- Email: [email protected]
Hyperammonemic encephalopathy in a child with ornithine transcarbamylase deficiency due to a novel combined heterozygous mutations
American Journal of Emergency Medicine 33 (2015) 474.e1–474.e3
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Hyperammonemic encephalopathy in a child with ornithine transcarbamylase deficiency due to a novel combined heterozygous mutations ☆, ☆☆ Abstract Ornithine transcarbamylase deficiency (OTCD) is an X-linked disorder of metabolism of the urea cycle. It usually causes hyperammonemic encephalopathy in males during the neonatalto-infantile period, whereas female carriers present with variable manifestations depending on their pattern of random chromosome X inactivation in the liver. Early clinical manifestations of hyperammonemia are nonspecific often leading to a delay in the diagnosis of OTCD. Unfortunately, delays in initiating treatment often lead to poor neurologic outcomes and overall survival. Presentation of hyperammonemic encephalopathy in children with OTCD is rare, and the mortality and morbidity rates are high. The diagnosis of OTCD and aggressive management of hyperammonemia were of paramount importance for appropriate treatment and successful recovery. Here, we report the clinical, biochemical, and molecular findings in a child with OTCD who presented with acute hyperammonemic encephalopathy. A 2.5-year-old girl presented to the emergency department due to irritability and vomiting that had continued for 2 months. During the recent 10 days, she displayed increasing somnolence and altered mental status with ataxia. The patient was born at term after an uneventful pregnancy and delivery with birth weight of 3.9 kg. Antenatal history and the neonatal period were unremarkable. She was the first child to nonconsanguineous healthy parents. She had normal physical and mental development, and her protein intake was adequate for age. Physical examination revealed apathy, ataxia, and liver enlargement (below xiphoid bone 4.5 cm). Blood chemistries revealed markedly elevated plasma ammonia (311 μmol/L), lactic acid (2.7 mmol/L), serum alanine transaminase (ALT) (417 U/L), and serum aspartate transaminase (AST) (100 U/L) (Table). Arteries blood gas analysis, blood glucose concentration, electrolytes, total protein, bilirubin levels, renal function, thyroid stimulating hormone and free thyroxine, full blood count, erythrocyte sedimentation rate, and C-reactive protein were all within reference ranges. The chest radiograph, electrocardiogram, electroencephalography, abdominal ultrasound, and lumbar puncture were all normal. She was admitted for observation and received intravenous fluids (110 mL/kg body
☆ Supported by the National Natural Science Foundation of China (no. 81201511) and Education Bureau of Zhejiang Province (no. Y201225805). ☆☆ The authors declare no conflicts of interest. 0735-6757/© 2014 Elsevier Inc. All rights reserved.
weight [BW] per day with 4.0 mg glucose/kg BW per minute), reduced glutathione (0.3 g/d), potassium magnesium asparaginate (2.5 mL/d), and lactulose (7.5 mL twice a day). At the third day of admission, the patient was transferred to intensive care unit because of a decreased level of consciousness, increased plasma ammonia (420 μmol/L), and remarkable elevation of ALT (1328 U/L) and AST (1014 U/L). Clotting assays showed prothrombin time was markedly prolonged (Table). Stool occult blood test was positive. The measurement of plasma amino acids revealed low leucine; others were normal. The sudden changes in sensorium with acute hyperammonemia without evidence of hepatic decompensation suggested the possibility of an abnormality of amino acid metabolism (urea cycle disorder). She received neomycin 50 mg/kg BW per day in 3 doses for reduction of ammonia, arginine 0.2 g/kg BW per day for promoting ornithine cycle, a protein restriction of 1.5 g natural protein/kg BW per day, and a supplement of essential amino acids with 0.8 g/kg BW per day in 2 doses. The level of consciousness was gradually aggravated. At the ninth day of admission, the patient was transferred to Shanghai hospital for gene diagnosis and treatment. In urine, orotic acid