Ornithine metabolism in mammals

Ornithine is a free amino acid that is not incorporated into proteins. The amino acid is a member of the urea cycle (Fig. 1), which plays an important role in detoxification of NH₃ to produce urea. In the existence of two liver compartments, the urea cycle is expressed in the periportal hepatocytes (portal triad region) and the ornithine degradation pathway is expressed in the pericentral hepatocytes (central vein region) and many peripheral tissues that also express the glutamine synthase pathway. Ornithine is synthesised from arginine and metabolised by ornithine aminotransferase (OAT), ornithine decarboxylase and ornithine transcarbamylase. Mitochondrial ornithine carrier 1 or ornithine transporter 1, present in the inner mitochondrial membrane, is identified as a member of the mitochondrial carrier family of proteins by SLC25A15 gene and participates in importing the amino acid from the cytosol to the mitochondria⁽Reference Palmieri⁵⁾. Ornithine in the blood is derived from the cellular cytosol and diet and is excreted in the urine.

Fig. 1 Ornithine metabolic pathways and the urea cycle. This schema is based on the illustrations of Palmieri⁽Reference Palmieri⁵⁾ and Kaneko et al. ⁽Reference Kaneko, Ueda-Yamada and Ando⁸⁶⁾. The urea cycle and ornithine degradation pathway exist in different cell types. OAT, ornithine aminotransferase; OTC, ornithine transcarbamylase; ODC, ornithine decarboxylase; P5C, pyrroline-5-carboxylate; P5CDH, P5C dehydrogenase; P5CRD, P5C reductase; Proline OXD, proline oxidase; ORC1, isoform 1 of ornithine carrier; GAT, glycine amidinotransferase; GI, gastrointestinal.

Ornithine supplementation

In nutrition, internal medicine, gerontology and sports medicine, ornithine supplementation has been reported to be useful, particularly for NH₃ detoxification. Elam⁽Reference Elam⁸⁾ described that short-term exercise with a diet supplemented with arginine and ornithine reduced body mass and body fat in adult males. Elam et al. ⁽Reference Elam, Hardin and Sutton⁹⁾ orally administered arginine and ornithine to adult men who participated in a 5-week progressive strength-training programme and found that the supplements increased total strength and lean body mass. Bucci et al. ⁽Reference Bucci, Hickson and Pivarnik¹⁰⁾ administered l-ornithine (40, 100 and 170 mg/kg) to bodybuilders and found that the amino acid levels in the serum 45 min after ingestion increased to 330, 400 and 570 μmol/l, respectively; however, the amino acid elicited a predictable rise in serum levels of growth hormone that has anabolic effects on skeletal muscle protein, only at the highest dosage. Müting et al. ⁽Reference Müting, Kalk and Klein¹¹⁾ reported long-term (over 13 years) effectiveness of high-dose (9 g daily) ornithine-aspartate on the urea synthesis rate and portal hypertension in twenty-five patients with liver cirrhosis. Brocker et al. ⁽Reference Brocker, Vellas and Albarede¹²⁾ found that administration of ornithine oxoglutarate (10 g daily) for 2 months seemed to be a cost-effective nutritional supplement in ninety-two elderly, ambulatory, convalescent patients, compared with ninety-three patients treated with placebo and that there was a significant improvement in the quality of life in the ornithine oxoglutarate group. Debry & Poynard⁽Reference Debry and Poynard¹³⁾ administered ornithine α-ketoglutarate (10 g daily) for 60 d to 203 convalescent, malnourished elderly patients and placebo to 167 subjects and found a significant beneficial effect on weight, BMI and serum albumin gain in the ornithine α-ketoglutarate group compared with the placebo group. Gebhardt et al. ⁽Reference Gebhardt, Beckers and Gaunitz¹⁴⁾ reported that treatment of CCl₄-induced cirrhotic rats with l-ornithine-l-aspartate (2 g/kg daily) for 2 weeks improved urea production and lowered serum NH₃ levels; however, NH₃ detoxification was limited. De Bandt et al. ⁽Reference De Bandt, Coudray-Lucas and Lioret¹⁵⁾ found that enteral ornithine α-ketoglutarate (10, 20 or 30 g daily) administration for 21 d improved N balance, reduced α-methylhistidine and hydroxyproline urinary elimination, and improved wound healing in burn patients. Blonde-Cynober et al. ⁽Reference Blonde-Cynober, Aussel and Cynober¹⁶⁾ reported that ornithine α-ketoglutarate supplementation improved clinical outcomes in elderly patients with chronic malnutrition. Meneguello et al. ⁽Reference Meneguello, Mendonca and Lancha¹⁷⁾ reported that in trained rats that received arginine, ornithine and citrulline supplementation, the flux of substrate increased through the reaction catalysed by glutamine synthetase, leading to increased glutamine production after exhaustive exercise. Cynober⁽Reference Cynober¹⁸⁾ reported ornithine α-ketoglutarate as a potent precursor of arginine and NO (which is not shown with ornithine hydrochloride). Sugino et al. ⁽Reference Sugino, Shirai and Kajimoto²⁾ examined the effects of oral l-ornithine (2000 mg/d for 7 d and 6000 mg/d for 1 d) for 8 d on physical fatigue in seventeen healthy volunteers and found that administration promoted lipid metabolism, activated urea cycle, and improved fatigue and physical performance in women. The authors have also reported that changes in the blood NH₃ levels between the before physical exercise and recovery were not significant, but the change from post-exercise to post-recovery was lower in the l-ornithine group than in the placebo group, and the authors have recommended ornithine intake as a supplement. Shibasaki⁽Reference Shibasaki, Kadowaki, Torii and Takahashi¹⁾ reported that oral ornithine (2 g/kg) reduced the blood alcohol levels in mice pretreated with oral ethanol intake (4 g/kg) compared with controls and that ornithine has been used as a food or supplement in Japan since 2002.

