The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
Bang-ce Ye - One of the best experts on this subject based on the ideXlab platform.
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Recent Advances of L-Ornithine Biosynthesis in Metabolically Engineered Corynebacterium glutamicum.
Frontiers in Bioengineering and Biotechnology, 2020Co-Authors: Xiao-yu Wu, Bin Zhang, Yan Jiang, Bang-ce YeAbstract:Abstract: L-Ornithine, a valuable non-protein amino acid, has a wide range of applications in the pharmaceutical and food industries. Currently, microbial fermentation is a promising, sustainable, and environment-friendly method to produce L-Ornithine. However, the industrial production capacity of L-Ornithine by microbial fermentation is low and rarely meets the market demands. Various strategies have been employed to improve the L-Ornithine production titers in the model strain, Corynebacterium glutamicum, which serves as a major indicator for improving the cost-effectiveness of L-Ornithine production by microbial fermentation. This review focuses on the development of high L-Ornithine-producing strains by metabolic engineering and reviews the recent advances in breeding strategies, such as reducing by-product formation, improving the supplementation of precursor glutamate, releasing negative regulation and negative feedback inhibition, increasing the supply of intracellular cofactors, modulating the central metabolic pathway, enhancing the transport system, and adaptive evolution for improving L-Ornithine production.
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Metabolic engineering of Corynebacterium glutamicum S9114 to enhance the production of L-Ornithine driven by glucose and xylose
Bioresource Technology, 2019Co-Authors: Bin Zhang, Bang-ce YeAbstract:Abstract l -ornithine, an important amino acid, is widely used in food and medicine industries. l -ornithine production mainly relies on microbial fermentation, which may not meet the industrial requirement owing to the poor fermentation ability of available strains. Herein, mscCG2 deletion, CgS9114_12202 (gdh2) overexpression and rational modulation in tricarboxylic acid cycle was firstly demonstrated to increase l -ornithine production in engineered Corynebacterium glutamicum S9114. By further modulate glucose utility result in strain SO26 that produced 38.5 g/L or 43.6 g/L of l -ornithine in shake flask and fed-batch fermentation, respectively. This was 25% higher than that of the original strain (30.8 g/L) and exhibits highest titer reported in shake-flask. Moreover, the incorporation of xylose pathway in the engineered strain resulted in the highest l -ornithine production titer (18.9 g/L) and yield (0.40 g/g xylose) with xylose substrate. These results illustrate the tremendous potential of the engineered strain C. glutamicum S9114 in l -ornithine production.
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Improvement of L-Ornithine production by attenuation of argF in engineered Corynebacterium glutamicum S9114.
AMB Express, 2018Co-Authors: Bin Zhang, Miao Yu, Ying Zhou, Bang-ce YeAbstract:L-Ornithine, a non-essential amino acid, has enormous industrial applications in food, pharmaceutical, and chemical industries. Currently, L-Ornithine production is focused on microorganism fermentation using Escherichia coli or Corynebacterium glutamicum. In C. glutamicum, development of high L-Ornithine producing C. glutamicum was achieved by deletion of argF, but was accompanied by growth deficiency and arginine auxotrophy. l-Arginine has been routinely added to solve this problem; however, this increases production cost and causes feedback inhibition of N-acetyl-l-glutamate kinase activity. To avoid the drawbacks of growth disturbance due to disruption of ArgF, strategies were adopted to attenuate its expression. Firstly, ribosome binding site substitution and start codon replacement were introduced to construct recombinant C. glutamiucm strains, which resulted in an undesirable L-Ornithine production titer. Then, we inserted a terminator (rrnB) between argD and argF, which significantly improved L-Ornithine production and relieved growth disturbance. Transcription analysis confirmed that a terminator can be used to downregulate expression of argF and simultaneously improve the transcriptional level of genes in front of argF. Using disparate terminators to attenuate expression of argF, an optimal strain (CO-9) with a T4 terminator produced 6.1 g/L of L-Ornithine, which is 42.8% higher than that produced by strain CO-1, and is 11.2-fold higher than that of the parent CO strain. Insertion of terminators with gradient termination intensity can be a stable and powerful method to exert precise control of the expression level of argF in the development of L-Ornithine producing strains, with potential applications in metabolic engineering and synthetic biology.
