Glutamine supplementation in a child with inherited GS deficiency improves the clinical status and partially corrects the peripheral and central amino acid imbalance

Abstract

Glutamine synthetase (GS) is ubiquitously expressed in mammalian organisms and is a key enzyme in nitrogen metabolism. It is the only known enzyme capable of synthesising glutamine, an amino acid with many critical roles in the human organism. A defect in GLUL, encoding for GS, leads to congenital systemic glutamine deficiency and has been described in three patients with epileptic encephalopathy. There is no established treatment for this condition.Here, we describe a therapeutic trial consisting of enteral and parenteral glutamine supplementation in a four year old patient with GS deficiency. The patient received increasing doses of glutamine up to 1020 mg/kg/day. The effect of this glutamine supplementation was monitored clinically, biochemically, and by studies of the electroencephalogram (EEG) as well as by brain magnetic resonance imaging and spectroscopy.Treatment was well tolerated and clinical monitoring showed improved alertness. Concentrations of plasma glutamine normalized while levels in cerebrospinal fluid increased but remained below the lower reference range. The EEG showed clear improvement and spectroscopy revealed increasing concentrations of glutamine and glutamate in brain tissue. Concomitantly, there was no worsening of pre-existing chronic hyperammonemia.In conclusion, supplementation of glutamine is a safe therapeutic option for inherited GS deficiency since it corrects the peripheral biochemical phenotype and partially also improves the central biochemical phenotype. There was some clinical improvement but the patient had a long standing severe encephalopathy. Earlier supplementation with glutamine might have prevented some of the neuronal damage.

Figure 1

Glutamine dosing regimen and plasma concentrations during the 4 weeks trial. Glutamine was initially given 8 doses per day (blue line) but switched to 12 doses per day (blue dotted line) after 14 days treatment. Fasting plasma glutamine concentrations are given (with red ▪) as obtained every morning and for CSF glutamine concentrations (with turquoise ) illustrating the increase in plasma and CSF glutamine concentrations, respectively, under glutamine supplementation.

Figure 2

EEG before and at the end of the therapeutic trial. EEG recordings before supplementation of glutamine (2a,b) and at the end of the therapeutic trial (2c,d) showing the significant improvement of the background activity and the reduction of multifocal sharp waves both in the awake state (2c) and during sleep (2d).

Figure 3

MRI investigations. T2 weighted images obtained at age 11 months (left column) and at the beginning of the therapeutic trial (at age 3 ^9/12 years; right column) illustrating the severe brain atrophy caused by loss of cerebral white matter with consequent thinning of the corpus callosum.

Figure 4

MRS investigations. Brain MRS obtained from the patient at baseline (4a, d) and at the end of the therapeutic trial (4b,e). In addition, an average spectrum from 3 comparison subjects is shown (4c, f). Note the absence of Gln (glutamine) at baseline (4a, d) and the increase of Glu + Gln (glutamate and glutamine) at the end of the trial (4b,e). Figures 4a-c show the spectra acquired with the standard PRESS sequence, and figures 4d-f show the MEGA-PRESS data.