Congenital Glutamine Deficiency with Glutamine Synthetase Mutations

Abstract

Häberle et al. (Nov. 3 issue)¹ state that “the concentration of glutamate . . . was not elevated in either of the two patients, but this lack of elevation might be due to the various other pathways of glutamate catabolism.” We suggest that low-to-deficient glutamate concentrations in cerebrospinal fluid indicate a chronic depletion of neuronal glutamate stores, since astrocytic glutamine synthase is crucial for their replenishment. After the bioenergetic coupling of and metabolite trafficking between astrocytes and neurons occur,² a complete deficiency of this enzyme should result in a severe depletion of neuronal glutamate stores in the long run and, subsequently, a drain of intermediates of the tricarboxylic acid cycle due to increased new synthesis of glutamate and insufficient anaplerosis through pyruvate carboxylation in neurons.³ As a consequence, concentrations of glutamate in the cerebrospinal fluid may decrease, as seen in both patients mentioned above. Neurotransmission of glutamate is important for the developing brain, for modulating neuronal migration, for growth spurts of the brain, and for apoptosis.⁴ Dysfunction of these mechanisms probably induces brain damage and malformations,^5,6 as displayed in both patients.