43 results on '"Ornithine deficiency"'
Search Results
2. Hyperornithinemia-hyperammonemia-homocitrullinuria: a rare neurometabolic disorder in two siblings.
- Author
-
Rizkallah D, Daher RT, Haddad L, and Karam PE
- Subjects
- Humans, Male, Female, Ornithine blood, Ornithine deficiency, Citrulline analogs & derivatives, Adolescent, Child, Mitochondrial Membrane Transport Proteins genetics, Mutation, Hyperammonemia genetics, Siblings, Urea Cycle Disorders, Inborn genetics, Urea Cycle Disorders, Inborn complications
- Abstract
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is an extremely rare disorder of urea cycle, with few patients reported worldwide. Despite hyperammonemia control, the long-term outcome remains poor with progressive neurological deterioration. We report the clinical, biochemical, and molecular features of two Lebanese siblings diagnosed with this disorder and followed for 8 and 15 years, respectively. Variable clinical manifestations and neurological outcome were observed. The patient with earlier onset of symptoms had a severe neurological deterioration while the other developed a milder form of the disease at an older age. Diagnosis was challenging in the absence of the complete biochemical triad and the non-specific clinical presentations. Whole exome sequencing revealed a homozygous variant, p.Phe188del, in the SLC25A15 gene, a French- Canadian founder mutation previously unreported in Arab patients. Hyperammonemia was controlled in both patients but hyperonithinemia persisted. Frequent hyperalaninemia spikes and lactic acidosis occured concomitantly with the onset of seizures in one of the siblings. Variable neurological deterioration and outcome were observed within the same family. This is the first report from the Arab population of the long-term outcome of this devastating neurometabolic disorder., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2024
- Full Text
- View/download PDF
3. Amyloidogenic Propensity of Metabolites in the Uric Acid Pathway and Urea Cycle Critically Impacts the Etiology of Metabolic Disorders.
- Author
-
Patel M, Jaiswal A, Naseer A, Tripathi A, Joshi A, Minocha T, Kautu A, Gupta S, Joshi KB, Pandey MK, Kumar R, Dubey KD, Nazir A, Verma S, and Gour N
- Subjects
- Animals, Caenorhabditis elegans, Amyloid metabolism, Ornithine metabolism, Urea, Uric Acid, Urea Cycle Disorders, Inborn metabolism, Urea Cycle Disorders, Inborn pathology, Ornithine deficiency, Hyperammonemia
- Abstract
Novel insights into the etiology of metabolic disorders have recently been uncovered through the study of metabolite amyloids. In particular, inborn errors of metabolism (IEMs), including gout, Lesch-Nyhan syndrome (LNS), xanthinuria, citrullinemia, and hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, are attributed to the dysfunction of the urea cycle and uric acid pathway. In this study, we endeavored to understand and mechanistically characterize the aggregative property exhibited by the principal metabolites of the urea cycle and uric acid pathway, specifically hypoxanthine, xanthine, citrulline, and ornithine. Employing scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM), we studied the aggregation profiles of the metabolites. Insights obtained through molecular dynamics (MD) simulation underscore the vital roles of π-π stacking and hydrogen bonding interactions in the self-assembly process, and thioflavin T (ThT) assays further corroborate the amyloid nature of these metabolites. The in vitro MTT assay revealed the cytotoxic trait of these assemblies, a finding that was substantiated by in vivo assays employing the Caenorhabditis elegans ( C. elegans ) model, which revealed that the toxic effects were more pronounced and dose-specific in the case of metabolites that had aged via longer preincubation. We hence report a compelling phenomenon wherein these metabolites not only aggregate but transform into a soft, ordered assembly over time, eventually crystallizing upon extended incubation, leading to pathological implications. Our study suggests that the amyloidogenic nature of the involved metabolites could be a common etiological link in IEMs, potentially providing a unified perspective to study their pathophysiology, thus offering exciting insights into the development of targeted interventions for these metabolic disorders.
- Published
- 2024
- Full Text
- View/download PDF
4. Clinical, biochemical, and genotypical characteristics in urea cycle mitochondrial transporter disorders.
- Author
-
Bilgin H, Bilge S, Binici M, and Tekes S
- Subjects
- Child, Humans, Retrospective Studies, Mitochondrial Membrane Transport Proteins genetics, Urea, Citrullinemia, Ornithine deficiency, Hyperammonemia, Urea Cycle Disorders, Inborn
- Abstract
Background: This study aimed to evaluate clinical, biochemical, and genotypic findings of patients diagnosed with urea cycle mitochondrial transporter disorders., Case Series: In this study, patients followed up with the diagnosis of urea cycle mitochondrial transporter disorders in the pediatric metabolism outpatient clinic of Diyarbakir Children's Hospital were retrospectively examined. Height, weight, head circumference, gender, age at diagnosis, follow-up period, consanguinity history between parents, and treatments of the patients included in the study were evaluated. Eight patients suffering from urea cycle mitochondrial transporter disorders were enrolled in the study. Five patients were found to have biallelic variants of the SLC25A15 gene. Two patients were found to have biallelic variants of the SLC25A13 gene. Two of our patients presented with gait disturbances and were diagnosed with HHH syndrome. One patient presented with liver failure and was diagnosed with HHH syndrome. The other three patients were identified by family screening. Citrin deficiency was detected in two patients with cholestasis and hepatomegaly in the infantile period. Ornithine levels increased in three of our patients with HHH syndrome during the first month of treatment despite a protein-restricted diet and adequate caloric intake., Conclusions: Increasing patients' caloric intake with HHH syndrome improves their ornithine levels. Our patients with citrin deficiency recovered clinically and biochemically before seven months.
- Published
- 2024
- Full Text
- View/download PDF
5. Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report.
- Author
-
Silvera-Ruiz SM, Gemperle C, Peano N, Olivero V, Becerra A, Häberle J, Gruppi A, Larovere LE, and Motrich RD
- Subjects
- Amino Acid Transport Systems, Basic genetics, Child, Preschool, Female, Humans, Mitochondrial Membrane Transport Proteins, Ornithine deficiency, Quality of Life, Hyperammonemia complications, Hyperammonemia diagnosis, Urea Cycle Disorders, Inborn complications, Urea Cycle Disorders, Inborn diagnosis, Urea Cycle Disorders, Inborn genetics
- Abstract
The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the SLC25A15 gene. Besides the well-known metabolic complications, patients often present intercurrent infections associated with acute hyperammonemia and metabolic decompensation. However, it is currently unknown whether intercurrent infections are associated with immunological alterations besides the known metabolic imbalances. Herein, we describe the case of a 3-years-old girl affected by the HHH syndrome caused by two novel SLC25A15 gene mutations associated with immune phenotypic and functional alterations. She was admitted to the hospital with an episode of recurrent otitis, somnolence, confusion, and lethargy. Laboratory tests revealed severe hyperammonemia, elevated serum levels of liver transaminases, hemostasis alterations, hyperglutaminemia and strikingly increased orotic aciduria. Noteworthy, serum protein electrophoresis showed a reduction in the gamma globulin fraction. Direct sequencing of the SLC25A15 gene revealed two heterozygous non-conservative substitutions in the exon 5: c.649G>A (p.Gly217Arg) and c.706A>G (p.Arg236Gly). In silico analysis indicated that both mutations significantly impair protein structure and function and are consistent with the patient clinical status confirming the diagnosis of HHH syndrome. In addition, the immune analysis revealed reduced levels of serum IgG and striking phenotypic and functional alterations in the T and B cell immune compartments. Our study has identified two non-previously described mutations in the SLC25A15 gene underlying the HHH syndrome. Moreover, we are reporting for the first time functional and phenotypic immunologic alterations in this rare inborn error of metabolism that would render the patient immunocompromised and might be related to the high frequency of intercurrent infections observed in patients bearing urea cycle disorders. Our results point out the importance of a comprehensive analysis to gain further insights into the underlying pathophysiology of the disease that would allow better patient care and quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Silvera-Ruiz, Gemperle, Peano, Olivero, Becerra, Häberle, Gruppi, Larovere and Motrich.)
- Published
- 2022
- Full Text
- View/download PDF
6. Reversible Leukoencephalopathy in a Man with Childhood-onset Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome.
- Author
-
Hoshino Y, Kodaira M, Matsuno A, Kaneko T, Fukuyama T, Takano K, Yazaki M, and Sekijima Y
- Subjects
- Ammonia, Child, Humans, Male, Middle Aged, Ornithine deficiency, Hyperammonemia diagnosis, Hyperammonemia genetics, Leukoencephalopathies, Urea Cycle Disorders, Inborn complications, Urea Cycle Disorders, Inborn diagnosis, Urea Cycle Disorders, Inborn genetics
- Abstract
A 49-year-old Japanese man had shown developmental delay, learning difficulties, epilepsy, and slowly progressive gait disturbance in elementary school. At 46 years old, he experienced repeated drowsiness with or without generalized convulsions, and hyperammonemia was detected. Brain magnetic resonance imaging detected multiple cerebral white matter lesions. An electroencephalogram showed diffuse slow basic activities with 2- to 3-Hz δ waves. Genetic tests confirmed a diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Leukoencephalopathy was resolved following the administration of L-arginine and lactulose with a decrease in plasma ammonia levels and glutamine-glutamate peak on magnetic resonance spectroscopy. Leukoencephalopathy in HHH syndrome may be reversible with the resolution of hyperammonemia-induced glutamine toxicity.
