HHH syndrome is an autosomal recessive disorder, where ammonia builds up in the body due to a defective transportation of ornithine, which prevents ammonia being converted to urea and being excreted through the urine. HHH syndrome is a very rare metabolic disorder, with less than 100 affected individuals having been reported worldwide. The severity and the age of onset are variable, with the condition being present at birth, during childhood or even adulthood. Neonatal onset accounts for about 12% of affected individuals. Affected neonates may develop symptoms related to hyperammonemia within 24-48 hours of birth, including poor feeding, vomiting, lethargy, low temperature, and rapid breathing. Infancy, childhood, and adult presentation accounts for approximately 88% of the affected individuals. These patients present with chronic neurocognitive deficits including, developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits and/or unexplained seizures, acute encephalopathy secondary to hyperammonemic crisis, and chronic liver dysfunction.
Diagnosis for newborns can be done by screening of dried blood spots using tandem mass spectrometry (MS/MS) to identify ornithine. Affected patients have ornithine levels five to ten times that of normal. This diagnosis can be confirmed by in vitro demonstration of impaired transportation of ornithine into the mitochondria. Dietary restriction of protein is the basic treatment, with supporting therapy to prevent and control the hyperammonemia.