HERVs expression in Autism Spectrum Disorders.

BACKGROUND: Autistic Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder, resulting from complex interactions among genetic, genomic and environmental factors. Here we have studied the expression of Human Endogenous Retroviruses (HERVs), non-coding DNA elements with potential regulatory functions, and have tested their possible implication in autism. METHODS: The presence of retroviral mRNAs from four HERV families (E, H, K and W), widely implicated in complex diseases, was evaluated in peripheral blood mononuclear cells (PBMCs) from ASD patients and healthy controls (HCs) by qualitative RT-PCR. We also analyzed the expression of the env sequence from HERV-H, HERV-W and HERV-K families in PBMCs at the time of sampling and after stimulation in culture, in both ASD and HC groups, by quantitative Real-time PCR. Differences between groups were evaluated using statistical methods. RESULTS: The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3. CONCLUSIONS: Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.

MTHFR C677T and A1298C polymorphisms and cerebral stroke in two twin gestations.

BACKGROUND: Stroke in pediatric age is a rare event with a multifactorial genesis which could involve genetic factors as methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphism. At the same time, twin gestation with co-twin demise is an important potential risk factor for premature brain damage. PATIENTS AND METHODS: We describe two children presenting with presumed cerebral stroke born from two MC twin pregnancies in which the other co-twin had died in utero associated to maternal and fetal homozygosity for MTHFR C677T and MTHFR A1298C, respectively. Brain damage was diagnosed immediately before the delivery. CONCLUSION: Our observations underline the necessity to make a thrombophilia workup in women before or during pregnancy and, above all, in twin pregnancy. Data of literature are not clear about what kind of genetic polymorphism is prominent in the genesis of cerebral stroke (factor V leiden, MTHFR, activated protein C resistance, factor II G20210A). A multifactorial genesis for severe fetal and perinatal cerebral vascular alterations has been supposed; for this reason an early folate supplementation both to mother and infant could reduce the risk of brain damage due to fetal/perinatal stroke and eventual recurrence of thrombotic events.

Preterm birth and neurodevelopmental outcome: a review.

BACKGROUND: The incidence of preterm delivery and the survival rate of preterm newborns are rising, due to the increased use of assisted reproductive technology associated with multiple gestations and improved technology in obstetrics and neonatology, which allow saving preterm infants at earlier gestational ages. As a consequence, the risk of developmental disabilities in preterm children is high, and clinical pictures need to be fully defined. METHODS: Narrative review including articles regarding neurodevelopmental disorders published in the international medical literature and reported in PubMed between the years 2000 and January 2010. RESULTS: Although survival rates of extremely low birth weight infants (ELBW) significantly increased during the last decade, the substantial stability of disability trends in this population was disappointing. Late-preterm infants, who account for about 75% of all preterm births and had not been considered at risk for adverse long-term neurodevelopmental outcomes in the past, are now reconsidered as more likely to develop such events, though their risk remains lower than in ELBW. CONCLUSIONS: The findings of the studies discussed in our article support the importance of early diagnosis in order to make decision about appropriate treatment of preterm infants.

Efficacy of intensive versus nonintensive physiotherapy in children with cerebral palsy: a meta-analysis.

UNLABELLED: A commonly used treatment for cerebral palsy in children is so-called 'conventional therapy', which includes physiotherapy or the neurodevelopmental approach. Although more intensive rehabilitative treatment is thought to be more effective than less intensive interventions, this assumption has not been proven. In this study we compared the efficacy of intensive versus nonintensive rehabilitative treatment in children with cerebral palsy. A meta-analysis of the studies published between January 1996 and July 2007 was performed. INCLUSION CRITERIA: infants/children/adolescents (1-18 years old); randomized controlled trials using, as outcome measure, the Gross Motor Function Measure score. EXCLUSION CRITERIA: studies that included therapies not generally used in 'so-called' conventional treatment (i.e. constraint, taping). Treatment effects were combined using the weighted mean difference method. Fixed and random effect meta-analyses were carried out and results were compared. Heterogeneity was also assessed. Funnel plots were examined and the presence of small-study effects was tested. Intensive therapy tended to have a greater effect than nonintensive therapy (1.32; 95% confidence interval: 0.55-2.10). The effect of intensive treatment tended to be apparently stronger for children 2 years of age. Our meta-analysis shows that, in children with cerebral palsy, intensive conventional therapy may improve the functional motor outcome, but the effect size seems to be modest.

Chikungunya and the nervous system: what we do and do not know.

Chikungunya virus (CHIKV), an alphavirus transmitted by mosquitoes of the Aedes genus, has recently re-emerged, causing epidemics on Indian Ocean Islands and the Indian subcontinent, and an unexpected outbreak in north-eastern Italy. CHIKV infection was first reported to affect the nervous system in the 1960s; in the early 1970s it was found to be associated with meningoencephalopathy, myelitis, and choroiditis, and animal studies appeared to confirm that CHIKV was neurotropic. Nonetheless, CHIKV has never been considered as a 'true' neurotropic virus. The re-emergence of CHIKV infection in areas with efficient clinical facilities has allowed CHIKV-related neurological disease to be better defined both in adults and children. Encephalopathy appears to represent the most common clinical manifestation among newborns infected through mother-to-child transmission. Although data are still scarce, the ratio between cases with and without CNS involvement for CHIKV appears to be comparable with that for other neurotropic viruses. Unfortunately, the neurotropism of CHIKV has not been completely defined, and different animal studies show inconsistencies with regard to the capacity of the virus to invade and replicate in the brain parenchyma. This merits further investigation in light of the emergence of the virus in previously unaffected areas and of the clinical evidence of CNS involvement in a considerable proportion of symptomatic cases.

Lack of evidence for association between D2S124 and D2S111 polymorphisms of the SCN2A gene and idiopathic generalized epilepsy with generalized tonic clonic seizures.

Idiopathic generalized epilepsy syndromes are generally considered as brain channelopathies due to alteration of several genes. The aim of our study was to compare the distribution of D2S124 and D2S111 genetic polymorphisms of the SCN2A gene between cases with a specific idiopathic generalized epilepsy subtype (with generalized tonic-clonic seizures) and healthy controls. Allele frequencies of both the D2S111 and the D2S124 polymorphisms were not significantly different between cases and control. Further studies are needed to investigate if possible polymorphic variants of SCN2A gene may influence seizures susceptibility of idiopathic generalized epilepsy with tonic-clonic seizures.

Does cesarean section prevent mortality and cerebral ultrasound abnormalities in preterm newborns?

OBJECTIVE: Despite the increased use of the cesarean section (CS), the rates of cerebral palsy, a frequent consequence of brain damage, have remained stable over the last decades. Whether an actual decrease in cerebral palsy has been masked by increased survival of infants delivered by CS or not, remains undefined. To investigate the role of CS, we compared risks of mortality and brain damage, as defined by ultrasound (US) abnormalities, in preterm newborns by mode of delivery. METHODS: Information on fetal, maternal, and neonatal risk factors was collected from the paired clinical records of preterm newborns and mothers. Crude and adjusted odds ratios (OR) of mortality and ultrasound abnormalities, according to mode of delivery (i.e., vaginal, elective CS, and emergency CS) were calculated. All the analyses were controlled for possible confounding by indication. RESULTS: In newborns of gestational age <32 weeks, no effect of CS on cerebral US abnormalities was found (OR 0.71 and 0.73 for emergency CS and elective CS, respectively). None of the maternal and neonatal factors were associated with both cerebral US abnormalities and mode of delivery. Among newborns of gestational age >or=32 weeks, after controlling for known and potential confounders in a multivariate model, the adjusted ORs remained close to one for both elective CS and emergency CS. CONCLUSIONS: CS does not reduce overall mortality in preterm newborns. No protective effect of CS on US abnormalities was found after stratifying by gestational age and controlling for possible confounding. These results do not encourage the widespread use of CS in preterm labor.

Disentangling the effects of Tourette syndrome and attention deficit hyperactivity disorder on cognitive and behavioral phenotypes.