- Published
- 2022
- Full Text
- View/download PDF
7. Adult-onset diagnosis of urea cycle disorders: Results of a French cohort of 71 patients.
- Author
-
Toquet S, Spodenkiewicz M, Douillard C, Maillot F, Arnoux JB, Damaj L, Odent S, Moreau C, Redonnet-Vernhet I, Mesli S, Servais A, Noel E, Charriere S, Rigalleau V, Lavigne C, Kaphan E, Roubertie A, Besson G, Bigot A, Servettaz A, Mochel F, and Garnotel R
- Subjects
- Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Argininosuccinic Aciduria diagnosis, Female, France, Humans, Hyperammonemia diagnosis, Male, Middle Aged, Ornithine deficiency, Ornithine Carbamoyltransferase Deficiency Disease diagnosis, Retrospective Studies, Sex Factors, Urea Cycle Disorders, Inborn mortality, Young Adult, Urea Cycle Disorders, Inborn diagnosis
- Abstract
Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. The aim was to describe a cohort of patients with adult onset of UCDs in a multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years of age of UCDs due to a deficiency in one of the 6 enzymes (arginase, ASL, ASS, CPS1, NAGS, OTC) or the two transporters (ORNT1 or citrin). Seventy-one patients were included (68% female, 32% male). The diagnosis was made in the context of (a) a metabolic decompensation (42%), (b) family history (55%), or (c) chronic symptoms (3%). The median age at diagnosis was 33 years (range 16-86). Eighty-nine percent of patients were diagnosed with OTC deficiency, 7% CPS1 deficiency, 3% HHH syndrome and 1% argininosuccinic aciduria. For those diagnosed during decompensations (including 23 OTC cases, mostly female), 89% required an admission in intensive care units. Seven deaths were attributed to UCD-6 decompensations and 1 epilepsy secondary to inaugural decompensation. This is the largest cohort of UCDs diagnosed in adulthood, which confirms the triad of neurological, gastrointestinal and psychiatric symptoms during hyperammonemic decompensations. We stress that females with OTC deficiency can be symptomatic. With 10% of deaths in this cohort, UCDs in adults remain a life-threatening condition. Physicians working in adult care must be aware of late-onset presentations given the implications for patients and their families., (© 2021 SSIEM.)
- Published
- 2021
- Full Text
- View/download PDF
8. Successful liver transplantation in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: Case report.
- Author
-
De Bruyne P, Verloo P, Van Hove JLK, de Hemptinne B, Vande Velde S, Van Winckel M, Van Biervliet S, and De Bruyne R
- Subjects
- Child, Humans, Male, Hyperammonemia surgery, Liver Transplantation, Ornithine deficiency, Urea Cycle Disorders, Inborn surgery
- Abstract
Background: HHH syndrome is a rare autosomal recessive disorder of the urea cycle, caused by a deficient mitochondrial ornithine transporter. We report the first successful liver transplantation in HHH syndrome performed in a seven-year-old boy. The patient presented at 4 weeks of age with hyperammonemic coma. The plasma amino acid profile was suggestive of HHH syndrome, and the diagnosis was confirmed when sequencing of the SLC25A15 gene identified two mutations p.R275Q and p.A76D. Although immediate intervention resulted in normalization of plasma ammonia levels within 24 hours, he developed cerebral edema, coma, convulsions, and subsequent neurological sequelae. Metabolic control was difficult requiring severe protein restriction and continued treatment with sodium benzoate and L-arginine. Despite substantial developmental delay, he was referred to our center for liver transplantation because of poor metabolic control. Following cadaveric split liver transplantation, there was complete normalization of his plasma ammonia and plasma amino acid levels under a normal protein-containing diet. This excellent metabolic control was associated with a markedly improved general condition, mood and behavior, and small developmental achievements. Twelve years after liver transplantation, the patient has a stable cognitive impairment without progression of spastic diplegia., Conclusion: This first case of liver transplantation in HHH syndrome demonstrates that this procedure is a therapeutic option for HHH patients with difficult metabolic control., (© 2020 Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
9. Role of early management of hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome in pregnancy.
- Author
-
Billingham MJ and Rizk R
- Subjects
- Citrulline, Female, Humans, Ornithine deficiency, Pregnancy, Hyperammonemia diagnosis, Hyperammonemia therapy, Urea Cycle Disorders, Inborn complications, Urea Cycle Disorders, Inborn diagnosis, Urea Cycle Disorders, Inborn genetics
- Abstract
Hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome is a rare inherited metabolic disorder of the urea cycle. Few reports exist to guide practices during pregnancy and fetal delivery. Yet, with affected patients often surviving into reproductive age, appropriate management of the peripartum phase is essential to ensure positive maternal and fetal outcomes.Reassuringly, the vast majority of offspring of parturients with HHH syndrome have normal developmental outcomes; yet as seen here, fetal growth restriction does appear more frequently. Furthermore, 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.Unregulated dietary intake is one proposed factor for the observed disruption in fetal growth and early cerebral development. These stipulations not only reinforce the importance of extensive planning and teamwork, but also demonstrate the importance of timely intervention by a metabolic dietician and dietary compliance in the early organogenesis stage of pregnancy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
- Full Text
- View/download PDF
10. CUGC for hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.
- Author
-
Martinelli D, Fiermonte G, Häberle J, Boenzi S, Goffredo BM, Travaglini L, Agolini E, Porcelli V, and Dionisi-Vici C
- Subjects
- Genetic Testing standards, Humans, Hyperammonemia epidemiology, Hyperammonemia pathology, Mitochondrial Membrane Transport Proteins genetics, Mutation, Ornithine genetics, Phenotype, Sensitivity and Specificity, Urea Cycle Disorders, Inborn epidemiology, Urea Cycle Disorders, Inborn pathology, Genetic Testing methods, Hyperammonemia genetics, Ornithine deficiency, Urea Cycle Disorders, Inborn genetics
- Published
- 2020
- Full Text
- View/download PDF
11. Evaluation of dietary treatment and amino acid supplementation in organic acidurias and urea-cycle disorders: On the basis of information from a European multicenter registry.
- Author
-
Molema F, Gleich F, Burgard P, van der Ploeg AT, Summar ML, Chapman KA, Barić I, Lund AM, Kölker S, and Williams M
- Subjects
- Adolescent, Adult, Amino Acid Metabolism, Inborn Errors epidemiology, Child, Child, Preschool, Cross-Sectional Studies, Europe epidemiology, Feasibility Studies, Female, Humans, Hyperammonemia diet therapy, Hyperammonemia epidemiology, Infant, Male, Ornithine deficiency, Propionic Acidemia epidemiology, Registries, Retrospective Studies, Treatment Outcome, Urea Cycle Disorders, Inborn epidemiology, Young Adult, Amino Acid Metabolism, Inborn Errors diet therapy, Amino Acids administration & dosage, Dietary Supplements, Propionic Acidemia diet therapy, Urea Cycle Disorders, Inborn diet therapy
- Abstract
Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)
- Published
- 2019
- Full Text
- View/download PDF
12. Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia.
- Author
-
Olivieri G, Pro S, Diodato D, Di Capua M, Longo D, Martinelli D, Bertini E, and Dionisi-Vici C
- Subjects
- Adolescent, Adult, Brain metabolism, Brain physiology, Child, Female, Humans, Hyperammonemia physiopathology, Magnetic Resonance Imaging, Male, Middle Aged, Mutation genetics, Neural Conduction physiology, Ornithine metabolism, Spastic Paraplegia, Hereditary metabolism, Spastic Paraplegia, Hereditary pathology, Spastic Paraplegia, Hereditary physiopathology, Spinal Cord metabolism, Spinal Cord physiology, Urea Cycle Disorders, Inborn physiopathology, Young Adult, Hyperammonemia metabolism, Hyperammonemia pathology, Ornithine deficiency, Urea Cycle Disorders, Inborn metabolism, Urea Cycle Disorders, Inborn pathology
- Abstract
Background: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare disorder of urea cycle characterized by progressive pyramidal and cerebellar dysfunction, whose pathophysiology is not yet fully understood. Here we describe the spectrum of the long fibers involvement in HHH syndrome, attempting a correlation between clinical, electrophysiological and neuro-radiological data., Methods: Nine HHH patients were longitudinally evaluated by clinical examination, neurophysiological assessment including motor (MEPs), somato-sensory evoked potentials (PESS) and nerve conduction velocity (NCV), brain and spinal cord MRI RESULTS: All patients had pyramidal dysfunction and 3/9 an overt spastic paraplegia. Mild to moderate cerebellar signs were found in 7/9, intellectual disability in 8/9. At lower limbs, MEPs resulted abnormal in 7/8 patients and PESS in 2/8; peripheral sensory-motor neuropathy was found in 1/9. MRI documented atrophic changes in supra-tentorial brain regions in 6/9 patients, cerebellum in 6/9, spinal cord in 3/7., Conclusions: A predominant corticospinal dysfunction is evident in HHH syndrome, along with milder cerebellar signs, intellectual disability of variable degree and rare peripheral neuropathy. Phenotypical similarities with other disorders affecting the urea cycle (argininemia and pyrroline-5-carboxylate synthetase deficiency) suggest possible common mechanisms contributing in the maintenance of the corticospinal tract integrity. HHH syndrome phenotype largely overlaps with complex Hereditary Spastic Paraplegias (HSPs), in the list of which it should be included, emphasizing the importance to screen all the unsolved cases of HSPs for metabolic biomarkers.
