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,
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
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
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
Argininemia: Urea cycle disorders that lead to hyperammonemia and
neurologic symptoms, which are less severe than in other forms of urea cycle
Methylmalonic Acidemia (MMA): Heterogeneous inborn error of ...