Carla Arpino

Preterm birth and neurodevelopmental outcome: a review

BackgroundThe 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.MethodsNarrative review including articles regarding neurodevelopmental disorders published in the international medical literature and reported in Pub Med between the years 2000 and January 2010.ResultsAlthough 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.ConclusionsThe 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.

RISK FACTORS FOR THE COOCCURRENCE OF PARTIAL EPILEPSY, CEREBRAL PALSY AND MENTAL RETARDATION

A case‐control study (64 cases and 209 controls) was carried out to identify risk factors for the cooccurrence of early‐onset partial epilepsy, cerebral palsy and mental retardation in children with and without cerebral malformations. History of epilepsy in first‐degree relatives, maternal diseases in the two years before pregnancy, placental pathologies, low gestational age, being small for dates, neonatal convulsions and the need for cardiopulmonary resuscitation were associated with partial epilepsy, cerebral palsy and mental retardation. A family history of epilepsy in first‐degree relatives was surprisingly frequent in both groups, suggesting that genetic factors play an important role for children with and without cerebral malformations.

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

Downs 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.

Association between presenilin-1 −48C/T polymorphism and Down’s syndrome

Individuals with Downs syndrome (DS), i.e., trisomy 21, over 40 years of age, are likely to develop neuropathological changes characteristic of Alzheimers 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.

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 associa t e d w i t h t h i s d i s o r d e r. F i n a l l y, w e d i s c u s s testosterone supplementation in the treatment of this syndrome. (J Child Neurol 2003;18:501—504).

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

BackgroundStroke 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 methodsWe 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.ConclusionOur 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.

Educational, cognitive, behavioral and language development issues.

Publisher Summary Cerebral malformations are responsible for several developmental disabilities that are heterogeneous both in type and severity. Virtually any type of disorder—cognitive, motor, behavioral, speech, and language—can be present. The cognitive, language, and educational treatment for children affected by brain malformations is complex and requires a multidisciplinary approach. Treatment can range from therapy to management according the severity of the clinical picture and type of disorder. The current knowledge on treatment efficacy is still limited, although a lot of progress has been made. A better integration of a functional approach with up-to-date information on genetics and natural history may lead to the identification of undetected deficits that are known to be associated with a specific genetic disorder or malformation, possibly leading to earlier and better treatment. A correct analysis of the childs environment and the appropriate involvement of the family in sharing the therapeutic objectives are essential because the quality of life of both family and child represents the final goal of every rehabilitative process.

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

Virtually all patients with Downs 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.

Does HHV-8 have a protective role on the development of HIV encephalopathy?

OBJECTIVE To evaluate risk factors for HIV encephalopathy and whether Kaposis sarcoma (KS) and coinfection with human herpesvirus 8 (HHV-8) protect against this disease in a cohort of HIV seroconverters. METHODS Individuals with known dates of HIV seroconversion belonging to different HIV exposure categories (intravenous drug users, homosexual men, heterosexual contacts) were recruited by 17 clinical centers throughout Italy. Antibodies to HHV-8 lytic antigens were detected in a subgroup of participants using an immunofluorescence assay. Risk factors for HIV encephalopathy were evaluated using Cox proportional models. The association between KS or HHV-8 infection and HIV encephalopathy was evaluated using standard statistical techniques. RESULTS During the study period, 485 of the 1,520 participants developed acquired immunodeficiency syndrome, 38 of whom developed HIV encephalopathy. HHV-8 serologic status was determined for 390 participants. Male gender, injecting drug use, and low CD4 T-cell count were associated with HIV encephalopathy; none of the 63 participants with KS developed this disease. The risk of HIV encephalopathy did not differ significantly by HHV-8 serologic status. CONCLUSIONS HIV encephalopathy was found to be associated with male gender and intravenous drug use. The risk increased at lower CD4 T-cell counts. Although HIV encephalopathy occurred less frequently in patients with KS, no association with HHV-8 infection was found.