- Email: [email protected]
Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency
Brain & Development xxx (2019) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency Mayumi Matsufuji a,⇑, Eiko Takeshita a, Masayuki Nakashima a, Yoriko Watanabe b Kaori Fukui b, Toshio Hanai a, Hiromi Ishibashi a, Sachio Takashima a b
a Yanagawa Institute for Developmental Disabilities, Japan Department of Pediatrics and Child Health, Kurume University School of Medicine, Japan
Received 25 February 2019; received in revised form 29 August 2019; accepted 2 September 2019
Abstract An adult female patient was diagnosed with arginase 1 deficiency (ARG1-D) at 4 years of age, and had been managed with protein restriction combined with sodium benzoate therapy. Though the treatment was successful in ameliorating hyperammonemia, hyperargininemia persisted. After being under control with a strict restriction of dietary protein, severe fall of serum albumin levels appeared and her condition became strikingly worsened. However, after sodium phenylbutyrate (NaPB) therapy was initiated, the clinical condition and metabolic stability was greatly improved. Current management of ARG1-D is aimed at lowering plasma arginine levels. The nitrogen scavengers, such as NaPB can excrete the waste nitrogen not through the urea cycle but via the alternative pathway. The removal of nitrogen via alternative pathway lowers the flux of arginine in the urea cycle. Thereby, the clinical complications due to insufficient amount of protein intake can be prevented. Thus, NaPB therapy can be expected as a useful therapeutic option, particularly in patients with ARG1-D. Ó 2019 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Hyperargininemia; Alternative pathway; Sodium phenylbutyrate
1. Introduction Arginase 1 deficiency (ARG1-D) is an autosomal recessive metabolic disease in the urea cycle which leads to impaired ureagenesis. It is thought to be one of the least common of the urea cycle defects and the incidence has been estimated at between 1:350,000 and 1:1,000,000. However, the true incidence in non-related populations is unknown [1]. ARG1 is the sixth and final enzyme of the urea cycle, catalyzing the hydrolysis of ⇑ Corresponding author at: Yanagawa Institute for Developmental Disabilities, 218-1, Mitsuhashimachi-Tanomachi, Yanagawa, Fukuoka 832-0813, Japan. E-mail address: [email protected] (M. Matsufuji).
arginine to ornithine and urea. ARG1-D represents hyperargininemia with spasticity, impaired mobility, progressive neurological and intellectual impairment, and rare episodes of severe hyperammonemia, presenting a clinical pattern that differs strikingly from other urea cycle disorders (UCDs) [2]. Indeed, ARG1-D rarely results in hyperammonemia in the newborn period. The clinical severity is extensive, some patients had occasionally been misdiagnosed as cerebral palsy [1]. The mechanism of neurological symptoms in ARG1-D was speculated, not hyperammonemia but the accumulation of arginine or guanidine compounds (arginine’s metabolites) may lead to increased neurotoxicity and may result in demyelination or may affect GABAergic neurotrans-
https://doi.org/10.1016/j.braindev.2019.09.002 0387-7604/Ó 2019 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002
2
M. Matsufuji et al. / Brain & Development xxx (2019) xxx–xxx
mission, resulting in epileptogenic properties. Argininemia is also a precursor of nitric oxide [2]. In management of ARG1-D, the restriction of dietary protein combined with alternative pathway drugs such as sodium benzoate and/or sodium phenylbutyrate (NaPB) are the main therapeutic modalities [1]. The guideline suggests that treatment follows the standard UCD recommendation (without the use of L-arginine) but requires particularly severe protein restriction to reduce plasma arginine [3]. However, minimal protein intake needs to maintain protein biosynthetic function, growth, and near-normal plasma amino acid concentrations, using an arginine-free essential amino acid mixture [1]. Pharmacological treatment of UCDs involves alternative nitrogen-scavenging pathways. NaPB is a well-known long-term treatment of UCDs. It has been used since 1987 as an investigational new drug, and was approved for marketing in 1996 in US and also in 2012 in Japan. NaPB, as a precursor of sodium phenylacetate, provides an alternative pathway of nitrogen excretion by conjugation with glutamine. The nitrogen-scavenger drugs prevent the accumulation of ammonia providing an alternative pathway for nitrogen disposal through the combination with glycine in sodium benzoate and glutamine in NaPB in which 1 and 2 mol of ammonia are eliminated into the urine, respectively [4]. Administration of oral NaPB at a dose of 350–600 mg/kg/day in patients weighing less than 20 kg, or 9.9–13.0 g/m2/day in larger patients is required [1]. The treatment goal is to reduce plasma arginine below 200 lmol/L, since arginine and its metabolites are likely to be toxic [3]. On the other hand, if these conventional therapies are ineffective or hepatic fibrosis and cirrhosis have developed, a liver transplantation may be considered [1]. We herein report the successful treatment of an adult patient with ARG1-D to whom the NaPB therapy was applied. 