SLC25A15 gene

Also known: Ornitine Translocase Deficiency; HHH syndrome; 3H syndrome


1. The Disease

A rare, genetic disorder of urea cycle metabolism characterized by either a neonatal-onset with manifestations of lethargy, poor feeding, vomiting and tachypnea or, more commonly, presentations in infancy, childhood or adulthood with chronic neurocognitive deficits, acute encephalopathy and/or coagulation defects or other chronic liver dysfunction.

2. The Symptoms

Age of onset can range from the neonatal period to adulthood and a wide phenotypic spectrum is noted. Clinical manifestations and age of onset vary among individuals even in the same family. Lack of early signs or symptoms does not exclude the diagnosis.

  • Neonatal onset (~8% all cases). Manifestations of high ammonia usually begin 24-48 hours after feeding begins and can include lethargy, somnolence, refusal feeding, vomiting, tachypnea with respiratory alkalosis, and/or seizures.
  • Infantile, childhood, and adult onset (~92%). May present with: chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities and/or unexplained seizures); or acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and chronic liver dysfunction (elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance).
  • Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia.

3. Actions to take in case of early diagnosis

  • Babies with a positive genetic test (having 2 mutations or 2 copies of a single mutations in the SLC25A15 gene) should continue breastfeeding.
  • Biochemical correlation is essential for confirming diagnosis with plasma quantitative amino acids and urinary organic acids. Biochemical NBS with tandem mass spectrometry can also help.
  • The classic metabolic triad is: episodic or postprandial hyperammonemia, persistent hyperornithinemia and urinary excretion of homocitrulline.
  • HHH syndrome is a lifelong disease that requires lifetime compliance to dietary management and regular follow-up with a metabolic disease specialist and a multidisciplinary approach to care.
  • Emergency UCD protocols to rapidly control hyperammonemic episodes by discontinuation of protein intake, intravenous infusion of glucose and, as needed, infusion of supplemental arginine and nitrogen scavengers drugs to remove ammonia as sodium benzoate or sodium phenylacetate. Hemodialysis is performed if hyperammonemia persists and/or the neurologic status deteriorates.
  • Agents/circumstances to avoid: nonprescribed protein supplements such as those used during exercise regimens; prolonged fasting during an illness or weight loss; oral and intravenous steroids; and valproic acid, which increases ammonia.
  • Liver transplantation is not indicated as the dietary metabolic control is possible.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

4. For more information