These reports on the nutritional effects of ornithine supplementation did not mention the retinal risk of the amino acid.

Hyperornithinaemia–hyperammonaemia–homocitrullinuria syndrome

In 1969, Shih et al. ⁽Reference Shih, Efron and Moser³⁾ reported for the first time irritability and seizures in a child with ataxia, in whom intermittent hyperammonaemia (360–1850 μg/l; normal, < 600 μg/l) was associated with hyperornithinaemia and homocitrullinuria. The plasma ornithine levels rose intermittently to 915 μmol/l (9-fold higher than controls) in the patient on a meat-based diet and were 200–300 μmol/l (about 3-fold higher than controls) on a low-protein diet ( < 1·5 g protein/kg per d; Fig. 2). Thereafter, many authors⁽Reference Fell, Pollitt and Sampson^19–Reference Tessa, Fiermonte and Dionisi-Vici³¹⁾ have reported on patients with the HHH syndrome. Clinical symptoms, such as episodes of confusion, lethargy and coma resulting from hyperammonaemia, develop at any age⁽Reference Palmieri⁵⁾ but usually in early childhood. Neurological and muscular findings such as spastic paraparesis, seizures, cognitive impairment, pyramidal dysfunction and muscle atrophy also occur⁽Reference Fell, Pollitt and Sampson^19, Reference Shigeto, Yamada and Kobayashi^28, Reference Lemay, Lambert and Mitchell^29, Reference Salvi, Santorelli and Bertini³²⁾. Many authors⁽Reference Palmieri^5, Reference Fell, Pollitt and Sampson^19, Reference Kirsch and McInnes^21–Reference Zammarchi, Ciani and Pasquini³⁰⁾ have reported that plasma ornithine levels in the HHH syndrome were 5- to 10-fold higher than controls. Dionisi Vici et al. ⁽Reference Dionisi Vici, Bachmann and Gambarara²³⁾ reported low creatine excretion in the HHH syndrome. Shimizu et al. ⁽Reference Shimizu, Maekawa and Eto³³⁾ reported abnormal urinary excretion of polyamines in this syndrome.

