Molecular Characterization of New FBXL4 Mutations in Patients With mtDNA Depletion Syndrome.

Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is a rare genetic disorder caused by defects in F-box leucine-rich repeat protein 4 (FBXL4). Although FBXL4 is essential for the bioenergetic homeostasis of the cell, the precise role of the protein remains unknown. In this study, we report two cases of unrelated patients presenting in the neonatal period with hyperlactacidemia and generalized hypotonia. Severe mtDNA depletion was detected in muscle biopsy in both patients. Genetic analysis showed one patient as having in compound heterozygosis a splice site variant c.858+5G>C and a missense variant c.1510T>C (p.Cys504Arg) in FBXL4. The second patient harbored a frameshift novel variant c.851delC (p.Pro284LeufsTer7) in homozygosis. To validate the pathogenicity of these variants, molecular and biochemical analyses were performed using skin-derived fibroblasts. We observed that the mtDNA depletion was less severe in fibroblasts than in muscle. Interestingly, the cells harboring a nonsense variant in homozygosis showed normal mtDNA copy number. Both patient fibroblasts, however, demonstrated reduced mitochondrial transcript quantity leading to diminished steady state levels of respiratory complex subunits, decreased respiratory complex IV (CIV) activity, and finally, low mitochondrial ATP levels. Both patients also revealed citrate synthase deficiency. Genetic complementation assays established that the deficient phenotype was rescued by the canonical version of FBXL4, confirming the pathological nature of the variants. Further analysis of fibroblasts allowed to establish that increased mitochondrial mass, mitochondrial fragmentation, and augmented autophagy are associated with FBXL4 deficiency in cells, but are probably secondary to a primary metabolic defect affecting oxidative phosphorylation.

Rethinking classification of prematurity: a new clinical algorithm that improves etiologic assignment of preterm births.

BACKGROUND: There is a need for a better etiologic classification of preterm births and for tools to help to determine the possible etiologies of these births. OBJECTIVE: Having previously developed the Barcelona Etiology of Prematurity (BEP) algorithm, based on a new classification for preterm births, we sought to validate this algorithm in clinical studies whereby doctors retrospectively assigned the etiology of preterm birth according to principal cause and associated causes. METHOD: In phase 1 of the study, 91 preterm neonates consecutively admitted to a tertiary hospital were etiologically classified by doctors using the BEP algorithm. In phase 2, another 29 cases, representing the full spectrum of standard clinical scenarios, were classified by 20 doctors randomly divided into two groups of 10: one group used the algorithm and the other did not. RESULTS: In phase 1, the doctors were able to assign the etiology of all 91 clinical cases using the BEP algorithm, showing a 95.6% level of agreement with the etiologies set by the authors. In phase 2, for the 572 total evaluations, the group that used the BEP algorithm had significantly fewer errors in assigning the principal cause of prematurity than the group that did not use the algorithm (4.51 vs. 16.20%, respectively; p < 0.0001), and also demonstrated a higher level of correlation in assigning the associated causes. CONCLUSIONS: The proposed classification may be used to retrospectively categorize the etiology of preterm births, and the BEP algorithm facilitates this task enabling greater accuracy and precision in clinical data.

Impact of histological chorioamnionitis, funisitis and clinical chorioamnionitis on neurodevelopmental outcome of preterm infants.

BACKGROUND: The role of chorioamnionitis in neurodevelopment of preterm infants is not fully understood. AIM: To examine the association between different indicators of intrauterine inflammation (clinical chorioamnionitis, histological chorioamnionitis and funisitis) and neurodevelopmental impairment in very preterm infants. METHODS: Preterm infants with a birth weight of <1500 g or a gestational age of <32 weeks were included. Follow-up evaluation up to 2 years of age consisted of neurological examination, neurodevelopmental assessment and visual and audiologic tests. Outcome data were compared between the chorioamnionitis and the control groups, controlling for gestational age, birth weight and Apgar score at 5 min. RESULTS: One hundred seventy-seven patients comprised the study population (mean gestational age 29±2 weeks, mean birth weight 1167±344 g). Histological chorioamnionitis was present in 49% of placentas, whereas funisitis was observed in 25%. In 57% cases clinical maternal chorioamnionitis was suspected. Follow-up was available for 130 (82%) patients. Infants with funisitis, compared with controls, had a significantly higher incidence of moderate to severe disability (18% vs 5%, OR 4.07; 95% CI 1.10-15.09). CONCLUSION: The results of this study suggest that, unlike a broad definition of histological chorioamnionitis including inflammation of maternal or fetal placental tissues, funisitis may entail a higher risk of moderate to severe disability at 2 years of age in preterm infants.

[Compliance with a culture-based strategy to prevent perinatal Group B streptococcal infection in a third-level hospital]. / Evaluación de la aplicación del cribado de estreptococo del grupo B para la prevención de la infección perinatal en un hospital de tercer nivel.

Protocols for the prevention of group B streptococcal disease are being widely used with proven efficacy. The aim of this study was to assess compliance with a culture-based approach recommending universal culture screening at 35-37 weeks' gestation, established in our hospital. A retrospective cohort study was undertaken from January 2003 to January 2004. Compliance with the culture-based approach was considered to be good (92.1%) and only partially amenable to improvements. Effectively, there are inherent limitations to the protocol that can be resolved with the use of other strategies, such as tests for quick identification of genital carrier status.

Bronchial complication of a closed-tube endotracheal suction catheter.

Iatrogenic bronchial complications in intubated premature infants are rare. The authors present one case of rupture of a closed-tube endotracheal suction catheter. Clinical presentation was a persistent pneumothorax that required chest tube placement in several days. A foreign body was confirmed in x-ray and computed tomography (CT) scan. Flexible bronchoscopy showed a piece of catheter in the left bronchus and using a rigid bronchoscope was possible to remove. No perforation was found. There are a few reports in the literature of iatrogenic bronchial complication in premature infants caused by closed-tube endotracheal suctioning catheters. Endobronchial rupture of this catheter has never been reported.