Analysis of Catecholamines and Pterins in Inborn Errors of Monoamine Neurotransmitter Metabolism—From Past to Future

Abstract

Inborn errors of monoamine neurotransmitter biosynthesis and degradation belong to the rare inborn errors of metabolism. They are caused by monogenic variants in the genes encoding the proteins involved in (1) neurotransmitter biosynthesis (like tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC)), (2) in tetrahydrobiopterin (BH4) cofactor biosynthesis (GTP cyclohydrolase 1 (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SPR)) and recycling (pterin-4a-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR)), or (3) in co-chaperones (DNAJC12). Clinically, they present early during childhood with a lack of monoamine neurotransmitters, especially dopamine and its products norepinephrine and epinephrine. Classical symptoms include autonomous dysregulations, hypotonia, movement disorders, and developmental delay. Therapy is predominantly based on supplementation of missing cofactors or neurotransmitter precursors. However, diagnosis is difficult and is predominantly based on quantitative detection of neurotransmitters, cofactors, and precursors in cerebrospinal fluid (CSF), urine, and blood. This review aims at summarizing the diverse analytical tools routinely used for diagnosis to determine quantitatively the amounts of neurotransmitters and cofactors in the different types of samples used to identify patients suffering from these rare diseases.

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

“…An online list of iNTD affiliated laboratories is available at the website www.intd-online.org. Collection and analysis of CSF metabolites requires the use of strict protocols and timing to avoid analytical pitfalls [65]. Since normal results of single parameters may be found, CSF analyses should always consist of a combination of monoamines (ideally including 3-O-methyldopa (3-OMD), l-3,4-dihydroxyphenylalanine (L-Dopa), 5-hydroxytryptophan (5-HTP)), pterins, and 5-MTHF to ensure the correct interpretation of results by pattern recognition.…”

“…R#14 (GPP): CSF measurements should always include standard measurements (cell count, protein, glucose, lactate) considering possible differential diagnosis e.g. infection or inflammation of different origin [65]. Collection and handling of CSF should be performed by strictly following standardized procedures to ensure correct interpretation of results.…”

Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action

“…Meanwhile, to a lesser degree, catechol-O-methyltransferase (COMT) methylation of catecholamines also occurs (not shown). Aldehyde reductase, alcohol dehydrogenase, and aldehyde dehydrogenase complete metabolic degradation to form homovanilic acid from dopamine and vanillyl mandelic acid from (nor)epinephrine (Eisenhofer et al, 2004;Fernstrom and Fernstrom, 2007;Jung-Klawitter and Kuseyri Hubschmann, 2019;Nolan and Gaskill, 2019;Goldstein, 2020).…”

Improved LC-MS/MS method for the determination of 42 neurologically and metabolically important molecules in urine

“…Neurotransmitters, kynurenines and pterins play important role for various neurologic, metabolic and psychiatric disorders [1][2][3]. Concurrent measurement of these metabolites in human serum, cerebrospinal fluid (CSF) and urine helps to diagnose diverse diseases and gives opportunity to better understand differences in metabolic pathways.…”