Fig. 2 Ornithine levels in the blood of patients with the hyperornithinaemia–hyperammonaemia–homocitrullinuria syndrome (HHH syn) and gyrate atrophy of the choroid and retina (GA). Plasma or serum ornithine concentrations are shown. Values are means, ranges or averages, with standard deviations represented by vertical bars. The numbers in parentheses indicate numbers of subjects. This schema is based on the studies of Shih et al. ⁽Reference Shih, Efron and Moser³⁾, Takki & Simell⁽Reference Takki and Simell⁴⁶⁾, Hayasaka et al. ⁽Reference Hayasaka, Shiono and Mizuno⁵⁴⁾, Saito et al. ⁽Reference Saito, Omura and Hayasaka⁵⁰⁾ and Kaiser-Kupfer et al. ⁽Reference Kaiser-Kupfer, Caruso and Valle⁷⁶⁾. ○, Normal retina; ♦, very slow progression of retinal degeneration; ●, retinal degeneration; on diet, arginine-restricted diet.

The HHH syndrome is transmitted as an autosomal recessive mode of inheritance⁽Reference Palmieri⁵⁾. Molecular heterogeneity of ORC1 gene mutations has been reported in patients with the HHH syndrome among several populations including Canadians, Italians, Japanese, Mexicans and others⁽Reference Salvi, Santorelli and Bertini^32, Reference Camacho, Obie and Biery^34–Reference Camacho, Mardach and Rioseco-Camacho³⁶⁾. Ornithine carrier 1, which is deficient in the HHH syndrome, catalyses a highly active ornithine/citrulline exchange⁽Reference Palmieri^5, Reference Indiveri, Tonazzi and Palmieri^37–Reference Fiermonte, Dolce and David³⁹⁾. Ornithine carrier 1 deficiency induces accumulation of ornithine in the cytosol and citrulline and carbamyl phosphate within the mitochondria, resulting in a urea cycle disorder and NH₃ intoxication⁽Reference Palmieri⁵⁾. Intramitochondrial carbamyl phosphate accumulation leads to the formation of homocitrulline⁽Reference Palmieri⁵⁾ and orotate⁽Reference Burlina, Ferrari and Dionisi-Vici⁴⁰⁾. Amaral et al. ⁽Reference Amaral, Lerpnitz and Fernandes⁴¹⁾ reported that the major metabolites, ornithine and homocitrulline, accumulating in the HHH syndrome induce oxidative stress in the brain of young rats.

Shih et al. ⁽Reference Shih, Efron and Moser³⁾ showed that a low-protein diet reduced plasma NH₃ levels and prevented clinical symptoms. Dionisi Vici et al. ⁽Reference Dionisi Vici, Bachmann and Gambarara²³⁾ examined the effects of citrulline, arginine or ornithine supplementation and stated that citrulline supplementation combined with a protein-restricted diet appears to allow better metabolic control, avoiding secondary creatine deficiency. Fell et al. ⁽Reference Fell, Pollitt and Sampson¹⁹⁾, Kirsch & McInnes⁽Reference Kirsch and McInnes²¹⁾, Nakajima et al. ⁽Reference Nakajima, Ishii and Mito²⁵⁾ and Shigeto et al. ⁽Reference Shigeto, Yamada and Kobayashi²⁸⁾ reported that supplementary ornithine lowered plasma NH₃ levels, although Simell et al. ⁽Reference Simell, Mackenzie and Clow²⁰⁾ showed that ornithine loading was ineffective in alanine-induced hyperammonaemia in a patient with the HHH syndrome. Palmieri⁽Reference Palmieri⁵⁾ and Torisu⁽Reference Torisu⁶⁾ reported that a low-protein diet is usually accompanied by supplementation of citrulline and ornithine for treatment in the HHH syndrome.

