Elevated glutamate and decreased glutamine levels in the cerebrospinal fluid of patients with MELAS syndrome

Abstract

Background Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA) mutations in the MT-TL1 gene. The pathophysiology of neurological manifestations is still unclear, but neuronal hyperexcitability and neuron-astrocyte uncoupling have been suggested. Glutamatergic neurotransmission is linked to glucose oxidation and mitochondrial metabolism in astrocytes and neurons. Given the relevance of neuron-astrocyte metabolic coupling and astrocyte function regulating energetic metabolism, we aimed to assess glutamate and glutamine CSF levels in MELAS patients. Methods This prospective observational case-control study determined glutamate and glutamine CSF levels in patients with MELAS syndrome and compared them with controls. The plasma and CSF levels of the remaining amino acids and lactate were also determined. Results Nine adult patients with MELAS syndrome (66.7% females mean age 35.8 ± 3.2 years) and 19 controls (63.2% females mean age 42.7 ± 3.8 years) were included. The CSF glutamate levels were significantly higher in patients with MELAS than in controls (18.48 ± 1.34 vs. 5.31 ± 1.09 μmol/L, p < 0.001). Significantly lower glutamine concentrations in patients with MELAS than controls were shown in CSF (336.31 ± 12.92 vs. 407.06 ± 15.74 μmol/L, p = 0.017). Moreover, the CSF levels of alanine, the branched-chain amino acids (BCAAs) and lactate were significantly higher in patients with MELAS. Conclusions Our results suggest the glutamate-glutamine cycle is altered probably due to metabolic imbalance, and as a result, the lactate-alanine and BCAA-glutamate cycles are upregulated. These findings might have therapeutic implications in MELAS syndrome.

High‐dose oral glutamine supplementation reduces elevated glutamate levels in cerebrospinal fluid in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes syndrome

“…This study demonstrates that high‐dose glutamine oral supplementation for 12 weeks significantly reduces CSF glutamate and increases CSF glutamine levels in patients with MELAS syndrome. However, the CSF levels of alanine, branched‐chain amino acids (BCAAs) and lactate, which were significantly higher before treatment with glutamine [13], did not change.…”

“…Our approach was completely different. It was hypothesized that significantly higher CSF glutamate levels and lower CSF glutamine levels found in patients with MELAS syndrome might reflect that the glutamate–glutamine cycle is altered due to insufficient energy production to maintain glia–neuron coupling [13]. This quasi‐experimental study showed that glutamine supplementation helps restore equilibrium, reducing glutamate and increasing glutamine in CSF.…”

“…The baseline characteristics of the treated patients are shown in Table 1, and they have been previously described [13]. Nine patients (six females; mean age 35.8 ± 3.2 years) were included.…”

“…It was recently shown that patients diagnosed with MELAS syndrome had significantly increased cerebrospinal fluid (CSF) glutamate and significantly decreased CSF glutamine levels compared to controls. Furthermore, most amino acids (including glutamine) showed significantly reduced levels in plasma [13].…”

Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure

“…Thus, increased amino acid levels, including glutamate levels, are consistent with a compensatory response to the primary MELAS OXPHOS defect [ 39 , 50 ]. A recent study aimed to assess glutamate and glutamine levels in plasma and cerebrospinal fluid in MELAS patients showed an elevated glutamate level in the CSF but not in the plasma [ 51 ] and in contrast, the CSF glutamine level was lower than controls [ 51 ]. These data raise the question of glutamate-glutamine balance in the pathophysiology of MELAS.…”