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Enhanced L-Ornithine production by systematic manipulation of L-Ornithine metabolism in engineered Corynebacterium glutamicum S9114
Bioresource Technology, 2017Co-Authors: Bin Zhang, Miao Yu, Ying Zhou, Bang-ce YeAbstract:Abstract l -Ornithine is a non-protein amino acid with extensive applications in medicine and the food industry. Currently, l -ornithine is produced by microbial fermentation; however, this process needs to be further improved in terms of l -ornithine productivity and cost reduction. In this study, overexpression of LysE was observed to increase l -ornithine production in engineered Corynebacterium glutamicum S9114. To overcome the drawbacks of using a plasmid to express LysE, Ptac, a strong promoter, was inserted in the upstream region of lysE on the chromosome. This strain was further engineered by attenuating the expression of ncgl2228 and proB, and enhancing the expression of gdh and argCJBD. Combination of those targets resulted in l -ornithine production at a titer of 25 g/L, which was 63.4% higher than that produced by the original strain (15.3 g/L). These results demonstrated the positive effects of overexpressing LysE on l -ornithine production and provided novel targets for developing l -ornithine-producing C. glutamicum strains.
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Systematic pathway engineering of Corynebacterium glutamicum S9114 for L-Ornithine production.
Microbial Cell Factories, 2017Co-Authors: Bin Zhang, Miao Yu, Ying Zhou, Yixue Li, Bang-ce YeAbstract:L-Ornithine is a non-protein amino acid with extensive applications in medicine and the food industry. Currently, L-Ornithine production is based on microbial fermentation, and few microbes are used for producing L-Ornithine owing to unsatisfactory production titer. In this study, Corynebacterium glutamicum S9114, a high glutamate-producing strain, was developed for L-Ornithine production by pathway engineering. First, argF was deleted to block L-Ornithine to citrulline conversion. To improve L-Ornithine production, ncgl1221 encoding glutamate transporter, argR encoding arginine repressor, and putP encoding proline transporter were disrupted. This base strain was further engineered by attenuating oxoglutarate dehydrogenase to increase L-Ornithine production. Plasmid-based overexpression of argCJBD operon and lysine/arginine transport protein LysE was tested to strengthen L-Ornithine synthesis and transportation. This resulted in efficient L-Ornithine production at a titer of 18.4 g/L. These results demonstrate the potential of Corynebacterium glutamicum S9114 for efficient L-Ornithine production and provide new targets for strain development.
Bin Zhang - One of the best experts on this subject based on the ideXlab platform.
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Recent Advances of L-Ornithine Biosynthesis in Metabolically Engineered Corynebacterium glutamicum.
Frontiers in Bioengineering and Biotechnology, 2020Co-Authors: Xiao-yu Wu, Bin Zhang, Yan Jiang, Bang-ce YeAbstract:Abstract: L-Ornithine, a valuable non-protein amino acid, has a wide range of applications in the pharmaceutical and food industries. Currently, microbial fermentation is a promising, sustainable, and environment-friendly method to produce L-Ornithine. However, the industrial production capacity of L-Ornithine by microbial fermentation is low and rarely meets the market demands. Various strategies have been employed to improve the L-Ornithine production titers in the model strain, Corynebacterium glutamicum, which serves as a major indicator for improving the cost-effectiveness of L-Ornithine production by microbial fermentation. This review focuses on the development of high L-Ornithine-producing strains by metabolic engineering and reviews the recent advances in breeding strategies, such as reducing by-product formation, improving the supplementation of precursor glutamate, releasing negative regulation and negative feedback inhibition, increasing the supply of intracellular cofactors, modulating the central metabolic pathway, enhancing the transport system, and adaptive evolution for improving L-Ornithine production.
