A Novel Mutation of ORNT1 Detected in a Hyperornithinemia–Hyperammonemia–Homocitrullinuria Syndrome Child by Clinical Whole-Exome Sequencing

Abstract

Hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome, an inborn error of metabolism, is an inherited syndrome caused by loss-of-function mutations in the SLC25A15, resulting in ornithine translocase1 (ORNT1) deficiency. Disrupted ornithine transportation in an affected individual usually manifests with the accumulation of intermediate metabolites, leading to neurological impairment, hepatitis, and/or protein intolerance at various ages of onset. In this paper, we report a compound heterozygous mutation in SLC25A15 from a 2-year-old girl who presented with neurological alterations and hepatic failure. Before developing neurological sequelae, she had signs of globally delayed development. The accumulation of toxic metabolites may explain these neurological consequences. After biochemical confirmation of HHH, whole-exome sequencing (WES) was performed, which identified mutations at codons 21 and 179 of SLC25A15 that are predicted to result in the loss of function of ORNT1. Each of the mutations was found to be inherited from one of her parents. After therapy, her toxic metabolites decreased significantly. In conclusion, HHH syndrome frequently manifests with nonspecific symptoms and unapparent biochemical profiles, which may lead to delayed diagnosis. Correction of the accumulating metabolites is necessary to prevent irreversible neurological impairment. Furthermore, performing a WES provides a shortcut for accurate diagnosis.

Keywords

SLC25A15 gene - whole-exome sequencing - urea cycle disorders

Publikationsverlauf

Eingereicht: 24. August 2021

Angenommen: 21. Dezember 2021

Artikel online veröffentlicht:
10. Februar 2022

• References

• 1 Summar ML, Koelker S, Freedenberg D. et al; European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). Electronic address: http://www.e-imd.org/en/index.phtml, Members of the Urea Cycle Disorders Consortium (UCDC). Electronic address: http://rarediseasesnetwork.epi.usf.edu/ucdc/. The incidence of urea cycle disorders. Mol Genet Metab 2013; 110 (1-2): 179-180
• 2 Camacho JA, Obie C, Biery B. et al. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet 1999; 22 (02) 151-158
• 3 Martinelli D, Diodato D, Ponzi E. et al. The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Orphanet J Rare Dis 2015; 10 (01) 29
• 4 Debray F-G, Lambert M, Lemieux B. et al. Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15. J Med Genet 2008; 45 (11) 759-764
• 5 Salvi S, Santorelli FM, Bertini E. et al. Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology 2001; 57 (05) 911-914
• 6 Häberle J, Boddaert N, Burlina A. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012; 7 (01) 32
• 7 Ou J, Zhu LJ. trackViewer: a bioconductor package for interactive and integrative visualization of multi-omics data. Nat Methods 2019; 16 (06) 453-454
• 8 Matsumoto S, Häberle J, Kido J, Mitsubuchi H, Endo F, Nakamura K. Urea cycle disorders-update. J Hum Genet 2019; 64 (09) 833-847
• 9 Batshaw ML, Tuchman M, Summar M, Seminara J. Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab 2014; 113 (1-2): 127-130
• 10 Ho B, MacKenzie J, Walia J. et al. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in pregnancy: considerations for management and review of the literature. JIMD Rep 2019; 46 (01) 28-34
• 11 Tessa A, Fiermonte G, Dionisi-Vici C. et al. Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. Hum Mutat 2009; 30 (05) 741-748