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Purpose: Besides their developmental and neurological phenotype, most patients with MECP2/IRAK1 duplication syndrome present with recurrent and severe infections, accompanied by strong inflammation. Respiratory infections are the most common cause of death. Standardized pneumological diagnostics, targeted anti-infectious treatment, and knowledge of the underlying pathomechanism that triggers strong inflammation are unmet clinical needs. We investigated the influence of IRAK1 overexpression on the canonical NF-κB signaling as a possible cause for excessive inflammation in these patients. Methods: NF-κB signaling was examined by measuring the production of proinflammatory cytokines and evaluating the IRAK1 phosphorylation and degradation as well as the IκBα degradation upon stimulation with IL-1β and TLR agonists in SV40-immortalized fibroblasts, PBMCs, and whole blood of 9 patients with MECP2/IRAK1 duplication syndrome, respectively. Results: Both, MECP2/IRAK1-duplicated patients and healthy controls, showed similar production of IL-6 and IL-8 upon activation with IL-1β and TLR2/6 agonists in immortalized fibroblasts. In PBMCs and whole blood, both patients and controls had a similar response of cytokine production after stimulation with IL-1β and TLR4/2/6 agonists. Patients and controls had equivalent patterns of IRAK1 phosphorylation and degradation as well as IκBα degradation upon stimulation with IL-1β. Conclusion: Patients with MECP2/IRAK1 duplication syndrome do not show increased canonical NF-κB signaling in immortalized fibroblasts, PBMCs, and whole blood. Therefore, we assume that these patients do not benefit from a therapeutic suppression of this pathway. [ABSTRACT FROM AUTHOR]

Background: The postnatal intestinal colonization of human milk-fed and formula-fed infants differs substantially, as does the susceptibility to infectious diseases during infancy. Specific ingredients in human milk, such as prebiotic human milk oligosaccharides and a specifically structured fat composition with high proportion of beta-palmitic acid (beta-PA) promote the growth of intestinal bifidobacteria, which are associated with favorable effects on infants' health. The present study investigates whether addition of prebiotic galactooligosaccharides (GOS) in combination with higher amounts of beta-PA from cow's milk fat in infant formula positively affects gut microbiota and the incidence of infections in formula-fed infants. Methods: In a double-blind controlled trial, formula-fed infants were randomly assigned to either receive an experimental formula containing a higher proportion of beta-PA (20–25%) from natural cow's milk fat, and a prebiotic supplement (0.5 g GOS/100 ml), or a standard infant formula with low beta-PA (< 10%), without prebiotics. A breast-fed reference group was also enrolled. After 12 weeks, fecal samples were collected to determine the proportion of fecal bifidobacteria. The number of infections during the first year of life was recorded. Results: After 12 weeks, the proportion of fecal bifidobacteria was significantly higher in infants receiving formula with high beta-PA and GOS compared to control, and was similar to the breast-fed group (medians 8.8%, 2.5%, and 5.0% respectively; p < 0.001). The incidence of gastrointestinal or other infections during the first year of life did not differ between groups. Conclusions: The combination of higher amounts of beta-PA plus GOS increased significantly the proportion of fecal bifidobacteria in formula-fed infants, but did not affect the incidence of infections. Trial registration: The study protocol was registered with Clinical Trials (Protocol Registration and Results System Trial ID: NCT01603719) on 05/15/2012 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Gastrointestinal complications during the neonatal period, i.e. necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP), are associated with adverse short-term outcome in very-low-birthweight infants (VLBWI, <1500 g birth weight). However, little is known about the neurological outcome of survivors at school age. We analysed data of 2241 infants followed-up at the age of 6 years. To determine the effect of NEC and SIP on cognitive outcome in consideration of other important confounding factors, we used multivariable logistic regression models. In addition, infants with surgical diagnosis of NEC (n = 43) or SIP (n = 41) were compared to NEC (n = 43) or SIP (n = 41) negative controls using Mahalanobis distance matching. Infants with a history for NEC had a three times increased risk (RR 3.0 [1.8–4.2], p < 0.001) to develop IQ scores <85 while history of surgical SIP did not increase the relative risk for lower IQs at school age (RR 1.0 [0.4–2.1], p = 1.000). In a matched-cohort analysis, we confirmed that infants with surgical NEC had lower mean IQ results than unaffected controls (±SD) (85±17 vs. 94±14, p = 0.023) while no differences were found for history of SIP. Our results reflect that the different aetiology and inflammatory extent of NEC and SIP may lead to disparate neurodevelopment trajectories. Hence, our data suggest a potential role of early gut-brain axis distortion in infants with NEC which needs to be further explored. [ABSTRACT FROM AUTHOR]

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MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria ( S.pneumoniae, H.influenzae) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG-deficiency was detected - in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG-levels were detected in 11/21 patients and supra-normal IgG-levels were seen in 8/21 patients - in 6 of the patients as combined elevation of IgG and IgG. Three of the four patients with IgA/IgG-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG may benefit from prophylactic substitution of sIgA and IgG. [ABSTRACT FROM AUTHOR]

Ifosfamide (IFO) chemotherapy has been reported to result in deToni-Debré-Fanconi syndrome in a minority of patients only, but evaluation of tubular transport capacities has identified a substantial number of patients as having subclinical tubular dysfunction. After completion of combination chemotherapy employing IFO ( n=37) or IFO plus cisplatinum (CPL) ( n=27), glomerular and tubular function was assessed in 64 patients by the urinary excretion of transferrin, IgG, albumin, α-microglobulin (A1M) and N-acetyl-β- d-glucosaminidase. Sodium dodecyl sulphate polyacrylamide gel electrophoresis was performed in 21 patients. The determination of urinary marker proteins was compared with the glomerular filtration rate, the fractional phosphate and percent amino acid reabsorption. A reduced glomerular filtration rate was observed in 9.8% of patients. Tubular dysfunction was frequent, with a predominance of renal amino acid (57%) and A1M (48%) loss. IFO-mediated renal toxicity was dose dependent. CPL treatment resulted in significant enhancement of tubular toxicity induced by IFO, whereas concomitant gentamicin therapy did not affect tubular function. Measurement of urinary protein cannot replace other tests for tubular dysfunction in IFO-treated patients, because the spectrum of IFO-induced nephrotoxicity includes dysfunction of different and independent transport mechanisms of the proximal tubular system. Increased urinary A1M excretion is an important indicator of impaired tubular protein reabsorption. [ABSTRACT FROM AUTHOR]

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin pbinding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals. [ABSTRACT FROM AUTHOR]

Reports on prolonged survival of an infant with congenital alveolar capillary dysplasia (ACD) syndrome, using treatment with inhaled nitric oxide (iNO) as a bridge to lung transplantation. Description of symptoms; Discovery of prematurely muscularized arterioles within the pulmonary acini, the typical findings of ACD combined with misalignment of pulmonary veins (MPV); Confirmation of ACD/MPV being a fatal disease by death of child both of respiratory distress and permanent pulmonary hypertension (PPHN).