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Proteome analysis guided genetic engineering of Corynebacterium glutamicum S9114 for tween 40-triggered improvement in l -ornithine production
Microbial Cell Factories, 2020Co-Authors: Yan Jiang, Ming-zhu Huang, Xue-lan Chen, Bin ZhangAbstract:L-Ornithine is a valuable amino acid with a wide range of applications in the pharmaceutical and food industries. However, the production of L-Ornithine by fermentation cannot compete with other methods, because of the low titers produced with this technique. Development of fermentation techniques that result in a high yield of L-Ornithine and efficient strategies for improving L-Ornithine production are essential. This study demonstrates that tween 40, a surfactant promoter of the production of glutamate and arginine, improves L-Ornithine production titers in engineered C. glutamicum S9114. The intracellular metabolism under tween 40 triggered fermentation conditions was explored using a quantitative proteomic approach, identifying 48 up-regulated and 132 down-regulated proteins when compared with the control. Numerous proteins were identified as membrane proteins or functional proteins involved in the biosynthesis of the cell wall. Modulation of those genes revealed that the overexpression of CgS9114_09558 and the deletion of CgS9114_13845, CgS9114_02593, and CgS9114_02058 improved the production of L-Ornithine in the engineered strain of C. glutamicum Orn8. The final strain with all the exploratory metabolic engineering manipulations produced 25.46 g/L of L-Ornithine, and a yield of 0.303 g L-Ornithine per g glucose, which was 30.6% higher than that produced by the original strain (19.5 g/L). These results clearly demonstrate the positive effect of tween 40 addition on L-Ornithine accumulation. Proteome analysis was performed to examine the impact of tween 40 addition on the physiological changes in C. glutamicum Orn8 and the results showed several promising modulation targets for developing L-Ornithine-producing strains.
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Metabolic engineering of Corynebacterium glutamicum S9114 to enhance the production of L-Ornithine driven by glucose and xylose
Bioresource Technology, 2019Co-Authors: Bin Zhang, Bang-ce YeAbstract:Abstract l -ornithine, an important amino acid, is widely used in food and medicine industries. l -ornithine production mainly relies on microbial fermentation, which may not meet the industrial requirement owing to the poor fermentation ability of available strains. Herein, mscCG2 deletion, CgS9114_12202 (gdh2) overexpression and rational modulation in tricarboxylic acid cycle was firstly demonstrated to increase l -ornithine production in engineered Corynebacterium glutamicum S9114. By further modulate glucose utility result in strain SO26 that produced 38.5 g/L or 43.6 g/L of l -ornithine in shake flask and fed-batch fermentation, respectively. This was 25% higher than that of the original strain (30.8 g/L) and exhibits highest titer reported in shake-flask. Moreover, the incorporation of xylose pathway in the engineered strain resulted in the highest l -ornithine production titer (18.9 g/L) and yield (0.40 g/g xylose) with xylose substrate. These results illustrate the tremendous potential of the engineered strain C. glutamicum S9114 in l -ornithine production.
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Improvement of L-Ornithine production by attenuation of argF in engineered Corynebacterium glutamicum S9114.
AMB Express, 2018Co-Authors: Bin Zhang, Miao Yu, Ying Zhou, Bang-ce YeAbstract:L-Ornithine, a non-essential amino acid, has enormous industrial applications in food, pharmaceutical, and chemical industries. Currently, L-Ornithine production is focused on microorganism fermentation using Escherichia coli or Corynebacterium glutamicum. In C. glutamicum, development of high L-Ornithine producing C. glutamicum was achieved by deletion of argF, but was accompanied by growth deficiency and arginine auxotrophy. l-Arginine has been routinely added to solve this problem; however, this increases production cost and causes feedback inhibition of N-acetyl-l-glutamate kinase activity. To avoid the drawbacks of growth disturbance due to disruption of ArgF, strategies were adopted to attenuate its expression. Firstly, ribosome binding site substitution and start codon replacement were introduced to construct recombinant C. glutamiucm strains, which resulted in an undesirable L-Ornithine production titer. Then, we inserted a terminator (rrnB) between argD and argF, which significantly improved L-Ornithine production and relieved growth disturbance. Transcription analysis confirmed that a terminator can be used to downregulate expression of argF and simultaneously improve the transcriptional level of genes in front of argF. Using disparate terminators to attenuate expression of argF, an optimal strain (CO-9) with a T4 terminator produced 6.1 g/L of L-Ornithine, which is 42.8% higher than that produced by strain CO-1, and is 11.2-fold higher than that of the parent CO strain. Insertion of terminators with gradient termination intensity can be a stable and powerful method to exert precise control of the expression level of argF in the development of L-Ornithine producing strains, with potential applications in metabolic engineering and synthetic biology.
