibited a minichromosome had kidney malformations and after birth showed clinical features consistent with the Duane anomaly. One previous case with Duane anomaly and abnormalities of urogenital tract associated to a bisatellitated marker derived from chromosome 22 was reported. These findings indicate that a gene or genes located in the region of chromosome 22pter-->q11 may be associated with the Duane anomaly and the development of the urogenital tract.

The pervasiveness of abnormal brain development caused by prenatal exposure to ionizing radiation is still largely unknown. The relationship between A-bomb radiation dose and two measures of neuromuscular performance, one of grip strength and the other of the fine motor coordination required in repetitive action, is described. A multivariate analysis of covariance was used to evaluate the effect of several covariates, such as prenatal radiation exposure and some physical measurements or IQ adding city and sex as categorical factors. When mentally retarded cases were included, a statistically significant effect of radiation exposure on the grip strength and repetitive-action test scores was seen in the 8-15-week postovulation period, and a statistically suggestive effect at 16-25 weeks postovulation. No effect of radiation exposure on the two test scores was noted for prenatal exposure in either of the aforementioned periods when mentally retarded cases were excluded, but a statistically significant diminution of IQ was noted for exposures > or = 16 weeks postovulation. We discuss, from the biological perspective, the projected standard scores for exposures > or = 16 weeks postovulation, and the possibility of lower IQ, small head and mild mental retardation related to radiation exposures < or = 15 weeks postovulation with mentally retarded cases excluded.

Fetal alcohol exposure has multiple deleterious effects on brain development, and represents a leading known cause of mental retardation. This review of the effects of alcohol exposure on the developing brain evaluates results from human, animal and in vitro studies, but focuses on key research issues, including possible mechanisms of damage. Factors that affect the risk and severity of fetal alcohol damage also are considered.

Objective: Our goal was to review the perinatal characteristics of 48 singleton term infants with central nervous system neurologic impairment., Study Design: Medical records were retrospectively reviewed for maternal characteristics, prenatal and intrapartum care patterns, neonatal course, and long-term outcome. Those patients without evidence of an obvious acute asphyxial event, traumatic delivery, or preterm birth were excluded. The study population was then subclassified according to the admission fetal heart rate pattern., Results: Of these 48 term infants the admission fetal heart rate pattern was nonreactive in 33 (69%) and reactive in 15 (31%). Maternal characteristics, prenatal care, and long-term outcome were statistically similar between the two groups. However, the nonreactive group exhibited significantly more characteristics consistent with a prior asphyxial event: thick "old" meconium, "fixed" nonreactive baseline fetal heart rate, meconium-stained skin, and meconium aspiration syndrome. In contrast, in the reactive group a fetal heart rate pattern developed that was consistent with Hon's theory for intrapartum asphyxia and manifested by a prolonged tachycardia in association with persistent nonreactivity, diminished fetal heart rate variability, and fetal heart rate decelerations., Conclusions: Among fetuses later found to be neurologically impaired, a persistent nonreactive fetal heart rate tracing obtained from admission to delivery appears to be evidence of prior neurologic injury.

Thirty years after the publication of Smith et al. [1964: J Pediatr 64:210-217] of 3(4) cases of the RSH/SLO ("Smith-Lemli-Opitz") syndrome and after the publication by Roux [1964: Arch Franç Pédiatr 21:451-464] on the teratogenic action of Triparanol, a defect of cholesterol metabolism was discovered by Tint and his co-workers in the blood of the patients of Irons and Elias [Irons et al., 1993: Lancet 341:1414]. In this manner, the RSH syndrome has been identified as another metabolic multiple congenital anomalies/mental retardation (MCA/MR) syndrome (prototype Zellweger syndrome) in which deficient cholesterol synthesis must be held responsible for all parts of the syndrome, including blastogenetic and organogenetic malformations, minor anomalies, more or less severe abnormalities of CNS and PNS structure and function, postnatal failure to thrive, and, in some cases, stillbirth or infancy/childhood death.

