1607211
Enzyme 1990;43:160-168
© 1990 S. Karger AG, Basel 0013-9432/90/0433-0160S2.75/0
Ornithine Transcarbamylase Deficiency in Male Adolescence and Adulthood M. Yoshinoa,./. NishiyorF, F. Yamashitaa, R. Kumashiroh, H. Abeh, K. Tanikawab, T. Ohnoc, K. Nakaoc, N. Kakuc, H. Fukushimad, K. Kubotae a Department of Pediatrics and Child Health, b Second Department of Internal Medicine, c Critical Care Center, Kurume University School of Medicine, Kurume; Departments of d Internal Medicine and e Pediatrics, Higashi-Saga Hospital, Nakabaru, Saga, Japan
Key Words. Hyperammonemia • Ornithine transcarbamylase deficiency • Adolescence and adulthood, male Abstract. A discrete deficiency of hepatic ornithine transcarbamylase (OTC) was found in male patients who were 58, 46 and 17 years old. Each had developed hyperammonemic coma. The mother and a sister of the 17-year-old patient exhibited orotic aciduria either spontaneously or after protein loading, thus demonstrating heterozygosity. A sister of one other patient and a daughter of the third patient showed a smaller orotic aciduria after protein loading. These observations indicate that inherited deficiency of OTC should be included in the differential diagnosis of hyperammonemic states in adult male patients. riod, and the initial episode is usually fa tal [2], A few male patients with enzyme variants survive neonatal period and early infancy and develop clinical signs of hyperammon emia in late infancy or childhood [3-21], In none of these patients was the onset of symp toms delayed until late childhood. In this report, we present 3 male patients with OTC deficiency whose disease became manifest in late adolescence or in adulthood. Nevertheless, they eventually succumbed to the disease. These observations indicate that inherited OTC deficiency should be in cluded in the catalogue of the etiology of hyperammonemic states in male adults. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 8:17:43 AM
Ornithine transcarbamylase (OTC, EC 2.1.3.3) is an essential enzyme of ureagenesis. Inherited deficiency of this enzyme (McKusick 31125) is transmitted in an Xlinked dominant manner [1], Heterozygous females may be asymptomatic or symptom atic, and may have hyperammonemia of varying severity depending on one hand upon the levels of residual activity of the enzyme due to lyonization and on the other hand on the endogenous and exoge nous nitrogen load to the urea cycle. In contrast, hemizygous male patients usually exhibit markedly reduced levels of OTC ac tivity and virtually always present with a hyperammonemic crisis in the neonatal pe
Ornithine Transcarbamylase Deficiency in Male Adulthood
Patient 1 K.Ni., a 58-year-old male, was admitted because of coma and clonic convulsion. He had had no his tory of hepatic or neurological disease. He had been well until 56 years of age, when he began to have epi sodes of intermittent nausea and malaise. Seven days before admission, his family noticed that his speech and behavior were abnormal, and he developed uri nary incontinence 2 days later. One day before ad mission, his consciousness became depressed sud denly. A convulsion occurred the next day, and he was admitted. The maximum plasma concentration of ammonia was 4,322 pg/dl on the second day of hospitalization. Orotic acid concentration in urine obtained on the same day was markedly elevated (663 mmol/mol cre atinine, the normal fasting maximum is 1.5 mmol/ mol creatinine). Serum transaminase levels were nor mal (aspartate aminotransferase: 11.2 IU/1, alanine aminotransferase: 16.4 IU/1), and bilirubin (1.5 mg/ dl) was only slightly elevated on the first hospital day. The patient died on the fourth hospital day. Hepatic histology revealed moderate fatty metamorphosis and minimal hepatocellular necrosis. Family history revealed that his brother (fig. 1, Ni-II-4) had died at the age of 48 years with a similar clinical presentation. A grandson (Ni-IV-3) of this sib ling developed a hyperammonemic coma associated with orotic aciduria at the age of 6 years [Dr. T. Kuno, pers. commun.].