and uracil were highly increased (semiquantitative analysis by gas chromatography– mass spectroscopy), suggesting a urea cycle defect. Tandem mass spectrometry showed decreased concentrations of leucine, valine, and ornithine but normal citrulline, arginine, glutamic acid, and glutamine levels. Molecular genetic analysis using DNA from blood cells revealed the novel combined heterozygotic OTC gene mutation exon 6 c.548A N T (p.Tyr183Phe) and c.552-553insGACC (p.Ser185Aspfs*41). Her parents and sister showed no OTC gene mutation. Under an increased infusion regimen (110 mL/kg body BW per day with 7.6 mg glucose/kg BW per minute), ammonia concentration fell to 166 μmol/L, and the patient became more alert. Consecutively, she received neomycin, arginine, protein restriction, and a supplement of essential amino acids. After proactive treatment, the serum ammonium and liver enzymes were gradually decreased. The encephalopathy resolved, and the patient slowly recovered. She was discharged after 30 days in a normal physical and neurologic state, and the metabolic situation remained stable under the low-protein diet, essential amino acid substitution, and medication. Within a few years, the girl discontinued arginine treatment because of the unpleasant taste and inadequate understanding by their parents; the frequency of hyperammonemic attacks increased. When the patient was 4.5 years old, she died owing to hyperammonemic encephalopathy. Ornithine transcarbamylase deficiency (OTCD) is a urea cycle disorders where in a genetic alteration of ornithine transcarbamylase enzyme in the hepatic mitochondria leads to the accumulation of ammonia and its metabolites [1,2]. The OTCD diagnosis was based on
474.e2
J. Gao et al. / American Journal of Emergency Medicine 33 (2015) 474.e1–474.e3
Table Blood chemistries, plasma, and urine amino acids levels Admission Ninth Discharge from Normal hospital day hospital values pH Glu
7.431 5.5
7.402 6.1
7.405 4.7
Lac
2.7
4.2
0.7
Sodium
142
135
137
Potassium
3.5
3.2
3.7
Chloride
115
110
110
ALT AST GGT Ammonium Plasma amino acids Citrulline Ornithine Arginine Leucine
417 100 53 311
1328 1014 76 420
87 65 51 95
13.17 66.58 14.02 72.96
16.66 14.94
Valine
7.15 41.26
96.29
74.13
Glutamine Glutamate Urine amino acids Orotic acid Uracil Clotting assays Prothrombin time 17.9 INR 1.49 Partial thromboplastin 25.7 time
22.37 143.91
7.35-7.45 3.60-6.11 mmol/L 0.5-1.6 mmol/L 135-145 mmol/L 3.5-5.5 mmol/L 98-106 mmol/L 5-50 U/L 5-55 U/L 5-50 U/L 9-47 μmol/L 7-35 μmol/L 15-80 μmol/L 1.5-25 μmol/L 88-328 μmol/L 80-300 μmol/L 6-30 μmol/L 45-200 μmol/L
315.64 942.4
265.32 697.8
0-7 0-1.5
20.1 1.68 32.1
11.2 0.93 30.8
9.0-14.0 s 0.8-1.5 23.0-38.0 s
Abbreviations: GGT, γ-glutamyltransferase; INR, international normalized ratio.
decreased citrulline and arginine levels and increased ornithine, glutamic, and aspartic acids in plasma and increased urinary orotic acid. Definitive diagnosis can be obtained only by liver biopsy to measure OTC enzyme activity and mutation analysis. As such, the diagnosis of OTCD is often missed, often until late acute neurologic deterioration occurs, or sometimes the diagnosis remains undiscovered until postmortem investigation. Ornithine transcarbamylase deficiency is a genetic disorder involving a mutation of the OTC gene, located on the short arm of the X chromosome (Xp21.1) including 10 exons [3,4]. This makes the expression of the gene most common in homozygous males, but heterozygous females can also be affected and may be more likely to have serious morbidity. To date, more than 350 different mutations, including missense, nonsense, splice site changes, small deletions or insertions, and gross deletions, have been reported [5]. In our patient, hyperammonemia and increased urinary orotic acid were consistent with the diagnosis of OTCD. However, the concentrations of plasma ornithine, citrulline, and arginine were normal, and hyperammonemia did not manifest any long-term complications, indicating that the patient may be heterozygote. Molecular genetic analysis revealed the novel combined heterozygous OTC gene mutations exon 6 c.548A N T (p.Tyr183Phe) and c.552-553insGACC (p.Ser185Aspfs*41). This mutation has not been described before. The novel combined heterozygous genetic mutation may lead to the slightly altered phenotype (later presentation and no elevation of ornithine, citrulline, and arginine). Hyperammonemia shifts the equilibrium of the glutamate dehydrogenase reaction toward the direction of glutamate forma-