2. Case report A 42-year-old female patient was born by normal delivery at 42 weeks of gestation. She had been well until the 18th day of life, when she began to vomit after feeding milk. At the age of 23 days, she developed clonic convulsions. Since then, convulsive episodes continued in spite of treatments with several kinds of anticonvulsants. At 4 months of age, her mother noticed that the baby appeared ‘‘drowsy” after feeding. Prior to one year old, microcephaly (below 2SD) and marked brain atrophy on computed tomography were revealed. Head control was difficult for her. Her extremities progressed severely spasticity with opisthotonic posture, and subsequent developmental milestones were arrested. At the age of 4 years, she was admitted to the hospital because of pneumonia, where she was found for the first time to
have hyperammonemia (960 lg/dl) and hyperargininemia (1049 lmol/L). The diagnosis was confirmed by identification of biallelic ARG1 pathogenic variants on molecular genetic testing concomitant with virtually nil activity of arginase 1 in red blood cells (Fig. 1) [5]. The treatment with low-protein diet (0.5–1.0 g/kg/day) supplemented with short-term administration of an arginine-free essential amino acid mixture and sodium benzoate (0.25–0.33 g/kg/day) was started. She had been well controlled both hyperammonemia and hyperargininemia until her twenties. She could not communicate in the state of bedridden but the concrete episodes of her mental and physical abilities were not clear. She often suffered from infectious diseases in those days. Subsequently, the plasma arginine levels gradually increased (432–757 lmol/L) with aging [5]. Therefore, the protein intake was restricted at approximately 0.21–0.35 g/kg/day by using regular infant milk and special protein-free infant formula combined with sodium benzoate medication during 2006 –2011 (Fig. 2). Her plasma arginine levels had been stabilized ranging between 89 and 226 lmol/L. The plasma level were 154 lmol/L for glutamine (normal range; 418–739), 16.0 lmol/L for ornithine (normal range; 42–141), 10.0 lmol/L for citrulline (normal range; 17–48), and 2.4 g/dl –3.3 g/dl for albumin. Between February 2011 and April 2012, her body weight was gradually gained, so that the dietary protein restriction was toned up (0.16–0.21 g/kg/day). In addition, administration of sodium benzoate was stopped to reduce vomiting. These attempts made her condition strikingly worse than before. This severe protein restriction yielded crucial fall of serum albumin levels to 1.96 g/dl. The decrease of serum albumin levels might contribute to the hemodilution and the circulating intravascular blood volume loss which leads to the systemic/pulmonary edema and prerenal failure. An active catabolic state accompanied by intractable infection, and amenorrhea arose from this poor nutritional state. Since March 2012, the infection was repeatedly occurred and became refractory. Two months later, marked systemic edema and oliguria were developed. Her condition presented low blood pressure with low oxygenation saturation in spite of 100% oxygen inhalation. She was kept under an intensive care receiving endotracheal intubation, albumin infusion, diuretic drugs, and intravenous administration of broadspectrum antibiotics. She underwent total parenteral nutrition to supply essential amino acids. Further, sodium benzoate was started, because her plasma arginine level showed as high as 660 lmol/L. Then her condition was gradually improved, but aspiration and vomiting due to the difficulty of bowel control were persisted. Gastrostomy, enterostomy and Nissen fundoplication were added to tracheotomy and tracheoesophageal anastomosis which lead declining recurrent vomiting.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002
M. Matsufuji et al. / Brain & Development xxx (2019) xxx–xxx
3
Fig. 1. The patient’s arginase activity of red blood cells. Bold character shows arginase activity of red blood cells (lmol/h/g hemoglobin). The figure in parentheses shows the arginine activity compared with normal control as 100%. Bottoms shows the result of molecular analysis showing ARG1 mutant alleles.
