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Carbamyl phosphate synthetase deficiency and postpartum hyperammonemia
Case Reports
www. AJOG.org
Carbamyl phosphate synthetase deficiency and postpartum hyperammonemia Yasushi Kotani, MD; Mitsuru Shiota, MD; Masahiko Umemoto, MD; Mitsuhiro Tsuritani, MD; Hiroshi Hoshiai, MD
C
arbamyl phosphate synthetase (CPS) is an enzyme that converts carbamyl phosphate into ammonia in the urea cycle (Figure).1,2 CPS deficiency is a genetic disorder of this active enzyme, and deficient enzyme activity causes hyperammonemia. CPS deficiency occurs with a frequency of 1 per 1 million.3 CPS deficiency is inherited as an autosomal recessive trait with its locus at 2q35; it almost always presents in newborns and infants, and the prognosis is poor, although the late onset occurs in some cases.1,4-6 Herein we report a very rare case in which a parturient developed hyperammonemia on 2 separate occasions following delivery of 2 children and was diagnosed with CPS deficiency.
C ASE R EPORT The patient is a 27 year old gravid 2, para 2. The histories of the present disease, family, drugs, and mental disorders were noncontributory. On becoming pregnant at 23 years of age, she visited a local doctor for prenatal care. The pregnancy culminated with a vaginal delivery at 38 weeks 6 days. On postpartum day 4, the patient’s level of awareness declined and she was brought to our hospital for emergency evaluation. She had a 5 on the Glasgow Coma Scale (motor response, 3; verbal response, 1; eye opening, 1) and showed
From the Department of Obstetrics and Gynecology, Kinki University School of Medicine, Osaka-sayama, Osaka, Japan. Received Dec. 11, 2009; revised March 1, 2010; accepted March 18, 2010. Reprints: Yasushi Kotani, MD, 377-2 Ohnohigashi, Osaka-sayama, Osaka 589-8511, Japan. [email protected]. 0002-9378/free © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.03.032
e10
Carbamyl phosphate synthetase (CPS) is an enzyme that converts ammonia to carbamyl phosphate in the urea cycle. CPS deficiency is a genetic disorder that causes hyperammonemia because of enzyme activity deficiency. It is primarily diagnosed in neonates and infants and has a poor prognosis. We report an adult woman with CPS deficiency who developed hyperammonemia postpartum. Key words: carbamyl phosphate synthetase deficiency, hyperammonemia, postpartum
neurologic impairments including the Babinski’s sign. A head computed tomography, magnetic resonance imaging, and electroencephalogram showed no abnormalities. Blood tests, including electrolyte levels, were performed to identify the cause of the decreased awareness. The blood ammonia was elevated at 262 g/dL. Intravenous fluids, lactulose, and kanamycin were administered for hepatic encephalopathy, but there was no improvement. On postpartum day 7, hemodialysis was started; the patient’s blood ammonia was 284 g/dL. The ammonia level declined thereafter to 22 g/ dL, and on postpartum day 11, hemodialysis was stopped. The clinical symptoms, including the decreased level of awareness, improved as the blood ammonia level was lowered. Analysis results of blood amino acid levels were as follows: citrinin, 5.2 nmol/mL (29.8-49.0 nmol/mL), and glutamine, 821.1 nmol/mL (478.3-658.5 nmol/mL). These results suggested an abnormal enzyme deficiency in the urea cycle, and a liver biopsy was performed. The histologic findings revealed normal ornithine transcarbamylase activity but no carbamyl phosphate synthetase activity, Thus, CPS deficiency was diagnosed. Protein restriction and arginine supplementation were implemented and the patient was followed up on an outpatient basis with no change. At 26 years of age, the patient became pregnant again and visited a local doctor for prenatal care. A cesarean section was
American Journal of Obstetrics & Gynecology JULY 2010
performed at 38 weeks 5 days because of a breech presentation. On postpartum day 8, the patient experienced lethargy leading to restlessness, and she was brought to our hospital for emergency evaluation. She had an elevated blood ammonia of 233 g/dL. Hemodialysis was performed for 6 days and the blood ammonia level improved to 33 g/dL. Protein restriction and arginine supplementation were implemented and the patient has been followed up on an outpatient basis. In the ensuing year, there have been no elevated ammonia levels.