Patient 2 This 46-year-old man, T.Ok., was admitted be cause of a depressed level of consciousness. Two days before admission, he developed general malaise and anorexia: he exhibited abnormal behavior and speech, as well as nausea and vomiting. He had been found to have abnormal liver function tests on a rou tine health examination ‘several years ago1. His level of consciousness depressed progressively and he died on the second hospital day. Blood concentrations of ammonia, determined on the first and second hospital days, were 305 and 1,322 pg/dl, respectively. Concentrations of urinary orotic acid, determined twice on the second hospital day, were 497 and 634 mmol/mol creatinine, respec tively. There were minimal increases in serum aspar tate aminotransferase (19.6 IU/1) and alanine amino
transferase (27.6 IU/1), markedly elevated alkaline phosphatase (132 KA units), slightly elevated total bilirubin (1.2 mg/dl), and a normal blood urea nitro gen value of 15 mg/dl. One of his maternal uncles (fig. 2, Ok-I-9) had died at the age of 51 years from ‘fulminant hepatitis’, and his mother (Ok-I-5) died of a hepatoma at the age of 68 years.
Patient 3 A 17-year-old boy, K.In., was admitted because of a depressed level of consciousness. He had com plained of fatigue and had had several episodes of nausea and vomiting after he came home from a ski tour. Six days after the emergence of these signs, he became combative and drowsy and began to scream. He was hospitalized the next day as the level of con sciousness was further depressed and convulsions oc curred. He died on the second hospital day. A maximum plasma concentration of ammonia was 4,300 pg/dl, and the value of orotic acid in urine determined on the first hospital day was 677 mmol/ mol creatinine. Aspartate aminotransferase (25.2 IU/1) alanine aminotransferase (72.0 IU/1), and bilirubin (1.5 mg/dl) in the serum were moderately to mini mally elevated on the same day. Family history revealed that the patient’s younger sister (fig. 3, In-III-4) had had 2 episodes of nausea and vomiting each of which lasted for 1 week at the age of 13 years. His mother’s previous 2 pregnancies resulted in a miscarriage of undetermined etiology, and a hydatid-form mole. The mother had no signs suggestive of hyperammonemia.
Materials and Methods Liver tissues, obtained by autopsy from the 3 patients and control adults without known liver dis ease were isolated within 6-12 h after death, and the tissues were immediately frozen on dry ice and stored at -80 °C until they were analyzed.
Biochemical Analyses Liver tissue was homogenized in 10 volumes of a solution containing 20 mmol/1 potassium-HEPES buffer, 0.5 g/dl Triton X-100, 20g/dl glycerol, and 1 mmol/1 dithiothreitol, at pH 7.4 [22]. The homoge-
Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 8:17:43 AM
Case Reports
161
Yoshino/Nishiyori/Y amashita/Kumashiro/Abe/Tanikawa/Ohno/N akao/Kaku/Fukushima/Kubota
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Il Spontaneous hyperammonemia and orotic aciduria ® Orotic aciduria after protein load
m
® after No hyperammonemia or orotic aciduria protein load
Fig. 1. Pedigree of Ni family. An elder brother of the proband (Ni-II-4) died with clinical manifestations similar to those of the proband at the age of 48 years. A grandson (Ni-IV-3) of this patient (Ni-II-4) developed a hyperammonemic crisis at the age of 6 years.
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assay. The OTC enzyme protein was analyzed by an immunoblotting technique. Proteins were separated by polyacrylamide gel electrophoresis, with concen trations of 10% for acrylamide and 0.1 % for sodium dodesylsulphate [24], and they were transferred to a nitrocellulose sheet electrophoretically [25]. OTC en zyme protein on the sheet was detected using an anti-
OÓÒ if-r-O
5
2
nate was centrifuged at 10,000 g for 10 min, and supernatant fluid was used for enzyme assays and for analyses by immunoblotting. Activities of hepatic carbamylphosphate synthe tase I (CPS-1) and OTC were measured by colorimet ric assays as previously described [23], with a few modifications. OTC activity was determined at 2 dif ferent pH levels. The incubation mixture consisted of 50 mmol/1 diethanolamine acetate buffer at pH 8.5, or 50 mmol/1 potassium phosphate buffer at pH 7.0, and 50 mmol/1 T-ornithine, preadjusted to either pH 8.5 or pH 7.0, 50 mmol/1 carbamylphosphate lithium, water and 5 pi of supernatant in a final vol ume of 200 pi. Incubation was at 37 °C for 15 min, and the reaction was terminated by the addition of 1.0 ml of 0.5 mol/1 perchloric acid. A zero time blank, containing supernatant, was run with each
H Spontaneous hyperammonemia and orotic aciduria ® Orotic aciduria after protein load □3 ® No hyperammonemia or orotic aciduria after protein load
Fig. 2. Pedigree of Ok family. A maternal uncle (Ok-I-9) of the proband died of what was reported to be ‘fulminant hepatitis’ at the age of 51 years.