- Published
- 2019
- Full Text
- View/download PDF
13. Late onset hyperornithinemia-hyperammonemia-homocitrullinuria syndrome - how web searching by the family solved unexplained unconsciousness: a case report.
- Author
-
Silfverberg T, Sahlander F, Enlund M, Oscarson M, and Hårdstedt M
- Subjects
- Female, Humans, Internet, Male, Middle Aged, Hyperammonemia complications, Hyperammonemia diagnosis, Hyperammonemia etiology, Ornithine deficiency, Unconsciousness etiology, Urea Cycle Disorders, Inborn complications, Urea Cycle Disorders, Inborn diagnosis
- Abstract
Background: Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a rare inherited urea cycle disorder, can remain undiagnosed for decades and suddenly turn into an acute life-threatening state. Adult presentation of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome has rarely been described, but is potentially underdiagnosed in the emergency room. In the case of acute hyperammonemia, prompt diagnosis is essential to minimize the risk of brain damage and death., Case Presentation: We present the diagnostics, clinical course, and treatment of a 48-year-old Caucasian man presenting with unexplained unconsciousness in the emergency room. A web search by a family member led to the suspicion of urea cycle disorder. Subsequent analysis of plasma ammonia and amino acids in plasma and urine demonstrated a pattern typical for hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. The diagnosis was confirmed by genetic analysis which revealed two heterozygous mutations in the SLC25A15 gene. The cause of the hyperammonemia crisis was acute upper gastrointestinal hemorrhage, leading to protein overload and subsequent cerebral edema. Continuous renal replacement therapy, scavenger treatment, and tightly controlled nutrition were useful in preventing hyperammonemia and recurrence of cerebral edema., Conclusions: The case emphasizes the importance of taking rare metabolic genetic disorders into consideration in patients with prolonged unexplained unconsciousness.
- Published
- 2018
- Full Text
- View/download PDF
14. Lactate/pyruvate in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.
- Author
-
Ono H, Tamada T, and Shigematsu Y
- Subjects
- Arginine therapeutic use, Diet, Protein-Restricted methods, Humans, Hyperammonemia blood, Hyperammonemia therapy, Infant, Male, Ornithine blood, Urea Cycle Disorders, Inborn blood, Urea Cycle Disorders, Inborn therapy, Hyperammonemia diagnosis, Lactates blood, Ornithine deficiency, Pyruvates blood, Urea Cycle Disorders, Inborn diagnosis
- Published
- 2018
- Full Text
- View/download PDF
15. [Clinical diagnosis and treatment of three cases with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome].
- Author
-
Guan HZ, Ding Y, Li DX, Dong H, Song JQ, Jin Y, Zhu ZJ, Sun LY, and Yang YL
- Subjects
- Arginine, Asian People, Carnitine, Child, Child, Preschool, Genetic Testing, Homozygote, Humans, Infant, Ornithine therapeutic use, Orotic Acid, Proteins, Diet, Protein-Restricted, Hyperammonemia diagnosis, Mutation, Ornithine deficiency, Phenotype, Urea Cycle Disorders, Inborn diagnosis
- Abstract
Objective: To study the clinical characteristics, methods of diagnosis and treatment of hyperornithinemia-hyperammonemia- homocitrullinuria (HHH) syndrome. Method: From July 2011 to August 2016, 3 Chinese patients with HHH syndrome were enrolled in this study. The clinical course, biochemical features, brain MRI findings, and gene mutations were analyzed. Result: The three patients' age at onset of symptoms was 3 months to 7 years, and the age of diagonosis was 3 years and 10 months to 9 years and 10 months. All of them presented with intolerance to protein-rich foods from the infant period, development retardation and abnormal posture. Case 1 and 2 had moderate mental retardation. Serum ammonia 25-276 μmol/L (reference range<60 μmol/L), alanine aminotransferase (ALT) 20-139 IU/L (reference range 9-50 IU/L), ornithine 29.12-99.44 μmol/L(reference range 15-100 μmol/L), urinary orotic acid 1.49-29.75 mmol/mol Cr (reference range 0-7 mmol/mol Cr), uracil 6.09-103.97 mmol/mol Cr (reference range 0-1.5 mmol/mol Cr). The cranial MRI revealed lesions in the basal ganglia, abnormal white matter signal, progressive demyelination and cerebral atrophy. On their SLC25A15 gene, a novel homozygous missense mutation c. 416A>G (p.E139G) was identified in case 1, a known pathogenic homozygous nonsense mutation c. 535C>T was found in case 2 and 3. Liver transplantation had been performed when case 1 was 6 years old. Significant improvements were observed in dietary habit, mental and motor functions, and biochemical parameters. After the dietary intervention with the supplements of arginine, L-carnitine, case 2 was improved, spastic paraplegia of case 3 had no mitigation. Liver transplant was recommended. Conclusion: HHH syndrome has an aversion to protein-rich food, and the patients have recurrent vomiting and progressive neurological dysfunction. Clinical diagnosis of HHH syndrome is difficult and patients may present with incomplete biochemical phenotype. The genetic analysis is key for the diagnosis. Depending on their condition, individuals with HHH syndrome can be treated with a low-protein diet, drugs and liver transplantation.
- Published
- 2017
- Full Text
- View/download PDF
16. Milder Form of Urea Cycle Defect Revisited: Report and Review of Hyperornithinaemia-Hyperammonaemia-Homocitrullinuria (HHH) Syndrome Diagnosed in a Teenage Girl Presenting with Recurrent Encephalopathy.
- Author
-
Qadri SK, Ting TW, Lim JS, and Jamuar SS
- Subjects
- Amino Acid Transport Systems, Basic genetics, Brain Diseases etiology, Child, DNA Mutational Analysis, Diet, Protein-Restricted, Female, Humans, Hyperammonemia complications, Hyperammonemia diet therapy, Hyperammonemia genetics, Mitochondrial Membrane Transport Proteins, Ornithine genetics, Recurrence, Severity of Illness Index, Urea Cycle Disorders, Inborn complications, Urea Cycle Disorders, Inborn diet therapy, Urea Cycle Disorders, Inborn genetics, Brain Diseases diagnosis, Hyperammonemia diagnosis, Ornithine deficiency, Urea Cycle Disorders, Inborn diagnosis
- Published
- 2016
17. Ornithine and Homocitrulline Impair Mitochondrial Function, Decrease Antioxidant Defenses and Induce Cell Death in Menadione-Stressed Rat Cortical Astrocytes: Potential Mechanisms of Neurological Dysfunction in HHH Syndrome.
- Author
-
Zanatta Â, Rodrigues MD, Amaral AU, Souza DG, Quincozes-Santos A, and Wajner M
- Subjects
- Amino Acid Transport Systems, Basic drug effects, Animals, Antioxidants metabolism, Antioxidants pharmacology, Astrocytes metabolism, Cell Death drug effects, Citrulline pharmacology, Hyperammonemia drug therapy, Hyperammonemia metabolism, Male, Mitochondria metabolism, Ornithine deficiency, Ornithine metabolism, Rats, Wistar, Tumor Necrosis Factor-alpha metabolism, Urea Cycle Disorders, Inborn drug therapy, Urea Cycle Disorders, Inborn metabolism, Astrocytes drug effects, Citrulline analogs & derivatives, Mitochondria drug effects, Ornithine pharmacology
- Abstract
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is caused by deficiency of ornithine translocase leading to predominant tissue accumulation and high urinary excretion of ornithine (Orn), homocitrulline (Hcit) and ammonia. Although affected patients commonly present neurological dysfunction manifested by cognitive deficit, spastic paraplegia, pyramidal and extrapyramidal signs, stroke-like episodes, hypotonia and ataxia, its pathogenesis is still poorly known. Although astrocytes are necessary for neuronal protection. Therefore, in the present study we investigated the effects of Orn and Hcit on cell viability (propidium iodide incorporation), mitochondrial function (thiazolyl blue tetrazolium bromide-MTT-reduction and mitochondrial membrane potential-ΔΨm), antioxidant defenses (GSH) and pro-inflammatory response (NFkB, IL-1β, IL-6 and TNF-α) in unstimulated and menadione-stressed cortical astrocytes that were previously shown to be susceptible to damage by neurotoxins. We first observed that Orn decreased MTT reduction, whereas both amino acids decreased GSH levels, without altering cell viability and the pro-inflammatory factors in unstimulated astrocytes. Furthermore, Orn and Hcit decreased cell viability and ΔΨm in menadione-treated astrocytes. The present data indicate that the major compounds accumulating in HHH syndrome impair mitochondrial function and reduce cell viability and the antioxidant defenses in cultured astrocytes especially when stressed by menadione. It is presumed that these mechanisms may be involved in the neuropathology of this disease.