tion, depleting alpha-ketoglutarate, and resulting in decreased cellular oxidation and ATP production, leaving the brain vulnerable due to its high energy consumption. Glutamine synthetase catalyzes the formation of glutamine from ammonia and glutamate in cerebral astrocytes, leading to increased intracellular osmolarity, cell loss, and cytokine release; oxidative stress; and cerebral vasodilatation [6]. These osmotic and vasodilatory actions can acutely cause cerebral edema, manifesting clinically with depression in consciousness, loss of higher central nervous system functions, and seizures, and chronically result in cerebral atrophy, ventricular enlargement, and delayed myelination. In general, hyperammonemia treatment is based on the following objectives: decreasing waste products from endogenous protein breakdown by reducing the nitrogen intake, minimizing protein catabolism, and providing substrates lacking in the urea cycle and substances that may facilitate ammonia removal from the blood [7,8]. However, patients with the serious hyperammonemia require hemodiafiltration to quickly remove ammonia from the circulation [9]. Liver, liver cell, and stem cell transplantation is considered in patients with recurrent hyperammonemia or resistant to medical conventional therapy [10]. Despite aggressive medical management, morbidity and mortality from associated hyperammonemia remain significant. Plasma ammonia levels (200-500 μmol/L) are associated with poor neurologic outcomes and death. In our patient, the novel combined heterozygous genetic mutation may lead to the slightly altered phenotype, yet the high plasma ammonia levels may be associated with poor neurologic outcomes. In the duration of hospital stay, the patient was immediately started on ammonia scavenging medications, promotion ornithine cycle, protein elimination, and essential amino acids supplement. The hyperammonemic encephalopathy resolved, and the patient slowly recovered. After leaving hospital, the patient's plasma ammonia levels were not well controlled, and the frequency of hyperammonemic attacks increased. Finally, the patient died of hyperammonemic encephalopathy. In conclusion, presentation of hyperammonemic encephalopathy in children with OTCD is rare, and the mortality and morbidity rates are high. The diagnosis of OTCD is usually not suspected by clinical findings alone, and specific laboratory investigations and molecular analysis are important to get a definitive diagnosis. Early and efficient treatment of hyperammonemia in these patients is crucial to prevent fatality.
Jiandi Gao, MD Feng Gao, MD Fang Hong, MD Huimin Yu, MD Peifang Jiang, MD Department of Neurology, Children's Hospital, School of Medicine Zhejiang University, Hangzhou 310003, China Email-address: [email protected] http://dx.doi.org/10.1016/j.ajem.2014.08.038
References [1] Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab 2013;110:179–80. [2] Yorifuji T, Muroi J, Uematsu A, et al. X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase (OTC) deficiency. Clin Genet 1998;54:349–53. [3] Gordon N. Ornithine transcarbamylase deficiency: a urea cycle defect. Eur J Paediatr Neurol 2003;7:115–21. [4] Sloas III HA, Ence TC, Mendez DR, et al. At the intersection of toxicology, psychiatry, and genetics: a diagnosis of ornithine transcarbamylase deficiency. Am J Emerg Med 2013;31:1420.e5-6.
J. Gao et al. / American Journal of Emergency Medicine 33 (2015) 474.e1–474.e3 [5] Jamroz E, Paprocka J, Sokol M, et al. Magnetic resonance spectroscopy and molecular studies in ornithine transcarbamylase deficiency novel mutation c.802ANG in exon 8 (p.Met268Val). Neurol Neurochir Pol 2013; 47:283–9. [6] Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest 2007;132:1368–78. [7] Enns GM, Berry SA, Berry GT, et al. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 2007;356:2282–92.
