HHH Syndrome

At a glance

HHH is an acronym that stands for Hyperornithinemia-Hyperammonemia-Homocitrullinuria. Homocitrullinuria is a key feature of the HHH Syndrome. It is a genetically transmitted inborn error of metabolism caused by a defect in the transport of ornithine into the mitochondrial matrix characterized clinically by early growth retardation, learning disabilities, periodic confusion, and ataxia.

Classification

The HHH Syndrome is clinically characterized by variable presentation determined by the age of onset.

• Neonatal Onset: It represents ≈12% of all affected individuals. The neonates are normal for the first 24 to 48 hours at which point it is followed by onset of symptoms related to hyperammonemia (poor feeding, vomiting, lethargy, low temperature, rapid breathing). Information on long-term outcome is limited.

• Infancy, Childhood, and Adult Presentation: This is the larger group as it represents 88% of all affected individuals. The clinical features are: (1) chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits, and/or unexplained seizures; (2) acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and (3) chronic liver dysfunction (unexplained elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance). Neurologic findings and cognitive function abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia.

Incidence

Approximately 50 cases reported worldwide, mostly in French-Canadian populations of Quebec, Canada.

Genetic inheritance

Autosomal recessive; gene map locus is 13q14.

Pathophysiology

Defect of ornithine transport into mitochondria leads to accumulation of ornithine in cytosol and deficiency of ornithine inside mitochondria, thus altering the urea cycle. This results in hyperornithinemia and hyperammonemia.

Diagnosis

High plasma levels of ornithine and homocitrulline. At the time of initial diagnosis, plasma concentration of ornithine can range from 200 to 1100 µmol/L (normal: 30-110 µmol/L). The presence of homocitrullinuria is considered a key feature of the disease. However, two exceptions may exist in infants with neonatal-onset of HHH Syndrome whom do not excrete homocitrulline in significant amounts and individuals with HHH Syndrome who self-restrict protein intake may excrete minimal or no homocitrulline in the urine.

Clinical aspects

Clinical findings in these patients are the result of neurologic toxicity. There is failure to thrive, spastic paraparesis, mental retardation, myoclonus, and seizures. There may be retinal depigmentation and chorioretinal thinning. Protein restriction is beneficial. The presentation is associated to the age of presentation:

• Neonatal-Onset Type: Vomiting and lethargy following feeding of high-protein formula leading to severe hyperammonemia with rapidly progressive deterioration (asymptomatic in breastfed infants)

• Infant-Onset Type: Choreoathetosis episodes, seizures, hypotonia, and developmental and growth retardation (often coinciding with introduction of high-protein solid food)

• Childhood-Onset Type: Mental retardation, ...