Berson et al. ⁽Reference Berson, Schmidt and Rabin⁴²⁾ found that the child with the HHH syndrome, described previously by Shih et al. ⁽Reference Shih, Efron and Moser³⁾, had normal-appearing ocular fundi and normal electroretinographic (ERG) responses, and stated that high levels of ornithine alone do not necessarily cause retinal degeneration. Lemay et al. ⁽Reference Lemay, Lambert and Mitchell²⁹⁾ also reported normal results of clinical retinal testing in all six patients with the HHH syndrome. In 2009, Morini et al. ⁽Reference Morini, Capozzi and Boenzi⁴³⁾ reported on retinal degeneration in a patient with the HHH syndrome. The characteristics of the HHH syndrome are summarised in Table 1.

Table 1 Comparison of the hyperornithinaemia–hyperammonaemia–homocitrullinuria (HHH) syndrome and gyrate atrophy of the choroid and retina (GA)

ORC1, ornithine carrier 1; OAT, ornithine aminotransferase; Arg/Cit/Orn, arginine, citrulline, ornithine.

Gyrate atrophy of the choroid and retina

In 1973, Simell & Takki⁽Reference Simell and Takki⁴⁾ first reported highly increased plasma ornithine concentrations in patients with GA in Finland. Thereafter, many authors have confirmed long-term hyperornithinaemia in patients with GA including Japanese subjects with GA⁽Reference Takki^44–Reference Kondo, Yamamoto and Imai⁵⁷⁾. Despite constant hyperornithinaemia from birth, retinal lesions developed in children in early childhood (2–3 years of age). A boy with hyperornithinaemia had normal ocular fundi at 2 years of age, yellow spots at the peripheral fundi at 4 years of age and subnormal ERG responses (reduced a- and b-waves) at 5 years of age⁽Reference Hayasaka, Saito and Nakajima⁴⁹⁾. Some patients with GA complained of visual disturbances or night blindness in childhood. The visual acuities decreased to 0·2 or worse in the second or third decade of life⁽Reference Hayasaka, Shiono and Mizuno⁵⁴⁾. Myopia developed late in the first decade⁽Reference Takki^44, Reference Hayasaka, Shiono and Mizuno⁵⁴⁾. Tunnel vision occurred at age 20 years⁽Reference Hayasaka, Shiono and Mizuno⁵⁴⁾. Chorioretinal atrophy with a scalloped border resembling gyrus enlarged and approached the posterior pole with age⁽Reference Takki⁴⁴⁾. The primary site of the degeneration in GA was thought to be at the level of the RPE–choriocapillaris, because of the pathological findings on electro-oculography and fluorescein angiography⁽Reference Takki⁴⁴⁾. Cataract⁽Reference Kaiser-Kupfer, Kuwabara and Uga⁵¹⁾, lens dislocation⁽Reference Akiya, Osawa and Ogata⁴⁷⁾, short and scanty ciliary processes⁽Reference Hayasaka, Saito and Nakajima⁴⁹⁾, recurrent vitreous haemorrhage⁽Reference Takahashi, Hayasaka and Kiyosawa⁵³⁾, skeletal muscle atrophy⁽Reference Heinanen, Nanto-Salonen and Komu^58, Reference Heinanen, Nanto-Salonen and Komu⁵⁹⁾ and minor abnormality in the brain⁽Reference Nanto-Salonen, Komu and Lundbom⁶⁰⁾ also were found in patients with GA. Plasma or serum ornithine levels in normal controls were 65 (sd 30) μmol/l (range 30–100 μmol/l), despite differences in age, sex and standard diet (Fig. 2)⁽Reference Saito, Omura and Hayasaka⁵⁰⁾. Those in relatives of patients with GA were 120 (range 65–180) μmol/l⁽Reference Saito, Omura and Hayasaka⁵⁰⁾. Those in patients with GA were 600–1300 μmol/l (10- to 20-fold higher than controls)⁽Reference Hayasaka, Saito and Nakajima⁵²⁾. Takki & Simell⁽Reference Takki and Simell⁴⁶⁾ reported that the mean ornithine levels in the plasma, aqueous humour, and cerebrospinal fluid in normal controls were 54·3, 46·1 and 8·1 μmol/l, respectively, and those in patients with GA were 1015, 897 and 288 μmol/l, respectively. The data indicated that ornithine passes easily through the blood–aqueous barrier, one of blood–ocular barriers. Plasma NH₃ levels were within the normal range in patients with GA⁽Reference Berson, Schmidt and Rabin⁴²⁾.

