HHH, syndrome

[MIM 238 970]

(Triple H syndrome, Hyperornithinemia-hyperammonemia-Homocitrullinuria)

Acronym for Hyperornithinemia - Hyperammonemia - Homocitrullinuria. Very rare. Autosomal recessive transmission of a mutation of the  ORNT1 or SLC24A15 gene on 13q14. More common among Canadians of French origin. Pathology of the urea cycle due to a disorder of the importation of ornithine into the mitochondria. It results in a secondary functional deficiency in ornithine transcarbamylase (see this term) and ornithine aminotransferase.

Clinical presentation :

-        neonatal period (50%): hyperammonemia with vomiting, lethargy or irritability;

-        childhood and adolescence: clinical picture of acute encephalopathy during stress (fever, postoperative period, protein catabolism) or progressive neurological signs (mental retardation, seizures, ataxia); aversion for proteins (meat); acute decompensation when starting of a treatment with valproate)

-        a few cases of hepatitis with reversible hepatocellular necrosis have been reported

-        the postpartum period is also a period at risk of decompensation due the catabolic reaction induced by uterine involution; some cases of postpartum psychosis could be explained in this way.

The diagnosis is sometimes made when a brutal decompensation occurs during an infectious episode (pseudo Reye syndrome). Basic principle of treatment: prevention of hyperammonemia with  a low-protein diet (the protein content is adapted to age to account for growth and must be reduced in case of infection or stress such as surgery to limit protein catabolism and the formation of NH4); moreover, it is often necessary to add sodium benzoate (0.25 g/kg/j), sodium phenylbutyrate (0.25 g/kg/day) to stimulate alternative metabolic pathways and decrease the synthesis of NH4.

Anesthetic implications:

-        shorten the duration of preoperative fasting: start an electrolyte-containing glucose solution as soon as the fasting period begins; in case of elective surgery, stop protein intake 24 to 48 h before the procedure and adapt the caloric supply with glucose and lipids;

-        empty the stomach to prevent any hidden protein intake through the digestive tract in case of surgery where blood may be swallowed (ENT, stomatology);

-        special monitoring: NH3 (nl: < 50 µmol/L or 20-80 µg/dL)), glucose;

-        opt for an anesthesia that decreases the endocrine stress response: LRA, morphine, postoperative analgesia of quality; avoid dexamethasone which increases the protein catabolism; titrated use of the antiemetics as they may hide early signs of encephalopathy.

-        supplement IV solutions with sodium benzoate (0.25 g/kg/day) and sodium phenylbutyrate (0.25 g/kg/day) to promote alternative metabolic pathways and decrease the synthesis of NH4. Caution : these solutions can cause hypokalemia

-        in case of hyperammonemia > 3 x the normal level: glucose 10 or 20% IV (200 mg/kg bolus then 5 ml/kg/h of G10% and insulin based on blood sugar levels), and IV loading dose of sodium benzoate (0.25-0. 5 g/kg) and sodium phenylbutyrate (0.25-0. 5 g/kg) and carnitine (0.2 mg/kg/day).

References : 

-        Baumgartner MR, Valle D. 
Disorders of ornithine metabolism, 
In  Inborn Metabolic Diseases, 5th edition by Saudubray, van den Berghe & Walter, p 323-32, Springer 2012 

-        Del Rio C, Martin-Hernandez E, Ruiz A, Quijada-Fraille P, Rubio P.
Perioperative management of children with urea cycle disorders.
Pediatr Anesth 2020; 30:780-91.

Updated: September 2020