Fig. 2. Clinical course from 2006 at the age of 30 years. TPN: total parenteral nutrition. ICU: intensive care unit.
Between April 2013 and July 2017, her protein restriction was toned down at approximately 0.37 g/kg/day using the argininemia formula without nitrogen scavenger drugs. Then, the serum albumin was increased to 3.3–3.5 g/dl. Though the frequency of infection was decreased, the systemic edema persisted and she sometimes developed pulmonary edema and needed respiratory support. The plasma arginine levels was ranged between 472 and 999 lmol/L. The plasma level were between 330 and 1030 lmol/L for glutamine, between 14 and 36 lmol/L for ornithine, between 350 and 1030 lmol/L for citrulline in her late thirties. The administration of NaPB was started at 180 mg/kg/day in August 2017 at the age of 41 years, when hyperammonemia (119 lg/dl) occurred at the chance of respiratory concomitant with urinary tract
infection. After initiating the NaPB therapy, both hyperammonemia and hyperargininemia gradually recovered. Ammonia and arginine levels being ranged between 49 and 76 lg/dl, and 67 and 202 lmol/L, respectively. Moreover, the serum albumin level kept over 4.0 g/dl and her systemic edema also disappeared. The plasma glutamine level was between 190 and 228 lmol/L, ornithine between 7 and 12 lmol/L, and citrulline between 15 and 21 lmol/L. At present, she is maintained on 0.5–0.6 g/kg/day protein restriction with NaPB therapy at 145 mg/kg/day. Her serum albumin levels keep above 4.0 g/dl, ammonia 44 lg/dl, and arginine 70 lmol/L. Despite the infection is well-controlled, her neurodegenerative symptoms, such as seizures or severe developmental delay which presenting since infancy are not improved.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002
4
M. Matsufuji et al. / Brain & Development xxx (2019) xxx–xxx
She has never shown liver dysfunction, protein synthetic disability and liver cirrhosis. The genetic study for ARG1-D protocol was approved by the Ethics Committees of Kurume University School of Medicine. Written informed consent for the collection of blood samples from the patient and her parents was obtained [4]. The NaPB therapy was approved by the Ethics Committees of Kurume University School of Medicine. This treatment for this patient was explained to patient’s father and informed consent was obtained for the use of sodium phenylbutyrate and sodium benzoate. 3. Discussion Current management of ARG1-D is aimed at lowering plasma arginine levels. The goal should be the maintenance of plasma arginine concentration near the normal level (41–114 lmol/L) as possible [6]. Unlike other UCDs, arginine supplementation is obviously contraindicated. Thus, in the treatment of hyperargininemia, the protein restriction plays a key role to minimize the synthesis of arginine in urea cycle [1]. In fact, it has been shown that severe dietary protein restriction can ameliorate arginine levels both in plasma and cerebral-spinal fluid. However, the response to dietary restriction is relatively poor and improvement of the clinical picture is unsatisfactory. Furthermore, in most patients, arginine levels remain elevated despite severe dietary protein restriction [6,7]. While several case reports demonstrated the improvement in neurotoxic effects after lowering plasma arginine through dietary protein restriction [7,8]. In our patient, the severe dietary protein restriction resulted in crucial fall of serum albumin levels. The patient exhibited a significant hemodilution and intravascular blood volume loss leading to edema, oliguria, and life-threatening hypotension and finally, the critical condition. Our patient was treated with severe protein restriction and sodium benzoate therapy during 2006–2011. The most of amino acid showed low value due to insufficient amount of protein intake. Thus, it is difficult to consider the effect of nitrogen removal by sodium benzoate. Between 2013 and July 2017, she was managed by only protein restriction using argininemia formula and enteral nutrition without nitrogen scavenger drug. All of aminogram relating to urea cycle were elevated to reflect the flux in the urea cycle. After the NaPB therapy was started, both hyperammonemia and hyperargininemia were immediately ameliorated. The plasma arginine levels remained within the reference range despite attenuating protein restriction. Then, we enable to increase protein intake safely. According to the atten-