GA is transmitted as an autosomal recessive mode of inheritance⁽Reference Takki and Simell⁴⁵⁾. Deficient activity of OAT, a pyridoxal phosphate-dependent mitochondrial matrix enzyme, was found in patients with GA⁽Reference Sengers, Trijbels and Brussaart^61–Reference Kaiser-Kupfer, Valle and Del Valle⁶³⁾. Molecular heterogeneity OAT gene mutations have been reported in patients with GA⁽Reference Ramesh, McClatchey and Ramesh^64–Reference Peltola, Nanto-Salonen and Heinonen⁷²⁾. High distribution in various ethnic groups was identified in Finland, Japan, England, Lebanon, India, Israel, Portugal and others⁽Reference Brody, Mitchell and Obie⁶⁸⁾. According to the gene mutation, the population is classified into three groups: normal controls (OAT ^+/+), relatives of patients with GA (heterozygotes, OAT ^+/ − ) and patients with GA (homozygotes, OAT ^− / − ). Patients with GA are further subdivided into two types: vitamin B₆-responsive and -unresponsive. Serum ornithine levels in vitamin B₆-responsive patients with GA decreased to 280 μmol/l after oral administration of pyridoxine⁽Reference Hayasaka, Saito and Nakajima⁵²⁾.

In vivo and in vitro experiments of ornithine-induced retinal pigment epithelial lesions

Kuwabara et al. ⁽Reference Kuwabara, Ishikawa and Kaiser-Kupfer⁷⁾ reported that intravitreal injection of l-ornithine (1 m, 0·01 ml for rats; 1 m, 0·1 ml for 2 kg monkeys) caused marked oedema in the RPE of Sprague–Dawley strain albino and Evans black-hooded rats and cynomologus monkeys. The authors have also reported that RPE cells gradually degenerated, resulting in patches of denuded areas, and the photoreceptor cells overlying the damaged RPE degenerated secondarily. Ishikawa et al. ⁽Reference Ishikawa, Kuwabara and Kaiser-Kupfer⁷⁷⁾ reported that intravitreal injection of 10 μl of 1 m-l-ornithine was toxic specifically to the RPE of adult Sprague–Dawley and Evans black-hooded rats and caused chorioretinal degeneration secondarily. They have also reported that d-ornithine induced degeneration of the outer retinal layer and that N-acetyl-l-ornithine, l-arginine, l-citrulline and α-methylornithine seemed non-toxic to the retina. Takeuchi et al. ⁽Reference Takeuchi, Itagaki and Takahashi⁷⁸⁾ showed that intravitreal injection of 0·03 ml of 0·5 m l-ornithine induced severe RPE damage mainly in the equatorial region of the ocular fundus in monkeys. The authors have reported early ultrastructural changes in the RPE after l-ornithine injection. Hiroi et al. ⁽Reference Hiroi, Yamamoto and Honda⁷⁹⁾ showed that intravitreal (0·2–0·5 m; 15 μl) or intravenous (0·2 m; 10 ml) injection of l-ornithine in cats diminished the ERG c-wave and suggested that l-ornithine affects RPE and Müller cells directly. These in vivo experiments showed that intravitreal injection of l-ornithine induces RPE lesions in rats, monkey and cats.