dfó ò è-T-o ó à 12
3
4
5
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6
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Cl Spontaneous hyperammonemia and orotic aciduria ® Orotic aciduria after protein load ® Hyperammonemia and orotic aciduria after protein load
Fig. 3. Pedigree of In family. The sister (In-IIl-4) of the proband has had 2 episodes suggestive of hyperammonemia at the age of 13 years. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 8:17:43 AM
162
Ornithine Transcarbamylase Deficiency in Male Adulthood
bovine liver OTC antibody as the first antibody, and goat antirabbit IgG conjugated with horse radish per oxidase as the second antibody. Bovine liver OTC [26], mouse liver OTC, and antibovine OTC antibody raised in rabbit [27] were purified as described, kindly supplied by Prof. M. Mori (Kumamoto University). Protein was determined with bovine serum albu min fraction V as standard [28].
Protein Loading Tests A meal containing 1 g natural food protein/kg body weight was given after overnight fasting to family members of the patients, and to 6 healthy adults. Plasma ammonia concentrations were deter mined before, and 1,2, 3, 4 and 6h after the ingestion of the meal. Urine samples were collected before the meal and in each time period between blood sam pling, up to 6 h after the ingestion of the meal. Ammonia was determined in plasma by an enzy matic method compled with glutamate dehydroge nase [29], with a few modifications. Orotic acid in urine was qantitated according to Adachi et al. [30], as modified by Goldstein et al. [31]. Values of the plasma ammonia or orotic acid con centrations in urine more than 2 SD above the respec tive control mean were regarded as elevated. The upper normal limits of plasma aspartate ami notransferase and alanine aminotransferase are 16.0 IU/1 and 14.0 IU/1, respectively.
163
in patient 3, the 37-kD bands which were weak, but obviously more intense than those in patients 1 and 2, were found. Protein Loading Tests in the Family Members Ni Pedigree. Among the family members of patient 1, 1 male, 3 female siblings, and 2 sons of the proband were available for the study (fig. 1). The younger sister (Ni-II-11) of the proband, a 56-year-old women, exhib ited a moderate increase in orotic acid excre tion (6.65 mmol/mol creatinine) in the 4th6th h of the test (table 2). All of the other individuals tested had responses to the protein load that could not be differentiated from controls either in lev els of plasma ammonia or orotic acid excre tion. Ok Pedigree. In the family of patient 2, the daughter of the proband (Ok-III-4), a 10year-old girl, showed moderately increased levels of orotic acid in all the time periods after loading (table 2). The elder sister and the son of the proband tolerated the protein load normally.
