Research Report

Journal of Inherited Metabolic Disease

, Volume 33, Supplement 3, pp 275-281

First online:

Diagnosis and high incidence of hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome in northern Saskatchewan

  • AbdulRazaq A. H. SokoroAffiliated withDepartment of Pathology, Diagnostic Services of Manitoba & University of Manitoba
  • , Joyce LepageAffiliated withSaskatchewan Disease Control Laboratory, Saskatchewan Health
  • , Nick AntonishynAffiliated withSaskatchewan Disease Control Laboratory, Saskatchewan Health
  • , Ryan McDonaldAffiliated withSaskatchewan Disease Control Laboratory, Saskatchewan Health
  • , Cheryl Rockman-GreenbergAffiliated withDepartment of Pediatrics and Child Health, Winnipeg Regional Health Authority & University of Manitoba
  • , James IrvineAffiliated withPopulation Health Unit, Athabasca, Keewatin Yatthé and Mamawetan Churchill River Health Authorities and University of Saskatchewan
  • , Denis C. LehotayAffiliated withSaskatchewan Disease Control Laboratory, Saskatchewan Health Email author 

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Mutations in the SLC25A15 gene, encoding the human inner mitochondrial membrane ornithine transporter, are thought to be responsible for hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome, a rare autosomal recessive condition. HHH syndrome has been detected in several small, isolated communities in northern Saskatchewan (SK). To determine the incidence of HHH syndrome in these communities, a PCR method was set up to detect F188Δ, the common French-Canadian mutation. Neonatal blood spots collected from all newborns from the high risk area were genotyped for the F188Δ mutation for seven consecutive years. Using DNA analysis, we estimated that the heterozygote frequency for the mutant allele for HHH syndrome to be about 1 in 19 individuals, predicting one affected child with HHH syndrome for approximately every 1,500 individuals (1 in 1,550 live births; 1 child every 12 years) in this isolated population. The frequency for the mutant allele for HHH syndrome in this isolated community is probably the highest in the world for this rare disorder. We determined that ornithine levels, by tandem mass spectrometry, were not abnormal in newborns with F188Δ mutation, carriers and normals. Ornithine rises to abnormally high levels at some time after birth well past the time that the newborn screening blood spot is collected. The timing or the reasons for the delayed rise of ornithine in affected children with HHH syndrome have not been determined. Newborn screening for HHH Syndrome in this high risk population is only possible by detection of the mutant allele using DNA analysis.