Seven novel mutations in the ORNT1 gene (SLC25A15) in patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome

  title={Seven novel mutations in the ORNT1 gene (SLC25A15) in patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome},
  author={Sergio Salvi and Carlo Dionisi-Vici and Enrico Bertini and Margherita Verardo and F M Santorelli},
  journal={Human Mutation},
Eight unrelated Italian patients with the hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome were analyzed for mutations in the ORNT1 gene. Seven novel mutations were identified (Q89X, G27R, G190D, R275Q, c.861insG, c.164insA, and IVS5+1G→A). Other previously described variants were a heterozygous deletion of a phenylalanine residue (F188del) in one allele and the R179X in two. The G27R mutation was carried by two patients. Analyses of ORNT1 mRNA in four patients showed… 
Identification of novel mutations in the SLC25A15 gene in hyperornithinemia‐hyperammonemia‐homocitrullinuria (HHH) syndrome: A clinical, molecular, and functional study
Although patient metabolic alterations responded well to low‐protein therapy, predictions concerning the long‐term evolution of HHH syndrome remain uncertain and the preference for a hepatic rather than a neurological presentation at onset continues to elude us.
A novel R275X mutation of the SLC25A15 gene in a Japanese patient with the HHH syndrome
Phenotypic variability among patients with hyperornithinaemia–hyperammonaemia–homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15
Long-term follow-up showed that variable intellectual impairment and lower limb spasticity often occur, together or separately, with no obvious relationship to age at diagnosis and compliance with treatment, and the need to better understand the pathophysiology of HHH is emphasised.
Diagnosis and high incidence of hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome in northern Saskatchewan
It was determined that ornithine levels, by tandem mass spectrometry, were not abnormal in newborns with F188Δ mutation, carriers and normals, and that newborn screening for HHH Syndrome in this high risk population is only possible by detection of the mutant allele using DNA analysis.
Insights into the Mutation-Induced HHH Syndrome from Modeling Human Mitochondrial Ornithine Transporter-1
According to the structural analysis, the relationship between the disease-causing mutations of human mitochondrial ornithine transporter-1 and the HHH syndrome can be classified into the following three categories: (i) the mutation occurs in the pseudo-repeat regions so as to change the region of the protein closer to the mitochondrial matrix; (ii) the mutations is directly affecting the substrate binding pocket so as as to reduce the substratebinding affinity.
The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review
All the mitochondrial carrier-related diseases known until now are reviewed, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.
Determination of homocitrulline in urine of patients with HHH syndrome by liquid chromatography tandem mass spectrometry
The current method solves specificity issues in homocitrulline determination often encountered with some ninhydrin-based systems (coelution with methionine) and some o-phthalaldehyde-based ones (coalution with taurine), and presents an attractive alternative with a relatively high throughput.
Role of early management of hyperornithinaemia‐hyperammonaemia‐homocitrullinuria syndrome in pregnancy
In addition to the absent fetal corpus callosum observed in this case, other fetal cerebral abnormalities, including speech delay and intellectual impairment, have been recognised and demonstrate the importance of timely intervention by a metabolic dietician and dietary compliance in the early organogenesis stage of pregnancy.


Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome
This study confirms that defects in the ORNT1 gene cause the HHH syndrome and that the genetic basis in Japanese patients is heterogeneous, and reports three novel mutations in the mitochondrial ornithine transporter gene (ORNT1).
Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X
A new patient with HHH syndrome is reported, a 52-year-old woman, who had the typical clinical features, except for an absence of mental retardation, suggesting that this is a common mutation in Japanese patients with H HH syndrome.
Hyperornithinemia, hyperammonemia, and homocitrullinuria. A new disorder of amino acid metabolism associated with myoclonic seizures and mental retardation.
There are several instances in which a low protein diet simultaneously caused clinical improvement and reduction or elimination of hyperammonemia.
Hyperornithinemia-Hyperammonemia- Homocitrullinuria Syndrome: Low Creatine Excretion and Effect of Citrulline, Arginine, or Ornithine Supplement
Citrulline supplement combined with a protein-restricted diet appears to allow a normal development, and the additional finding of a factor VII and X deficiency in one of the patient suggest that the genetic defect leading to the syndrome might be located on chromosome 13.
The Metabolic Basis Of Inherited Disease.
This volume, more than most, explains the contributions of the laboratory to clinical medicine, and shedding light on fundamental metabolic sequences and biologic mechanisms.
Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.
During therapy with citrulline and phenylbutyrate sodium, plasma ornithine levels increased in both patients, while plasma levels of glutamine and alanine decreased to normal, and no recurrent neurologic dysfunction has occurred during a follow-up period of 20 months.
Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter
The results show that ORNT1 encodes the mitochondrial ornithine transporter involved in UC function and is defective in HHH syndrome.
The hyperornithinemias
  • 1983