Low CSF branched chain amino acids: Evidence for increased brain glutamate synthesis due to impaired mitochondrial function?

In the central nervous system (CNS) the glucoplastic amino acid glutamate (Glu) functions as the major excitatory neurotransmitter. Besides this Glu also reveals excitotoxic effects that are discussed in the pathogenesis of several neurometabolic diseases. In CNS Glu is carefully compartmentalized and inactivated to glutamine (Gln) which is found in high amounts in CSF. CNS Glu synthesis occurs in astrocytes where it is connected to the Krebs cycle and the branched chain amino acids (BCAA) via BCAA amino transferase.

Patients and Methods: CSF amino acid analysis of 50 patients, who received a lumbar puncture for the purpose of a neurometabolic work up, were evaluated for Gln and BACC concentrations. Lumbar puncture was performed according to an internal protocol. In parallel plasma amino acids were compared. Amino acids were analyzed by standard procedure (Biotronic).

Results: From 50 patients 23 had a decreased concentration of one or more BCAA in CSF. In addition 5 of these 23 had an increased CSF Gln concentration. In another 5 patients an increased concentration of Gln/Glu in brain tissue was measured by MR-spectroscopy. From these, 13 patients were diagnosed to have mitochondrial dysfunction in muscle. 3 had an inborn error of metabolism potentially affecting mitochondrial function, 2 children had chromosomal lesions and unclear lactate elevation, 5 children were suspected to have a mitochondrial dysfunction by clinical presentation and blood measurements but are not finally characterized.

Discussion: In all patients with decreased CSF BCAA a mitochondrial dysfunction was found or suspected. In nearly half of these children evidence for an increased Gln/Glu synthesis was found. While CNS Glu synthesis is closely connected to mitochondria and BCAA availability we hypothesize that low CSF BCAA may reflect an increase in CNS Glu synthesis on BCAA expense. This should be discussed in detail on the background of the current knowledge of CNS metabolism and transport.