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Enhanced L-Ornithine production by systematic manipulation of L-Ornithine metabolism in engineered Corynebacterium glutamicum S9114
Bioresource Technology, 2017Co-Authors: Bin Zhang, Miao Yu, Ying Zhou, Bang-ce YeAbstract:Abstract l -Ornithine is a non-protein amino acid with extensive applications in medicine and the food industry. Currently, l -ornithine is produced by microbial fermentation; however, this process needs to be further improved in terms of l -ornithine productivity and cost reduction. In this study, overexpression of LysE was observed to increase l -ornithine production in engineered Corynebacterium glutamicum S9114. To overcome the drawbacks of using a plasmid to express LysE, Ptac, a strong promoter, was inserted in the upstream region of lysE on the chromosome. This strain was further engineered by attenuating the expression of ncgl2228 and proB, and enhancing the expression of gdh and argCJBD. Combination of those targets resulted in l -ornithine production at a titer of 25 g/L, which was 63.4% higher than that produced by the original strain (15.3 g/L). These results demonstrated the positive effects of overexpressing LysE on l -ornithine production and provided novel targets for developing l -ornithine-producing C. glutamicum strains.
Luc Cynober - One of the best experts on this subject based on the ideXlab platform.
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enteral administration of ornithine alpha ketoglutarate or arginine alpha ketoglutarate a comparative study of their effects on glutamine pools in burn injured rats
Critical Care Medicine, 1997Co-Authors: Le Boucher J, C Coudraylucas, E Lasnier, A Jardel, O G Ekindjian, Luc CynoberAbstract:Objectives: Ornithine α-ketoglutarate has proved to be an efficient nutritional support in trauma situations, especially after burn injury. To determine whether the action of ornithine α-ketoglutarate is due to its α-ketoglutarate moiety (as a glutamine precursor), we studied the effects of α-ketoglutarate administered to rats as ornithine α-ketoglutarate, or in combination with arginine salt (arginine α-ketoglutarate), as the two closely related amino acids have similar metabolic behavior. Design: Prospective, randomized trial. Setting: Animal laboratory. Subjects: Forty-six male Wistar rats, weighing -90 g. Interventions: Rats were burned over 20% of their body surface area, starved for 24 hrs, with water ad libitum, and then enterally refed for 48 hrs using Osmolite®(210 kcal/kg/day, 1.2 g of nitrogen/ kg/day), supplemented with one of the following: a) an amount of glycine isonitrogenous to ornithine α-ketoglutarate (group 1); b) 5 g of monohydrated ornithine α-ketoglutarate/kg/day (group 2); c) an amount of arginine α-ketoglutarate isonitrogenous to ornithine α-ketoglutarate (group 3); or d) an amount of arginine α-ketoglutarate isomolar to ornithine α-ketoglutarate (group 4). Measurements and Main Results: We measured amino acid concentrations in plasma, muscle, and liver, and plasma urea concentration. At refeeding, ornithine α-ketoglutarate increased plasma glutamine concentration (p <.05 vs. the three other groups), and counteracted the increase in plasma phenylalanine concentration. In muscle, although the three α-ketoglutarate combinations induced similar increases in the glutamate pool, ornithine α-ketoglutarate induced the highest increase in glutamine (7.0 ± 0.3 vs. 5.4 ± 0.3 μmol/g in group 3, 6.3 ± 0.3 in group 4, and 4.6 ± 0.2 in group 1, p <.01 between group 2 and groups 3 or 1). Also, only ornithine α-ketoglutarate increased liver glutamine concentration. Finally, isomolar arginine α-ketoglutarate increased plasma urea concentration (+50% vs. the three other groups, p <.01). Conclusions: Our results demonstrate, for the first time, the following: a) the action of ornithine α-ketoglutarate as a glutamine precursor cannot solely be ascribed to α-ketoglutarate since arginine α-ketoglutarate combinations did not exhibit this effect to the same extent; and b) the action of ornithine α-ketoglutarate is not due to its nitrogen content since isonitrogenous arginine α-ketoglutarate did not reproduce the effects of ornithine α-ketoglutarate.
