Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, also known as ornithine translocase deficiency or mitochondrial ornithine transporter deficiency, is a rare inherited disorder of the urea cycle and ornithine degradation pathway. It is caused by mutations in the SLC25A15 gene, which encodes the mitochondrial ornithine carrier (ORNT1) responsible for transporting ornithine across the inner mitochondrial membrane. When this transporter is deficient, ornithine accumulates in the cytoplasm while becoming depleted within mitochondria, leading to impaired urea cycle function and the characteristic biochemical triad of elevated plasma ornithine, hyperammonemia, and urinary excretion of homocitrulline. The syndrome primarily affects the nervous system and liver. Clinical manifestations are highly variable, ranging from severe neonatal-onset hyperammonemic encephalopathy to milder presentations in childhood or adulthood. Common symptoms include recurrent episodes of hyperammonemia (often triggered by protein intake or illness), intellectual disability, developmental delay, seizures, spastic paraplegia, ataxia, and liver dysfunction. Some patients present with lethargy, vomiting, and failure to thrive in infancy, while others may not be diagnosed until adulthood when they develop progressive neurological symptoms. Coagulopathy and elevated liver transaminases may also be observed. Treatment focuses on preventing hyperammonemic crises and minimizing neurological damage. This includes dietary protein restriction, supplementation with citrulline or arginine to support urea cycle function, and the use of nitrogen-scavenging agents such as sodium benzoate or sodium phenylbutyrate to reduce ammonia levels. Ornithine supplementation has also been used in some patients. Acute hyperammonemic episodes require emergency management, which may include intravenous glucose, nitrogen scavengers, and in severe cases, hemodialysis. Liver transplantation has been performed in select cases with recurrent severe hyperammonemia. Early diagnosis and treatment are important to optimize neurodevelopmental outcomes, though some degree of neurological impairment may still occur despite treatment.

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