C OMMENT CPS deficiency is a genetic disorder of the CPS enzyme that converts ammonia into carbamyl phosphate. A definitive diagnosis is established by liver biopsy to measure CPS activity; an absence of CPS indicates CPS deficiency. The treatment for hyperammonemia involves administering intravenous fluids, lactulose, and kanamycin to reduce the concentration of ammonia. Lactulose lowers the intestinal pH to produce less ammonia from the intestinal bacterial flora and thus facilitates defecation, whereas kanamycin controls intestinal ammonia-producing bacteria. If these supportive measures are ineffective, hemodialysis may be necessary.1 After the symptoms have improved, the intake of protein is restricted and arginine acid is administered to suppress the production of ammonia. In some cases with CPS defi-
Case Reports
www.AJOG.org
monemia on 2 separate occasions triggered by parturition. Considering that the second delivery triggered a recurrence of hyperammonemia, further pregnancies may necessitate extreme caution. Stresses other than pregnancy may precipitate a recurrence, and if symptoms occur, hemodialysis and other measures should be taken f immediately.
FIGURE
Urea cycle biochemistry
REFERENCES
Kotani. CPS deficiency and postpartum hyperammonemia. Am J Obstet Gynecol 2010.
ciency, ammonia levels rise suddenly, resulting in hepatic encephalopathy. If appropriate measures are not taken promptly, the patient may die or experience serious sequelae.7 In the present case, prompt hemodialysis was effective and the patient is currently leading a normal life without any sequelae. This disease almost always presents in newborns and infants, and the prognosis is poor.1 Delayed CPS deficiency is rare, but cases have been reported involving a 16 year old male with onset after a viral infection, and an 18 year old female with onset occurring in association with the menstrual cycle.5,6 Such late-onset occurrence is apparently triggered by some form of stress,
which in turn may result in decompensation of the ammonia metabolizing enzymes in the urea cycle and hyperammonemia. To date, reports of CPS deficiency during pregnancy and delivery are limited to the onset during pregnancy, resulting in fetal demise and onset after delivery with maternal mortality.7,8 Only supportive measures were initiated during the acute phase in these 2 cases, 1 of which resulted in the death of the patient.7,8 Considering this case and other cases of CPS deficiency in infants that resulted in death, hyperammonemia recalcitrant to supportive measures should be treated by hemodialysis.6 In the case of CPS deficiency reported herein, the patient developed hyperam-
1. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease, 8th ed. New York: McGraw-Hill, 2001:1906-63. 2. Rodwell VW. Biosynthesis of nutritionally nonessential amino acids. In: Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil PA, eds. Harper’s illustrated biochemistry, 28th ed. McGraw-Hill Medical Publishing; 2009:244. 3. Takeoka M, Soman TB, Shih VE, Caviness VS Jr, Krishnamoorthy KS. Carbamyl phosphate synthetase 1 deficiency: a destructive encephalopathy. Pediatr Neurol 2001;24:193-9. 4. Hoshide R, Soejima H, Ohta T, et al. Assignment of the human carbamyl phosphate synthetase I gene (CPS1) to 2q35 by fluorescence in situ hybridization. Genomics 1995;28:124-5. 5. Lo WD, Sloan HR, Sotos JF, Klinger RJ. Late clinical presentation of partial carbamyl phosphate synthetase I deficiency. Am J Dis Child 1993;147:265-6. 6. Wakutani Y, Nakayasu H, Takeshima T, et al. A case of late-onset carbamoyl phosphate synthetase I deficiency, presenting periodic psychotic episodes coinciding with menstrual periods [in Japanese]. Rinsho Shinkeigaku 2001; 41:780-5. 7. Wong LJ, Craien WJ, O’Brien WE. Postpartum coma and death due to carbamoyl-phosphate synthetase I deficiency. Ann Intern Med 1994;120:216-7. 8. Eather G, Coman D, Lander C, McGill J. Carbamyl phosphate synthase deficiency: diagnosed during pregnancy in a 41-year-old. J Clin Neurosci 2006;13:702-6.