Objective: To investigate whether maternal hypothyroidism before the onset of fetal thyroid function influences mental development of the offspring., Design: We examined IQs in children in whom the mothers had been hypothyroid during early pregnancy (group 1). The IQs were compared with those of siblings who were not exposed to maternal hypothyroidism during gestation (group 2)., Patients: Group 1 consisted of eight children. Mothers were examined for thyroid status during the fifth to 10th gestational weeks and were found to have distinctly low thyroxine levels and high thyrotropin levels; the levels became normal after thyroxine supplementation by 13 to 28 weeks of gestation. Seven of the eight children had nine siblings who had not been exposed to maternal hypothyroidism during gestation (group 2). Ages at examination were 4 to 10 years in group 1 and 4 to 15 years in group 2., Results: All children in group 1 showed normal IQs. There was no significant difference in the mean IQ between the children in group 1 who had siblings (112 +/- 11) and their siblings in group 2 (106 +/- 8). Even the subject whose mother had had the lowest thyroxine level (free thyroxine, 2.3 pmol/L) had an IQ similar to that of his sibling., Conclusion: These data provide evidence against the presence of adverse effects of maternal hypothyroidism during early pregnancy on the subsequent mental development of the offspring.

A stable-isotope dilution assay has been developed for quantitation of D- and L-2-hydroxyglutaric acids in physiologic fluids. D- and L-2-hydroxyglutaric acids are separated as the O-acetyl-di-(D)-2-butyl esters. The method uses D,L-[3,3,4,4-2H4]-2-hydroxyglutaric acid as internal standard with ammonia chemical ionization, selected ion monitoring gas chromatography-mass spectrometry. For 13 patients with L-2-hydroxyglutaric aciduria, the concentrations of L-2-hydroxyglutaric acid were urine, 1283 +/- 676 mmol/mol creatinine (range, 332-2742; n = 12 patients); plasma, 47 +/- 13 mumol/L (range, 27-62; n = 8); cerebrospinal fluid, 62 +/- 30 mumol/L (range, 34-100; n = 6). In a child with D-2-hydroxyglutaric aciduria, the levels of D-2-hydroxyglutaric acid were urine, 1565 +/- 847 mmol/mol creatinine (range, 729-2668; n = 4); plasma, 61 +/- 14 mumol/L (range, 46-73; n = 3); cerebrospinal fluid, 15 and 25 mumol/L (n = 2). Control concentrations of D- and L-2-hydroxyglutaric acids were (D:L): urine (n = 18), 6.0 +/- 3.6 mmol/mol creatinine (range, 2.8-17): 6.0 +/- 5.4 (range, 1.3-19); plasma (n = 10), 0.7 +/- 0.2 mumol/L (range, 0.3-0.9): 0.6 +/- 0.2 (range, 0.5-1.0); cerebrospinal fluid (n = 10), 0.1 +/- 0.1 mumol/L (range, 0.07-0.3): 0.7 +/- 0.6 (range, 0.3-2.3). Investigation of control amniotic fluid (n = 10) revealed the following values (D:L): 1.2 +/- 0.4 mumol/L (range, 0.6-1.8): 4.0 +/- 0.7 (range, 3.1-5.2), suggesting the feasibility of prenatal diagnosis in families at risk.

We report on the first case of phenylketonuria in a Bedouin woman with 3 children having the phenylketonuria embryofetopathy. Herein, we discuss briefly hazards of late diagnosis of maternal phenylketonuria.