Wang et al. ⁽Reference Wang, Milam and Steel⁸⁰⁾ produced an OAT-deficient mouse by gene targeting and found that the RPE cells were the site of the earliest pathological changes. Wang et al. ⁽Reference Wang, Steel and Milam⁸¹⁾ examined an arginine-restricted diet to maintain the long-term reduction of plasma ornithine in a mouse model of OAT-deficiency (Oat ^− / − ) produced by gene targeting. They observed that Oat ^− / −  mice on a standard diet had an increased plasma ornithine level (1300 μmol/l), reduced ERG amplitude and severe retinal degeneration, whereas Oat ^− / −  mice on an arginine-restricted diet had a decreased ornithine level (100–200 μmol/l), preserved ERG amplitudes and no retinal degeneration.

Ueda et al. ⁽Reference Ueda, Masu and Ando⁸²⁾ reported that when the human cultured RPE cells were treated with 0·5 mm-5-fluoromethylornithine (a specific inhibitor of OAT) for 30 min, ornithine exhibited time- and dose-dependent inhibition of DNA synthesis of the cells and ultimately cell death (ornithine cytotoxicity). They further stated that ornithine cytotoxicity of the RPE cells was prevented by proline, and that ornithine cytotoxicity was not found in the human HepG2 hepatoma cells or WI-38 fibroblast cells. Ando et al. ⁽Reference Ando, Ueda and Uyama⁸³⁾ reported that primary cultured RPE cells prepared from bovine eyes showed two phenotypes, epithelioid and fusiform, and that the epithelioid-type cells were damaged severely by 10 mm-ornithine and 0·5 mm-5-fluoromethyl ornithine. Nakauchi et al. ⁽Reference Nakauchi, Ando and Ueda-Yamada⁸⁴⁾ reported that ornithine cytotoxicity was prevented by non-polar side-chain amino acids in the human cultured RPE cells. Kaneko et al. ⁽Reference Kaneko, Ando and Okuda-Ashitaka⁸⁵⁾ suggested that ornithine transport via cationic amino acid transporter-1 may play a crucial role in ornithine cytotoxicity in human telomerase reverse transcriptase-RPE cells. Kaneko et al. ⁽Reference Kaneko, Ueda-Yamada and Ando⁸⁶⁾ showed that ornithine, arginine, glutamate, proline, creatine, glycine and putrescine did not affect the viability and proliferative activities of bovine cultured RPE cells, whereas 10 mm-spermidine and 10 mm-spermine (metabolites of ornithine via ornithine decarboxylase) inhibited [³H]thymidine incorporation by 13 and 89 %, respectively, and spermine induced apoptotic RPE cell death in a dose-dependent manner. These in vitro studies of cultured RPE cells may clarify the mechanism of RPE degeneration induced by ornithine or its metabolites.

Ornithine metabolism in the eye

Hayasaka et al. ⁽Reference Hayasaka, Shiono and Takaku⁸⁷⁾ showed that the RPE, ciliary body, iris and neuroretina in bovine eyes demonstrated high specific activity of OAT. Shiono et al. ⁽Reference Shiono, Hayasaka and Mizuno⁸⁸⁾ found that the choroid, retina, ciliary body and iris had high OAT enzyme activity in human ocular tissues. Takahashi et al. ⁽Reference Takahashi, Ishiguro and Mito⁸⁹⁾ observed immunohistochemical localisation of OAT in the epithelia of ciliary body, iris and lens and in the RPE in rat eyes. The investigators have also found only a small immunoreactive product in the choroid. Among bovine ocular tissues, arginase activity was high in the retina and uvea; pyrroline-5-carboxylate reductase activity was high in the lens, cornea and retina; pyrroline-5-carboxylate dehydrogenase activity was high in the uvea but low in the retina; and proline oxidase activity was negligible in all ocular tissues⁽Reference Hayasaka, Matsuzawa and Shiono⁹⁰⁾. Koshiyama et al. ⁽Reference Koshiyama, Gotoh and Miyanaka⁹¹⁾ reported that mRNA for ornithine transcarbamylase analysed by RT-PCR was not detected in the rat ocular tissues and that arginase II (non-hepatic-type) mRNA was detected in the retina and weakly in the cornea, whereas arginase I (hepatic-type) mRNA was not detected in rat eyes. Thus, the exact ornithine metabolism in the eye, particularly in the RPE, is unknown.

