Neurocognitive outcome of children exposed to perinatal mother-to-child Chikungunya virus infection: the CHIMERE cohort study on Reunion Island.

BACKGROUND: Little is known about the neurocognitive outcome in children exposed to perinatal mother-to-child Chikungunya virus (p-CHIKV) infection. METHODS: The CHIMERE ambispective cohort study compared the neurocognitive function of 33 p-CHIKV-infected children (all but one enrolled retrospectively) at around two years of age with 135 uninfected peers (all enrolled prospectively). Psychomotor development was assessed using the revised Brunet-Lezine scale, examiners blinded to infectious status. Development quotients (DQ) with subscores covering movement/posture, coordination, language, sociability skills were calculated. Predictors of global neurodevelopmental delay (GND, DQ ≤ 85), were investigated using multivariate Poisson regression modeling. Neuroradiologic follow-up using magnetic resonance imaging (MRI) scans was proposed for most of the children with severe forms. RESULTS: The mean DQ score was 86.3 (95%CI: 81.0-91.5) in infected children compared to 100.2 (95%CI: 98.0-102.5) in uninfected peers (P<0.001). Fifty-one percent (n = 17) of infected children had a GND compared to 15% (n = 21) of uninfected children (P<0.001). Specific neurocognitive delays in p-CHIKV-infected children were as follows: coordination and language (57%), sociability (36%), movement/posture (27%). After adjustment for maternal social situation, small for gestational age, and head circumference, p-CHIKV infection was found associated with GND (incidence rate ratio: 2.79, 95%CI: 1.45-5.34). Further adjustments on gestational age or breastfeeding did not change the independent effect of CHIKV infection on neurocognitive outcome. The mean DQ of p-CHIKV-infected children was lower in severe encephalopathic children than in non-severe children (77.6 versus 91.2, P<0.001). Of the 12 cases of CHIKV neonatal encephalopathy, five developed a microcephaly (head circumference <-2 standard deviations) and four matched the definition of cerebral palsy. MRI scans showed severe restrictions of white matter areas, predominant in the frontal lobes in these children. CONCLUSIONS: The neurocognitive outcome of children exposed to perinatal mother-to-child CHIKV infection is poor. Severe CHIKV neonatal encephalopathy is associated with an even poorer outcome.

Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy.

The human genome is densely populated with transposons and transposon-like repetitive elements. Although the impact of these transposons and elements on human genome evolution is recognized, the significance of subtle variations in their sequence remains mostly unexplored. Here we report homozygosity mapping of an infantile neurodegenerative disease locus in a genetic isolate. Complete DNA sequencing of the 400-kb linkage locus revealed a point mutation in a primate-specific retrotransposon that was transcribed as part of a unique noncoding RNA, which was expressed in the brain. In vitro knockdown of this RNA increased neuronal apoptosis, consistent with the inappropriate dosage of this RNA in vivo and with the phenotype. Moreover, structural analysis of the sequence revealed a small RNA-like hairpin that was consistent with the putative gain of a functional site when mutated. We show here that a mutation in a unique transposable element-containing RNA is associated with lethal encephalopathy, and we suggest that RNAs that harbor evolutionarily recent repetitive elements may play important roles in human brain development.

Congenital heart defects in La Réunion Island: a 6-year survey within a EUROCAT-affiliated congenital anomalies registry.