Objective: The present study was designed to determine the current prevalence of gestational hypothyroidism, since maternal thyroxine deficiency is associated with poor obstetric outcomes and mental retardation in the surviving offspring., Design: TSH concentrations were measured in the sera of women at 15-18 weeks of gestation. Those sera with TSH concentrations above 6 mU/l and the two sera closest in order with TSH concentrations below 6 mU/l were further analysed for T4, FT4, TBG, and antithyroid antibodies. Study criteria for hypothyroidism were sera with elevated concentrations of TSH plus both a free T4 concentration and a total T4 concentration and/or T4/TBG ratio more than two standard deviations below the mean for the control pregnant women., Patients: The sera were from 2000 consecutive women in Maine being tested for alpha-fetoprotein concentration at 15-18 weeks of gestation., Results: TSH concentrations above 6 mU/l were found in the sera of 49 women, 2.5% of the pregnant women. Six women with elevated TSH concentrations (range 6.9-54 mU/l) had both a FT4 concentration and a T4/TBG ratio and/or a T4 concentration more than two standard deviations below the respective control means, meeting the study criteria for thyroid deficiency, and thus giving a prevalence of 0.3%. The remaining 43 women with elevated TSH concentrations were classified as having compensated thyroid disease although some may have been hypothyroid. Fifty-eight per cent of women with TSH concentrations above 6 mU/l and 90% of the women with elevated TSH concentrations and at least one thyroxine index more than two standard deviations below the control means had positive titres of antithyroid antibodies as opposed to 11% of the controls., Conclusions: Although it is not known what severity of maternal thyroid deficiency is necessary to cause fetal brain damage, the present data indicate a sufficiently high prevalence of thyroid dysfunction to demand investigation of the mental development of the offspring of women with thyroid dysfunction and of the effect of replacement therapy.

The "justification hypothesis" attributes mental retardation in phenylketonuria (PKU) to an inability of the heterozygous mother to deliver an appropriate amount of tyrosine to the PKU fetus who, in turn, is unable to correct for this deficiency because of its genetic constitution. We tested this hypothesis by measuring concentrations of tyrosine and phenylalanine in cord blood obtained at delivery from nine infants with PKU and five infants with persistent (non-PKU) hyperphenylalaninemia (PHP). For each of these specimens there were four control cord-blood specimens from infants born on the same day and, generally, in the same hospital. PKU and PHP groups were similar with respect to cord-blood tyrosine and phenylalanine values. There was no biologically significant deficiency of tyrosine in cord blood of the pooled PKU and PHP deficiency of tyrosine in cord blood of the pooled PKU and PHP groups (54 +/- 10 microM, mean +/- SD) compared with controls (61 +/- 16 microM, P = 0.13). On the other hand, phenylalanine in cord blood of the pooled PKU and PHP groups was significantly increased (144 +/- 30 microM, mean +/- SD) compared with controls (128 +/- 24, P = 0.004). The mangitude of the differences in cord-blood tyrosine and phenylalanine between control and PKU subjects are so small that it is unlikely that they have any consequences for physical and mental development. The justification hypothesis, as it pertains to blood tyrosine at term, is not upheld.

Murine trisomy 19 (Ts19) can be regarded as a general model of human trisomies. It is the only autosomal trisomy in the mouse that survives the perinatal period. Therefore, it is the only animal model available for postnatal investigations of trisomy-specific mental retardation. To evaluate the extent of developmental retardation during the late-embryonic and fetal period of gestation, total body weight development was documented for 60 Ts19-fetuses and compared with that of 219 euploid in utero-mates. In addition, a postnatal study on body-weight development of 77 Ts19-neonates and 74 euploid littermates was performed starting on day 1 postpartum and continuing until spontaneous death or until day 22. Forty-seven Ts19-individuals were further tested in nine behavioural test systems in order to determine their neurophysiological developmental profile. Findings were compared with age-dependent morphologic and physiologic parameters. The data obtained in the present study show a significant retardation of organ- and body-weight development in Ts19-mice starting on day 14 of gestation. Retardation of physiological parameters is progressive and persists throughout the perinatal and postnatal periods. Furthermore, the trisomic individuals showed specific behavioural abnormalities.