474.e3
[8] Rao KV, Qureshi IA. Reduction in the MK-801 binding sites of the NMDA sub-type of glutamate receptor in a mouse model of congenital hyperammonemia: prevention by acetyl-L-carnitine. Neuropharmacology 1999;38:383–94. [9] Mathias RS, Kostiner D, Packman S. Hyperammonemia in urea cycle disorders: role of the nephrologist. Am J Kidney Dis 2001;37:1069–80. [10] Meyburg J, Hoffmann GF. Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects. Mol Genet Metab 2010;100:S77–83.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Hyperammonemic encephalopathy in a child with ornithine transcarbamylase deficiency due to a novel combined heterozygous mutations ☆, ☆☆ Abstract Ornithine transcarbamylase deficiency (OTCD) is an X-linked disorder of metabolism of the urea cycle. It usually causes hyperammonemic encephalopathy in males during the neonatalto-infantile period, whereas female carriers present with variable manifestations depending on their pattern of random chromosome X inactivation in the liver. Early clinical manifestations of hyperammonemia are nonspecific often leading to a delay in the diagnosis of OTCD. Unfortunately, delays in initiating treatment often lead to poor neurologic outcomes and overall survival. Presentation of hyperammonemic encephalopathy in children with OTCD is rare, and the mortality and morbidity rates are high. The diagnosis of OTCD and aggressive management of hyperammonemia were of paramount importance for appropriate treatment and successful recovery. Here, we report the clinical, biochemical, and molecular findings in a child with OTCD who presented with acute hyperammonemic encephalopathy. A 2.5-year-old girl presented to the emergency department due to irritability and vomiting that had continued for 2 months. During the recent 10 days, she displayed increasing somnolence and altered mental status with ataxia. The patient was born at term after an uneventful pregnancy and delivery with birth weight of 3.9 kg. Antenatal history and the neonatal period were unremarkable. She was the first child to nonconsanguineous healthy parents. She had normal physical and mental development, and her protein intake was adequate for age. Physical examination revealed apathy, ataxia, and liver enlargement (below xiphoid bone 4.5 cm). Blood chemistries revealed markedly elevated plasma ammonia (311 μmol/L), lactic acid (2.7 mmol/L), serum alanine transaminase (ALT) (417 U/L), and serum aspartate transaminase (AST) (100 U/L) (Table). Arteries blood gas analysis, blood glucose concentration, electrolytes, total protein, bilirubin levels, renal function, thyroid stimulating hormone and free thyroxine, full blood count, erythrocyte sedimentation rate, and C-reactive protein were all within reference ranges. The chest radiograph, electrocardiogram, electroencephalography, abdominal ultrasound, and lumbar puncture were all normal. She was admitted for observation and received intravenous fluids (110 mL/kg body
☆ Supported by the National Natural Science Foundation of China (no. 81201511) and Education Bureau of Zhejiang Province (no. Y201225805). ☆☆ The authors declare no conflicts of interest. 0735-6757/© 2014 Elsevier Inc. All rights reserved.
weight [BW] per day with 4.0 mg glucose/kg BW per minute), reduced glutathione (0.3 g/d), potassium magnesium asparaginate (2.5 mL/d), and lactulose (7.5 mL twice a day). At the third day of admission, the patient was transferred to intensive care unit because of a decreased level of consciousness, increased plasma ammonia (420 μmol/L), and remarkable elevation of ALT (1328 U/L) and AST (1014 U/L). Clotting assays showed prothrombin time was markedly prolonged (Table). Stool occult blood test was positive. The measurement of plasma amino acids revealed low leucine; others were normal. The sudden changes in sensorium with acute hyperammonemia without evidence of hepatic decompensation suggested the possibility of an abnormality of amino acid metabolism (urea cycle disorder). She received neomycin 50 mg/kg BW per day in 3 doses for reduction of ammonia, arginine 0.2 g/kg BW per day for promoting ornithine cycle, a protein restriction of 1.5 g natural protein/kg BW per day, and a supplement of essential amino acids with 0.8 g/kg BW per day in 2 doses. The level of consciousness was gradually aggravated. At the ninth day of admission, the patient was transferred to Shanghai hospital for gene diagnosis and treatment. In