ABSTRACT
To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of≥100kb and CNVs of≥10 Kb were markedly increased in probands over parents and in probands and parents over controls. Evaluation of CNVs≥1Mb by chromosomal FISH confirmed the molecular identity of a subset of the CNVs, some of which were associated with chromosomal rearrangements. In a number of the cases, CNVs were found to alter the copy number of genes that are important in mitochondrial oxidative phosphorylation (OXPHOS), ion and especially calcium transport, and synaptic structure. Hence, autism might result from alterations in multiple bioenergetic and metabolic genes required for mental function. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).
Subject(s)
Autistic Disorder/genetics , Gene Dosage , Ion Channels/genetics , Mitochondrial Proteins/genetics , Oxidative Phosphorylation , Synapses/genetics , Autistic Disorder/metabolism , Child , Child, Preschool , Female , Genome-Wide Association Study , Humans , Ion Channels/metabolism , Ion Transport/genetics , Male , Mitochondrial Proteins/metabolism , Synapses/metabolismABSTRACT
Neonatal metabolic emergencies require a multidisciplinary team approach for supportive management that has increasingly come to feature renal replacement therapies in addition to nutritional support, the use of pharmaceutical agents, and testing to guide management and provide a definitive diagnosis. An increased appreciation for the mechanisms involved in ammonia neurotoxicity has placed greater emphasis on the need for its rapid yet safe resolution to optimize long-term prognosis. We examined our experience of intermittent hemodialysis (HD) and considered (1) the feasibility of HD in low-weight neonates, (2) the rate of decrease in ammonia, (3) complications during HD in small neonates weighing <4 kg presenting at University Children's Hospital between 1999 and 2002. Additionally, we review the current cellular and molecular mechanism of ammonia-induced brain injury. All patients tolerated intermittent HD and all required pressor agents. We primed all our patients with 20 U/kg of heparin and there was no subsequent need for further heparinization. We also noted that hemodynamic instability persisted during the first 1-2 h of the procedure and improved thereafter, as indicated by a decreased need for pressor agents. All neonates are alive to date. In conclusion, HD remains an effective and practical mode of renal replacement therapy having readily managed complications in preterm neonates weighing <4 kg with metabolic disorders.