- Published
- 2016
- Full Text
- View/download PDF
18. An Acute Encephalopathy Accelerated by a Large Amount of Milk Consumption.
- Author
-
Moien-Afshari F, Mirhosseini NZ, Lemire EG, and Voll CL
- Subjects
- Adult, Animals, Drinking, Humans, Male, Native Hawaiian or Other Pacific Islander, Hyperammonemia, Milk adverse effects, Ornithine deficiency, Urea Cycle Disorders, Inborn
- Published
- 2016
- Full Text
- View/download PDF
19. Creatine biosynthesis and transport in health and disease.
- Author
-
Joncquel-Chevalier Curt M, Voicu PM, Fontaine M, Dessein AF, Porchet N, Mention-Mulliez K, Dobbelaere D, Soto-Ares G, Cheillan D, and Vamecq J
- Subjects
- AMP-Activated Protein Kinases metabolism, Amidinotransferases deficiency, Amidinotransferases genetics, Amino Acid Metabolism, Inborn Errors diagnosis, Amino Acid Metabolism, Inborn Errors enzymology, Amino Acid Metabolism, Inborn Errors genetics, Amino Acid Metabolism, Inborn Errors metabolism, Amino Acid Transport Systems, Basic deficiency, Amino Acid Transport Systems, Basic genetics, Amino Acid Transport Systems, Basic metabolism, Animals, Biological Transport, Active, Brain Diseases, Metabolic, Inborn diagnosis, Brain Diseases, Metabolic, Inborn enzymology, Brain Diseases, Metabolic, Inborn genetics, Brain Diseases, Metabolic, Inborn metabolism, Creatine biosynthesis, Creatine deficiency, Creatine genetics, Developmental Disabilities diagnosis, Developmental Disabilities enzymology, Developmental Disabilities genetics, Developmental Disabilities metabolism, Energy Metabolism, Guanidinoacetate N-Methyltransferase deficiency, Guanidinoacetate N-Methyltransferase genetics, Gyrate Atrophy diagnosis, Gyrate Atrophy enzymology, Gyrate Atrophy genetics, Gyrate Atrophy metabolism, Humans, Hyperammonemia diagnosis, Hyperammonemia enzymology, Hyperammonemia genetics, Hyperammonemia metabolism, Intellectual Disability diagnosis, Intellectual Disability enzymology, Intellectual Disability genetics, Intellectual Disability metabolism, Language Development Disorders diagnosis, Language Development Disorders enzymology, Language Development Disorders genetics, Language Development Disorders metabolism, Mental Retardation, X-Linked diagnosis, Mental Retardation, X-Linked enzymology, Mental Retardation, X-Linked genetics, Mental Retardation, X-Linked metabolism, Methylation, Mitochondrial Membrane Transport Proteins, Movement Disorders congenital, Movement Disorders diagnosis, Movement Disorders enzymology, Movement Disorders genetics, Movement Disorders metabolism, Mutation, Nerve Tissue Proteins deficiency, Nerve Tissue Proteins genetics, Ornithine deficiency, Ornithine genetics, Ornithine metabolism, Plasma Membrane Neurotransmitter Transport Proteins deficiency, Plasma Membrane Neurotransmitter Transport Proteins genetics, Prenatal Diagnosis, S-Adenosylmethionine metabolism, Speech Disorders diagnosis, Speech Disorders enzymology, Speech Disorders genetics, Speech Disorders metabolism, Urea Cycle Disorders, Inborn diagnosis, Urea Cycle Disorders, Inborn enzymology, Urea Cycle Disorders, Inborn genetics, Urea Cycle Disorders, Inborn metabolism, Amidinotransferases metabolism, Creatine metabolism, Guanidinoacetate N-Methyltransferase metabolism, Nerve Tissue Proteins metabolism, Plasma Membrane Neurotransmitter Transport Proteins metabolism
- Abstract
Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM [for glycine-amidinotransferase, mitochondrial]) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases [creatine-creatine phosphate cycle] and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by (1)H-MRS assessment of cerebral creatine levels and response to therapeutic measures., (Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
20. Ornithine In Vivo Administration Disrupts Redox Homeostasis and Decreases Synaptic Na(+), K (+)-ATPase Activity in Cerebellum of Adolescent Rats: Implications for the Pathogenesis of Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome.
- Author
-
Zanatta Â, Viegas CM, Hickmann FH, de Oliveira Monteiro W, Sitta A, de Moura Coelho D, Vargas CR, Leipnitz G, and Wajner M
- Subjects
- Animals, Antioxidants metabolism, Cerebellum metabolism, Glutathione metabolism, Homeostasis drug effects, Hyperammonemia metabolism, Lipid Peroxidation drug effects, Male, Malondialdehyde metabolism, Ornithine administration & dosage, Ornithine metabolism, Oxidation-Reduction drug effects, Rats, Rats, Wistar, Sexual Maturation physiology, Synapses metabolism, Urea Cycle Disorders, Inborn metabolism, Cerebellum drug effects, Hyperammonemia etiology, Ornithine deficiency, Ornithine pharmacology, Sodium-Potassium-Exchanging ATPase metabolism, Synapses drug effects, Urea Cycle Disorders, Inborn etiology
- Abstract
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an inborn error of metabolism caused by a defect in the transport of ornithine (Orn) into mitochondrial matrix leading to accumulation of Orn, homocitrulline (Hcit), and ammonia. Affected patients present a variable clinical symptomatology, frequently associated with cerebellar symptoms whose pathogenesis is poorly known. Although in vitro studies reported induction of oxidative stress by the metabolites accumulating in HHH syndrome, so far no report evaluated the in vivo effects of these compounds on redox homeostasis in cerebellum. Therefore, the present work was carried out to investigate the in vivo effects of intracerebellar administration of Orn and Hcit on antioxidant defenses (reduced glutathione concentrations and the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase), lipid oxidation (malondialdehyde concentrations), as well as on the activity of synaptic Na(+), K(+)-ATPase, an enzyme highly vulnerable to free radical attack, in the cerebellum of adolescent rats. Orn significantly increased malondialdehyde levels and the activities of all antioxidant enzymes, and reduced Na(+), K(+)-ATPase activity. In contrast, glutathione concentrations were not changed by Orn treatment. Furthermore, intracerebellar administration of Hcit was not able to alter any of these parameters. The present data show for the first time that Orn provokes in vivo lipid oxidative damage, activation of the enzymatic antioxidant defense system, and reduction of the activity of a crucial enzyme involved in neurotransmission. It is presumed that these pathomechanisms may contribute at least partly to explain the neuropathology of cerebellum abnormalities and the ataxia observed in patients with HHH syndrome.
- Published
- 2015
- Full Text
- View/download PDF
21. Pathogenic potential of SLC25A15 mutations assessed by transport assays and complementation of Saccharomyces cerevisiae ORT1 null mutant.
- Author
-
Marobbio CM, Punzi G, Pierri CL, Palmieri L, Calvello R, Panaro MA, and Palmieri F
- Subjects
- Arginine, Biological Transport, Culture Media, Escherichia coli genetics, Genetic Complementation Test, Humans, Hyperammonemia genetics, Liposomes metabolism, Mutation, Missense, Ornithine deficiency, Ornithine genetics, Recombinant Proteins, Saccharomyces cerevisiae growth & development, Urea Cycle Disorders, Inborn genetics, Amino Acid Transport Systems, Basic genetics, Amino Acid Transport Systems, Basic metabolism, Mitochondrial Membrane Transport Proteins genetics, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae Proteins genetics
- Abstract
HHH syndrome is an autosomal recessive urea cycle disorder caused by alterations in the SLC25A15 gene encoding the mitochondrial ornithine carrier 1, which catalyzes the transport of cytosolic ornithine into the mitochondria in exchange for intramitochondrial citrulline. In this study the functional effects of several SLC25A15 missense mutations p.G27R, p.M37R, p.N74A, p.F188L, p.F188Y, p.S200K, p.R275Q and p.R275K have been tested by transport assays in reconstituted liposomes and complementation of Saccharomyces cerevisiae ORT1 null mutant in arginine-less synthetic complete medium. The HHH syndrome-causing mutations p.G27R, p.M37R, p.F188L and p.R275Q had impaired transport and did not complement ORT1∆ cells (except p.M37R slightly after 5 days in solid medium). The experimentally produced mutations p.N74A, p.S200K and p.R275K exhibited normal or considerable transport activity and complemented ORT1∆ cells after 3 days (p.N74A, p.S200K) or 5 days (p.R275K) incubation. Furthermore, the experimentally produced p.F188Y mutation displayed a substantial transport activity but did not complement the ORT1∆ cells in both liquid and solid media. In view of the disagreement in the results obtained between the two methods, it is recommended that the method of complementing the S. cerevisiae ORT1 knockout strain is used complimentary with the measurement of the catalytic activity, in order to distinguish HHH syndrome-causing mutations from isomorphisms., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
22. The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.
- Author
-
Martinelli D, Diodato D, Ponzi E, Monné M, Boenzi S, Bertini E, Fiermonte G, and Dionisi-Vici C
- Subjects
- Aging, Humans, Hyperammonemia diagnosis, Mutation, Origin Recognition Complex genetics, Origin Recognition Complex metabolism, Ornithine genetics, Protein Conformation, Urea Cycle Disorders, Inborn diagnosis, Hyperammonemia genetics, Hyperammonemia pathology, Ornithine deficiency, Urea Cycle Disorders, Inborn genetics, Urea Cycle Disorders, Inborn pathology
- Abstract
Background: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia., Methods: A systematic review of publications reporting patients with HHH syndrome was performed., Results: We retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life., Conclusions: This paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
