The urea cycle is the succession of six successive enzymatic reactions to transform ammonia, the result of endogenous and exogenous protein catabolism, in urea which can be eliminated in the urine. It occurs only in the hepatocytes [5]. N-acetyl glutamate synthetase (NAGS) is one of the three mitochondrial enzyme participating to it. NAGS deficiency is transmitted as an autosomal recessive trait (NAGS gene, 17q21.31) and its prevalence is around 1/70,000. Its clinical signs vary according to the importance of the deficit and thus of the patient’s age:

The basic principle of the treatment of NAGS is avoiding protein catabolism. The children therefore need a special diet, the protein content of which is carefully adapted to the child’s age and decreased in case of infection or stress (e.g., surgery). They often also receive a daily dose of N-carbamyl glutamic acid (30–250 mg/kg/day) according to their blood urea and NH₃ level. Orthotopic liver transplantation can be performed to cure the disease.

Anesthetic implications:

In case of glycogenosis type III (also called Cori’s or Forbe’s disease), the absence of amylo-1, 6-glycosidase impairs complete degradation of glycogen in glucose: both a risk of hypoglycemia and accumulation of dextrin in hepatic and/or muscular cells ensue. Both the liver and the muscles are affected in type A while only muscles cells are affected in form B.

The accumulation of dextrin into the hepatocytes leads to hepatomegaly and progressively to hepatic fibrosis; in some cases, cirrhosis and hepatic adenomas develop during adolescence. These patients are often obese because they require frequent meals to avoid hypoglycemia. Cases of late hypertrophic cardiomyopathy have been described.

Anesthetic implications [6, 7]:

The mitochondrion is the main energy provider of the cell and many metabolic reactions occur at least partly into it: metabolism of glucose (tricarboxylic or Krebs cycle), lipids (β-oxidation of fatty acids with the carnitine shuttle system), and protein (urea cycle). In addition, many neurodegenerative diseases (e.g., some forms of Parkinson or Charcot-Marie-Tooth disease) are now known to be caused by defects in what can be called the “maintenance functions” of the mitochondrion. But the term mitochondrial cytopathy refers mainly to pathologies of the respiratory chain or oxidative phosphorylation system, a succession of reactions occurring in the inner membrane of the mitochondrion: it generates an active proton (H+) and a free electron gradient leading to the production of ATP. The five protein complexes involved in the respiratory chain are encoded by genes that are present in the mitochondrial or in the nuclear DNA: their mode of transmission is complex being either maternal or autosomic dominant or recessive. Moreover, their phenotypic expression is highly variable depending on the relative distribution of wild and mutated mitochondria within each cell and on the energetic needs of the tissue wherein they are distributed (threshold effect) [8]. Mitochondrial cytopathies are usually called according to acronyms such as MERFF (myoclonus, epilepsy, ragged red fibers), MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes), or their discoverer’s name (e.g., Leigh or Kearns-Sayre’s disease).

A peculiar aspect of the anesthetic care of mitochondrial cytopathies is that many anesthetic agents do interfere in vitro with the respiratory chain. Those data were obtained in vitro on wild mitochondria isolated from tissue: their relevance for clinical practice is thus difficult to define taking into account that almost all anesthetic agents have been used in patients with a mitochondrial cytopathy without observing major clinical effects. However, they should be kept in mind when planning anesthesia, for example: