HHH Syndrome

HHH is an acronym for hyperornithinemia-hyperammonemia-homocitrullinuria. It is a genetically transmitted inborn error of metabolism caused by a defect in the transport of ornithine into the mitochondrial matrix characterized clinically by early growth retardation, learning disabilities, periodic confusion, and ataxia.

Approximately 50 cases reported worldwide, mostly in French-Canadian populations of Quebec, Canada.

Autosomal recessive; gene map locus is 13q14.

Defect of ornithine transport into mitochondria leads to accumulation of ornithine in cytosol and deficiency of ornithine inside mitochondria, thus altering the urea cycle. This results in hyperornithinemia and hyperammonemia.

High plasma levels of ornithine and homocitrulline.

Clinical findings in these patients are the result of neurologic toxicity. There is failure to thrive, spastic paraparesis, mental retardation, myoclonus, and seizures. There may be retinal depigmentation and chorioretinal thinning. Protein restriction is beneficial. Four clinical types are described:

• Neonatal-Onset Type: Vomiting and lethargy following feeding of high-protein formula leading to severe hyperammonemia with rapidly progressive deterioration (asymptomatic in breast-fed infants)
• Infant-Onset Type: Choreoathetosis episodes, seizures, hypotonia, and developmental and growth retardation (often coinciding with introduction of high-protein solid food)
• Childhood-Onset Type: Mental retardation, seizures, refusal of milk, fish, and meat, behavioral disorders, and growth retardation
• Adult-Onset Type: Learning disabilities, avoidance of high-protein content food, confusion, and ataxia

Provide adequate hydration and calories in the perioperative period.

Problems with anesthesia have not been described in this condition. The stress of surgery may result in acute metabolic decompensation. The severity of the neurologic abnormalities determine the anesthetic management. Adequate hydration and supply of calories from dextrose-containing intravenous fluid should be ensured perioperatively and intraoperatively. Plasma glucose concentration must be monitored regularly.

Agents that may precipitate seizures, such as methohexitone and enflurane, should be avoided. The use of sevoflurane in these patients must be done judiciously by monitoring carefully the depth of anesthesia, preferably with an EEG monitor.

Ornithine Carbamoyltransferase Deficiency (OTCD): X-linked inborn error of metabolism of the urea cycle caused by a mutation in the OCT gene, resulting in impairment of the reaction, allowing condensation of carbamyl phosphate with ornithine to form citrulline, resulting in hyperornithinemia and hyperammonemia.

Carbamoylphosphate Synthetase I (CPS) Deficiency: Autosomal recessive inborn error of the urea cycle characterized by hyperammonemia (but low plasma levels of citrulline and arginine), resulting in persistent vomiting and mental confusion/coma. Gene located on 2p.

Citrullinemia: Inborn error of metabolism of the urea cycle caused by deficiency of argininosuccinic acid synthetase, leading to accumulation of citrulline and hyperammonemia. Gene map locus is 9q34 (20 mutations reported).

Argininemia: Urea cycle disorders that lead to hyperammonemia and neurologic symptoms, which are less severe than in other forms of urea cycle abnormalities.

Methylmalonic Acidemia (MMA): Heterogeneous inborn error of metabolism leading to metabolic acidosis and accumulation of methylmalonic acid and its byproducts.

N-Acetylglutamate Synthetase Deficiency: Congenital mitochondrial disorder affecting the metabolism of ammonium and results in hyperammonemia.

Propionic Acidemia: Inborn error of metabolism affecting the mitochondrial catabolism of valine and isoleucine. Untreated, the result in ketoacidosis, lethargy, coma, and finally death.