Modern Biomarkers for Autism Spectrum Disorder: Future Directions.

Autism spectrum disorder is an increasingly prevalent neurodevelopmental disorder in the world today, with an estimated 2% of the population being affected in the USA. A major complicating factor in diagnosing, treating, and understanding autism spectrum disorder is that defining the disorder is solely based on the observation of behavior. Thus, recent research has focused on identifying specific biological abnormalities in autism spectrum disorder that can provide clues to diagnosis and treatment. Biomarkers are an objective way to identify and measure biological abnormalities for diagnostic purposes as well as to measure changes resulting from treatment. This current opinion paper discusses the state of research of various biomarkers currently in development for autism spectrum disorder. The types of biomarkers identified include prenatal history, genetics, neurological including neuroimaging, neurophysiologic, and visual attention, metabolic including abnormalities in mitochondrial, folate, trans-methylation, and trans-sulfuration pathways, immune including autoantibodies and cytokine dysregulation, autonomic nervous system, and nutritional. Many of these biomarkers have promising preliminary evidence for prenatal and post-natal pre-symptomatic risk assessment, confirmation of diagnosis, subtyping, and treatment response. However, most biomarkers have not undergone validation studies and most studies do not investigate biomarkers with clinically relevant comparison groups. Although the field of biomarker research in autism spectrum disorder is promising, it appears that it is currently in the early stages of development.

Time dependent changes in the bioenergetics of peripheral blood mononuclear cells: processing time, collection tubes and cryopreservation effects.

OBJECTIVES: Bioenergetic measurements in peripheral blood mononuclear cells (PBMCs) using high-throughput respirometry is a promising minimally invasive approach to studying mitochondrial function in humans. However, optimal methods for collecting PBMCs are not well studied. METHODS: Bioenergetics and viability were measured across processing delays, tube type and cryopreservation. RESULTS: Storage of collection tubes on dry ice resulted in unrecoverable samples and using the Cell Preparation Tube (CPTTM) significantly reduced viability. Thus, storage in Sodium Citrate (NaC) and ethylenediaminetetraacetic acid (EDTA) tubes were studied in detail. Cell viability decreased by 0.5% for each hour the samples remained on wet ice prior to processing while cryopreservation decreased viability by 9.6% with viability remaining stable for about one month in liquid nitrogen. Adenosine triphosphate linked respiration (ALR) and proton-leak respiration (PLR) changed minimally while maximal respiratory capacity (MRC) and reserve capacity (RC) decreased markedly with collection tubes stored on wet ice over 24 hrs. Changes in respiratory parameters were more modest over the first 8 hours. Manipulations to replace media did not attenuate changes in respiratory parameters. Cryopreservation decreased ALR, MRC and RC by 17.20, 95.30 and 54.92 pmol/min, respectively and increased PLR by 2.65 pmol/min. PLR, MRC and RC changed moderately during the first month in liquid nitrogen for freshly frozen PBMCs. CONCLUSIONS: Our results suggest that bioenergetics in PBMCs vary based on the processing time from specimen collection and preservation method. Changes in bioenergetics can be minimized by processing samples with a minimal time delay. Changes in viability are minimal and may not correspond to changes in bioenergetics.

Folate Pathway Gene Single Nucleotide Polymorphisms and Neural Tube Defects: A Systematic Review and Meta-Analysis.

Neural tube defects (NTDs) are congenital abnormalities in the central nervous system. The exact etiology of NTDs is still not determined, but several genetic and epigenetic factors have been studied. Folate supplementation during gestation is recommended to reduce the risk of NTDs. In this review we examine single nucleotide polymorphisms (SNPs) of the genes in the folate pathway associated with NTD. We reviewed the literature for all papers discussing both NTDs and SNPs in the folate pathway. Data were represented through five different genetic models. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS) and Cohen's Kappa inter-rater coefficient assessed author agreement. Fifty-nine papers were included. SNPs in MTHFR, MTRR, RFC genes were found to be highly associated with NTD risk. NOS showed that high quality papers were selected, and Kappa Q-test was 0.86. Our combined results support the notion that SNPs significantly influence NTDs across the population, particularly in Asian ethnicity. Additional high-quality research from diverse ethnicities is needed and meta-regression analysis based on a range of criteria may provide a more complete understanding of the role of folate metabolism in NTDs.

A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome.

The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q- syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q- syndrome.