uation of particularly severe protein restriction, the patient’s clinical condition was significantly improved. In this case report, we described an ARG1-D adult patient being managed with a strict restriction of dietary protein leads to clinical crisis due to severe hypoalbuminemia. After receiving NaPB therapy, the clinical condition and metabolic stability were greatly improved. The nitrogen scavengers, such as NaPB can excrete the waste nitrogen not through the urea cycle, but via the alternative pathway. The removal of nitrogen via alternative pathway lowers the flux of arginine in the urea cycle, thereby being able to increase the patient’s protein intake safely. Consequently, NaPB therapy should be expected as a useful therapeutic option, particularly in patients with ARG1-D. Persistent high plasma arginine levels are believed to be the key driver of disease progression. Therefore, arginine control is important. Recently, several advanced approach are studied. Human recombinant arginase enzyme reduces plasma arginine in murine models of ARG1-D [9]. Meanwhile, ARG1 mRNA increased ARG1 protein expression in vitro and in vivo [10]. We are looking forward to further development of these approaches. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.braindev.2019.09. 002. References [1] Wong D, Cederbaum S, Crombez EA. Arginase deficiency. Gene Reviews at Gene Tests: Medical Genetics Information Resource (online database). Seattle: University of Washington. http:// www.genereviews.org. [2] Yuan YS, Garrett B, Andreas S, Colin DF. Arginase-1 deficiency. J Mol Med 2015;93:1287–96. [3] Haberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012;7:32. [4] Pena-Quintana L, Llarena M, Reyes-Suarez D, Aldamiz-Echevarria L. Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: patient perspectives. Patient Preference Adherence 2017;11:1489–96. [5] Segawa Y, Matsufuji M, Itokazu N, Utsunomiya H, Watanabe Y, Yoshino M, et al. A long-term survival case of arginase deficiency with severe multicystic white matter and compound mutations. Brain Dev 2011;33:45–8. [6] Huemer M, Carvalho DR, Brum JM, Unal O, Coskun T, Weisfeld-Adams JD, et al. Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency. J Inherit Metab Dis 2016;39:331–40. [7] Cederbaum SD, Moedjono SJ. Treatment of hyperargininaemia due to arginase deficiency with a chemically defined diet. J Inherit Metab Dis 1982;5:95–9.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002
M. Matsufuji et al. / Brain & Development xxx (2019) xxx–xxx [8] De Deyn PP, Marescau B, Qureshi IA, Cederbaum SD, Lambert M, Cerone R, et al. Hyperargininemia: a treatable inborn error of metabolism? In: De Deyn PP, Marescau B, Qureshi IA, Mori A, editors. Guanidino compounds in biology and medicine 2. London: John Libbey & Company Ltd; 1997. p. 53–69. [9] Burrage LG, Sun Q, Elsea SH, Jiang MM, Nagamani SCS, Frankel AE, et al. Human recombinant arginase enzyme reduces
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plasma arginine in mouse models of arginase deficiency. Hum Mol Genet 2015;24:6417–27. [10] Asrani KH, Cheng L, Cheng CJ, Subramanian RR. Arginase I mRNA therapy- a novel approach to rescue arginase 1 enzyme deficiency. RNA Biol 2018;15:914–22.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002
Case Report
Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency Mayumi Matsufuji a,⇑, Eiko Takeshita a, Masayuki Nakashima a, Yoriko Watanabe b Kaori Fukui b, Toshio Hanai a, Hiromi Ishibashi a, Sachio Takashima a b
a Yanagawa Institute for Developmental Disabilities, Japan Department of Pediatrics and Child Health, Kurume University School of Medicine, Japan
Received 25 February 2019; received in revised form 29 August 2019; accepted 2 September 2019
