A Metabolomics Approach to Screening for Autism Risk in the Children's Autism Metabolome Project.

Autism spectrum disorder (ASD) is biologically and behaviorally heterogeneous. Delayed diagnosis of ASD is common and problematic. The complexity of ASD and the low sensitivity of available screening tools are key factors in delayed diagnosis. Identification of biomarkers that reduce complexity through stratification into reliable subpopulations can assist in earlier diagnosis, provide insight into the biology of ASD, and potentially suggest targeted interventions. Quantitative metabolomic analysis was performed on plasma samples from 708 fasting children, aged 18 to 48 months, enrolled in the Children's Autism Metabolome Project (CAMP). The primary goal was to identify alterations in metabolism helpful in stratifying ASD subjects into subpopulations with shared metabolic phenotypes (i.e., metabotypes). Metabotypes associated with ASD were identified in a discovery set of 357 subjects. The reproducibility of the metabotypes was validated in an independent replication set of 351 CAMP subjects. Thirty-four candidate metabotypes that differentiated subsets of ASD from typically developing participants were identified with sensitivity of at least 5% and specificity greater than 95%. The 34 metabotypes formed six metabolic clusters based on ratios of either lactate or pyruvate, succinate, glycine, ornithine, 4-hydroxyproline, or α-ketoglutarate with other metabolites. Optimization of a subset of new and previously defined metabotypes into a screening battery resulted in 53% sensitivity (95% confidence interval [CI], 48%-57%) and 91% specificity (95% CI, 86%-94%). Thus, our metabolomic screening tool detects more than 50% of the autistic participants in the CAMP study. Further development of this metabolomic screening approach may facilitate earlier referral and diagnosis of ASD and, ultimately, more targeted treatments. LAY SUMMARY: Analysis of a selected set of metabolites in blood samples from children with autism and typically developing children identified reproducible differences in the metabolism of about half of the children with autism. Testing for these differences in blood samples can be used to help screen children as young as 18 months for risk of autism that, in turn, can facilitate earlier diagnoses. In addition, differences may lead to biological insights that produce more precise treatment options. We are exploring other blood-based molecules to determine if still a higher percentage of children with autism can be detected using this strategy. Autism Res 2020, 13: 1270-1285. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC.

Amino Acid Dysregulation Metabotypes: Potential Biomarkers for Diagnosis and Individualized Treatment for Subtypes of Autism Spectrum Disorder.

BACKGROUND: Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD. This is the first article to report results from the Children's Autism Metabolome Project (CAMP), a large-scale effort to define autism biomarkers based on metabolomic analyses of blood samples from young children. METHODS: Dysregulation of AA metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 age-matched typically developing children recruited into the CAMP. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation. RESULTS: We identified groups of AAs with positive correlations that were, as a group, negatively correlated with BCAA levels in ASD. Imbalances between these two groups of AAs identified three ASD-associated amino acid dysregulation metabotypes. The combination of glutamine, glycine, and ornithine amino acid dysregulation metabotypes identified a dysregulation in AA/BCAA metabolism that is present in 16.7% of the CAMP subjects with ASD and is detectable with a specificity of 96.3% and a positive predictive value of 93.5% within the ASD subject cohort. CONCLUSIONS: Identification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions.

Spinal cord infarction following cervical transforaminal epidural injection: a case report.

STUDY DESIGN: Case report. OBJECTIVE: A review of the literature about spinal cord infarction with epidural steroid injections and report of one case. SUMMARY OF BACKGROUND DATA: A 53-year-old man with a history of chronic cervical pain and multilevel degenerative disc disease with multiple posterior disc protrusions on cervical imaging. The patient received a left C6 tranforaminal injection for therapeutic pain relief, with fluoroscopic confirmation of left C6 nerve root sheath spread of injectable contrast. Approximately 10 to 15 minutes post-procedure, he noted weakness in his left arm and bilateral lower limbs. Initial cervical magnetic resonance imaging revealed no cord signal change, but a follow-up study 24 hours later demonstrated patchy increased T2 and short tau inversion recovery signal in the cervical cord from the odontoid to C4-C5 vertebral levels. This was consistent with a diffuse vascular infarct to the cervical cord, resulting in motor-incomplete tetraplegia. RESULTS: This is one of a few reported cases of spinal cord infarction after cervical epidural injections. No direct cord trauma occurred. Previously reported risk factors of spinal infarction, such as hypotension and large injectate volumes, were noncontributory in this case. CONCLUSIONS: Cervical epidural injections, despite careful localization, carry a risk of vascular infarction to the spinal cord, even in the absence of direct cord trauma. The etiology of these infarctions and identifying those patients at risk remain uncertain.