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Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

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Journal of Inherited Metabolic Disease

Abstract

Amino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis of l-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor of l-glycine and d-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases. For instance, increased plasma l-phenylalanine concentrations impair cerebral biosynthesis of protein and bioamines in phenylketonuria, while elevated cerebral l-phenylalanine directly acts via ionotropic glutamate receptors. In succinic semialdehyde dehydrogenase deficiency, the neurotransmitter GABA and neuromodulatory γ-hydroxybutyric acid are elevated. Chronic hyperGABAergic state results in progressive downregulation of GABAA and GABAB receptors and impaired mitophagy. In glycine encephalopathy, the neurological phenotype is precipitated by l-glycine acting both via cortical NMDA receptors and glycine receptors in spinal cord and brain stem neurons. Serine deficiency syndromes are biochemically characterized by decreased biosynthesis of l-serine, an important neurotrophic factor, and the neurotransmitters d-serine and l-glycine. Supplementation with l-serine and l-glycine has a positive effect on seizure frequency and spasticity, while neurocognitive development can only be improved if treatment starts in utero or immediately postnatally. With novel techniques, the study of synaptic dysfunction in inherited metabolic diseases has become an emerging research field. More and better therapies are needed for these difficult-to-treat diseases.

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Abbreviations

GABA:

γ-Aminobutyric acid

GE:

Glycine encephalopathy (synonym, non-ketotic hyperglycinemia)

GHB:

γ-Hydroxybutyric acid

LNAA:

Large neutral amino acids

PKU:

Phenylketonuria

SSADH:

Succinic semialdehyde dehydrogenase

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Acknowledgements

I thank Dr. Angeles Garcia-Cazorla for the fruitful discussion and valuable input.

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  1. Division of Pediatric Neurology and Metabolic Medicine, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany

    Stefan Kölker

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Communicated by: Robert Steiner

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Kölker, S. Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases. J Inherit Metab Dis 41, 1055–1063 (2018). https://doi.org/10.1007/s10545-018-0201-4

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