Abstract An adult female patient was diagnosed with arginase 1 deficiency (ARG1-D) at 4 years of age, and had been managed with protein restriction combined with sodium benzoate therapy. Though the treatment was successful in ameliorating hyperammonemia, hyperargininemia persisted. After being under control with a strict restriction of dietary protein, severe fall of serum albumin levels appeared and her condition became strikingly worsened. However, after sodium phenylbutyrate (NaPB) therapy was initiated, the clinical condition and metabolic stability was greatly improved. Current management of ARG1-D is aimed at lowering plasma arginine levels. The nitrogen scavengers, such as NaPB can excrete the waste nitrogen not through the urea cycle but via the alternative pathway. The removal of nitrogen via alternative pathway lowers the flux of arginine in the urea cycle. Thereby, the clinical complications due to insufficient amount of protein intake can be prevented. Thus, NaPB therapy can be expected as a useful therapeutic option, particularly in patients with ARG1-D. Ó 2019 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Hyperargininemia; Alternative pathway; Sodium phenylbutyrate
1. Introduction Arginase 1 deficiency (ARG1-D) is an autosomal recessive metabolic disease in the urea cycle which leads to impaired ureagenesis. It is thought to be one of the least common of the urea cycle defects and the incidence has been estimated at between 1:350,000 and 1:1,000,000. However, the true incidence in non-related populations is unknown [1]. ARG1 is the sixth and final enzyme of the urea cycle, catalyzing the hydrolysis of ⇑ Corresponding author at: Yanagawa Institute for Developmental Disabilities, 218-1, Mitsuhashimachi-Tanomachi, Yanagawa, Fukuoka 832-0813, Japan. E-mail address: [email protected] (M. Matsufuji).
arginine to ornithine and urea. ARG1-D represents hyperargininemia with spasticity, impaired mobility, progressive neurological and intellectual impairment, and rare episodes of severe hyperammonemia, presenting a clinical pattern that differs strikingly from other urea cycle disorders (UCDs) [2]. Indeed, ARG1-D rarely results in hyperammonemia in the newborn period. The clinical severity is extensive, some patients had occasionally been misdiagnosed as cerebral palsy [1]. The mechanism of neurological symptoms in ARG1-D was speculated, not hyperammonemia but the accumulation of arginine or guanidine compounds (arginine’s metabolites) may lead to increased neurotoxicity and may result in demyelination or may affect GABAergic neurotrans-
https://doi.org/10.1016/j.braindev.2019.09.002 0387-7604/Ó 2019 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002
2
M. Matsufuji et al. / Brain & Development xxx (2019) xxx–xxx
mission, resulting in epileptogenic properties. Argininemia is also a precursor of nitric oxide [2]. In management of ARG1-D, the restriction of dietary protein combined with alternative pathway drugs such as sodium benzoate and/or sodium phenylbutyrate (NaPB) are the main therapeutic modalities [1]. The guideline suggests that treatment follows the standard UCD recommendation (without the use of L-arginine) but requires particularly severe protein restriction to reduce plasma arginine [3]. However, minimal protein intake needs to maintain protein biosynthetic function, growth, and near-normal plasma amino acid concentrations, using an arginine-free essential amino acid mixture [1]. Pharmacological treatment of UCDs involves alternative nitrogen-scavenging pathways. NaPB is a well-known long-term treatment of UCDs. It has been used since 1987 as an investigational new drug, and was approved for marketing in 1996 in US and also in 2012 in Japan. NaPB, as a precursor of sodium phenylacetate, provides an alternative pathway of nitrogen excretion by conjugation with glutamine. The nitrogen-scavenger drugs prevent the accumulation of ammonia providing an alternative pathway for nitrogen disposal through the combination with glycine in sodium benzoate and glutamine in NaPB in which 1 and 2 mol of ammonia are eliminated into the urine, respectively [4]. Administration of oral NaPB at a dose of 350–600 mg/kg/day in patients weighing less than 20 kg, or 9.9–13.0 g/m2/day in larger patients is required [1]. The treatment goal is to reduce plasma arginine below 200 lmol/L, since arginine and its metabolites are likely to be toxic [3]. On the other hand, if these conventional therapies are ineffective or hepatic fibrosis and cirrhosis have developed, a liver transplantation may be considered [1]. We herein report the successful treatment of an adult patient with ARG1-D to whom the NaPB therapy was applied. 