Ornithine Translocase Deficiency (also known as hyperornithinemia-hyperammonemia-homocitrullinuria or HHH Syndrome)
Ornithine translocase is a transport protein that moves ornithine and citrulline molecules within the urea cycle. When this transport does not work properly, it causes the urea cycle to slow down and ammonia builds up in the blood. A number of other molecules also build up including ornithine in the blood and homocitrulline in the urine. Most patients have episodic hyperammonemia, accompanied by vomiting, sleepiness and (in extreme cases) coma. Growth is abnormal and learning can be affected. Common symptoms include seizures and muscle control problems. Patients that have partial activity of the transporter (mild type of disorder) have symptoms beginning in adulthood. They typically self-select low protein diets without being aware they have this disorder. Diagnosis can be made by detecting elevated levels of plasma ornithine and urinary homocitrulline. Testing of a skin biopsy can also confirm the diagnosis.
Clinical presentations and symptoms of HHH
Many individuals experience neurological symptoms related to elevated ammonia levels. These may include recurrent vomiting, excessive sleepiness or lethargy, fatigue, headaches, confusion, difficulty concentrating, behavioral or mood changes, and, in more severe cases, seizures or loss of consciousness. Some people develop problems with balance or coordination, muscle stiffness or spasticity—particularly in the legs—and progressive difficulty walking over time. Learning challenges or developmental delays may also be present, especially when symptoms begin in childhood.
Symptoms of this disease may start to appear at a variety of ages.
The age symptoms may begin to appear differs between diseases. Symptoms may begin in a single age range, or during several age ranges. The symptoms of some diseases may begin at any age. Knowing when symptoms may have appeared can help medical providers find the correct diagnosis.
In infants and young children, early signs can include poor feeding, failure to thrive, low muscle tone, irritability, frequent vomiting, and delayed developmental milestones. In older children, teens, and adults, symptoms may be more subtle or episodic and can include protein intolerance, migraines, cognitive or executive functioning difficulties, and psychiatric or behavioral changes. Episodes are often triggered by illness, fasting, stress, pregnancy, or a high-protein diet.
HHH syndrome is characterized by periods of relative stability punctuated by acute metabolic crises. During these episodes, ammonia levels can rise rapidly and cause severe symptoms such as persistent vomiting, confusion, extreme lethargy, seizures, or coma. These signs represent a medical emergency and require immediate treatment.
Although HHH syndrome presents differently in each individual, early diagnosis and ongoing management can significantly improve quality of life. With appropriate care, including dietary management, medications, and an emergency treatment plan, many people with HHH syndrome are able to manage symptoms and reduce the risk of serious complications.
How Is It Managed or Treated?
Management focuses on preventing ammonia buildup, treating acute hyperammonemic episodes, and supporting long-term health and quality of life. Because symptoms and severity vary widely, management plans are individualized and overseen by a metabolic or genetics care team.
Long-term management typically includes a carefully controlled, protein-modified diet to reduce ammonia production while still supporting normal growth and nutrition. Individuals are often guided by a metabolic dietitian to ensure adequate calories, essential amino acids, vitamins, and minerals.