- Published
- 2015
- Full Text
- View/download PDF
23. Ocular manifestations in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: a rare association.
- Author
-
Kumar K, Agarwal A, Agarwal A, Dhawan A, Chandani N, and Raj P
- Subjects
- Adolescent, Diagnosis, Differential, Fluorescein Angiography, Fundus Oculi, Humans, Hyperammonemia diagnosis, Male, Myopia diagnosis, Retinal Degeneration diagnosis, Tomography, Optical Coherence, Urea Cycle Disorders, Inborn diagnosis, Fovea Centralis pathology, Hyperammonemia complications, Myopia etiology, Ornithine deficiency, Retinal Degeneration etiology, Urea Cycle Disorders, Inborn complications, Vitreous Body pathology
- Abstract
Purpose: To report ophthalmic features in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, an uncommon presentation., Methods: Case report., Results: An 18-year-old Indian boy presented with progressive diminution of vision, night blindness, lenticular opacities, and midperipheral chorioretinal atrophy. Spectral domain optical coherence tomography revealed myopic foveoschisis, and Humphrey visual fields 30-2 showed peripheral field constriction. He had no neurocognitive disabilities. Serum biochemical analysis revealed hyperornithinemia, hyperglycinemia, and raised ornithine/citrulline ratio suggestive of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome., Conclusion: Ocular findings of midperipheral chorioretinal degeneration with myopic foveoschisis can be the initial presenting manifesation of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.
- Published
- 2015
- Full Text
- View/download PDF
24. High-throughput tandem mass spectrometry multiplex analysis for newborn urinary screening of creatine synthesis and transport disorders, Triple H syndrome and OTC deficiency.
- Author
-
Auray-Blais C, Maranda B, and Lavoie P
- Subjects
- Biomarkers urine, Creatine urine, Creatinine urine, Filtration, Glycine analogs & derivatives, Glycine urine, Humans, Infant, Newborn, Ornithine urine, Orotic Acid urine, Paper, Reference Values, Reproducibility of Results, Tandem Mass Spectrometry standards, Uracil urine, Urinalysis standards, Hyperammonemia diagnosis, Hyperammonemia urine, Ornithine deficiency, Ornithine Carbamoyltransferase Deficiency Disease diagnosis, Ornithine Carbamoyltransferase Deficiency Disease urine, Tandem Mass Spectrometry methods, Urea Cycle Disorders, Inborn diagnosis, Urea Cycle Disorders, Inborn urine, Urinalysis methods
- Abstract
Background: Creatine synthesis and transport disorders, Triple H syndrome and ornithine transcarbamylase deficiency are treatable inborn errors of metabolism. Early screening of patients was found to be beneficial. Mass spectrometry analysis of specific urinary biomarkers might lead to early detection and treatment in the neonatal period. We developed a high-throughput mass spectrometry methodology applicable to newborn screening using dried urine on filter paper for these aforementioned diseases., Methods: A high-throughput methodology was devised for the simultaneous analysis of creatine, guanidineacetic acid, orotic acid, uracil, creatinine and respective internal standards, using both positive and negative electrospray ionization modes, depending on the compound., Results: The precision and accuracy varied by <15%. Stability during storage at different temperatures was confirmed for three weeks. The limits of detection and quantification for each biomarker varied from 0.3 to 6.3 μmol/l and from 1.0 to 20.9 μmol/l, respectively. Analyses of urine specimens from affected patients revealed abnormal results. Targeted biomarkers in urine were detected in the first weeks of life., Conclusions: This rapid, simple and robust liquid chromatography/tandem mass spectrometry methodology is an efficient tool applicable to urine screening for inherited disorders by biochemical laboratories., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
25. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis.
- Author
-
Lee HH, Poon KH, Lai CK, Au KM, Siu TS, Lai JP, Mak CM, Yuen YP, Lam CW, and Chan AY
- Subjects
- Amino Acid Transport Systems, Basic genetics, Amino Acids blood, Child, Child, Preschool, Heterozygote, Humans, Hyperammonemia genetics, Hyperammonemia therapy, Infant, Infant, Newborn, Male, Mitochondrial Membrane Transport Proteins, Ornithine genetics, Prenatal Diagnosis, Urea Cycle Disorders, Inborn genetics, Urea Cycle Disorders, Inborn therapy, Hyperammonemia diagnosis, Neonatal Screening, Ornithine deficiency, Urea Cycle Disorders, Inborn diagnosis
- Abstract
Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is an autosomal recessive disorder caused by a defect in ornithine translocase. This condition leads to variable clinical presentations, including episodic hyperammonaemia, hepatic derangement, and chronic neurological manifestations. Fewer than 100 affected patients have been reported worldwide. Here we report the first two cases in Hong Kong Chinese, who were compound heterozygous siblings for c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile) in the SLC25A15 gene. When the mother refused prenatal diagnosis for the second pregnancy, urgent genetic testing provided the definitive diagnosis within 24 hours to enable specific treatment. Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases.
- Published
- 2014
- Full Text
- View/download PDF
26. Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome in adulthood: a rare recognizable condition.
- Author
-
Filosto M, Alberici A, Tessa A, Padovani A, and Santorelli FM
- Subjects
- Adult, Amino Acid Sequence, Amino Acid Transport Systems, Basic chemistry, Amino Acid Transport Systems, Basic genetics, Base Sequence, Humans, Hyperammonemia physiopathology, Male, Mitochondrial Membrane Transport Proteins, Molecular Sequence Data, Mutation, Ornithine genetics, Urea Cycle Disorders, Inborn physiopathology, Hyperammonemia diagnosis, Hyperammonemia genetics, Ornithine deficiency, Urea Cycle Disorders, Inborn diagnosis, Urea Cycle Disorders, Inborn genetics
- Published
- 2013
- Full Text
- View/download PDF
27. Disturbance of redox homeostasis by ornithine and homocitrulline in rat cerebellum: a possible mechanism of cerebellar dysfunction in HHH syndrome.
- Author
-
Zanatta A, Viegas CM, Tonin AM, Busanello EN, Grings M, Moura AP, Leipnitz G, and Wajner M
- Subjects
- Aconitate Hydratase metabolism, Animals, Cerebellum pathology, Citrulline pharmacology, Creatine Kinase metabolism, Electron Transport, Glutathione metabolism, Hydrogen Peroxide metabolism, Hyperammonemia pathology, Ketoglutarate Dehydrogenase Complex metabolism, Nerve Tissue Proteins metabolism, Nitrates metabolism, Nitrites metabolism, Ornithine deficiency, Ornithine metabolism, Oxidation-Reduction drug effects, Rats, Rats, Wistar, Sodium-Potassium-Exchanging ATPase metabolism, Thiobarbituric Acid Reactive Substances metabolism, Urea Cycle Disorders, Inborn pathology, Cerebellum metabolism, Citrulline analogs & derivatives, Homeostasis drug effects, Hyperammonemia metabolism, Ornithine pharmacology, Urea Cycle Disorders, Inborn metabolism
- Abstract
Aims: Cerebellar ataxia is commonly observed in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, an inherited metabolic disorder biochemically characterized by ornithine (Orn), homocitrulline (Hcit) and ammonia accumulation. Since the pathophysiology of cerebellum damage in this disorder is still unknown, we investigated the effects of Hcit and Orn on important parameters of redox and energy homeostasis in cerebellum of young rats., Material and Methods: We determined thiobarbituric acid-reactive substance (TBA-RS) levels, carbonyl content, nitrate and nitrite production, hydrogen peroxide production, GSH concentrations, sulfhydryl content, as well as activities of respiratory chain complexes I-IV, creatine kinase, Na(+),K(+)-ATPase, aconitase and α-ketoglutarate dehydrogenase., Key Findings: Orn and Hcit significantly increased TBA-RS levels (lipid oxidation), that was totally prevented by melatonin and reduced glutathione (GSH). We also found that nitrate and nitrite production was not altered by any of the metabolites, in contrast to hydrogen peroxide production which was significantly enhanced by Hcit. Furthermore, GSH concentrations were significantly reduced by Orn and Hcit and sulfhydryl content by Orn, implying an impairment of antioxidant defenses. As regards energy metabolism, Orn and Hcit provoked a significant reduction of aconitase activity, without altering the other parameters. Furthermore, Orn-elicited reduction of aconitase activity was totally prevented by GSH, indicating that the critical groups of this enzyme were susceptible to oxidation caused by this amino acid., Significance: Taken together, our data indicate that redox homeostasis is disturbed by the major metabolites accumulating in HHH syndrome and that this mechanism may be implicated in the ataxia and cerebellar abnormalities observed in this disorder., (© 2013.)