Blood ornithine levels after oral administration

Bucci et al. ⁽Reference Bucci, Hickson and Pivarnik¹⁰⁾ administered l-ornithine (40, 100 and 170 mg/kg) to bodybuilders. The serum ornithine levels 45 min after ingestion increased to 300, 400 and 570 μmol/l, respectively. Shih et al. ⁽Reference Shih, Efron and Moser³⁾ studied the effects of acute and chronic ornithine loading. A patient with the HHH syndrome, the parents and controls received l-ornithine (100 mg/kg) orally. Plasma ornithine levels in controls 2 h after loading were 200–700 μmol/l, and those in the patient increased from 350 to 1100 μmol/l (Fig. 2). The changes in the parents were within the level of the normal controls. The patient received ornithine (1 g daily) for 1 week. The plasma ornithine level in the child increased from 348 to 502 μmol/l, which apparently did not affect the clinical condition. Fell et al. ⁽Reference Fell, Pollitt and Sampson¹⁹⁾ reported that adding lysine (6 g daily) and ornithine (6 g daily) for 10 d to the basic diet increased the plasma ornithine level from 630 to 1100 μmol/l in a patient with the HHH syndrome. Koike et al. ⁽Reference Koike, Fujimori and Yuasa²²⁾ showed that the serum ornithine level increased to 1120 μmol/l after administration of ornithine (100 mg/kg) in a patient with the HHH syndrome. Dionisi Vici et al. ⁽Reference Dionisi Vici, Bachmann and Gambarara²³⁾ showed that peroral treatment with ornithine (2 mmol/kg per d) for 2 weeks increased the plasma ornithine level from 504 to 837 μmol/l in a patient with the HHH syndrome and from 419 to 496 μmol/l in another patient. Nakajima et al. ⁽Reference Nakajima, Ishii and Mito²⁵⁾ reported that after oral administration of ornithine (200 mg/kg), a patient with the HHH syndrome had a markedly high serum ornithine level, and the parents had normal ornithine loading test results.

Takki & Simell⁽Reference Takki and Simell⁴⁵⁾ reported that plasma ornithine concentrations in controls, parents of patients with GA and patients with GA 60 min after oral loading of the amino acid (100 mg/kg) were 300–400, 800 and 1700–1900 μmol/l, respectively (Fig. 2). Saito et al. ⁽Reference Saito, Omura and Hayasaka⁵⁰⁾ showed that serum ornithine levels in controls, relatives of patients with GA and patients with GA 1 h after oral loading of the amino acid (100 mg/kg) were 300, 525 and 1200 μmol/l, respectively (Fig. 2). Their ERG responses before and after oral loading were unchanged, suggesting that transient ornithine increases are not associated with retinal changes. These data indicated that the blood concentration of ornithine in normal controls increased after oral administration of the amino acid and that the blood levels after oral loading of ornithine in relatives of patients with GA, patients with GA and patients with the HHH syndrome were higher than in controls.

Conclusion

Short-term, low-dose or transient high-dose ornithine intake is safe for the retina. Its nutritional usefulness and efficacy of NH₃ detoxification are supported by many researchers, but the effects may be somewhat limited. Long-term, high-dose ornithine intake may be risky for the retina.