The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, and of other patients with undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer a gain-of-function - so that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes. We identified both causative mutations in 686 patients from seven European centers. On the basis of the phenotypic characteristics of 297 functionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the cases, and in only 5 of 184 patients was the observed phenotype more than one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4%-23% (P<.0001), suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype-phenotype inconsistencies. Our data indicate that the PAH-mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency. In the present study, the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in >10,000 genotypes, which may be useful for the management of hyperphenylalaninemia in newborns.
A direct influence of dietary long-chain polyunsaturated fatty acids (LC-PUFA) on the developmental quotient (DO) of the healthy term infant remains unexplored. To test this hypothesis, we designed a prospective study of three types of diet. 'I'wentynine infants received a LC-PUFA-supplemented formula, 31 received a standard infant formula. and 30 infants were breastfed exclusively. Neurodevelopmental response was measured by the Brunet-LCzine psychomotor development test at 4 mo. The fatty acid status was also assessed among three diet subgroups (59 subjects) at 4 mo. Formula-fed infants who received LC-PUFA supplementation scored significantly higher (p < 0.01) on the Brunet-IRzine scale than infants who received the standard formula. Breast-fed infants also performed better than those fed the standard formula. Arachidonic acid and docosahexaenoic acid levels in circulating lipids and erythrocyte phospholipids were higher among breast-fed infants and among the group fed the arachidonic-and docosahexaenoic acid-supplemented for-
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