- Published
- 2013
- Full Text
- View/download PDF
28. Long-term follow-up of four patients affected by HHH syndrome.
- Author
-
Kim SZ, Song WJ, Nyhan WL, Ficicioglu C, Mandell R, and Shih VE
- Subjects
- Adult, Amino Acid Transport Systems, Basic genetics, Amino Acids blood, Chromatography, High Pressure Liquid, Chromatography, Ion Exchange, DNA Mutational Analysis, Disease Progression, Female, Follow-Up Studies, Humans, Hyperammonemia blood, Hyperammonemia genetics, Male, Middle Aged, Mitochondrial Membrane Transport Proteins, Ornithine blood, Ornithine deficiency, Ornithine genetics, Phenotype, Time Factors, Urea Cycle Disorders, Inborn blood, Urea Cycle Disorders, Inborn genetics, Hyperammonemia physiopathology, Urea Cycle Disorders, Inborn physiopathology
- Abstract
Background: In hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome, impaired ornithine transport across the mitochondrial membrane causes ornithine accumulation in cytoplasm. The resulting mitochondrial ornithine deficiency leads to reduced clearance of ammonia through the urea cycle. First described in 1969, no long-term follow-up has been reported., Methods: Four patients were followed up for 11 to 38y. Diagnosis was made by plasma amino acid analysis using ion exchange chromatography, HPLC orotic acid measurement, and (14)C-ornithine incorporation study using cultured fibroblasts. DNA from fibroblasts was amplified and sequenced. Blood ammonia was controlled by restriction of protein intake., Results: All patients had reduced (14)C-ornithine incorporation. Mutation analysis revealed two novel mutations in the ORNT1 gene. Neurologic outcome included memory loss, low IQ, tremor, spasticity of extremities, bladder incontinence, and abnormal gait. Neuroimaging revealed subcortical, cerebral and cerebellar atrophy, sparing the basal ganglia. Individual examination showed pyramidal signs, cerebellar signs, paraplegia, movement disorder, dystonia, and epilepsy. One patient had 3 pregnancies, one of which resulted in intrauterine growth retardation., Conclusions: Our patients expand the clinical phenotype of adults with HHH. Long-term follow-up showed serious neurologic outcomes in all patients; three patients clearly exhibited progression of neurologic dysfunction despite control of hyperammonemia. Intracellular ornithine deficiency may adversely affect brain functions., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
29. Insights into the mutation-induced HHH syndrome from modeling human mitochondrial ornithine transporter-1.
- Author
-
Wang JF and Chou KC
- Subjects
- Amino Acid Sequence, Amino Acid Transport Systems, Basic metabolism, Binding Sites genetics, Computer Simulation, Humans, Mitochondrial Membrane Transport Proteins, Molecular Dynamics Simulation, Molecular Sequence Data, Ornithine chemistry, Ornithine deficiency, Ornithine genetics, Ornithine metabolism, Protein Binding genetics, Protein Interaction Domains and Motifs genetics, Protein Interaction Mapping, Sequence Homology, Amino Acid, Amino Acid Transport Systems, Basic chemistry, Amino Acid Transport Systems, Basic genetics, Hyperammonemia genetics, Models, Molecular, Mutation physiology, Urea Cycle Disorders, Inborn genetics
- Abstract
Human mitochondrial ornithine transporter-1 is reported in coupling with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, which is a rare autosomal recessive disorder. For in-depth understanding of the molecular mechanism of the disease, it is crucially important to acquire the 3D structure of human mitochondrial ornithine transporter-1. Since no such structure is available in the current protein structure database, we have developed it via computational approaches based on the recent NMR structure of human mitochondrial uncoupling protein (Berardi MJ, Chou JJ, et al. Nature 2011, 476:109-113). Subsequently, we docked the ligand L-ornithine into the computational structure to search for the favorable binding mode. It was observed that the binding interaction for the most favorable binding mode is featured by six remarkable hydrogen bonds between the receptor and ligand, and that the most favorable binding mode shared the same ligand-binding site with most of the homologous mitochondrial carriers from different organisms, implying that the ligand-binding sites are quite conservative in the mitochondrial carriers family although their sequences similarity is very low with 20% or so. Moreover, according to our 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 mutation is directly affecting the substrate binding pocket so as to reduce the substrate binding affinity; (iii) the mutation is located in the structural region closer to the intermembrane space that can significantly break the salt bridge networks of the protein. These findings may provide useful insights for in-depth understanding of the molecular mechanism of the HHH syndrome and developing effective drugs against the disease.
- Published
- 2012
- Full Text
- View/download PDF
30. Retinal risks of high-dose ornithine supplements: a review.
- Author
-
Hayasaka S, Kodama T, and Ohira A
- Subjects
- Animals, Dose-Response Relationship, Drug, Haplorhini, Heterozygote, Humans, Mice, Models, Biological, Ornithine blood, Ornithine deficiency, Ornithine pharmacology, Rats, Rats, Sprague-Dawley, Retina drug effects, Retinal Degeneration chemically induced, Dietary Supplements adverse effects, Hyperammonemia drug therapy, Ornithine therapeutic use, Retinal Pigment Epithelium drug effects, Urea Cycle Disorders, Inborn drug therapy
- Abstract
We reviewed the literature on ornithine supplementation and related topics. Nutritionists and physicians have reported that ornithine supplementation is useful. Paediatricians and biochemists have reported that ornithine is supplemented for NH(3) detoxification in the hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome. In contrast, ophthalmic researchers have reported retinotoxicity associated with high-dose ornithine. In vivo and in vitro experiments have shown that high concentrations of ornithine or its metabolites are toxic to the retinal pigment epithelial (RPE) cells. Long-term (exceeding a few years) and high concentrations (exceeding 600 μmol/l) of ornithine in the blood induce retinal toxicity in gyrate atrophy of the choroid and retina (GA). Intermittent high levels of ornithine do not lead to retinal lesions. Constant blood ornithine levels between 250 and 600 μmol/l do not induce retinal lesions or cause a very slowly progressive retinal degeneration. Blood ornithine levels below 250 μmol/l do not produce retinal alteration. We concluded that short-term, low-dose or transient high-dose ornithine intake is safe for the retina; its nutritional usefulness and effect on NH(3) detoxification are supported by many researchers, but the effect may be limited; and long-term, high-dose ornithine intake may be risky for the retina. Patients with GA should avoid taking ornithine; amino acid supplementation should be administered carefully for patients with the HHH syndrome, relatives of patients with GA (heterozygotes) and subjects with RPE lesions; and blood ornithine levels and retinal conditions should be evaluated in individuals taking long-term, high-dose ornithine.
- Published
- 2011
- Full Text
- View/download PDF
31. Dual mechanism of brain damage induced in vivo by the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.
- Author
-
Viegas CM, Busanello EN, Tonin AM, de Moura AP, Grings M, Ritter L, Schuck PF, Ferreira Gda C, Sitta A, Vargas CR, and Wajner M
- Subjects
- Animals, Cerebral Cortex drug effects, Cerebral Cortex physiopathology, Citrulline administration & dosage, Citrulline metabolism, Citrulline toxicity, Hyperammonemia metabolism, Hyperammonemia physiopathology, Injections, Intraventricular, Lipid Peroxidation drug effects, Ornithine administration & dosage, Ornithine deficiency, Ornithine metabolism, Rats, Rats, Wistar, Urea Cycle Disorders, Inborn metabolism, Urea Cycle Disorders, Inborn physiopathology, Cerebral Cortex metabolism, Citrulline analogs & derivatives, Ornithine toxicity, Oxidative Stress drug effects
- Abstract
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder caused by a defect in the mitochondrial ornithine transporter, leading to accumulation of ornithine (Orn), homocitrulline (Hcit) and ammonia. Progressive neurological regression whose pathogenesis is not well established is common in this disease. The present work investigated the in vivo effects of intracerebroventricular administration of Orn and Hcit on important parameters of oxidative stress and energy metabolism in cerebral cortex from young rats. Orn and Hcit significantly increased thiobarbituric acid-reactive substances values and carbonyl formation, indicators of lipid and protein oxidative damage, respectively. Furthermore, N-acetylcysteine and the combination of the free radical scavengers ascorbic acid plus α-tocopherol attenuated the lipid oxidation and totally prevented the protein oxidative damage provoked by Orn and Hcit, suggesting that reactive species were involved in these effects. Hcit, but not Orn administration, also decreased glutathione concentrations, as well as the activity of catalase and glutathione peroxidase, indicating that Hcit provokes a reduction of brain antioxidant defenses. As regards to the parameters of energy metabolism, we verified that Orn and Hcit significantly inhibited the citric acid cycle function (inhibition of CO(2) synthesis from [1-(14)C] acetate), the aerobic glycolytic pathway (reduced CO(2) production from [U-(14)C] glucose) and complex I-III activity of the respiratory chain. Hcit also inhibited the activity of aconitase, an enzyme very susceptible to free radical attack. Taken together, our data indicate that mitochondrial homeostasis is disturbed by Orn and especially by Hcit. It is presumed that the impairment of brain bioenergetics and the oxidative damage induced by these metabolites may possibly contribute to the brain deterioration and neurological symptoms affecting patients with HHH syndrome., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
32. Diagnosis and high incidence of hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome in northern Saskatchewan.
- Author
-
Sokoro AA, Lepage J, Antonishyn N, McDonald R, Rockman-Greenberg C, Irvine J, and Lehotay DC
- Subjects
- Biomarkers blood, Dried Blood Spot Testing, Gene Frequency, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Hyperammonemia blood, Hyperammonemia genetics, Incidence, Infant, Newborn, Mitochondrial Membrane Transport Proteins, Ornithine blood, Ornithine genetics, Phenotype, Polymerase Chain Reaction, Predictive Value of Tests, Prospective Studies, Retrospective Studies, Saskatchewan epidemiology, Tandem Mass Spectrometry, Time Factors, Urea Cycle Disorders, Inborn blood, Urea Cycle Disorders, Inborn genetics, Amino Acid Transport Systems, Basic genetics, DNA Mutational Analysis, Genetic Testing methods, Hyperammonemia diagnosis, Hyperammonemia epidemiology, Mutation, Neonatal Screening methods, Ornithine deficiency, Urea Cycle Disorders, Inborn diagnosis, Urea Cycle Disorders, Inborn epidemiology
- 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.