JULY 2010 American Journal of Obstetrics & Gynecology
e11
www. AJOG.org
Carbamyl phosphate synthetase deficiency and postpartum hyperammonemia Yasushi Kotani, MD; Mitsuru Shiota, MD; Masahiko Umemoto, MD; Mitsuhiro Tsuritani, MD; Hiroshi Hoshiai, MD
C
arbamyl phosphate synthetase (CPS) is an enzyme that converts carbamyl phosphate into ammonia in the urea cycle (Figure).1,2 CPS deficiency is a genetic disorder of this active enzyme, and deficient enzyme activity causes hyperammonemia. CPS deficiency occurs with a frequency of 1 per 1 million.3 CPS deficiency is inherited as an autosomal recessive trait with its locus at 2q35; it almost always presents in newborns and infants, and the prognosis is poor, although the late onset occurs in some cases.1,4-6 Herein we report a very rare case in which a parturient developed hyperammonemia on 2 separate occasions following delivery of 2 children and was diagnosed with CPS deficiency.
C ASE R EPORT The patient is a 27 year old gravid 2, para 2. The histories of the present disease, family, drugs, and mental disorders were noncontributory. On becoming pregnant at 23 years of age, she visited a local doctor for prenatal care. The pregnancy culminated with a vaginal delivery at 38 weeks 6 days. On postpartum day 4, the patient’s level of awareness declined and she was brought to our hospital for emergency evaluation. She had a 5 on the Glasgow Coma Scale (motor response, 3; verbal response, 1; eye opening, 1) and showed
From the Department of Obstetrics and Gynecology, Kinki University School of Medicine, Osaka-sayama, Osaka, Japan. Received Dec. 11, 2009; revised March 1, 2010; accepted March 18, 2010. Reprints: Yasushi Kotani, MD, 377-2 Ohnohigashi, Osaka-sayama, Osaka 589-8511, Japan. [email protected]. 0002-9378/free © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.03.032
e10
Carbamyl phosphate synthetase (CPS) is an enzyme that converts ammonia to carbamyl phosphate in the urea cycle. CPS deficiency is a genetic disorder that causes hyperammonemia because of enzyme activity deficiency. It is primarily diagnosed in neonates and infants and has a poor prognosis. We report an adult woman with CPS deficiency who developed hyperammonemia postpartum. Key words: carbamyl phosphate synthetase deficiency, hyperammonemia, postpartum
neurologic impairments including the Babinski’s sign. A head computed tomography, magnetic resonance imaging, and electroencephalogram showed no abnormalities. Blood tests, including electrolyte levels, were performed to identify the cause of the decreased awareness. The blood ammonia was elevated at 262 g/dL. Intravenous fluids, lactulose, and kanamycin were administered for hepatic encephalopathy, but there was no improvement. On postpartum day 7, hemodialysis was started; the patient’s blood ammonia was 284 g/dL. The ammonia level declined thereafter to 22 g/ dL, and on postpartum day 11, hemodialysis was stopped. The clinical symptoms, including the decreased level of awareness, improved as the blood ammonia level was lowered. Analysis results of blood amino acid levels were as follows: citrinin, 5.2 nmol/mL (29.8-49.0 nmol/mL), and glutamine, 821.1 nmol/mL (478.3-658.5 nmol/mL). These results suggested an abnormal enzyme deficiency in the urea cycle, and a liver biopsy was performed. The histologic findings revealed normal ornithine transcarbamylase activity but no carbamyl phosphate synthetase activity, Thus, CPS deficiency was diagnosed. Protein restriction and arginine supplementation were implemented and the patient was followed up on an outpatient basis with no change. At 26 years of age, the patient became pregnant again and visited a local doctor for prenatal care. A cesarean section was
American Journal of Obstetrics & Gynecology JULY 2010
performed at 38 weeks 5 days because of a breech presentation. On postpartum day 8, the patient experienced lethargy leading to restlessness, and she was brought to our hospital for emergency evaluation. She had an elevated blood ammonia of 233 g/dL. Hemodialysis was performed for 6 days and the blood ammonia level improved to 33 g/dL. Protein restriction and arginine supplementation were implemented and the patient has been followed up on an outpatient basis. In the ensuing year, there have been no elevated ammonia levels.