A study on the etiology of MD was done on 3735 children with mental retardation. Selection of patients was verified by precise alphabetical train in order to obtain the different factors of MD with objectivity. The highest percentage of MD was constituted by pathology concerning pre- and/or peripartum problems (53.78%), being on the contrary very low the percentage of MD of unknown etiology (8.219%). Authors think that it is possible to verified correct diagnosis of cases with MD if the clinical knowledge is large the adequate para-clinical studies (biochemistry, EEG, EMG, cytogenetic and neuroradiology) are practised. The unknown etiology of MD must be low. In their opinion MD accompanying CNS malformations and dysmorphic syndromes must not be classified as MD of unknown etiology. Emphasis is done on the necessity of having in consideration real percentages of etiological factors when programs for education of subnormal children are developed.

The prevalence of mental retardation in children exposed in utero to the atomic bombs in Hiroshima and Nagasaki has been re-evaluated in reference to gestational age and tissue dose in the fetus. There was no risk at 0-8 weeks post-conception. The highest risk of forebrain damage occurred at 8-15 weeks of gestational age, the time when the most rapid proliferation of neuronal elements and when most, if not all, neuroblast migration to the cerebral cortex from the proliferative zones is occurring. Overall, the risk is five or more times greater in these weeks than in subsequent ones. In the critical period, damage expressed as the frequency of subsequent mental retardation appears to be linearly related to the dose received by the fetus. A linear model is not equally applicable to radiation-related mental retardation after the 15th week, the observed values suggesting that there a threshold may exist. The data are consistent with a probability of occurrence of mental retardation of 0.40% per cGy or 40% per gray.

Several approaches utilized in ontogenetic investigations in laboratory animals have been explored in preliminary studies of morphogenetic events in the human cerebral cortex. 1. Golgi studies of dendritic growth cones, filopodia, and other developmental processes have permitted specification of the maximal phase of dendritic growth and differentiation of pyramidal neurons in the hippocampus. This period spans the twentieth to twenty-eighth week of fetal development. 2. Studies of the temporal pattern of appearance of the axonal plexus of the stratum pyramidale suggest that axosomatic synaptic pathways in the hippocampus develop relatively late in respect to the appearance of axospinodendritic inputs. 3. Dendritic spine development is evident at 26 weeks g.a. in the hippocampus but not in the visual cortex. Most hippocampal pyramidal neurons have acquired a full complement of spines by 6 months postnatally. The presence of severe metabolic and cardiorespiratory disturbances and/or chromosomal abnormalities significantly influences dendritic spine morphology and development. 4. The general morphological features of several varieties of neurons in the cisual cortes of a 32-week-old preterm infant are considered in respect to the electrographic characteristics of this infant's visual evoked responses. The observations in this and other cases illustrate the manner in which ontogenetic problems susceptible to inquiry in laboratory animals can serve to guide similar morphophysiological studies of normal and aberrant developmental events in human brain.

Maternal hyperthermia of even short duration induces dramatic teratogenic (monster producing) effects in all experimental animals studied. In humans, several studies have reported cases analogous to some laboratory results in animal experiments, e.g., mental retardation, brain and nerve abnormalities and facial deformity. Recent computer-aided 3D reconstructions of pyramidal cells from guinea-pig brains subjected embryonically to a 1 hr stress at 44 degrees C environmental temperature, show that structural changes are induced in dendritic arbors. The alterations are greatest for dendritic segments closest to the cell body and are consistent with several reports linking topological and metrical anomalies with disturbances of brain function. We suggest that many cases of "idiopathic" subnormality are due to maternal hyperthermia during early pregnancy.

Pregnant rats an mice received a magnesium (Mg)-deficient diet with different Mg contents from 40 t 360 ppm. The control received 2,000 ppm. At the end of gestation, the Mg concentration in the maternal serum was found to have decreased by up to 0.3 mmole/liter, depending on the Mg content of the food. Mg-dose-dependent embryotoxic effects (resorptions, retardation, disturbed bone development, and skeletal malformations) were observed only below a threshold value of 0.7 mmole/liter of the maternal serum Mg concentration. Noise stress in rats, in addition to a mild Mg deficiency (360 ppm Mg), which by itself had no effects, increased the rate of resorptions only.