Adult-Onset Presentation of a Hyperornithinemia-Hyperammonemia-Homocitrullinuria Patient Without Prior History of Neurological Complications

Abstract

The Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway caused by mutations in the mitochondrial ornithine transporter, ORNT1 (SLC25A15). In general, the majority of patients with HHH syndrome come to medical attention during infancy or early school years with symptoms such as learning disabilities, changes in cognitive development, spasticity, or liver dysfunction. In this report, we describe a 35-year-old male of Indian descent who was diagnosed with HHH syndrome after he presented to the emergency room with gastroenteritis, disorientation, and slurred speech. Molecular analysis revealed that this patient was heterozygous for two ORNT1 mutations, p.[Gly220Arg(+)Arg275X] (c.[658G>A(+)823C>T]) that had been previously reported in homozygous probands who presented during the first year of life. Cellular studies revealed that the ORNT1 p.Gly220Arg mutation was nonfunctional but targeted to the mitochondria. Given that this patient was a successful college graduate on a vegetarian diet without a prior history of learning or neurological impairment, additional factors such as gene redundancy, environmental, and epigenetic factors may have contributed to the delay in onset of presentation and lack of any previous symptoms. To the best of our knowledge, this is the first reported case of an adult-onset HHH syndrome presentation without a prior history of neurological or cognitive deficiency.

Competing interests: None declared.

Appendices

Synopsis

Presentation of a 35-year-old HHH patient without prior history of neurological complications.

Authors’ Contributions

Kamer Tezcan and Kristal T. Louie – Main persons taking care of the patient and contributed to the writing and editing of the manuscript.

Yong Qu – Performed and interpreted all clinical biochemical analysis and contributed to the writing and editing of the manuscript.

Jorge Velasquez – Performed the site-directed mutagenesis experiments, sequenced and purified all constructs, conducted immunoflourescence studies and editing of the manuscript.

Frank Zaldivar – Responsible for establishing the B-lymphocyte cell lines of the patient and contributed to editing of the manuscript.

Natalia Rioseco-Camacho – Performed DNA and RNA isolation, all tissue culture related experiments, assisted in the design of experiments and contributed to the writing and editing of the manuscript.

José A. Camacho – Contributed to patient care, ORNT1 sequencing, experimental design, main manuscript writing and editing. In addition, will assume all the responsibility as guarantor for this manuscript.

Competing Interest Statement

All authors declare that the answers to all questions on the JIMD competing interest form are No, and therefore they have nothing to declare.

Funding

J.A. Camacho was supported by a Robert Wood Johnson Foundation-Dr. Harold Amos Faculty Development Award and F. Zaldivar by a Public Health Service research grant M01RR00827. Part of this work was previously presented in poster form at the Urea Cycle Disorders Satellite Symposium of the 11th International Congress of Inborn Errors of Metabolism in San Diego, CA (August 27–29, 2009). The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

Ethics Approval

This study was conducted under the Institutional IRB #2002-2608.

Patient Consent

No patient identifiers were used. Patient consented to the review of his medical records, laboratory studies, scans and the publication of his case.