- Published
- 2010
- Full Text
- View/download PDF
33. [Physiological functions of L-ornithine and L-aspartate in the body and the efficacy of administration of L-ornithine-L-aspartate in conditions of relative deficiency].
- Author
-
Sikorska H, Cianciara J, and Wiercińska-Drapało A
- Subjects
- Animals, Aspartic Acid administration & dosage, Disease Models, Animal, Female, Humans, Ornithine administration & dosage, Physical Exertion physiology, Pregnancy, Urea Cycle Disorders, Inborn drug therapy, Urea Cycle Disorders, Inborn metabolism, Wound Healing physiology, Aspartic Acid deficiency, Aspartic Acid metabolism, Ornithine deficiency, Ornithine metabolism
- Abstract
L-ornithine-L-aspartate (LOLA) is a stable salt of two natural nonessential L-amino acids: ornithine and aspartic acid. It is formulated and marketed in low and high doses. Low doses are used as a food supplement and high doses (above 5 g) as a medicinal product to lower blood ammonia concentration and to eliminate symptoms of hepatic encephalopathy associated with liver cirrhosis. The aim of this review is to present physiological roles of L-ornithine and L-aspartate in the human body, to assess conditions under which these amino acids could be deficient, to analyze consequences of these deficiencies, and to review the current state of knowledge on the effects of LOLA administration. The data used in this publication result from searches of different electronic databases such as Cochrane Trials Register, MEDLINE, PubMed, Medscape, or Google Scholar, with a cut-off date of November 29, 2009, using terms: L-ornithine-L-aspartate, ornithine aspartate, ornithine, Hepa-Merz, ornithine deficiency, hyperammonemia, hepatic encephalopathy, and liver cirrhosis. Both amino acids play key roles in ammonia detoxification and in proline and polyamine biosyntheses. Polyamines are considered critical for DNA synthesis and cell replication and have been shown to stimulate hepatic regeneration. Supplementation with ornithine in animal models demonstrated enhanced wound breaking strength and collagen deposition. It has been shown in vitro, in vivo and in perfused organs that urea synthesis from ammonia is limited by endogenous ornithine and that ornithine can pharmacologically promote urea formation to a greater degree than any ammonia supply. Administration of LOLA in high doses reduced high blood ammonia induced either by ammonium chloride or protein ingestion or existing as a clinical complication of cirrhosis. In health and with proper diet, L-ornithine and L-aspartate are synthesized de novo in sufficient quantities, but in the states of disease, tissue damage, organ insufficiency, excessive metabolic demand, growth, pregnancy, or urea cycle enzyme deficiencies, these amino acids need to be supplemented with the food. The review of available data indicate that there is direct and indirect (resulting from physiology) scientific rationale for dietary use of LOLA, depending on an individual's physiological, metabolic or pathological conditions. In conditional ornithine deficiency, daily supplementation with LOLA at doses about 1 g/day is safe and, as demonstrated in vitro, should be sufficient to saturate tissue ornithine concentration to prevent postprandial hyperammonemia and to stimulate tissue regeneration.
- Published
- 2010
34. Ornithine deficiency in the arginase double knockout mouse.
- Author
-
Deignan JL, Livesay JC, Yoo PK, Goodman SI, O'Brien WE, Iyer RK, Cederbaum SD, and Grody WW
- Subjects
- Animals, Arginase analysis, Arginine analysis, Arginine blood, Argininosuccinic Acid analysis, Brain Chemistry, Down-Regulation, Intestine, Small chemistry, Intestine, Small enzymology, Kidney chemistry, Liver chemistry, Mice, Mice, Knockout, Ornithine analysis, Ornithine blood, Ornithine-Oxo-Acid Transaminase analysis, Arginase genetics, Hyperammonemia genetics, Ornithine deficiency
- Abstract
Knockout mouse models have been created to study the consequences of deficiencies in arginase AI and AII, both individually and combined. The AI knockout animals die by 14 days of age from hyperammonemia, while the AII knockout has no obvious phenotype. The double knockout (AI(-/-)/AII(-/-)) exhibits the phenotype of the AI-deficient mice, with the additional absence of AII not exacerbating the observed phenotype of the AI knockout animals. Plasma amino acid measurements in the double knockout have shown arginine levels increased roughly 100-fold and ornithine decreased roughly 10-fold as compared to wildtype. Liver ornithine levels were reduced to 2% of normal in the double knockout with arginine very highly elevated. Arginine and ornithine were also altered in other tissues in the double knockout mice, such as kidney, brain, and small intestine. This is the first demonstration that the fatal hyperammonemia in the AI knockout mouse is almost certainly due to ornithine deficiency, the amino acid needed to drive the urea cycle. Others have shown that the expression of ornithine aminotransferase (OAT) rapidly decreases in the intestine at the same age when the AI-deficient animals die, indicating that this enzyme is critical to the maintenance of ornithine homeostasis, at least at this early stage of mouse development. Although most human AI-deficient patients have no symptomatic hyperammonemia at birth, it is possible that clinically significant ornithine deficiency is already present.
- Published
- 2006
- Full Text
- View/download PDF
35. A novel mutation, P126R, in a Japanese patient with HHH syndrome.
- Author
-
Miyamoto T, Kanazawa N, Hayakawa C, and Tsujino S
- Subjects
- Adolescent, Ammonia blood, Base Sequence, Brain Diseases diagnostic imaging, Brain Diseases pathology, Carrier Proteins genetics, Cysts diagnostic imaging, Cysts pathology, DNA Primers, Exons, Humans, Magnetic Resonance Imaging, Male, Methionine urine, Molecular Sequence Data, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, Septum Pellucidum pathology, Syndrome, Tomography, X-Ray Computed, Gene Expression genetics, Metabolism, Inborn Errors genetics, Metabolism, Inborn Errors metabolism, Mitochondrial Diseases genetics, Mitochondrial Diseases metabolism, Ornithine deficiency, Ornithine genetics, Point Mutation genetics
- Abstract
Mitochondrial ornithine transporter deficiency, or HHH syndrome, is a metabolic disorder resulting in various neurologic symptoms, including mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia, and episodic disturbance of consciousness or coma caused by hyperammonemia. Several mutations have been reported in the ORNT1 gene encoding mitochondrial ornithine transporter of patients with this disorder. In this article, we report a new patient, a male 15 years of age, who had typical clinical features of HHH syndrome. Because the patient did not have any of the three mutations previously described in other Japanese patients with HHH syndrome, and the only material available from the patient was peripheral leukocytes, we established a genomic polymerase chain reaction method using intronic primers to amplify every exon of the ORNT1 gene, and we directly sequenced the polymerase chain reaction products. Using this method, we documented a novel mutation in this patient, P126R, and demonstrated that HHH syndrome is genetically heterogeneous, even in the Japanese population.
- Published
- 2002
- Full Text
- View/download PDF
36. Effects of L-valine on growth and polyamine metabolism in human colon carcinoma cells.
- Author
-
Selamnia M, Robert V, Mayeur C, Duée PH, and Blachier F
- Subjects
- Arginine metabolism, Cell Differentiation drug effects, Cell Survival drug effects, Glutamine metabolism, Humans, Ornithine deficiency, Ornithine metabolism, Ornithine Decarboxylase metabolism, Polyamines analysis, Polyamines pharmacokinetics, Protein Biosynthesis, Putrescine pharmacokinetics, Spermidine pharmacokinetics, Cell Division drug effects, HT29 Cells drug effects, Polyamines metabolism, Valine pharmacology
- Abstract
HT-29 cells, originating from a human colon carcinoma, can proliferate in standard culture conditions with an absolute requirement for polyamines. The major precursor provided in the culture medium for polyamine biosynthesis is L-arginine. L-Arginine conversion to L-ornithine by arginase is followed by stepwise conversion of this latter amino acid to putrescine, spermidine and spermine. The aim of the present work was to document the consequences of a total inhibition of L-arginine flux through arginase, resulting in a decreased L-ornithine availability, on HT-29 cell proliferation and polyamine metabolism. L-Valine, a known arginase inhibitor, when used at a high concentration, i.e., 100 mM, inhibits L-arginine flux through arginase almost totally. The addition in the culture medium of 100 mM L-valine or 50 mM NaCl used to mimic the L-valine induced increase in medium osmolality both reduced equally cellular growth. Cell viability, protein synthesis or oxidative metabolism measured in isolated cells were unaffected by the L-valine treatment, suggesting that decreased proliferation was not associated with an acute toxic effect of this aminoacid, but was rather due to the increase in the medium osmolality. L-Valine treated cells displayed an altered polyamine metabolism when compared with control cells grown in the absence of the amino acid. After 4 days of treatment with 100 mM L-valine, L-ornithine flux through ornithine decarboxylase was significantly higher as well as putrescine and spermidine cellular uptakes in treated cells. However, the changes in polyamine metabolism led to similar polyamine cell contents in untreated and L-valine treated cells. In conclusion, we propose that the observed alterations of polyamine metabolism may reflect an adaptative response of HT-29 cells to the presence of L-valine which contribute together with the low amount of L-ornithine present in the culture medium to polyamine homeostasis.