Results
Analysis of OTC by Immunoblotting In patients 1 and 2, very faint 37 kD bands, consistent with that of human mature OTC protein, were detected (fig. 4), whereas
Table 1. Activities of CPS-I and OTC of the liver Enzyme
Enzyme activities pmol-h-1 - mg protein-1 control (n = 6)
CPS-I OTC, pH 7.0 OTC, pH 8.5 Activity ratio (pH 8.5/pH 7.0)
1.32 ± 0.34 13.4 ± 3.9 22.1 ±5.2
1.66 ± 0.11
patient 1
2
3
1.92 0.28 0.28 1.00
1.58 0.32 0.57 1.77
1.69 0.83 1.21 1.46
Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 8:17:43 AM
Activities of CPS-I and OTC Activities of CPS-I of the patients 1, 2, and 3 were 145, 120 and 128 % of the control mean value, respectively (table 1.). Activities of OTC were
Enzyme 1990;43:160-168
© 1990 S. Karger AG, Basel 0013-9432/90/0433-0160S2.75/0
Ornithine Transcarbamylase Deficiency in Male Adolescence and Adulthood M. Yoshinoa,./. NishiyorF, F. Yamashitaa, R. Kumashiroh, H. Abeh, K. Tanikawab, T. Ohnoc, K. Nakaoc, N. Kakuc, H. Fukushimad, K. Kubotae a Department of Pediatrics and Child Health, b Second Department of Internal Medicine, c Critical Care Center, Kurume University School of Medicine, Kurume; Departments of d Internal Medicine and e Pediatrics, Higashi-Saga Hospital, Nakabaru, Saga, Japan
Key Words. Hyperammonemia • Ornithine transcarbamylase deficiency • Adolescence and adulthood, male Abstract. A discrete deficiency of hepatic ornithine transcarbamylase (OTC) was found in male patients who were 58, 46 and 17 years old. Each had developed hyperammonemic coma. The mother and a sister of the 17-year-old patient exhibited orotic aciduria either spontaneously or after protein loading, thus demonstrating heterozygosity. A sister of one other patient and a daughter of the third patient showed a smaller orotic aciduria after protein loading. These observations indicate that inherited deficiency of OTC should be included in the differential diagnosis of hyperammonemic states in adult male patients. riod, and the initial episode is usually fa tal [2], A few male patients with enzyme variants survive neonatal period and early infancy and develop clinical signs of hyperammon emia in late infancy or childhood [3-21], In none of these patients was the onset of symp toms delayed until late childhood. In this report, we present 3 male patients with OTC deficiency whose disease became manifest in late adolescence or in adulthood. Nevertheless, they eventually succumbed to the disease. These observations indicate that inherited OTC deficiency should be in cluded in the catalogue of the etiology of hyperammonemic states in male adults. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 8:17:43 AM
Ornithine transcarbamylase (OTC, EC 2.1.3.3) is an essential enzyme of ureagenesis. Inherited deficiency of this enzyme (McKusick 31125) is transmitted in an Xlinked dominant manner [1], Heterozygous females may be asymptomatic or symptom atic, and may have hyperammonemia of varying severity depending on one hand upon the levels of residual activity of the enzyme due to lyonization and on the other hand on the endogenous and exoge nous nitrogen load to the urea cycle. In contrast, hemizygous male patients usually exhibit markedly reduced levels of OTC ac tivity and virtually always present with a hyperammonemic crisis in the neonatal pe
Ornithine Transcarbamylase Deficiency in Male Adulthood
Patient 1 K.Ni., a 58-year-old male, was admitted because of coma and clonic convulsion. He had had no his tory of hepatic or neurological disease. He had been well until 56 years of age, when he began to have epi sodes of intermittent nausea and malaise. Seven days before admission, his family noticed that his speech and behavior were abnormal, and he developed uri nary incontinence 2 days later. One day before ad mission, his consciousness became depressed sud denly. A convulsion occurred the next day, and he was admitted. The maximum plasma concentration of ammonia was 4,322 pg/dl on the second day of hospitalization. Orotic acid concentration in urine obtained on the same day was markedly elevated (663 mmol/mol cre atinine, the normal fasting maximum is 1.5 mmol/ mol creatinine). Serum transaminase levels were nor mal (aspartate aminotransferase: 11.2 IU/1, alanine aminotransferase: 16.4 IU/1), and bilirubin (1.5 mg/ dl) was only slightly elevated on the first hospital day. The patient died on the fourth hospital day. Hepatic histology revealed moderate fatty metamorphosis and minimal hepatocellular necrosis. Family history revealed that his brother (fig. 1, Ni-II-4) had died at the age of 48 years with a similar clinical presentation. A grandson (Ni-IV-3) of this sib ling developed a hyperammonemic coma associated with orotic aciduria at the age of 6 years [Dr. T. Kuno, pers. commun.].
