Journal of Inherited Metabolic Disease

, Volume 41, Issue 6, pp 1055–1063 | Cite as

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

  • Stefan KölkerEmail author


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.



γ-Aminobutyric acid


Glycine encephalopathy (synonym, non-ketotic hyperglycinemia)


γ-Hydroxybutyric acid


Large neutral amino acids




Succinic semialdehyde dehydrogenase



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

Compliance with ethical standards

Conflict of interest

Stefan Kölker declares that he has no conflict of interest.

Informed consent

Not applicable.

Animal rights

This article does not contain any studies with human or animal subjects performed by any of the authors.


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© SSIEM 2018

Authors and Affiliations

  1. 1.Division of Pediatric Neurology and Metabolic Medicine, Centre for Pediatric and Adolescent MedicineUniversity Hospital HeidelbergHeidelbergGermany

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