DISEASE CHARACTERISTICS: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is characterized by variable clinical presentation and age of onset. Neonatal onset (~12% of affected individuals). Infants are normal for the first 24-48 hours followed by onset of symptoms related to hyperammonemia (poor feeding, vomiting, lethargy, low temperature, rapid breathing). Information on long-term outcome is limited. Infancy, childhood, and adult presentation (~88%). Affected individuals may present with: Chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits and/or unexplained seizures); Acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and Chronic liver dysfunction (unexplained 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.
DIAGNOSIS/TESTING: HHH syndrome is caused by mutations in SLC25A15, the gene that encodes ORNT1 (mitochondrial ornithine transporter 1), which is involved in the urea cycle and the ornithine degradation pathway. The metabolic triad of persistent hyperornithinemia, episodic or postprandial hyperammonemia, and urinary excretion of homocitrulline establishes the diagnosis of HHH syndrome.
MANAGEMENT: Treatment of manifestations: Acute and long-term management is best performed in conjunction with a metabolic specialist. Of primary importance is the use of established protocols to rapidly control hyperammonemic episodes by discontinuation of protein intake, intravenous infusion of glucose and, as needed, infusion of supplemental arginine and the ammonia removal drugs, sodium benzoate and sodium phenylacetate. Hemodialysis is performed if hyperammonemia persists and/or the neurologic status deteriorates. Prevention of primary manifestations: Individuals with HHH syndrome should be maintained on an age-appropriate protein-restricted diet, citrulline supplementation, and sodium phenylbutyrate to maintain plasma concentrations of ammonia, glutamine, arginine, and essential amino acids within normal range. Note: Liver transplantation is not indicated: Although it may correct the hyperammonemia, it will not correct the neurologic pathology. Surveillance: Routine assessment of height, weight and head circumference from the time of diagnosis to adolescence. Routine assessment of plasma ammonia concentration, plasma and urine amino acid concentrations, urine organic acids, and urine orotic acid based on age and history of compliance and metabolic control. Attention to subtle changes in mood, behavior, and eating, and/or the onset of vomiting which may suggest that plasma concentrations of glutamine and ammonia are increasing. Periodic neurologic evaluation to monitor for neurologic deterioration even when metabolic control is optimal. Agents/circumstances to avoid: Excess dietary protein intake; non-prescribed protein supplements such as those used to during exercise regimens; prolonged fasting during an illness or weight loss; use of intravenous steroids; and valproic acid which exacerbates hyperammonemia in urea cycle disorders Evaluation of relatives at risk: If the disease-causing mutations in a family are known, use molecular genetic testing to clarify the genetic status of at-risk relatives to allow early diagnosis and treatment, perhaps even before symptoms occur. Pregnancy management: Pregnancy in a woman with symptomatic HHH syndrome has not been reported. There are no well-controlled epidemiologic studies of the fetal effects of sodium benzoate, phenylacetate or phenylbutyrate during human pregnancy.
GENETIC COUNSELING: HHH syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified. Of note, given the marked phenotypic variability that exists among individuals with the same SLC25A15 mutations it is possible that two affected sibs may have completely different clinical outcomes.
Pagon, RA; Adam, MP; Ardinger, HH; Bird, TD; Dolan, CR; Fong, CT; Smith, RJH; Stephens, K