OBJECTIVES: This study compares the prevalence and perinatal mortality of congenital heart defects on La Réunion with European (EUROCAT) standards. METHODS AND RESULTS: Data were extracted from a EUROCAT-affiliated congenital malformations registry, covering 88,025 births during the period 2002-2007, on the whole island territory. A total of 512 congenital heart defects were registered, including 424 live births, 18 foetal deaths from 16 weeks of gestation, and 70 terminations of pregnancy. The total prevalence of congenital heart defects was 5.8 per 1000 births and live birth prevalence was 4.8 per 1000. The total prevalence of non-chromosomal congenital heart defects was 5.1 per 1000 births, of which 3% were perinatal deaths, 33.3% prenatally diagnosed, and 11.6% termination of pregnancy. Severe non-chromosomal congenital heart defects - excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis - occurred in 2.1 per 1000 births, of which 10.3% were perinatal deaths, 59.1% prenatally diagnosed, and 24.3% termination of pregnancy. Of the severe congenital heart defects, the rates of single ventricle (0.20‰), Ebstein anomaly (0.11‰), common arterial trunk (0.25‰), and atrioventricular septal defect (0.62‰) exceeded averages found in Europe, although coarctation of the aorta was infrequent. Conversely, rates of ventricular septal defects, atrial septal defects, and pulmonary valve stenosis were inferior to European standards. Slightly less than half of the congenital heart defects of chromosomal origin were associated with Down syndrome. CONCLUSION: In La Réunion, the total prevalence of congenital heart defects is far inferior to that found in Europe. The difference can be attributable to lower prevalences of mild congenital heart defects.

Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).

X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions.

Chikungunya virus infection during pregnancy, Reunion, France, 2006.

Mother-to-child transmission of chikungunya virus was reported during the 2005-2006 outbreak on Reunion Island, France. To determine the effects of this virus on pregnancy outcomes, we conducted a study of pregnant women in Reunion in 2006. The study population was composed of 1,400 pregnant women (628 uninfected, 658 infected during pregnancy, 27 infected before pregnancy, and 87 infected on unknown dates). We compared pregnancy outcomes for 655 (628 + 27) women not infected during pregnancy with 658 who were infected during pregnancy. Infection occurred during the first trimester for 15% of the infected women, the second for 59%, and the third for 26%. Only hospital admission during pregnancy differed between infected and uninfected women (40% vs. 29%). Other outcomes (cesarean deliveries, obstetric hemorrhaging, preterm births, stillbirths after 22 weeks, birthweight, congenital malformations, and newborn admissions) were similar. This virus had no observable effect on pregnancy outcomes.

Deletion of 5' sequences of the CSB gene provides insight into the pathophysiology of Cockayne syndrome.

Cockayne syndrome is an autosomal recessive neurodegenerative disorder characterized by a specific defect in the repair of UV-induced DNA lesions. Most cases of Cockayne syndrome are caused by mutations in the CSB gene but the pathophysiological mechanisms are poorly understood. We report the clinical and molecular data of two severely affected Cockayne patients with undetectable CSB protein and mRNA. Both patients showed severe growth failure, microcephaly, mental retardation, congenital cataracts, retinal pigmentary degeneration, photosensitivity and died at the ages of 6 and 8 years. UV irradiation assays demonstrated that both patients had the classical DNA repair defect. Genomic DNA sequencing of the CSB gene showed a homozygous deletion involving non-coding exon 1 and upstream regulatory sequences, but none of the coding exons. Functional complementation using a wild-type CSB expression plasmid fully corrected the DNA repair defect in transfected fibroblasts. Horibata et al recently proposed that all type of CSB mutations result in a defect in UV damage repair that is responsible for the photosensitivity observed in the syndrome, but that only truncated CSB polypeptides generated by nonsense mutations have some additional inhibitory functions in transcription or in oxidative damage repair, which are necessary to lead to the other features of the phenotype. Our patients do not fit the proposed paradigm and new hypotheses are required to account for the pathophysiology of Cockayne syndrome, at the crossroads between DNA repair and transcription.

Mother-to-child transmission of Chikungunya virus infection.

