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Query: UMLS:C0025362 (mental retardation)
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Congenital human cytomegalovirus (HCMV) infection is the leading infectious cause of mental retardation and sensorineural deafness. Intrauterine transmission and adverse outcome are mainly related to primary maternal infection. Mechanisms of intrauterine transmission are slowly being unraveled and compelling evidence of the importance of using HCMV clinical strains rather than laboratory-adapted strains for in vitro studies is growing. In the absence of a vaccine or a specific antiviral therapy which could be safely administered to pregnant women with primary HCMV infection, the option of prenatal diagnosis has a crucial role in the management of pregnancy complicated by primary HCMV infection. Reliability of prenatal results, however, is still a major concern presenting the risk of either false-negative or false-positive results. However, as more light is shed on the natural history of HCMV infection during pregnancy and fetal life, the predictive value of negative prenatal diagnosis results is becoming more defined, thus improving the quality of counseling. In addition, the availability of different assays for detection of HCMV in both fetal blood and amniotic fluid samples will eventually reduce the risk of false-positive results. Finally, the identification of reliable prognostic markers of fetal disease remains the ultimate goal and a major challenge.
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PMID:Pathogenesis and prenatal diagnosis of human cytomegalovirus infection. 1474 24

Human cytomegalovirus (HCMV) represents one of the most medically important human viruses and causes a wide spectrum of human diseases, including birth defects and mental retardation in newborns, common opportunistic infections in acquired immunodeficiency syndrome (AIDS) patients (e.g., CMV-associated retinitis and pneumonia), and possibly cardiovascular diseases such as atherosclerosis. This chapter describes the utilization of RNase P ribozyme-specifically, M1GS ribozyme, as a gene-targeting agent for blocking HCMV gene expression and growth. The target for the RNase P ribozyme is the overlapping region of the mRNAs that code for HCMV major transcription factors IE1 and IE2, which are essential for viral gene expression and replication. The methods described in this chapter focus primarily on i) construction of the retroviral vector for expression of M1GS ribozymes in cultured cells, ii) generation of stable cell lines expressing ribozymes, iii) determination of the expression of M1GS RNAs in human cells, and iv) evaluation of the efficacy of ribozymes in inhibiting HCMV IE1/IE2 expression and viral growth. Using these methods, we successfully constructed M1GS RNAs against the IE1/IE2 mRNA sequence and recently showed that a reduction of up to 150- to 3000-fold in HCMV growth is found in cells that express the ribozymes.
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PMID:RNase P ribozyme as an antiviral agent against human cytomegalovirus. 1501 69

Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive developmental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases, Tenth Revision. Except for Rett syndrome--attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene--the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published between 1961 and 2003 yields convincing evidence for multiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of approximately 3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is approximately 2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affected. There are 3 main approaches to identifying genetic loci, chromosomal regions likely to contain relevant genes: 1) whole genome screens, searching for linkage of autism to shared genetic markers in populations of multiplex families (families with >1 affected family member; 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive contribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a "chromosome 15 phenotype" was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA(A) receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more children with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments. Genetic counseling justifies testing, but until autism genes are identified and their functions are understood, prenatal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormalities. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogenesis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elucidating the influences of their products on brain development and physiology.
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PMID:The genetics of autism. 1512 91

Congenital cytomegalovirus (CMV) infection is the leading cause of mental retardation and hearing impairment. Examination for the presence of CMV infection was carried out in a selected population of 70 neonates. Urine samples were tested for CMV by means of a nested polymerase chain reaction. CMV was detected in 6 (16.7%) of the 36 preterm newborns and in 5 (14.7%) of the 34 full-term newborns. One preterm neonate died and the remaining 10 newborns were followed up. Two children born at full-term did not excrete CMV at 2 years of age and were symptom-free. Of 8 CMV-excreting children (5 preterm and 3 full-term), 2 were symptom-free (1 preterm and 1 term). Symptomatic CMV disease developed in 6 children (4 preterm and 2 full-term), with mental retardation (n=4), hearing loss (n=1), strabismus (n=2) or bronchial asthma (n=1). Screening of such neonates is important; those identified as congenitally CMV-infected can be monitored to correct any sequelae immediately.
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PMID:Incidence and outcome of congenital cytomegalovirus infection in selected groups of preterm and full-term neonates under intensive care. 1564 27

Congenital human cytomegalovirus (CMV) infection is the leading infectious cause of mental retardation, sensorineural deafness and visual impairment. It is mainly related to a primary maternal infection. The placenta should be considered the most important site of both the protection of the fetus from CMV infection and the transmission of CMV from mother to fetus. The control of the passage of CMV across the placenta probably involves a cascade of regulatory events. Roles are played by factors relating to the host immune-selective pressures, such as local cytokines and maternal CMV-specific neutralizing antibodies. The presence of other pathogens at the maternal-fetal interface also influences the outcome of CMV infection. Further investigations are needed in which clinical CMV strains are applied in in vitro studies to unravel the molecular mechanism of the intrauterine transmission of CMV and to elucidate the complex regulation that leads to prevention of the in utero transmission of CMV in vivo.
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PMID:Mother-to-fetus transmission of cytomegalovirus. A review. 1570 29

Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. Some congenitally infected infants will develop sequelae later in life, especially sensorineural hearing loss (SNHL) and mental retardation. There is no generally accepted antiviral therapy for the treatment of symptomatic congenital CMV infections yet. We present a neonate with symptomatic congenital CMV infection, who was treated with intravenous (iv) ganciclovir (GCV) during 18 days and subsequently with oral valganciclovir (VGCV) for 5.5 months, in an attempt to prevent development of SNHL. GCV was given intravenously 10 mg/kg/day in two doses and VGCV doses ranged from 280-850 mg/m2 bidaily (bid). Our experience shows that it is not possible to give a fixed dosing regime for VGCV in neonates and that continuous adaptation of dose is necessary to achieve stable target levels of GCV and to keep the viral load in urine at undetectable level. At 18 months of age no hearing deterioration has occurred. While the current findings are encouraging, the limitations of a single case report with a relatively short follow-up emphasizes the need for further prospective randomized studies to evaluate pharmacokinetics, efficacy and safety of VGCV therapy in neonates with congenital CMV infection.
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PMID:Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir. 1621 80

Congenital and perinatal infections with cytomegalovirus (CMV) are responsible for considerable short- and long- term morbidity in infants. CMV is the most common congenital viral infection in the developed world, and is a common cause of neurodevelopmental injury, including mental retardation and sensorineural hearing loss (SNHL). Antiviral therapy has been shown to be valuable in ameliorating the severity of SNHL, but CMV disease control in newborns ultimately depends on successful development of a vaccine. Because CMVs are extremely species specific, preclinical evaluation of vaccines must be performed in animal models using the appropriate CMV of the animal being studied. Several small animal models available for CMV vaccine and pathogenesis research are described. The discussion focuses on the guinea pig model because guinea pig cytomegalovirus (GPCMV), which crosses the placenta and causes infection in utero, is uniquely useful. Examination of vaccines in the GPCMV and other nonprimate models should provide insights into the determinants of the host response that protect the fetus, and may help to prioritize potential vaccine strategies for use in human clinical trials related to this important public health problem.
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PMID:Nonprimate models of congenital cytomegalovirus (CMV) infection: gaining insight into pathogenesis and prevention of disease in newborns. 1639 32

Seroconversion to cytomegalovirus (CMV) occurs in 1-4% of pregnant women. The majority of these women are seropositive prior to pregnancy. In 0.2-2.5% of the newborn infants, there is evidence of intrauterine infection, most of them are born without any clinical findings. The typical clinical symptoms of congenital CMV (symptomatic congenital CMV) that are found in 10-20% of infected neonates include intrauterine growth restriction (IUGR), microcephaly, hepatosplenomegaly, petechiae, jaundice, chorioretinitis, thrombocytopenia, anemia and/or other atypical findings. Of special problem are the different neurodevelopmental sequelae such as mental retardation, motor impairment, sensorineural hearing loss or visual impairment, which may occur even in infants who are free of symptoms at birth. Most infants born with severe neonatal symptoms of congenital CMV are born to mothers with primary infection in pregnancy. However, since over 60% of the infants infected in utero with CMV are born to mothers with preconceptional immunity who have secondary infection in pregnancy, and more and more studies show severe sequelae in these infants, we have to conclude that congenital CMV may be a significant problem even in children born to mothers with pre-pregnancy immunization. This may justify the use of invasive methods for the detection of possible fetal infection even in cases of secondary CMV infection. This also brings in an additional problem, when considering the need for proper immunization against CMV, as immunization is primarily aimed for women without immunity.
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PMID:Fetal effects of primary and secondary cytomegalovirus infection in pregnancy. 1658 Sep 41

Human cytomegalovirus (HCMV) is the most common cause of congenital infections in developed countries, with an incidence varying between 0.5 and 2.2% and consequences varying from asymptomatic infection to lethal conditions for the fetus. Infants that are asymptomatic at birth may still develop neurological sequelae, such as hearing loss and mental retardation, at a later age. Infection of neural stem and precursor cells by HCMV and consequent disruption of the proliferation, differentiation, and/or migration of these cells may be the primary mechanism underlying the development of brain abnormalities. In the present investigation, we demonstrate that human neural precursor cells (NPCs) are permissive for HCMV infection, by both the laboratory strain Towne and the clinical isolate TB40, resulting in 55% and 72% inhibition of induced differentiation of human NPCs into neurons, respectively, when infection occurred at the onset of differentiation. This repression of neuronal differentiation required active viral replication and involved the expression of late HCMV gene products. This capacity of HCMV to prevent neuronal differentiation declined within 24 h after initiation of differentiation. Furthermore, the rate of cell proliferation in infected cultures was attenuated. Surprisingly, HCMV-infected cells exhibited an elevated frequency of apoptosis at 7 days following the onset of differentiation, at which time approximately 50% of the cells were apoptotic at a multiplicity of infection of 10. These findings indicate that HCMV has the capacity to reduce the ability of human NPCs to differentiate into neurons, which may offer one explanation for the abnormalities in brain development associated with congenital HCMV infection.
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PMID:Human cytomegalovirus inhibits neuronal differentiation and induces apoptosis in human neural precursor cells. 1694 May 5

Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates.
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PMID:Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation. 1739 28


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