Eighty participants (62 males; 18 females; age range: 6-16 years) took part in the study, comprising four groups of 20 subjects each: TS-only, ADHD-only, TS+ADHD, controls. The age distributions, did not differ significantly among the four groups. The severity of symptoms, assessed by the TSGS, did not differ significantly between the two TS groups. Standardised measures were used throughout. The "cases" (i.e. TS-only, TS+ADHD, ADHD-only) were significantly different from controls on most measures of behavior. There were also differences amongst the various clinical subgroups, with, in general, TS-only participants being similar to controls with regards to both "total behavior" ratings and cognitive testing results. A diagnosis of ADHD, either or its own or in association with TS, was associated with greater maladaptive behavior and worse cognitive functioning. With regards to affective symptoms and anxiety, the three clinical groups did not differ from each other, but each of them was more affected than the control group. One finding in our study which differed from previous literature was that TS-only patients were rated as more "delinquent" than controls by their parents: possible reasons for this are discussed. Oppositional defiant disorder (ODD) was seen in a few (2,3,3 ODD patients in each clinical group), but as numbers were small no statistics were undertaken. Family histories were in accord with both TS and ADHD being genetic disorders, but sharing an overlap in only some cases. The "additive effect" hypothesis is discussed in detail in the light of our results and recent literature.

Association between D18S474 locus on chromosome 18q12 and idiopathic generalized epilepsy.

Idiopathic generalized epilepsy is one of the most common forms of epilepsy. The aetiology of IGE is genetically determined, but the pattern of inheritance is still undefined. Recent studies in common IGE showed evidence for linkage on chromosome 18q12 at the D18S474 locus. The aim of our study was to compare the distribution of allelic variants of D18S474 locus in children affected by generalized tonic-clonic seizures and in healthy controls. We studied 295 children: 121 cases and 174 controls. We found that the D18S474(8) allele was significantly more frequent and D18S474(9) significantly less frequent in cases compared with controls (p<.001). In conclusions, our findings show the association between the D18S474 marker and IGE in which early onset GTCS represent the most prevalent seizure type.

Association of adenosine deaminase polymorphism with mild mental retardation.

The etiology of mild mental retardation remains undefined in about 60% of cases. Even though the causes of mild mental retardation are likely to be heterogeneous, the evidence for genetic involvement is increasing, along with the development of specific diagnostic techniques. To improve our understanding of the genetic basis of mild mental retardation, we explored the role of polymorphisms of adenosine deaminase, an enzyme that is supposed to act as a neuroregulatory protein. To this end, we conducted an association study comparing children with mild mental retardation of unknown origin with two groups of controls: (1) apparently healthy children and (2) children with moderate or severe mental retardation of known etiology. Overall, 338 participants were enrolled in the study. Cases (ie, 80 children) were more likely than controls (ie, 153 healthy children and 105 children with moderate or severe mental retardation) to have the low-activity ADA-Asn 8 (ADA(1) *2) polymorphism (P < .05) and to present the ADA(1) *2/ ADA(2) *1 haplotype. No significant differences were found with respect to adenosine deaminase polymorphisms when comparing the group with moderate or severe mental retardation of known causes and healthy controls. In conclusion, our findings suggest a possible role for a low-activity genotype (ADA-8Asn) (ADA(1) *2) of adenosine deaminase in the pathogenesis of mild mental retardation.

Brain damage in preterm infants: etiological pathways.

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.

Exanthematic diseases during pregnancy and attention-deficit/hyperactivity disorder (ADHD).

Rash causing viral diseases may be transmitted during pregnancy, causing severe congenital disease. Although neurological and psychiatric disorders are common consequences of congenital rubella, children born to women who developed a viral rash during pregnancy do not appear to be at increased risk of these disorders if they were asymptomatic at birth. In a case-control study conducted to evaluate risk factors for ADHD, we found an increased risk of this disorder among children born to women experiencing a viral rash during pregnancy. The viral rash (i.e. measles, varicella, or rubella) was reported by 4 of 71 mothers of children with ADHD and none of the 118 controls' mothers (P<0.01). The difference remained statistically significant after adjusting for potential confounders (i.e. other factors found associated with ADHD, such as gender and familiarity). Although, the viral disease reported by the mothers, in accordance with their physician's diagnosis, did not represent a homogeneous nosological group, the unexpectedly high rate found among ADHD cases' mothers suggest a role for viral diseases occurring during pregnancy in the development of ADHD.

Lack of association between IDE genetic variability and Down's syndrome.

