HHH syndrome is an autosomal recessive disorder, where ammonia builds up in the body due to a defective transportation of ornithine, which prevents ammonia being converted to urea and being excreted through the urine. HHH syndrome is a very rare metabolic disorder, with less than 100 affected individuals having been reported worldwide. The severity and the age of onset are variable, with the condition being present at birth, during childhood or even adulthood. Neonatal onset accounts for about 12% of affected individuals. Affected neonates may develop symptoms related to hyperammonemia within 24-48 hours of birth, including poor feeding, vomiting, lethargy, low temperature, and rapid breathing. Infancy, childhood, and adult presentation accounts for approximately 88% of the affected individuals. These patients present with chronic neurocognitive deficits including, developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits and/or unexplained seizures, acute encephalopathy secondary to hyperammonemic crisis, and chronic liver dysfunction.
Diagnosis for newborns can be done by screening of dried blood spots using tandem mass spectrometry (MS/MS) to identify ornithine. Affected patients have ornithine levels five to ten times that of normal. This diagnosis can be confirmed by in vitro demonstration of impaired transportation of ornithine into the mitochondria. Dietary restriction of protein is the basic treatment, with supporting therapy to prevent and control the hyperammonemia.
HHH syndrome is caused by mutations in the SLC25A15 gene, which encodes the mitochondrial ornithine transporter 1 (ORNT1) protein. ORNT1 is involved in the urea cycle and the ornithine degradation pathway. It transports ornithine across the inner membrane of mitochondria to the mitochondrial matrix. Mutations in the SLC25A15 gene causes an interruption of the urea cycle and the accumulation of ammonia, resulting in the signs and symptoms of HHH syndrome.
Tessa et al. (2009) identified homozygosity for the p.R179X mutation in affected members of two unrelated families with HHH syndrome from Senegal and Morocco, respectively. In the Moroccan family, one child had onset in infancy of lethargy and coma, and later had liver involvement and coagulopathy, but the other child, who was homozygous for the p.R179X mutation, had no symptoms by age 4 years.
Korman et al. (2004) described two Palestinian brothers with HHH Syndrome born to first cousin consanguineous parents. The index patient presented at 22 months of age with delayed development and seizures. He had an aversion to meat and dairy products and weight, length and OFC were all below the 5th centile. Metabolic investigations showed hyperornithinemia, homocitrullinaria and hyperammonemia. Urinalysis revealed elevated excretion of orotic acid and uracil, as well as lactic acid, 2-hydroxybutyric acid, Krebs cycle intermediates, and glutaric acid. There was no elevated excretion of glutarylcarnities or acylcarnitines, a finding indicative of mitochondrial dysfunction. A diagnosis of HHH syndrome was made, and his older brother with a similar clinical history was also investigated. He was also found to have hyperornithinemia in the absence of hyperammonemia. Both brothers were found to carry homozygous mutations in the SLC25A15 gene.
Al-Hassnan et al. (2008) described three Saudi siblings with HHH syndrome. The proband was a 4-year old girl who was born to consanguineous parents. She presented with recurrent Reye-like episodes, hypotonia, and multiple stroke-like lesions. She was found to have hyperammonemia, elevated liver enzymes, elevated partial thromboplastin time, increased serum levels of ornithine and glutamine and urine orotic acid. Brain MRI showed multiple supratentorial stroke-like lesions. Her 13-year old sister and 7-year old brother were also affected, but with much milder phenotype. They both had protein intolerance and learning problems, but had normal brain MRI. The proband significantly improved on protein restriction, sodium benzoate, and vitamin K. All affected members were found to carry a homozygous mutation in the ORNT1 gene.
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