Understanding Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome

Understanding Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome

Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome, also known as ornithine translocation deficiency, is a rare autosomal recessive disorder characterized by mental retardation, progressive spastic paraparesis, seizures, and myoclonus epilepsy. This condition arises due to defective activities of the mitochondrial carrier responsible for exchanging ornithine for glutamine, which leads to the accumulation of toxic levels of ammonia in the blood.

Causes and Symptoms

HHH syndrome is caused by mutations in the solute carrier family 25 (mitochondrial ornithine transporter) member 15 (SLC25A15) gene, which encodes the mitochondrial ornithine transporter-1 enzyme. The disease-causing mutations can be classified into three types: those occurring in the pseudo-repeat regions, altering the mitochondrial matrix structure; those affecting the substrate binding pocket to decrease substrate affinity; and those located in the cytoplasmic domain, breaking salt bridge networks.

Symptoms of the disorder typically manifest in infancy or early childhood, although some people may develop them later in life. These symptoms include poor appetite, irregular breathing rates, unexplained body movements, and seizures. Additionally, episodes of vomiting, fatigue, difficulty coordinating, confusion, and visual disturbances may occur as a result of acute ammonia build-up after consuming high-protein diets or fasting. Over time, HHH syndrome can cause intellectual disability, developmental delays, learning difficulties, and stiffness due to muscle tension.

Diagnosis and Management

Diagnosing HHH syndrome involves assessing blood concentrations of ammonia, homocitrulline, and ornithine, along with genetic testing to identify specific mutations. Treatment strategies focus on controlling hyperammonemia through dietary modifications, medications, and in some cases, liver transplantation.

Impact of HHH on Brain Development and Function

Neuroimaging studies show that HHH syndrome is associated with progressive degeneration of the corticospinal tract and subcortical white matter, leading to pyramidal dysfunction. Neurological examinations reveal impaired motor responses and reduced sensitivity to electrical stimuli. Although the disease course is generally stable, complications can arise when patients consume high-protein foods or during periods of fasting, resulting in acute ammonia elevation and potentially triggering neurological crises.