- Published
- 1998
- Full Text
- View/download PDF
37. Endogenous ornithine in search for CNS functions and therapeutic applications.
- Author
-
Seiler N and Daune-Anglard G
- Subjects
- Ammonia blood, Animals, Brain Diseases blood, Humans, Ornithine antagonists & inhibitors, Ornithine deficiency, Ornithine-Oxo-Acid Transaminase metabolism, Polyamines metabolism, gamma-Aminobutyric Acid metabolism, Brain physiology, Brain Diseases drug therapy, Ornithine physiology
- Abstract
The vertebrate brain has the machinery to transport arginine and ornithine, and to form within nerve endings from these amino acids glutamate and GABA, the major excitatory and inhibitory neurotransmitters. Ornithine aminotransferase is a key enzyme of the Arg-->Orn-->Glu-->GABA pathway; the physiological significance of this pathway is still unclear. With 5-fluoromethylornithine, a selective inactivator of ornithine aminotransferase, a tool is in our hands that allows us to study biochemical and behavioral consequences of elevated tissue ornithine concentrations. Increase of the rate of hepatic urea formation, and of ornithine decarboxylation are the most important changes in vertebrates following inactivation of ornithine aminotransferase. Administration of 5-fluoromethylornithine prevented the accumulation of lethal concentrations of ammonia in brain, and ameliorated pathological consequences of thioacetamide intoxication. Inhibition of ornithine catabolism has, therefore, potentials in the therapy of those hyperammonemic states which are characterized by a conditional deficiency of ornithine. The enhancement of polyamine formation due to elevated ornithine concentrations may allow us to favorably affect tissue regeneration following injury.
- Published
- 1993
- Full Text
- View/download PDF
38. Conditional deficiencies of ornithine or arginine.
- Author
-
Zieve L
- Subjects
- Amino Acids administration & dosage, Amino Acids, Branched-Chain analysis, Ammonia toxicity, Animals, Citrulline physiology, Female, Glycine toxicity, Hepatic Encephalopathy blood, Humans, Liver Cirrhosis blood, Lysine toxicity, Models, Biological, Orotic Acid urine, Pregnancy, Protein Deficiency complications, Urease metabolism, Arginine deficiency, Ornithine deficiency
- Abstract
Relative deficiencies of ornithine or arginine occur in the presence of excessive ammonia, excessive lysine, growth, pregnancy, trauma, or protein deficiency and malnutrition. Ammonia excess may occur in the presence of a normal liver when amino acid mixtures lacking ornithine, arginine, or citrulline are infused; when specific amino acids such as glycine are injected; when ammonium salts, urea, or urease are injected; or when the gastrointestinal tract contains an excess of protein, urea, or NH4+, as occurs after a gastrointestinal hemorrhage. In these states, ornithine is often rate-limiting for urea cycle function. Ornithine is also rate-limiting when ammonia excess occurs in the presence of hepatic failure. In three of the inherited urea cycle disorders, ornithine insufficiency and ammonia excess also occur. These disorders are citrullinemia, argininosuccinic aciduria, and argininemia. In the presence of excessive lysine the availability of arginine is reduced and the formation of ornithine is decreased in the liver; urea synthesis is reduced, but orotic acid synthesis is increased, and orotic aciduria results as carbamyl phosphate is directed toward the pyrimidine pathway. Hereditary lysinuric protein intolerance results in ornithine depletion, hyperammonemia, and orotic acid uria. Optimal growth in several species of animals requires 0.4-1.0% arginine in the diet. Diets deficient in arginine are associated with poor wound healing as well as stunted growth. The measurement of orotic acid excretion has been a convenient indicator of insufficiency of ornithine or arginine during growth or pregnancy in animals and should prove useful in assessing the requirement for arginine after trauma. Normal human pregnancy is associated with low-grade orotic aciduria. Protein deficiency and malnutrition increase the vulnerability of the animal or child to ammonia toxicity. This is presumably due to insufficient ornithine for normal urea cycle responsiveness.
- Published
- 1986
- Full Text
- View/download PDF
39. Polyamine starvation causes accumulation of cadaverine and its derivatives in a polyamine-dependent strain of Chinese-hamster ovary cells.
- Author
-
Hölttä E and Pohjanpelto P
- Subjects
- Animals, Cadaverine analogs & derivatives, Cells, Cultured, Cricetinae, Cricetulus, Eflornithine, Female, Ornithine analogs & derivatives, Ornithine pharmacology, Ovary cytology, Ovary drug effects, Proteins metabolism, Cadaverine metabolism, Diamines metabolism, Ornithine deficiency, Ovary metabolism, Polyamines metabolism
- Abstract
Starvation of the polyamine-dependent Chinese-hamster ovary cells for ornithine or ornithine-derived polyamines in serum-free culture resulted in the formation of cadaverine and its aminopropyl derivatives, N-(3-aminopropyl)cadaverine and NN'-bis(3-aminopropyl)cadaverine. The synthesis of these unusual amines was inhibited by treatment of the cells with DL-2-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase (EC 4.1.1.17). In the absence of ornithine (the normal substrate), ornithine decarboxylase thus appeared to catalyse the decarboxylation of lysine to cadaverine. Cell proliferation was markedly inhibited by ornithine deprivation of the cells, and further depressed by exposure of the cultures to difluoromethylornithine.
- Published
- 1983
- Full Text
- View/download PDF
40. Nutrition and retinal degenerations. Vitamin A, taurine, ornithine, and phytanic acid.
- Author
-
Berson EL
- Subjects
- Animal Nutritional Physiological Phenomena, Animals, Electroretinography, Fluorescein Angiography, Fundus Oculi, Humans, Nutritional Requirements, Ornithine deficiency, Phytanic Acid metabolism, Retinal Degeneration pathology, Taurine deficiency, Vitamin A Deficiency complications, Nutrition Disorders complications, Retinal Degeneration etiology
- Published
- 1982
41. Metabolic products of microorganisms. 135. Uptake of iron by Neurospora crassa. IV. Iron transport properties of semisynthetic coprogen derivatives.
- Author
-
Ernst J and Winkelmann G
- Subjects
- Acetates metabolism, Binding Sites, Biological Transport, Butyrates metabolism, Carbon Radioisotopes, Cell Membrane metabolism, Fusarium, Hydroxamic Acids metabolism, Iron Radioisotopes, Mutation, Ornithine deficiency, Phenethylamines metabolism, Phenylbutyrates metabolism, Propionates metabolism, Spheroplasts metabolism, Succinates metabolism, Growth Substances metabolism, Iron Chelating Agents metabolism, Neurospora metabolism, Neurospora crassa metabolism
- Published
- 1974
- Full Text
- View/download PDF
42. Arginine: an acutely essential amino acid for the near-adult cat.
- Subjects
- Ammonia blood, Animal Nutritional Physiological Phenomena, Animals, Cats, Growth Disorders chemically induced, Ornithine deficiency, Ammonia poisoning, Arginine deficiency
- Published
- 1979
- Full Text
- View/download PDF
43. Urinary metabolites characteristic of urea-cycle amino acid deficiency.
- Author
-
Milner JA and Visek WJ
- Subjects
- Amino Acids, Essential deficiency, Ammonia metabolism, Animal Nutritional Physiological Phenomena, Animals, Arginine deficiency, Biotransformation, Body Weight, Carbamyl Phosphate metabolism, Citrates urine, Citrulline deficiency, Diet, Male, Nitrogen metabolism, Ornithine deficiency, Orotic Acid urine, Pyrimidines biosynthesis, Rats, Amino Acids deficiency, Deficiency Diseases metabolism, Urea metabolism
- Abstract
Experiments with 45-75-g male rats gave conclusive evidence that the simultaneous absence from the diet of arginine, ornithine, or citrulline caused an immediate and persistent elevation of orotic and citric acids in the urine. The experiments also demonstrated that a deficiency of no other individual amino acid increased urinary citrate and orotate. Elevated urinary excretion of orotic and citric acid occurred independently of the form of nonessential nitrogen. Replacement of arginine isonitrogenously with ornithine or citrulline prevented the rise in urinary orotic acid, but had different effects on growth, urinary citrate, and urinary urea. These differences were probably due to differential uptake of arginine, ornithine, and citrulline by tissues; In the reported experiments employing L-amino acids as sources of dietary nitrogen, a deficiency of any amino acid indispensable for growth and nitrogen balance or a deficiency of arginine, ornithine, or citrulline retarded growth, increased urinary urea, and decreased urinary ammonia. It is concluded that the severe loss of orotic acid during urea-cycle amino acid deficiency arises from a decreased capacity of the urea cycle to detoxify ammonia, thereby causing increased shunting of intramitochondrial carbamyl phosphate into pyrimidine synthesis. The similarities in metabolism during arginine deficiency and ammonia intoxication are discussed. The evidence shows that urinary orotic acid may be a valuable measure of arginine nutrition in mammals.
- Published
- 1975
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.