Mitsuhiro Furuse - One of the best experts on this subject based on the ideXlab platform.
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Oral administration of L-Ornithine increases the content of both collagen constituting amino acids and polyamines in mouse skin.
Biochemical and Biophysical Research Communications, 2019Co-Authors: Daiki Harada, Satsuki Nagamachi, Kazuki Ikeda, Yoshihiro Takahashi, Mitsuhiro FuruseAbstract:Abstract l -Ornithine is found in animals as a free amino acid and is a vital component of the urea cycle in the liver; it is reported to have various functions such as promoting wound healing, promoting growth hormone secretion, hypnotic effects, and so on. The present study aimed to investigate the effects of a single oral administration of l -ornithine on 1) the metabolism of amino acids in the liver and skin of mice and 2) the metabolism of polyamines in the skin of mice. To this end, ICR mice were separated into five groups; four groups were administered l -ornithine dissolved in fresh water (3.0 mmol/10 ml/kg) and a fifth group, the control, was not administered l -ornithine. The four groups comprised mice sampled at specific times (30, 60, 120 and 180 min) after oral administration of l -ornithine. We found that metabolism of l -ornithine to l -citrulline was rapid and that l -citrulline concentration remained high in mice sampled at later stages. Similarly, the concentrations of l -proline and glycine, both of which are important components of collagen, also rapidly increased in the skin following l -ornithine treatment. The concentrations of polyamines (putrescine, spermidine and spermine), which are known to increase the synthesis of certain proteins and enhance the epidermal barrier function, were also significantly increased in the skin. Our study shows that oral administration of l -ornithine significantly influences the chemical composition of the skin of mice through increases in both amino acids and polyamines after a short period of time.
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Effects of time of L-Ornithine administration on the diurnal rhythms of plasma growth hormone, melatonin, and corticosterone levels in mice
Chronobiology International, 2014Co-Authors: Haruka Matsuo, Mami Aoki, Mitsuhiro Furuse, Saori Akiduki, Yukihiro Hishida, Ayaka Iwamoto, Tsuyoshi Otsuka, Shinobu YasuoAbstract:The synthesis and secretion of many hormones such as growth hormone (GH), melatonin, and corticosterone, exhibit temporal variations over each day and night. Oral administration of several nutritional factors, including L-Ornithine, modulates these hormonal secretions and induces an acute increase in plasma GH levels. However, the impact of L-Ornithine on the diurnal rhythms of hormone secretion remains unclear. In this study, we evaluated whether the diurnal rhythms of plasma GH, melatonin, and corticosterone secretion were altered by the daily administration of L-Ornithine as well as the timing of the administration, in CBA/N mice. Our results showed that the plasma GH levels that peaked at light phase were amplified by L-Ornithine (500 mg/kg) administered at Zeitgeber time (ZT) 22, but not at ZT10. Additionally, L-Ornithine (1000 mg/kg) administered at ZT22 advanced the onset of the nocturnal rise of melatonin, which resulted in the elongation of the melatonin peak. On the other hand, L-Ornithine (500 ...
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Orally administered L-Ornithine reduces restraint stress-induced activation of the hypothalamic-pituitary-adrenal axis in mice.