urine, orotic acid and uracil were highly increased (semiquantitative analysis by gas chromatography– mass spectroscopy), suggesting a urea cycle defect. Tandem mass spectrometry showed decreased concentrations of leucine, valine, and ornithine but normal citrulline, arginine, glutamic acid, and glutamine levels. Molecular genetic analysis using DNA from blood cells revealed the novel combined heterozygotic OTC gene mutation exon 6 c.548A N T (p.Tyr183Phe) and c.552-553insGACC (p.Ser185Aspfs*41). Her parents and sister showed no OTC gene mutation. Under an increased infusion regimen (110 mL/kg body BW per day with 7.6 mg glucose/kg BW per minute), ammonia concentration fell to 166 μmol/L, and the patient became more alert. Consecutively, she received neomycin, arginine, protein restriction, and a supplement of essential amino acids. After proactive treatment, the serum ammonium and liver enzymes were gradually decreased. The encephalopathy resolved, and the patient slowly recovered. She was discharged after 30 days in a normal physical and neurologic state, and the metabolic situation remained stable under the low-protein diet, essential amino acid substitution, and medication. Within a few years, the girl discontinued arginine treatment because of the unpleasant taste and inadequate understanding by their parents; the frequency of hyperammonemic attacks increased. When the patient was 4.5 years old, she died owing to hyperammonemic encephalopathy. Ornithine transcarbamylase deficiency (OTCD) is a urea cycle disorders where in a genetic alteration of ornithine transcarbamylase enzyme in the hepatic mitochondria leads to the accumulation of ammonia and its metabolites [1,2]. The OTCD diagnosis was based on
474.e2
J. Gao et al. / American Journal of Emergency Medicine 33 (2015) 474.e1–474.e3
Table Blood chemistries, plasma, and urine amino acids levels Admission Ninth Discharge from Normal hospital day hospital values pH Glu
7.431 5.5
7.402 6.1
7.405 4.7
Lac
2.7
4.2
0.7
Sodium
142
135
137
Potassium
3.5
3.2
3.7
Chloride
115
110
110
ALT AST GGT Ammonium Plasma amino acids Citrulline Ornithine Arginine Leucine
417 100 53 311
1328 1014 76 420
87 65 51 95
13.17 66.58 14.02 72.96
16.66 14.94
Valine
7.15 41.26
96.29
74.13
Glutamine Glutamate Urine amino acids Orotic acid Uracil Clotting assays Prothrombin time 17.9 INR 1.49 Partial thromboplastin 25.7 time
22.37 143.91
7.35-7.45 3.60-6.11 mmol/L 0.5-1.6 mmol/L 135-145 mmol/L 3.5-5.5 mmol/L 98-106 mmol/L 5-50 U/L 5-55 U/L 5-50 U/L 9-47 μmol/L 7-35 μmol/L 15-80 μmol/L 1.5-25 μmol/L 88-328 μmol/L 80-300 μmol/L 6-30 μmol/L 45-200 μmol/L
315.64 942.4
265.32 697.8
0-7 0-1.5
20.1 1.68 32.1
11.2 0.93 30.8
9.0-14.0 s 0.8-1.5 23.0-38.0 s
Abbreviations: GGT, γ-glutamyltransferase; INR, international normalized ratio.
decreased citrulline and arginine levels and increased ornithine, glutamic, and aspartic acids in plasma and increased urinary orotic acid. Definitive diagnosis can be obtained only by liver biopsy to measure OTC enzyme activity and mutation analysis. As such, the diagnosis of OTCD is often missed, often until late acute neurologic deterioration occurs, or sometimes the diagnosis remains undiscovered until postmortem investigation. Ornithine transcarbamylase deficiency is a genetic disorder involving a mutation of the OTC gene, located on the short arm of the X chromosome (Xp21.1) including 10 exons [3,4]. This makes the expression of the gene most common in homozygous males, but heterozygous females can also be affected and may be more likely to have serious morbidity. To date, more than 350 different mutations, including missense, nonsense, splice site changes, small deletions or insertions, and gross deletions, have been reported [5]. In our patient, hyperammonemia and increased urinary orotic acid were consistent with the diagnosis of OTCD. However, the concentrations of plasma ornithine, citrulline, and arginine were normal, and hyperammonemia did not manifest any long-term complications, indicating that the patient may be heterozygote. Molecular genetic analysis revealed the novel combined heterozygous OTC gene mutations exon 6 c.548A N T (p.Tyr183Phe) and c.552-553insGACC (p.Ser185Aspfs*41). This mutation has not been described before. The novel combined heterozygous genetic mutation may lead to the slightly altered phenotype (later presentation and no elevation of ornithine, citrulline, and arginine). Hyperammonemia shifts the equilibrium of the glutamate dehydrogenase reaction toward the direction of glutamate forma-
