Glutamine supplementation in glutamine synthetase deficiency

Abstract

An inherited defect of glutamine synthetase (GS), the only known enzyme catalysing the endogenous synthesis of glutamine in the mammalian organism, has been described in only three patients so far. GS deficiency can therefore be regarded as an ultra-rare disorder. All three patients presented immediately after birth or early in the neonatal period and were affected by severe chronic encephalopathy with severe developmental delay and seizures. Diagnosis of GS deficiency depends on the cognition of decreased levels of glutamine in plasma, urine or cerebrospinal fluid (CSF) posing a particular challenge to the physician since most metabolic disorders present on the contrary with elevated levels of a single or several amino acid(s). This chapter mainly describes the therapeutic intervention in a patient with an inherited defect of GS who well tolerated a four week trial with enteral or parenteral l-glutamine. During the trial, increasing doses of glutamine were given (maximum and final dose of 1,020 mg/kg on and after day 21 of the trial) resulting in a complete correction of the systemic glutamine deficiency and in a partial correction of the lack of glutamine in the brain. Importantly, preexisting chronic moderate hyperammonemia was not aggravated nor were toxic CSF ammonia or glutamate levels provoked by the high-dose glutamine treatment. In future patients, glutamine supplementation should begin as early as possible in order to completely avoid the consequences of systemic glutamine deficiency in the milder cases and to alleviate the consequences by replenishing glutamine pools in those patients already affected by severe glutamine deficiency due to insufficient compensation during pregnancy. It remains however to be established whether an earlier intervention can prevent the devastating natural course of chronic encephalopathy in GS deficiency.