Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome

Concise clinical and biochemical summary: genetics, diagnostic triad, presentation, investigations, and management.

Overview

HHH syndrome is a disorder of mitochondrial ornithine transport caused by pathogenic variants in SLC25A15, the gene encoding the mitochondrial ornithine transporter (ornithine carrier protein). Impaired transport of ornithine into mitochondria disrupts the urea cycle, leading to accumulation of ornithine, episodic or persistent hyperammonemia, and formation and urinary excretion of homocitrulline.

Pathophysiology

• Defect in mitochondrial ornithine transport prevents efficient entry of cytosolic ornithine into the mitochondrial matrix where ornithine transcarbamylase (OTC) uses it, impairing urea cycle flux.
• Carbamoyl phosphate reacts with lysine to produce homocitrulline, which is excreted in urine.
• Resulting metabolic disturbances include persistent hyperornithinemia, postprandial or episodic hyperammonemia, and homocitrullinuria.

Diagnostic Triad

Clinical Presentation

• Chronic neurodevelopmental delay and cognitive deficits.
• Ataxia and motor dysfunction; progressive spasticity may occur.
• Acute encephalopathy during hyperammonemic crises with lethargy, vomiting, seizures, and possible coma.
• Chronic liver disease with intermittent elevation of liver function tests and ± mild coagulopathy.
• Onset is variable: neonatal to adult presentations reported; stressors (infection, high protein intake, fasting) precipitate crises.

Investigations

• Urgent plasma ammonia in any encephalopathic patient.
• Plasma amino acid profile: elevated ornithine; variable levels of other amino acids.
• Urine amino acids/organic acids: homocitrulline detection is diagnostic.
• Liver function tests: may be intermittently elevated; assess synthetic function (albumin, INR).
• Neuroimaging and EEG as indicated for neurologic symptoms.
• Genetic testing: sequencing of SLC25A15 confirms diagnosis; consider family testing and genetic counseling.

Management

• Acute hyperammonemic crises: follow urea cycle disorder emergency protocol — stabilize airway/breathing/circulation, stop protein intake, provide high-calorie nonprotein calories, initiate rapid ammonia removal (prefer hemodialysis if severe), and administer nitrogen scavengers (sodium benzoate, sodium phenylbutyrate/phenylacetate) as indicated.
• Chronic management mirrors general urea cycle disorder strategies:
  • Protein-restricted diet tailored to growth and neurologic needs with essential amino acid supplementation.
  • Oral nitrogen-scavenging agents for maintenance therapy.
• Citrulline supplementation: provides an alternative substrate to support urea cycle flux by supplying mitochondrial aspartate/argininosuccinate pathway intermediates and helps promote nitrogen disposal in HHH syndrome.
• Consider carglumic acid for NAGS-like presentations only if indicated by metabolic team; not specific for ornithine carrier defects.
• Liver transplantation is reserved for medically refractory disease or progressive liver failure; multidisciplinary assessment required.
• Regular monitoring: plasma ammonia, amino acids (ornithine), liver function, growth, and neurodevelopmental progress.
• Genetic counseling for family and carrier testing; discuss reproductive options and newborn screening considerations.

Prognosis and Special Considerations

• Outcome is variable and depends on severity, age at diagnosis, frequency and severity of hyperammonemic episodes, and promptness of treatment.
• Early diagnosis and metabolic management improve neurologic outcome and reduce crises.
• Long-term neurological impairment, movement disorders, and learning disabilities are common without optimal control.

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