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International audience; Sudden unexpected death in infancy occurs in apparently healthy infants and remains largely unexplained despite thorough investigation. The vast majority of cases are sporadic. Here we report seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome sequencing revealed compound heterozygous missense mutations in PPA2 in affected infants of each family. PPA2 encodes the mitochondrial pyrophosphatase, which hydrolyzes inorganic pyrophosphate into two phosphates. This is an essential activity for many biosynthetic reactions and for energy metabolism of the cell. We show that deletion of the orthologous gene in yeast (ppa2Δ) compromises cell viability due to the loss of mitochondria. Expression of wild-type human PPA2, but not PPA2 containing the mutations identified in affected individuals, preserves mitochondrial function in ppa2Δ yeast. Using a regulatable (doxycycline-repressible) gene expression system, we found that the pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent the maintenance of a sufficient electrical potential across the inner membrane, which explains the subsequent disappearance of mitochondria from the mutant yeast cells. Altogether these data demonstrate that PPA2 is an essential gene in yeast and that biallelic mutations in PPA2 cause a mitochondrial disease leading to sudden cardiac arrest in infants.

International audience; The temporal association between sudden infant death syndrome (SIDS) and sleep suggests that the arousability from sleep provides a protective mechanism for survival. Recently, the hypocretin system, which promotes wakefulness, has been implicated in SIDS, since it has been reported that SIDS victims have fewer hypocretin neurons than infants who have died from other causes. To understand the role of hypocretin in SIDS, it is essential to better understand how this system matures. The present study compared cerebrospinal fluid (CSF) hypocretin in children aged 2-6 months, which is the age of peak incidence for SIDS, to both younger and older children. METHOD: Hypocretin levels were measured in CSF samples from 101 children who underwent a clinically relevant lumbar puncture. Children were separated into five age groups: 0-2 months, 2-6 months, 1-5 years, 5-10 years, and 10-18 years. RESULTS: Hypocretin levels were not significantly different between 1-5 years, 5-10 years, and 10-18 years. Therefore, these three groups were pooled into a single one (1-18 years) for further analysis. Between the 0-2 month, 2-6 month, and 1-18 year groups, a significant difference in CSF hypocretin levels existed (p~=~0.001). Simple comparisons showed that CSF hypocretin levels in the 2-6 month age group were significantly lower than hypocretin levels in both the 0-2 month and 1-18 year group (p~\textless~0.001 and p~=~0.008, respectively), but not significantly between 0-2 month and 1-18 year children. CONCLUSIONS: The CSF hypocretin levels were lower at the age of peak incidence for SIDS. This could underlie an increased vulnerability to SIDS at this specific age.

Despite the dramatic decline in the incidence of sudden infant death syndrome (SIDS) by 50–90% over the past two decades, SIDS continues to be the leading cause of death in infants aged between 1 month and 1 year in developed countries.

Resume Les campagnes de prevention contre la Mort Subite du Nourrisson (MSN) ont conduit a une diminution significative du nombre de deces inattendus et inexpliques du nourrisson pendant le sommeil. Malgre une recherche intensive dans ce domaine, la comprehension des mecanismes responsables d’une MSN est encore incomplete. Les resultats des recherches epidemiologiques, genetiques, efectrophysio-logiques et anatomopathologiques les plus recentes seront revus. De ces donnees, un modele pour la MSN peut etre elabore : le deces resulterait de la survenue concomitante de trois facteurs (une vulnerabilite prenatale, une periode critique du developpement et des facteurs de stress postnataux) et de 3 mecanismes potentiels (une deficience respiratoire, autonome et des mecanismes d’eveil). Le reveil etant souvent la derniere chance de survie d’un individu soumis a un stress vital, une deficience de ce mecanisme pourrait etre un des facteurs cles du processus conduisant a une MSN. Un nourrisson dont les controles cardiorespiratoires et les mecanismes d’eveil sont alteres peut etre a risque de MSN. Des facteurs genetiques, metaboliques, nutritionnels ou toxiques pourraient etre responsables de lesions prenatales du systeme nerveux central et en particulier du tronc cerebral. Ces deficiences resteraient latentes dans les premieres semaines de vie, jusqu’a une periode du developpement particulierement critique entre 2 et 6 mois, quand des changements significatifs surviennent au niveau de la structure du sommeil, des controles respiratoire et cardiaque. L’incident a de grande chance de survenir lorsque l’enfant est expose a une infection ou a un milieu environnemental defavorable qui aggravera l’instabilite des controles cardiorespiratoires et d’eveils.

