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

Abstract

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.

The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

“…However, it may be missed on newborn screening because some affected neonates may not show in the first days of life elevated plasma ornithine levels that can be detected by tandem mass spectroscopy [90]. Authors suggested that the typical rise of plasma ornithine levels occurs after the first few days of life when blood samples for newborn screening are obtained.…”

Metabolomics as a Tool for Discovery of Biomarkers of Autism Spectrum Disorder in the Blood Plasma of Children

“…These patients can exhibit behavioral abnormalities similar to ASD such as developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits and/or unexplained seizures [57]. Rats treated with intracerebroventricular administration of homocitrulline are also observed to have disrupted brain redox status and energy metabolism [58], [59]. These observations suggest that elevated brain levels of homocitrulline are deleterious; however additional studies are needed to define the brain levels of homocitrulline and the potential role in the development of ASD.…”

Comprehensive population screening in the Ashkenazi Jewish population for recurrent disease‐causing variants

“…Except for one variant ( SLC25A15 p.F188del), our calculated carrier frequencies correlated with published data. The SLC25A15 p.F188del variant is common in French‐Canadians with an extremely high carrier rate of 1 in 19 in an isolated northern Saskatchewan region . This variant is almost exclusively reported in French‐Canadian HHH patients and had not been reported in AJ individuals except for a 1 in 94 carrier rate in a small control group with less than 300 self‐reported AJ individuals.…”