Diagnostic Criteria
Suggestive Findings Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome should be suspected in symptomatic individuals with the following age-related clinical, laboratory, and neuroimaging findings. Clinical Findings Neonatal presentation (~8% of individuals). Manifestations of hyperammonemia usually begin 24-48 hours after the start of feeding and can include lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. Infantile, childhood, and adolescent/adult presentation (~92% of individuals) may exhibit any of the following: • Chronic neurocognitive deficits including developmental and speech delay, ataxia, spasticity, learning disabilities, cognitive deficits, and/or unexplained seizures • Acute encephalopathy secondary to hyperammonemic crisis, which can be precipitated by infection, fasting, or injury (or occur for no apparent reason) and can manifest as lethargy, decreased appetite, nausea, vomiting, increased respiratory rate, and seizures • Chronic liver dysfunction characterized by unexplained elevation of liver enzymes (AST and ALT) with or without mild coagulopathy and with or without mild hyperammonemia. • Mild encephalopathy manifesting as disorientation, irritability, and episodic confusion with mild hyperammonemia, which is difficult to detect as it may resolve spontaneously without treatment or quickly normalize with IV solutions that include glucose . Laboratory Findings Episodic or postprandial mild to moderate hyperammonemia. Plasma ammonia concentrations at the time of diagnosis are summarized in . Note that neonates have a higher median plasma ammonia level than older affected individuals. Note: (1) In HHH syndrome the degree of hyperammonemia is usually significantly less than in other urea cycle disorders such as OTC, ASS, or CPS-I deficiency (see Urea Cycle Disorders). (2) Once an affected individual is placed on a protein-restricted diet and treated with sodium phenylbutyrate , plasma ammonia concentrations return to normal. Table 1. Plasma Ammonia Concentrations Observed in HHH Syndrome by Age of Diagnosis Plasma Ammonia Concentration in mol/L by Age of Diagnosis1
Neonatal (birth – 1 mo) (n=6) | Infantile (1 mo – 1 yr) (n=5) | Childhood (1 yr – 12 yrs) (n=36) | Adolescence to Adulthood (12 yrs) (n=17) | Total (n=64) |
|---|
Median | 300 | 173 | 120 | 117 |
Mean | 560 | 577 | 160 | 119 |
SD | 507 | 965 | 121 | 69 |
|
Source: GeneReviews — "Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome"