Patient 2 This 46-year-old man, T.Ok., was admitted be cause of a depressed level of consciousness. Two days before admission, he developed general malaise and anorexia: he exhibited abnormal behavior and speech, as well as nausea and vomiting. He had been found to have abnormal liver function tests on a rou tine health examination ‘several years ago1. His level of consciousness depressed progressively and he died on the second hospital day. Blood concentrations of ammonia, determined on the first and second hospital days, were 305 and 1,322 pg/dl, respectively. Concentrations of urinary orotic acid, determined twice on the second hospital day, were 497 and 634 mmol/mol creatinine, respec tively. There were minimal increases in serum aspar tate aminotransferase (19.6 IU/1) and alanine amino
transferase (27.6 IU/1), markedly elevated alkaline phosphatase (132 KA units), slightly elevated total bilirubin (1.2 mg/dl), and a normal blood urea nitro gen value of 15 mg/dl. One of his maternal uncles (fig. 2, Ok-I-9) had died at the age of 51 years from ‘fulminant hepatitis’, and his mother (Ok-I-5) died of a hepatoma at the age of 68 years.
Patient 3 A 17-year-old boy, K.In., was admitted because of a depressed level of consciousness. He had com plained of fatigue and had had several episodes of nausea and vomiting after he came home from a ski tour. Six days after the emergence of these signs, he became combative and drowsy and began to scream. He was hospitalized the next day as the level of con sciousness was further depressed and convulsions oc curred. He died on the second hospital day. A maximum plasma concentration of ammonia was 4,300 pg/dl, and the value of orotic acid in urine determined on the first hospital day was 677 mmol/ mol creatinine. Aspartate aminotransferase (25.2 IU/1) alanine aminotransferase (72.0 IU/1), and bilirubin (1.5 mg/dl) in the serum were moderately to mini mally elevated on the same day. Family history revealed that the patient’s younger sister (fig. 3, In-III-4) had had 2 episodes of nausea and vomiting each of which lasted for 1 week at the age of 13 years. His mother’s previous 2 pregnancies resulted in a miscarriage of undetermined etiology, and a hydatid-form mole. The mother had no signs suggestive of hyperammonemia.
Materials and Methods Liver tissues, obtained by autopsy from the 3 patients and control adults without known liver dis ease were isolated within 6-12 h after death, and the tissues were immediately frozen on dry ice and stored at -80 °C until they were analyzed.
Biochemical Analyses Liver tissue was homogenized in 10 volumes of a solution containing 20 mmol/1 potassium-HEPES buffer, 0.5 g/dl Triton X-100, 20g/dl glycerol, and 1 mmol/1 dithiothreitol, at pH 7.4 [22]. The homoge-
Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 8:17:43 AM
Case Reports
161
Yoshino/Nishiyori/Y amashita/Kumashiro/Abe/Tanikawa/Ohno/N akao/Kaku/Fukushima/Kubota
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Il Spontaneous hyperammonemia and orotic aciduria ® Orotic aciduria after protein load
m
® after No hyperammonemia or orotic aciduria protein load
Fig. 1. Pedigree of Ni family. An elder brother of the proband (Ni-II-4) died with clinical manifestations similar to those of the proband at the age of 48 years. A grandson (Ni-IV-3) of this patient (Ni-II-4) developed a hyperammonemic crisis at the age of 6 years.
I
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2
3
4
6
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4
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assay. The OTC enzyme protein was analyzed by an immunoblotting technique. Proteins were separated by polyacrylamide gel electrophoresis, with concen trations of 10% for acrylamide and 0.1 % for sodium dodesylsulphate [24], and they were transferred to a nitrocellulose sheet electrophoretically [25]. OTC en zyme protein on the sheet was detected using an anti-
OÓÒ if-r-O
5
2
nate was centrifuged at 10,000 g for 10 min, and supernatant fluid was used for enzyme assays and for analyses by immunoblotting. Activities of hepatic carbamylphosphate synthe tase I (CPS-1) and OTC were measured by colorimet ric assays as previously described [23], with a few modifications. OTC activity was determined at 2 dif ferent pH levels. The incubation mixture consisted of 50 mmol/1 diethanolamine acetate buffer at pH 8.5, or 50 mmol/1 potassium phosphate buffer at pH 7.0, and 50 mmol/1 T-ornithine, preadjusted to either pH 8.5 or pH 7.0, 50 mmol/1 carbamylphosphate lithium, water and 5 pi of supernatant in a final vol ume of 200 pi. Incubation was at 37 °C for 15 min, and the reaction was terminated by the addition of 1.0 ml of 0.5 mol/1 perchloric acid. A zero time blank, containing supernatant, was run with each
H Spontaneous hyperammonemia and orotic aciduria ® Orotic aciduria after protein load □3 ® No hyperammonemia or orotic aciduria after protein load
Fig. 2. Pedigree of Ok family. A maternal uncle (Ok-I-9) of the proband died of what was reported to be ‘fulminant hepatitis’ at the age of 51 years.
