Kynurenine pathway and autism spectrum phenotypes: an investigation among adults with autism spectrum disorder and their first-degree relatives

Abstract

Background Increasing literature highlighted alterations of tryptophan (TRP) metabolism and kynurenine (KYN) pathway in children with autism spectrum disorder (ASD). However, no study specifically focused on adult samples. Meanwhile, several authors stressed the relevance of investigating neurobiological correlates of adult forms of ASD and of those subthreshold ASD manifestations frequently found in relatives of ASD probands, known as broad autism phenotype (BAP). This work aimed to evaluate circulating levels of TRP and metabolites of KYN pathway in a sample of ASD adults, their first-degree relatives and controls (CTLs), investigating also the correlations between biochemical variables’ levels and ASD symptoms. Methods A sample of ASD adults, together with a group of first-degree relatives (BAP group) and unrelated CTLs were assessed by means of psychometric scales. Circulating levels of TRP, KYN, quinolinic acid (QA), and kynurenic acid (KYNA) were assessed in all subjects. Results ASD patients reported significantly higher total scores than the other groups on all psychometric scales. BAP subjects scored significantly higher than CTLs. ASD patients reported significantly lower TRP levels than BAP and CTL groups. Moreover, significantly lower levels of KYNA were reported in both ASD and BAP groups than in CTLs. Specific patterns of associations were found between autism symptoms and biochemical variables. Conclusions Our findings confirm in adult samples the presence of altered TRP metabolism through KYN pathway. The intermediate alterations reported among relatives of ASD patients further stress the presence of a continuum between subthreshold and full-threshold ASD phenotypes also from a biochemical perspective.

The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta‐analysis

“…Some studies found a significant elevation in serum and urinary levels of the neurotoxic XA and QA (Gevi et al, 2016;Lim et al, 2016), while other studies revealed no significant difference in QA between ASD and controls (Bryn, Verkerk, et al, 2017;Ormstad, Bryn, Verkerk, et al, 2018). Another study conducted on platelet-rich plasma found no significant difference in QA between the study groups (Carpita et al, 2022).…”

“…Intriguingly, researchers have discovered that several TRYCATs are considerably altered in ASD, including elevated serum QA and KA levels (Bilgiç et al, 2022; Lim et al, 2016), whereas other studies reported significantly lower QA and KA levels in ASD (Bryn, Verkerk, et al, 2017; Carpita et al, 2022; Ormstad, Bryn, Verkerk, et al, 2018).…”

Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder

“…Additionally, Carpita et al investigated the changes in KP metabolites in ASD adults, and they found significantly lower levels of Trp and QUIN and no changes in Kyn and Kyna [ 2 ]. Recently, a meta-analysis comprising all KP metabolites and keywords related to maternal pregnancy and the fetal outcome showed that an altered KP metabolite concentration is significantly related to a high risk of preeclampsia, fetal growth restriction, and preterm birth [ 129 ].…”

“…These are all considered risk factors for ASD [ 204 , 205 , 206 ]. Even though single compound changes of KP are still controversial in each clinical study ( Table 1 ) [ 1 , 2 , 8 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 ], it is clear that an abnormal balance of KP metabolites may be associated with adverse fetal neurodevelopment and the pathogenesis of ASD.…”

“…Studies have shown that elevated inflammation and Kyn metabolites during pregnancy are associated with an increased risk of several CNS disorders, including autism spectrum disorder (ASD) [ 1 , 2 , 3 ], schizophrenia (SCZ) [ 4 , 5 ], and depression [ 3 , 6 , 7 ]. In ASD patients, for example, alterations in the Kyn pathway (KP) have been observed in both the peripheral and central nervous systems [ 1 , 2 , 8 ]. It has been shown that inflammation during pregnancy may contribute to the dysregulation of the KP and increase the risk of ASD.…”