Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

CLINICAL CHARACTERISTICS

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway. Clinical manifestations and age of onset vary among individuals even in the same family. (8% of affected individuals). Manifestations of hyperammonemia usually begin 24-48 hours after feeding begins and can include lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. (92%). 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: The biochemical diagnosis of HHH syndrome is established in a proband with the classic metabolic triad of episodic or postprandial hyperammonemia, persistent hyperornithinemia, and urinary excretion of homocitrulline. The molecular diagnosis of HHH syndrome is established in a symptomatic individual with or without suggestive metabolic/biochemical findings by identification of biallelic pathogenic variants in

MANAGEMENT

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. 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 when metabolic control can be achieved with this regimen as liver transplantation may correct the hyperammonemia but will not correct tissue-specific metabolic abnormalities that also contribute to the neuropathology. 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 adherence and metabolic control. Routine developmental and educational assessment to assure optional interventions. 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. Excess dietary protein intake; 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 exacerbates hyperammonemia in urea cycle disorders. Once the pathogenic variants 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. In general, pregnant women should continue dietary protein restriction and supplementation with citrulline and ammonia-scavenging medications based on their clinical course before pregnancy. Due to increased protein and energy requirements in pregnancy and, oftentimes, difficulty with patient adherence, weekly to every two-week monitoring of plasma amino acids and ammonia is recommended, especially in the first and third trimester, and close monitoring immediately after delivery.

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. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. However, the identification of familial pathogenic variants cannot predict clinical outcome because of significant intrafamilial phenotypic variability.