Neuroscience Letters, 2011Co-Authors: Koji Kurata, Shozo Tomonaga, Mami Aoki, Koji Morishita, Mao Nagasawa, D. Michael Denbow, Saori Akiduki, Mitsuhiro FuruseAbstract:Abstract In a previous study, we confirmed that orally administered l -ornithine can be transported into the brain of mice. In addition, orally administered l -ornithine, within a limited dose range, had an anxiolytic-like effect in the elevated plus-maze test. However, the mechanism by which orally administered l -ornithine reduced the stress response in mice is still unclear. Experiment 1 determined whether orally administered l -ornithine could reduce the stress-induced activation of hypothalamic-pituitary-adrenal axis. Mice were orally administered l -ornithine (0, 0.75, 1.5 and 3 mmol/10 ml/kg, p.o.), and restrained for 30 min from 30 min post administration. There was a significant decrease in the corticosterone levels in the group receiving 0.75 mmol of l -ornithine compared to the control group. In Experiment 2, the effect of orally administered l -ornithine (0 and 0.75 mmol/10 ml/kg, p.o.) on endogenous monoamine release was investigated using in vivo microdialysis. Only the monoamines metabolites 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC) and homovallinic acids (HVA) were detected in the present study. Dialysate concentrations of 5-HIAA, DOPAC and HVA were not significantly changed immediately after administration of l -ornithine and restraint stress. In conclusion, changes of corticosterone concentrations by orally administered l -ornithine were not related to alterations in brain monoamine metabolisms.
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Orally administered L-Ornithine elevates brain L-Ornithine levels and has an anxiolytic-like effect in mice.
Nutritional Neuroscience, 2011Co-Authors: Koji Kurata, Shozo Tomonaga, Mami Aoki, Koji Morishita, Mao Nagasawa, D. Michael Denbow, Mitsuhiro FuruseAbstract:AbstractIntracerebroventricular injection of L-Ornithine has demonstrated sedative and hypnotic effects in neonatal chicks exposed to acute stressful conditions. However, whether orally administered L-Ornithine can reduce acute mental stress remains to be defined. To clarify the nutritional importance of L-Ornithine in controlling the stress response, in Experiment 1 we first investigated whether orally administered L-Ornithine can be transported into the brain of mice. Mice were orally administered L-Ornithine (3 mmol/water 10 ml/kg, per os). L-Ornithine levels were significantly elevated in the cerebral cortex and hippocampus at 30 and 60 minutes post-administration. In Experiment 2, the effect of orally administered L-Ornithine (0, 0.1875, 0.75 and 3 mmol/water 10 ml/kg, per os) on anxiety-like behavior in mice exposed to the elevated plus-maze test was examined at 30 minutes post-administration. There was a significant increase in the percentage of time spent and entries in the open arms in the group ...
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L-Ornithine attenuates corticotropin-releasing factor-induced stress responses acting at GABAA receptors in neonatal chicks.
Neuroscience, 2010Co-Authors: Koji Kurata, Kazutaka Shigemi, Shozo Tomonaga, Mami Aoki, Koji Morishita, D. M. Denbow, Mitsuhiro FuruseAbstract:Abstract I.c.v. injection of l -ornithine has been shown to have sedative and hypnotic effects on neonatal chicks exposed to acute stressful conditions. To clarify the mechanism, we conducted three experiments under strengthened stressful conditions with corticotropin-releasing factor (CRF). In Experiment 1, the effect of i.c.v. injection of CRF, l -ornithine (0.5 μmol) or CRF with l -ornithine on the stressful response of chicks was investigated. Compared with the vehicle control, CRF increased distress vocalizations and the time spent in active wakefulness. l -Ornithine increased the time spent in sleeping posture, even following stimulation with CRF. In Experiment 2, dose-dependent effects of l -ornithine were investigated using i.c.v. administration with vehicle, CRF alone or CRF plus l -ornithine (0.125, 0.25 or 0.5 μmol). l -Ornithine decreased the CRF-stimulated distress vocalizations in a dose-dependent manner. In Experiment 3, the chicks were injected i.c.v. with either CRF, CRF plus l -ornithine (0.5 μmol), CRF plus the γ-aminobutyric acid (GABA) A receptor antagonist picrotoxin or l -ornithine with picrotoxin. The sedative and hypnotic effects induced by l -ornithine were blocked with co-administration of picrotoxin. These results suggest that l -ornithine could attenuate CRF-stimulated stress behaviors acting at GABA A receptors.
V E Shih - One of the best experts on this subject based on the ideXlab platform.
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Long-term follow-up of four patients affected by HHH syndrome
Clin Chim Acta, 2012Co-Authors: S Z Kim, Robert Mandell, Can Ficicioglu, William L. Nyhan, W J Song, V E ShihAbstract: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.