The sudden and unexplained death of sleeping infants aged less than 1 year, the sudden infant death syndrome (SIDS), is still the principal cause of postneonatal mortality in many industrialized countries. Since initiation of education and information campaigns to inform the public on preventable risk factors, SIDS incidence has dropped significantly in most countries. Questions have, however, been raised on the physiological mechanisms underlying the environmental factors increasing the risk for SIDS. From the scientific literature, it appears that various mechanisms responsible for the control of respiratory, cardiac, thermoregulation, neurovegetative, and waking systems could be impaired before or after birth of future victims of SIDS. To understand how various factors contribute to SIDS deaths, we studied the characteristics of sleeping infants in two different populations, in future SIDS victims and in healthy infants exposed to conditions known to favor SIDS. This paper will review research carried out by our laboratory over the past 20 years.

Although data documenting the frequency and severity of human parechovirus type 3 (HPeV-3) infection in infants have been published in Canada, the USA, the UK and the Netherlands, no data from France are available.To determine the detection frequency of HPeV in cerebrospinal fluid (CSF) samples collected from children aged5 years hospitalized between 2008 and 2010 in the University Hospital of Lyon and to describe the clinical, virological and biological characteristics associated with HPeV infection.A total of 1128 CSF samples were retrospectively tested using the Parechovirus-Rgene™ real-time RT-PCR assay. Positive samples were typed by sequencing using the CDC method. Retrospective analysis of the medical charts was performed.Over a 3-year period, 33/1128 (2.9%) CSF samples were found to be HPeV-positive. In 2010, 9.3% of the children aged3 months (32% in June) were detected HPeV-positive. The median age at diagnosis was 26 days (8-131 days). Most patients (86%) presented with fever or a sepsis-like syndrome. Three patients (2 with septic shock syndrome, 1 with severe respiratory distress) required hospitalization in an intensive care unit. An HPeV-3 acute infection was identified in an 11-day-old girl who died from sudden infant death syndrome. Of 29 patients genotyped, 28 were infected with HPeV-3 and one with HPeV-4.HPeV is a significant cause of sepsis and severe sepsis in children3 months. Routine screening for HPeV in CSF and blood should thus be performed more extensively and could improve clinical management.

Various entities and genetic etiologies, including inherited long QT syndrome type 3 (LQT3), contribute to sudden infant death syndrome (SIDS). The goal of our research was to biophysically characterize a new SCN5A mutation (S1333Y) in a SIDS infant. S1333Y channels showed the gain of Na+ channel function characteristic of LQT3, including a persistent inward Na+ current and an enhanced window current that was generated by a −8mV shift in activation and a +7mV shift in inactivation. The correlation between the biophysical data and arrhythmia susceptibility suggested that the SIDS was secondary to the LQT3-associated S1333Y mutation.

International audience; OBJECTIVE: Previous data have suggested that a prolonged QTc interval during the first days of life can be associated with some cases of sudden infant death syndrome (SIDS). Analysis of heart rate variability during sleep in future SIDS victims has shown findings compatible with an imbalance in autonomic tone. We hypothesized that some future SIDS infants could have longer QTc intervals during sleep, compared with healthy control infants, and that this difference would correlate with the autonomic imbalance already found in these infants. METHODS: QTc intervals and a heart rate autoregressive power spectral analysis were calculated during the same periods in the polysomnographic sleep recordings of 18 infants who eventually died of SIDS and of 18 control infants. The control infants were matched for sex, gestational age, postnatal age, birth weight, and sleep position. The median postnatal age was 8 weeks. RESULTS: Compared with control infants, future SIDS victims were characterized by having longer QTc intervals during total sleep (P = 0.019), rapid eye movement sleep (P = 0.045) and non-rapid eye movement sleep (P = 0.029). When the night was divided into 3 equal parts, this difference was always present but was most marked during the last part of the night. There was, respectively, a negative and a positive correlation between parasympathetic activity and sympathovagal balance and median and maximum QTc interval values. CONCLUSION: Compared with QTc intervals in matched control infants, QTc intervals were increased in future SIDS victims. Such a prolongation could be related to the autonomic dysfunction already reported in these patients.