BACKGROUND: In 2005-2006 Reunion Island experienced a massive outbreak of chikungunya, a mosquito-borne alphavirus infection. During this epidemic, early neonatal cases were observed with a highly probable mother-to-child transmission. METHODS: A retrospective descriptive study was conducted in 5 neonatal medicine departments. Chikungunya virus infection was confirmed by reverse transcription-polymerase chain reaction or specific serology in mothers and their newborns. Mothers were screened if they presented signs at delivery or if their neonates became ill on the first days of life. RESULTS: Thirty-eight neonates were enrolled. All mothers, except 2 asymptomatic mothers, presented signs during the perinatal period (range, day(D) -4 to D+1). All neonates were symptomatic and presented symptoms on D3 to D7 (mean, D4). The mean interval between onset of maternal illness and onset of neonatal illness was 5 days (range, 3-9). The most frequent clinical signs in neonates were fever (79%), pain (100%), rash (82%), and peripheral edema (58%). Thrombocytopenia (76%), lymphopenia (47%), decreased prothrombin value (65%), and elevation of aspartate aminotransferase (77%) were detected. Complications included seizures (6), hemorrhagic syndrome (6), and hemodynamic disorders (10). Reverse transcription-polymerase chain reaction in cerebrospinal fluid was positive in 22 of 24 cases, and abnormal findings on brain magnetic resonance imaging (14 of 25) with white matter lesions or intraparenchymal hemorrhages or both were found. Echocardiography (16) showed myocardial hypertrophy (5), ventricular dysfunction (2), pericarditis (2), and coronary artery dilatation (6). One neonate died of necrotizing enterocolitis. CONCLUSIONS: The chikungunya epidemic that occurred on La Reunion Island revealed for the first time the possibility of mother-to-child transmission in the perinatal period with a high rate of morbidity.

[Early maternal-fetal transmission of the Chikungunya virus]. / Transmission materno-foetale précoce du virus Chikungunya.

INTRODUCTION: Since the onset of the Chikungunya outbreak in Reunion Island, vertical maternal-fetal transmission of the virus has been observed in newborns, but no such transmission has been demonstrated early during pregnancy. We report here the first three cases of maternal-fetal transmission of the Chikungunya virus (CHIKV) before 16 weeks' gestational age. CASES: Maternal infections occurred at terms of 12 weeks and 4 days, 15 weeks and 5 days, and 15 weeks and were confirmed by positive findings for specific anti-CHIKV IgM. Fetal deaths were subsequently observed, and at that point, CHIKV RT-PCR was negative for all three maternal blood samples. Amniocentesis preceded rupture of membranes in all three cases. RT-PCR showed viral genome in the amniotic fluid of the three fetuses, in the placentas of two, and in the brains of two. Autopsy found no malformations, and all other bacterial and viral test results were negative. DISCUSSION: These findings demonstrate early maternal-fetal transmission of CHIKV, which is suspected to be directly linked to the fetal deaths. This vertical transmission, probably abortifacient, should be considered in the light of human and animal responses to other arboviruses.

[Vertical maternal fetal transmission of the chikungunya virus. Ten cases among 84 pregnant women]. / Transmission verticale materno-foetale du virus chikungunya. Dix cas observés sur l'île de la Réunion chez 84 femmes enceintes.

INTRODUCTION: In March 2005, an epidemic of chikungunya virus began in the southern portion of Reunion Island (French overseas district in the Indian Ocean) and spread to the northern part of the island at the end of 2005. The Reunion-South Hospital Group observed the first cases of pregnant women infected with the virus in June 2005. We report here for the first time maternal-fetal transmission of this virus. CASES: From June 2005 through the end of January 2006, 84 pregnant women had acute chikungunya infections during pregnancy. In 88% of these cases (n=74)--all involving infections relatively distant from delivery--the newborns appeared asymptomatic. Conversely, 10 newborns had severe attacks (4 with meningoencephalitis and 3 with intravascular coagulations) after birth and required prolonged neonatal hospitalization (6 in the neonatal intensive care unit with intubation and assisted ventilation). No infants died, but there was one case of severe intracerebral hemorrhage after severe thrombocytopenia. These cases were confirmed by specific serology testing or PCR or both for mothers and newborns. We note that all severe cases involved women with viremia and fever in the intrapartum period.

Case report: a prenatal case of Jarcho-Levin syndrome diagnosed during the first trimester of pregnancy.

The Jarcho-Levin syndrome is a specific form of spondylocostal/spondylothoracic dysostosis. There have been various classifications of this syndrome. We present the case of a severe prenatal Jarcho-Levin syndrome, diagnosed by ultrasound examination during the first trimester of pregnancy in a family with no previous medical history of an affected child. X-ray exploration, high-resolution spiral computed tomography and autopsy confirmed the diagnosis.