2. Case report A 42-year-old female patient was born by normal delivery at 42 weeks of gestation. She had been well until the 18th day of life, when she began to vomit after feeding milk. At the age of 23 days, she developed clonic convulsions. Since then, convulsive episodes continued in spite of treatments with several kinds of anticonvulsants. At 4 months of age, her mother noticed that the baby appeared ‘‘drowsy” after feeding. Prior to one year old, microcephaly (below 2SD) and marked brain atrophy on computed tomography were revealed. Head control was difficult for her. Her extremities progressed severely spasticity with opisthotonic posture, and subsequent developmental milestones were arrested. At the age of 4 years, she was admitted to the hospital because of pneumonia, where she was found for the first time to
have hyperammonemia (960 lg/dl) and hyperargininemia (1049 lmol/L). The diagnosis was confirmed by identification of biallelic ARG1 pathogenic variants on molecular genetic testing concomitant with virtually nil activity of arginase 1 in red blood cells (Fig. 1) [5]. The treatment with low-protein diet (0.5–1.0 g/kg/day) supplemented with short-term administration of an arginine-free essential amino acid mixture and sodium benzoate (0.25–0.33 g/kg/day) was started. She had been well controlled both hyperammonemia and hyperargininemia until her twenties. She could not communicate in the state of bedridden but the concrete episodes of her mental and physical abilities were not clear. She often suffered from infectious diseases in those days. Subsequently, the plasma arginine levels gradually increased (432–757 lmol/L) with aging [5]. Therefore, the protein intake was restricted at approximately 0.21–0.35 g/kg/day by using regular infant milk and special protein-free infant formula combined with sodium benzoate medication during 2006 –2011 (Fig. 2). Her plasma arginine levels had been stabilized ranging between 89 and 226 lmol/L. The plasma level were 154 lmol/L for glutamine (normal range; 418–739), 16.0 lmol/L for ornithine (normal range; 42–141), 10.0 lmol/L for citrulline (normal range; 17–48), and 2.4 g/dl –3.3 g/dl for albumin. Between February 2011 and April 2012, her body weight was gradually gained, so that the dietary protein restriction was toned up (0.16–0.21 g/kg/day). In addition, administration of sodium benzoate was stopped to reduce vomiting. These attempts made her condition strikingly worse than before. This severe protein restriction yielded crucial fall of serum albumin levels to 1.96 g/dl. The decrease of serum albumin levels might contribute to the hemodilution and the circulating intravascular blood volume loss which leads to the systemic/pulmonary edema and prerenal failure. An active catabolic state accompanied by intractable infection, and amenorrhea arose from this poor nutritional state. Since March 2012, the infection was repeatedly occurred and became refractory. Two months later, marked systemic edema and oliguria were developed. Her condition presented low blood pressure with low oxygenation saturation in spite of 100% oxygen inhalation. She was kept under an intensive care receiving endotracheal intubation, albumin infusion, diuretic drugs, and intravenous administration of broadspectrum antibiotics. She underwent total parenteral nutrition to supply essential amino acids. Further, sodium benzoate was started, because her plasma arginine level showed as high as 660 lmol/L. Then her condition was gradually improved, but aspiration and vomiting due to the difficulty of bowel control were persisted. Gastrostomy, enterostomy and Nissen fundoplication were added to tracheotomy and tracheoesophageal anastomosis which lead declining recurrent vomiting.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002
M. Matsufuji et al. / Brain & Development xxx (2019) xxx–xxx
3
Fig. 1. The patient’s arginase activity of red blood cells. Bold character shows arginase activity of red blood cells (lmol/h/g hemoglobin). The figure in parentheses shows the arginine activity compared with normal control as 100%. Bottoms shows the result of molecular analysis showing ARG1 mutant alleles.