Objective. The Neonatal Individualized Developmental Care Program (NIDCAP) for very low birth weight (VLBW) preterm infants has been suggested by Als et al to improve several medical outcome variables such as time on ventilator, time to nipple feed, the duration of hospital stay, better behavioral performance on Assessment of Preterm Infants' Behavior (APIB), and improved neurodevelopmental outcomes. We have tested the hypothesis of whether the infants who had received NIDCAP would show advanced sleep-wake pattern, behavioral, and neurodevelopmental outcome.Methods. Thirty-five VLBW infants were randomly assigned to receive NIDCAP or routine infant care. The goals for NIDCAP intervention were to enhance comfort and stability and to reduce stress and agitation for the preterm infants by: a) altering the environment by decreasing excess light and noise in the neonatal intensive care unit (NICU) and by using covers over the incubators and cribs; b) use of positioning aids such as boundary supports, nests, and buntings to promote a balance of flexion and extension postures; c) modification of direct hands-on caregiving to maximize preparation of infants for, tolerance of, and facilitation of recovery from interventions; d) promotion of self-regulatory behaviors such as holding on, grasping, and sucking; e) attention to the readiness for and the ability to take oral feedings; and f) involving parents in the care of their infants as much as possible. The infants' sleep was recorded at 36 weeks postconceptional age (PCA) and at 3 months corrected age (CA) using the Motility Monitoring System (MMS), an automated, nonintrusive procedure for determining sleep state from movement and respiration patterns. Behavioral and developmental outcome was assessed by the Neurobehavioral Assessment of the Preterm Infant (NAPI) at 36 weeks PCA, the APIB at 42 weeks PCA, and by the Bayley Scales of Infant Development (BSID) at 4, 12, and 24 months CA.Results. Sleep developmental measures at 3 months CA showed a clear developmental change compared with 36 weeks PCA. These include: increased amount of quiet sleep, reduced active sleep and indeterminate sleep, decreased arousal, and transitions during sleep. Longest sleep period at night showed a clear developmental effect (increased) when comparing nighttime sleep pattern of infants at 3 months with those at 36 weeks of age. Day-night rhythm of sleep-wake increased significantly from 36 weeks PCA to 3 months CA. However, neither of these sleep developmental changes showed any significant effects of NIDCAP intervention. Although all APIB measures showed better organized behavior in NIDCAP patients, neither NAPI nor Bayley showed any developmental advantages for the intervention group. The neurodevelopmental outcome measured by the Bayley at 4, 12, and 24 months CA showed 64% of the NIDCAP intervention group at the lowest possible score compared with 33% of the control group. These findings could not be explained by the occurrence of intraventricular hemorrhage or the socioeconomic status of the parents, which showed no significant group effect.Conclusion. The results of this study, including measures of sleep maturation and neurodevelopmental outcome up to 2 years of age did not demonstrate that the NIDCAP intervention results in increased maturity or development.Buehler et al (Pediatrics. 1995;96:923–932) have reported that premature infants (N = 12; mean gestational age 32 weeks, mean birth weight 1700 g) who received developmental care compared with a similar group of infants who received routine care showed better organized behavioral performance on an APIB assessment at 42 weeks PCA. None of the medical outcome measures were significantly different in this study. Although our APIB results are in agreement, the results of the NAPI, the Bayley and sleep measures do not show an increase in neurodevelopmental maturation. In the earlier report by Als et al (Journal of the American Medical Association.1994;272:853–858), both medical and neurofunctional improvements were found in very low birth weight premature infants (mean gestational age 27 weeks, mean birth weight ∼870 g) in which 20 infants who received NIDCAP were compared with 18 infants who received routine care. At 42 weeks PCA the APIB was better in the intervention group as was the Bayley at 6 months CA. Later neurodevelopmental assessments in this study population have not been reported. Furthermore, as was indicated in the editorial by Merenstein in the same issue of the Journal of the American Medical Association, a significant problem with the study was that the number of intraventricular hemorrhages was higher in the control group (10 of 18 vs 1 of 20) and the study was conducted before the widespread use of surfactant and prenatal steroids. The study was performed in a single nursery with nurses who volunteered for developmental intervention and cared for the experimental group. No assessment was performed on differences in nursing, intervention, lighting, or sound between the two groups. Apnea, bradycardia, and desaturation data were not reported also. NIDCAP has been shown to reduce stress and agitation in the infants in our study (Heller C, et al. Journal of Perinatology.1997;17:107–112); however, there was no difference in the incidence of apnea or bradycardia.Additional studies are needed to determine which specific interventions facilitate recovery in the high-risk preterm infant when interventions are efficacious, what may be adverse or ineffective, and what mechanisms are involved. Distinctions should be made between medical improvement, neurobehavioral responses (APIB), and neurodevelopmental maturation. Not only the duration of NICU hospitalization, but indeed, long-term outcomes must be carefully evaluated. We recommend that clinicians should be aware that preterm infants who have received NIDCAP during their hospitalization do not appear to be more mature at the time of discharge home.