dfó ò è-T-o ó à 12
3
4
5
3
6
7
4
Cl Spontaneous hyperammonemia and orotic aciduria ® Orotic aciduria after protein load ® Hyperammonemia and orotic aciduria after protein load
Fig. 3. Pedigree of In family. The sister (In-IIl-4) of the proband has had 2 episodes suggestive of hyperammonemia at the age of 13 years. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 8:17:43 AM
162
Ornithine Transcarbamylase Deficiency in Male Adulthood
bovine liver OTC antibody as the first antibody, and goat antirabbit IgG conjugated with horse radish per oxidase as the second antibody. Bovine liver OTC [26], mouse liver OTC, and antibovine OTC antibody raised in rabbit [27] were purified as described, kindly supplied by Prof. M. Mori (Kumamoto University). Protein was determined with bovine serum albu min fraction V as standard [28].
Protein Loading Tests A meal containing 1 g natural food protein/kg body weight was given after overnight fasting to family members of the patients, and to 6 healthy adults. Plasma ammonia concentrations were deter mined before, and 1,2, 3, 4 and 6h after the ingestion of the meal. Urine samples were collected before the meal and in each time period between blood sam pling, up to 6 h after the ingestion of the meal. Ammonia was determined in plasma by an enzy matic method compled with glutamate dehydroge nase [29], with a few modifications. Orotic acid in urine was qantitated according to Adachi et al. [30], as modified by Goldstein et al. [31]. Values of the plasma ammonia or orotic acid con centrations in urine more than 2 SD above the respec tive control mean were regarded as elevated. The upper normal limits of plasma aspartate ami notransferase and alanine aminotransferase are 16.0 IU/1 and 14.0 IU/1, respectively.
163
in patient 3, the 37-kD bands which were weak, but obviously more intense than those in patients 1 and 2, were found. Protein Loading Tests in the Family Members Ni Pedigree. Among the family members of patient 1, 1 male, 3 female siblings, and 2 sons of the proband were available for the study (fig. 1). The younger sister (Ni-II-11) of the proband, a 56-year-old women, exhib ited a moderate increase in orotic acid excre tion (6.65 mmol/mol creatinine) in the 4th6th h of the test (table 2). All of the other individuals tested had responses to the protein load that could not be differentiated from controls either in lev els of plasma ammonia or orotic acid excre tion. Ok Pedigree. In the family of patient 2, the daughter of the proband (Ok-III-4), a 10year-old girl, showed moderately increased levels of orotic acid in all the time periods after loading (table 2). The elder sister and the son of the proband tolerated the protein load normally.
Results
Analysis of OTC by Immunoblotting In patients 1 and 2, very faint 37 kD bands, consistent with that of human mature OTC protein, were detected (fig. 4), whereas
Table 1. Activities of CPS-I and OTC of the liver Enzyme
Enzyme activities pmol-h-1 - mg protein-1 control (n = 6)
CPS-I OTC, pH 7.0 OTC, pH 8.5 Activity ratio (pH 8.5/pH 7.0)
1.32 ± 0.34 13.4 ± 3.9 22.1 ±5.2
1.66 ± 0.11
patient 1
2
3
1.92 0.28 0.28 1.00
1.58 0.32 0.57 1.77
1.69 0.83 1.21 1.46
Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 8:17:43 AM
Activities of CPS-I and OTC Activities of CPS-I of the patients 1, 2, and 3 were 145, 120 and 128 % of the control mean value, respectively (table 1.). Activities of OTC were
