Inborn errors of metabolism associated with psychosis: literature review and case–control study using exome data from 5090 adult individuals

Abstract

A literature review was conducted, using the computerized "Online Mendelian Inheritance in Man" (OMIM) and PubMed, to identify inborn errors of metabolism (IEM) in which psychosis may be a predominant feature or the initial presenting symptom. Different combinations of the following keywords were searched using OMIM: "psychosis", "schizophrenia", or "hallucinations" and "metabolic", "inborn error of metabolism", "inborn errors of metabolism", "biochemical genetics", or "metabolic genetics". The OMIM search generated 126 OMIM entries, 40 of which were well known IEM. After removing IEM lacking evidence in PubMed for an association with psychosis, 29 OMIM entries were identified. Several of these IEM are treatable. They involve different small organelles (lysosomes, peroxisomes, mitochondria), iron or copper accumulation, as well as defects in other met-abolic pathways (e.g., defects leading to hyperammonemia or homocystinemia). A clinical checklist summarizing the key features of these conditions and a guide to clinical approach are provided. The genes corresponding to each of these con-ditions were identified. Whole exome data from 2545 adult cases with schizophrenia and 2545 unrelated controls, accessed via the Database of Genotypes and Phenotypes (dbGaP), were analyzed for rare functional variants in these genes. The odds ratio of having a rare functional variant in cases versus controls was calculated for each gene. Eight genes are significantly associated with schizophrenia (p < 0.05, OR >1) using an unselected group of adult patients with schizophrenia. Increased awareness of clinical clues for these IEM will optimize referrals and timely metabolic interventions.

Biomarkers for major depressive and bipolar disorders using metabolomics: A systematic review

“…Phenylketonuria (PKU-OMIM #261600) is a condition caused by a mutation in the PAH gene, which leads to a deficiency in phenylalanine hydroxylase, ultimately resulting in the build-up of Phe in the body. It can present with elevated levels of Val, Ile, and Leu, as well as allo-isoleucine, and different neuropsychiatric symptoms(Muelly et al, 2013;Trakadis, Fulginiti, & Walterfang, 2017).Moreover, mitochondrial diseases, such as myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome (OMIM #540000), present with increased levels of Lac and Ala in blood and multisystemic symptomatology, including psychiatric features (Magner et al, 2014; Morava et al, 2010; Trakadis et al, 2017).Furthermore, a number of genetic conditions exist that are caused by deficiencies in glutamate metabolism and glutathione metabolism, respectively. Meanwhile, Tyrosinemia types I (OMIM #276700), II (OMIM #276600), and III (OMIM #276710) are all genetic conditions known to impact on the Tyr metabolism pathways, which can lead to neurodevelopmental or behavioral abnormalities(Bendadi et al, 2014;Ellaway et al, 2001;Fois et al, 1986;Mayorandan et al, 2014;Pohorecka et al, 2012).Another aminoacidopathy that needs to be mentioned is Maple syrup urine disease (MSUD -OMIM #248600).…”

Aceruloplasminemia: Neurodegeneration with brain iron accumulation associated with psychosis

“…Inborn errors of metabolism (IEM) are associated with various psychiatric manifestations. As reported by Trakadis et al, psychosis can be a predominant feature or even isolated presenting manifestation of IEM . We read with great interest the authors' overview of IEM that may be phenotypically difficult to distinguish from psychiatric illness.…”

“…As reported by Trakadis et al, psychosis can be a predominant feature or even isolated presenting manifestation of IEM. 1 We read with great interest the authors' overview of IEM that may be phenotypically difficult to distinguish from psychiatric illness. Within the group of metal storage disorders, pantothenate kinase-associated neurodegeneration and neuroferritinopathy represent two forms of neurodegeneration with brain iron accumulation (NBIA) that have been associated with psychosis.…”

“…3 Trakadis et al recommended screening for IEM in psychotic patients with an atypical presentation, atypical response to therapy or specific hallmarks in physical examination, family-or past medical history. 1 Main characteristics that should raise suspicion of aceruloplasminemia, are summarized in Table 1. Brain MRI findings are illustrated in Figure 1.…”

Enrichment of gene variants associated with treatable genetic disorders in psychiatric populations

“…6 Trakadis et al (2017) recently reported a significant mild enrichment (odds ratios between 1·13-1·64) in an unselected group of 2545 adults with SCZ from the Database of Genotypes and Phenotypes of rare, presumed functional variants in several IEM genes, including NPC1 and NPC2 (associated with Niemann-Pick disease type C (NPC)), ATP7B (associated with Wilson disease (WD), and CBS (associated with homocystinuria (HOM)). 7 It is unclear how well the patient cohort was characterized, as well as how many of the identified rare variants are known to be associated with disease or how strongly they are predicted to be pathogenic. The authors suggest the need for a prospective study to document the prevalence of such IEMs in patients with psychosis.…”