Fig. 2. Clinical course from 2006 at the age of 30 years. TPN: total parenteral nutrition. ICU: intensive care unit.
Between April 2013 and July 2017, her protein restriction was toned down at approximately 0.37 g/kg/day using the argininemia formula without nitrogen scavenger drugs. Then, the serum albumin was increased to 3.3–3.5 g/dl. Though the frequency of infection was decreased, the systemic edema persisted and she sometimes developed pulmonary edema and needed respiratory support. The plasma arginine levels was ranged between 472 and 999 lmol/L. The plasma level were between 330 and 1030 lmol/L for glutamine, between 14 and 36 lmol/L for ornithine, between 350 and 1030 lmol/L for citrulline in her late thirties. The administration of NaPB was started at 180 mg/kg/day in August 2017 at the age of 41 years, when hyperammonemia (119 lg/dl) occurred at the chance of respiratory concomitant with urinary tract
infection. After initiating the NaPB therapy, both hyperammonemia and hyperargininemia gradually recovered. Ammonia and arginine levels being ranged between 49 and 76 lg/dl, and 67 and 202 lmol/L, respectively. Moreover, the serum albumin level kept over 4.0 g/dl and her systemic edema also disappeared. The plasma glutamine level was between 190 and 228 lmol/L, ornithine between 7 and 12 lmol/L, and citrulline between 15 and 21 lmol/L. At present, she is maintained on 0.5–0.6 g/kg/day protein restriction with NaPB therapy at 145 mg/kg/day. Her serum albumin levels keep above 4.0 g/dl, ammonia 44 lg/dl, and arginine 70 lmol/L. Despite the infection is well-controlled, her neurodegenerative symptoms, such as seizures or severe developmental delay which presenting since infancy are not improved.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002
4
M. Matsufuji et al. / Brain & Development xxx (2019) xxx–xxx
She has never shown liver dysfunction, protein synthetic disability and liver cirrhosis. The genetic study for ARG1-D protocol was approved by the Ethics Committees of Kurume University School of Medicine. Written informed consent for the collection of blood samples from the patient and her parents was obtained [4]. The NaPB therapy was approved by the Ethics Committees of Kurume University School of Medicine. This treatment for this patient was explained to patient’s father and informed consent was obtained for the use of sodium phenylbutyrate and sodium benzoate. 3. Discussion Current management of ARG1-D is aimed at lowering plasma arginine levels. The goal should be the maintenance of plasma arginine concentration near the normal level (41–114 lmol/L) as possible [6]. Unlike other UCDs, arginine supplementation is obviously contraindicated. Thus, in the treatment of hyperargininemia, the protein restriction plays a key role to minimize the synthesis of arginine in urea cycle [1]. In fact, it has been shown that severe dietary protein restriction can ameliorate arginine levels both in plasma and cerebral-spinal fluid. However, the response to dietary restriction is relatively poor and improvement of the clinical picture is unsatisfactory. Furthermore, in most patients, arginine levels remain elevated despite severe dietary protein restriction [6,7]. While several case reports demonstrated the improvement in neurotoxic effects after lowering plasma arginine through dietary protein restriction [7,8]. In our patient, the severe dietary protein restriction resulted in crucial fall of serum albumin levels. The patient exhibited a significant hemodilution and intravascular blood volume loss leading to edema, oliguria, and life-threatening hypotension and finally, the critical condition. Our patient was treated with severe protein restriction and sodium benzoate therapy during 2006–2011. The most of amino acid showed low value due to insufficient amount of protein intake. Thus, it is difficult to consider the effect of nitrogen removal by sodium benzoate. Between 2013 and July 2017, she was managed by only protein restriction using argininemia formula and enteral nutrition without nitrogen scavenger drug. All of aminogram relating to urea cycle were elevated to reflect the flux in the urea cycle. After the NaPB therapy was started, both hyperammonemia and hyperargininemia were immediately ameliorated. The plasma arginine levels remained within the reference range despite attenuating protein restriction. Then, we enable to increase protein intake safely. According to the atten-