C OMMENT CPS deficiency is a genetic disorder of the CPS enzyme that converts ammonia into carbamyl phosphate. A definitive diagnosis is established by liver biopsy to measure CPS activity; an absence of CPS indicates CPS deficiency. The treatment for hyperammonemia involves administering intravenous fluids, lactulose, and kanamycin to reduce the concentration of ammonia. Lactulose lowers the intestinal pH to produce less ammonia from the intestinal bacterial flora and thus facilitates defecation, whereas kanamycin controls intestinal ammonia-producing bacteria. If these supportive measures are ineffective, hemodialysis may be necessary.1 After the symptoms have improved, the intake of protein is restricted and arginine acid is administered to suppress the production of ammonia. In some cases with CPS defi-
Case Reports
www.AJOG.org
monemia on 2 separate occasions triggered by parturition. Considering that the second delivery triggered a recurrence of hyperammonemia, further pregnancies may necessitate extreme caution. Stresses other than pregnancy may precipitate a recurrence, and if symptoms occur, hemodialysis and other measures should be taken f immediately.
FIGURE
Urea cycle biochemistry
REFERENCES
Kotani. CPS deficiency and postpartum hyperammonemia. Am J Obstet Gynecol 2010.
ciency, ammonia levels rise suddenly, resulting in hepatic encephalopathy. If appropriate measures are not taken promptly, the patient may die or experience serious sequelae.7 In the present case, prompt hemodialysis was effective and the patient is currently leading a normal life without any sequelae. This disease almost always presents in newborns and infants, and the prognosis is poor.1 Delayed CPS deficiency is rare, but cases have been reported involving a 16 year old male with onset after a viral infection, and an 18 year old female with onset occurring in association with the menstrual cycle.5,6 Such late-onset occurrence is apparently triggered by some form of stress,
which in turn may result in decompensation of the ammonia metabolizing enzymes in the urea cycle and hyperammonemia. To date, reports of CPS deficiency during pregnancy and delivery are limited to the onset during pregnancy, resulting in fetal demise and onset after delivery with maternal mortality.7,8 Only supportive measures were initiated during the acute phase in these 2 cases, 1 of which resulted in the death of the patient.7,8 Considering this case and other cases of CPS deficiency in infants that resulted in death, hyperammonemia recalcitrant to supportive measures should be treated by hemodialysis.6 In the case of CPS deficiency reported herein, the patient developed hyperam-
1. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease, 8th ed. New York: McGraw-Hill, 2001:1906-63. 2. Rodwell VW. Biosynthesis of nutritionally nonessential amino acids. In: Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil PA, eds. Harper’s illustrated biochemistry, 28th ed. McGraw-Hill Medical Publishing; 2009:244. 3. Takeoka M, Soman TB, Shih VE, Caviness VS Jr, Krishnamoorthy KS. Carbamyl phosphate synthetase 1 deficiency: a destructive encephalopathy. Pediatr Neurol 2001;24:193-9. 4. Hoshide R, Soejima H, Ohta T, et al. Assignment of the human carbamyl phosphate synthetase I gene (CPS1) to 2q35 by fluorescence in situ hybridization. Genomics 1995;28:124-5. 5. Lo WD, Sloan HR, Sotos JF, Klinger RJ. Late clinical presentation of partial carbamyl phosphate synthetase I deficiency. Am J Dis Child 1993;147:265-6. 6. Wakutani Y, Nakayasu H, Takeshima T, et al. A case of late-onset carbamoyl phosphate synthetase I deficiency, presenting periodic psychotic episodes coinciding with menstrual periods [in Japanese]. Rinsho Shinkeigaku 2001; 41:780-5. 7. Wong LJ, Craien WJ, O’Brien WE. Postpartum coma and death due to carbamoyl-phosphate synthetase I deficiency. Ann Intern Med 1994;120:216-7. 8. Eather G, Coman D, Lander C, McGill J. Carbamyl phosphate synthase deficiency: diagnosed during pregnancy in a 41-year-old. J Clin Neurosci 2006;13:702-6.
JULY 2010 American Journal of Obstetrics & Gynecology
e11