A 38 year old thin, Native American female with no known past medical history presented to the hospital with combativeness, confusion and then obtundation. She was in her normal state of health according to her family and then developed confusion and erratic behavior at work. She had no history of seizures. She did have a mild developmental delay according to her family. At presentation, she was afebrile, normotensive, non-tachypnic. Neurologic exam was significant for intermittently following commands, withdrawing to painful stimuli, reflexes 2+ in upper and lower extremities. Laboratory studies showed CBC was normal. BMP was normal. AST was 28 unit/L, ALT was 62 unit/L and ammonia level was 425 umol/L. CT head was negative. Further studies obtained during hospitalization revealed elevated serum ornithine level (436 umol/L) and elevated urine homocitrulline levels (1791 umol/g). She was diagnosed with acute metabolic encephalopathy due to hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. She was kept NPO and treated with IV dextrose. Her mentation improved to baseline and her ammonia level improved to normal. She was discharged on Buphenyl, an ammonia scavenger mediation utilized to bypass a block in the urea cycle, and instructed to follow up in Metabolic Clinic.
Discussion:
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare disorder of the urea cycle first defined in 1969 with about 100 cases reported so far. It is an autosomal recessive mutation in the SLC25A15 gene, encoding for ORC1. ORC1 is a mitochondrial ornithine carrier important in the urea cycle. Deficiencies of ORC1 affect multiple tissue including cells in the liver and the brain which lead to various acute or chronic presentations of HHH. Symptom onset occurs more commonly in infancy and childhood, rarely into adulthood. There is significant clinical variability, from mild learning difficulties to coma, lethargy, hepatic involvement and seizures. Acute treatment includes no protein intake and IV glucose administration with replacing urea cycle intermediates or starting ammonia scavenger medications. Long term treatment goals include maintaining a low protein diet and using ammonia scavenger medications to maintain safe serum ammonia levels. Prognosis is variable, depending on disease severity. Appropriate management with low protein diet and ammonia scavenger medications may lead to an entirely normal life span.
Conclusions:
Obtundation in a hospital setting may arise from various causes. Hyperammonemia is an unusual cause of lethargy and obtundation, when due to a urea cycle disorder in an adult. Hyperammonemia at any age should prompt further testing. HHH syndrome is included on newborn screening panels but it may be missed. The presence of this urea cycle disorder in the Pueblo Native American population is rare.