uation of particularly severe protein restriction, the patient’s clinical condition was significantly improved. In this case report, we described an ARG1-D adult patient being managed with a strict restriction of dietary protein leads to clinical crisis due to severe hypoalbuminemia. After receiving NaPB therapy, the clinical condition and metabolic stability were greatly improved. The nitrogen scavengers, such as NaPB can excrete the waste nitrogen not through the urea cycle, but via the alternative pathway. The removal of nitrogen via alternative pathway lowers the flux of arginine in the urea cycle, thereby being able to increase the patient’s protein intake safely. Consequently, NaPB therapy should be expected as a useful therapeutic option, particularly in patients with ARG1-D. Persistent high plasma arginine levels are believed to be the key driver of disease progression. Therefore, arginine control is important. Recently, several advanced approach are studied. Human recombinant arginase enzyme reduces plasma arginine in murine models of ARG1-D [9]. Meanwhile, ARG1 mRNA increased ARG1 protein expression in vitro and in vivo [10]. We are looking forward to further development of these approaches. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.braindev.2019.09. 002. References [1] Wong D, Cederbaum S, Crombez EA. Arginase deficiency. Gene Reviews at Gene Tests: Medical Genetics Information Resource (online database). Seattle: University of Washington. http:// www.genereviews.org. [2] Yuan YS, Garrett B, Andreas S, Colin DF. Arginase-1 deficiency. J Mol Med 2015;93:1287–96. [3] Haberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012;7:32. [4] Pena-Quintana L, Llarena M, Reyes-Suarez D, Aldamiz-Echevarria L. Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: patient perspectives. Patient Preference Adherence 2017;11:1489–96. [5] Segawa Y, Matsufuji M, Itokazu N, Utsunomiya H, Watanabe Y, Yoshino M, et al. A long-term survival case of arginase deficiency with severe multicystic white matter and compound mutations. Brain Dev 2011;33:45–8. [6] Huemer M, Carvalho DR, Brum JM, Unal O, Coskun T, Weisfeld-Adams JD, et al. Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency. J Inherit Metab Dis 2016;39:331–40. [7] Cederbaum SD, Moedjono SJ. Treatment of hyperargininaemia due to arginase deficiency with a chemically defined diet. J Inherit Metab Dis 1982;5:95–9.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002
M. Matsufuji et al. / Brain & Development xxx (2019) xxx–xxx [8] De Deyn PP, Marescau B, Qureshi IA, Cederbaum SD, Lambert M, Cerone R, et al. Hyperargininemia: a treatable inborn error of metabolism? In: De Deyn PP, Marescau B, Qureshi IA, Mori A, editors. Guanidino compounds in biology and medicine 2. London: John Libbey & Company Ltd; 1997. p. 53–69. [9] Burrage LG, Sun Q, Elsea SH, Jiang MM, Nagamani SCS, Frankel AE, et al. Human recombinant arginase enzyme reduces
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plasma arginine in mouse models of arginase deficiency. Hum Mol Genet 2015;24:6417–27. [10] Asrani KH, Cheng L, Cheng CJ, Subramanian RR. Arginase I mRNA therapy- a novel approach to rescue arginase 1 enzyme deficiency. RNA Biol 2018;15:914–22.
Please cite this article in press as: Matsufuji M et al. Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.09.002