tion, depleting alpha-ketoglutarate, and resulting in decreased cellular oxidation and ATP production, leaving the brain vulnerable due to its high energy consumption. Glutamine synthetase catalyzes the formation of glutamine from ammonia and glutamate in cerebral astrocytes, leading to increased intracellular osmolarity, cell loss, and cytokine release; oxidative stress; and cerebral vasodilatation [6]. These osmotic and vasodilatory actions can acutely cause cerebral edema, manifesting clinically with depression in consciousness, loss of higher central nervous system functions, and seizures, and chronically result in cerebral atrophy, ventricular enlargement, and delayed myelination. In general, hyperammonemia treatment is based on the following objectives: decreasing waste products from endogenous protein breakdown by reducing the nitrogen intake, minimizing protein catabolism, and providing substrates lacking in the urea cycle and substances that may facilitate ammonia removal from the blood [7,8]. However, patients with the serious hyperammonemia require hemodiafiltration to quickly remove ammonia from the circulation [9]. Liver, liver cell, and stem cell transplantation is considered in patients with recurrent hyperammonemia or resistant to medical conventional therapy [10]. Despite aggressive medical management, morbidity and mortality from associated hyperammonemia remain significant. Plasma ammonia levels (200-500 μmol/L) are associated with poor neurologic outcomes and death. In our patient, the novel combined heterozygous genetic mutation may lead to the slightly altered phenotype, yet the high plasma ammonia levels may be associated with poor neurologic outcomes. In the duration of hospital stay, the patient was immediately started on ammonia scavenging medications, promotion ornithine cycle, protein elimination, and essential amino acids supplement. The hyperammonemic encephalopathy resolved, and the patient slowly recovered. After leaving hospital, the patient's plasma ammonia levels were not well controlled, and the frequency of hyperammonemic attacks increased. Finally, the patient died of hyperammonemic encephalopathy. In conclusion, presentation of hyperammonemic encephalopathy in children with OTCD is rare, and the mortality and morbidity rates are high. The diagnosis of OTCD is usually not suspected by clinical findings alone, and specific laboratory investigations and molecular analysis are important to get a definitive diagnosis. Early and efficient treatment of hyperammonemia in these patients is crucial to prevent fatality.
Jiandi Gao, MD Feng Gao, MD Fang Hong, MD Huimin Yu, MD Peifang Jiang, MD Department of Neurology, Children's Hospital, School of Medicine Zhejiang University, Hangzhou 310003, China Email-address: [email protected] http://dx.doi.org/10.1016/j.ajem.2014.08.038
References [1] Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab 2013;110:179–80. [2] Yorifuji T, Muroi J, Uematsu A, et al. X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase (OTC) deficiency. Clin Genet 1998;54:349–53. [3] Gordon N. Ornithine transcarbamylase deficiency: a urea cycle defect. Eur J Paediatr Neurol 2003;7:115–21. [4] Sloas III HA, Ence TC, Mendez DR, et al. At the intersection of toxicology, psychiatry, and genetics: a diagnosis of ornithine transcarbamylase deficiency. Am J Emerg Med 2013;31:1420.e5-6.
J. Gao et al. / American Journal of Emergency Medicine 33 (2015) 474.e1–474.e3 [5] Jamroz E, Paprocka J, Sokol M, et al. Magnetic resonance spectroscopy and molecular studies in ornithine transcarbamylase deficiency novel mutation c.802ANG in exon 8 (p.Met268Val). Neurol Neurochir Pol 2013; 47:283–9. [6] Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest 2007;132:1368–78. [7] Enns GM, Berry SA, Berry GT, et al. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 2007;356:2282–92.
474.e3
[8] Rao KV, Qureshi IA. Reduction in the MK-801 binding sites of the NMDA sub-type of glutamate receptor in a mouse model of congenital hyperammonemia: prevention by acetyl-L-carnitine. Neuropharmacology 1999;38:383–94. [9] Mathias RS, Kostiner D, Packman S. Hyperammonemia in urea cycle disorders: role of the nephrologist. Am J Kidney Dis 2001;37:1069–80. [10] Meyburg J, Hoffmann GF. Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects. Mol Genet Metab 2010;100:S77–83.