Virtually all patients with Down's syndrome develop Alzheimer disease (AD) during their life; thus, it is extremely important to investigate potential determinants of AD in this population. Previous studies found an association of DS with -48C/T presenilin-1 and with the -850 tumor necrosis factor-alpha, two polymorphisms of genes involved in amyloid beta modulation In this study, we evaluated whether the insulin-degrading enzyme (IDE), a protease involved in the degradation of endogenous brain-derived Abeta peptides, is involved in DS-related AD. To this end, 287 DS patients were compared with 251 apparently healthy controls, in order to assess the association between DS and two single nucleotide polymorphisms located on the introns 14 and 24 of the IDE gene. The comparison of allele and genotype distribution between cases and controls showed no evidence for an association with regard to IDE polymorphism, for both the SNPs (i.e., IDE 185 and IDE 199). In conclusion, the findings of our study suggest that the two IDE polymorphisms considered in the analysis do not appear to play a major role in DS-related AD.

Association between presenilin-1 -48C/T polymorphism and Down's syndrome.

Individuals with Down's syndrome (DS), i.e., trisomy 21, over 40 years of age, are likely to develop neuropathological changes characteristic of Alzheimer's disease (AD). The involvement of chromosome 21 both in DS and AD suggests a shared genetic susceptibility to these disorders, but genetic determinants are still undefined. The -48C/T polymorphism in the PSEN1 promoter is a possible candidate, since it has recently been associated with an increased risk of early onset AD. Based on the assumption that the excess of dementia in DS might be a consequence of a different distribution of the -48C/T polymorphism, we investigated the association between DS and this polymorphism in patients with trisomy 21 and controls. Overall, 260 DS patients and 197 controls were recruited at the Department of Neurosciences, Tor Vergata University of Rome. Cases and controls had similar age and gender distribution. High molecular weight DNA was extracted from whole blood samples collected in EDTANa(2) and -48C/T genotypes were determined. Genotype and allele frequencies were compared between cases and controls. Cases were less likely than controls to have the CC genotype ( P = 0.05). A significant difference for allele distribution between DS cases and controls was found, with DS showing a lower frequency of the allele C compared with the control population (OR: 0.57; 95% CI: 0.35-0.91; P = 0.01). No significant interaction of PSEN1 with age, gender, ApoE and -850 TNF-alpha polymorphisms was found. The association found suggests that the -48C/T polymorphism in the PSN1 gene promoter, which is involved in the modulation of amyloid beta load in human AD, is associated with DS. However, the biological role of this polymorphism in DS-related dementia remains unclear and merits further investigation.

The role of -850 tumor necrosis factor-alpha and apolipoprotein E genetic polymorphism in patients with Down's syndrome-related dementia.

Down's syndrome (DS) is a disease with a complex etiology. It is likely that other factors besides genes located on chromosome 21 may play a role in clinical features of affected patients. Tumor necrosis factor-alpha (TNF-alpha) (6p21.3) and apolipoprotein E (APOE) (19q13.2) are candidate genes as they interact with the brain deposition of Abeta, one of the neuropathological hallmarks in DS. We examined 136 DS patients and 113 controls for -850 TNF-alpha and APOE polymorphisms. The -850T frequency in DS was significantly higher than in controls (P<0.005, OR 2.05, 95% CI 1.22-3.49) while the APOE E4 allele was negatively selected in patients compared to normal subjects (P<0.005, OR 0.38, 95% CI 0.20-0.71). Our findings suggest that the -850T allele, which is more common among patients at high risk of dementia such as those with DS, might eventually play a role in the development of dementia; no inference on the role of the allele APOE E4 in DS-related dementia may be derived from our results.

Neurologic aspects of 49,XXXXY syndrome.

49,XXXXY syndrome is a rare sex chromosome aneuploidy syndrome characterized by mental retardation, severe speech impairment, craniofacial abnormalities, multiple skeletal defects, and genital abnormalities. We describe a 13-year-old boy with 49,XXXXY syndrome, language impairment, seizures, and left-hemisphere magnetic resonance imaging abnormalities and review the distinctive neurologic, cognitive, and behavioral phenotypes associated with this disorder. Finally, we discuss testosterone supplementation in the treatment of this syndrome.