hyperargininemia

Summary

Summary: A rare autosomal recessive disorder of the urea cycle. It is caused by a deficiency of the hepatic enzyme ARGINASE. Arginine is elevated in the blood and cerebrospinal fluid, and periodic HYPERAMMONEMIA may occur. Disease onset is usually in infancy or early childhood. Clinical manifestations include seizures, microcephaly, progressive mental impairment, hypotonia, ataxia, spastic diplegia, and quadriparesis. (From Hum Genet 1993 Mar;91(1):1-5; Menkes, Textbook of Child Neurology, 5th ed, p51)

Top Publications

  1. Scaglia F, Lee B. Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency. Am J Med Genet C Semin Med Genet. 2006;142C:113-20 pubmed
    ..The latter reenters the mitochondrion to continue the cycle. Hyperargininemia is an autosomal recessive disorder caused by a defect in the arginase I enzyme...
  2. Sin Y, Ballantyne L, Mukherjee K, St Amand T, Kyriakopoulou L, Schulze A, et al. Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. PLoS ONE. 2013;8:e80001 pubmed publisher
    ..ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes ..
  3. Deignan J, De Deyn P, Cederbaum S, Fuchshuber A, Roth B, Gsell W, et al. Guanidino compound levels in blood, cerebrospinal fluid, and post-mortem brain material of patients with argininemia. Mol Genet Metab. 2010;100 Suppl 1:S31-6 pubmed publisher
  4. Iyer R, Jenkinson C, Vockley J, Kern R, Grody W, Cederbaum S. The human arginases and arginase deficiency. J Inherit Metab Dis. 1998;21 Suppl 1:86-100 pubmed
    ..The evidence for the role of AII in nitric oxide and polyamine metabolism is presented and this appears consonant with the data on the tissue distribution...
  5. Deignan J, Marescau B, Livesay J, Iyer R, De Deyn P, Cederbaum S, et al. Increased plasma and tissue guanidino compounds in a mouse model of hyperargininemia. Mol Genet Metab. 2008;93:172-8 pubmed
    In humans, arginase I (AI)-deficiency results in hyperargininemia, a metabolic disorder with symptoms of progressive neurological and intellectual impairment, spasticity, persistent growth retardation, and episodic hyperammonemia...
  6. Grody W, Kern R, Klein D, Dodson A, Wissman P, Barsky S, et al. Arginase deficiency manifesting delayed clinical sequelae and induction of a kidney arginase isozyme. Hum Genet. 1993;91:1-5 pubmed
    Deficiency of liver arginase (AI) is characterized clinically by hyperargininemia, progressive mental impairment, growth retardation, spasticity, and periodic episodes of hyperammonemia...
  7. Shi O, Morris S, Zoghbi H, Porter C, O Brien W. Generation of a mouse model for arginase II deficiency by targeted disruption of the arginase II gene. Mol Cell Biol. 2001;21:811-3 pubmed
    ..Homozygous arginase II-deficient mice were viable and apparently indistinguishable from wild-type mice, except for an elevated plasma arginine level which indicates that arginase II plays an important role in arginine homeostasis...
  8. Prasad A, Breen J, Ampola M, Rosman N. Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review. J Child Neurol. 1997;12:301-9 pubmed
    ..Current and potential future therapies and long-term outcome are summarized...
  9. Jain Ghai S, Nagamani S, Blaser S, Siriwardena K, Feigenbaum A. Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported?. Mol Genet Metab. 2011;104:107-11 pubmed publisher
    ..been postulated to play a role in the pathogenesis of the neurological changes in ARG1 deficiency including hyperargininemia, elevated guanidino compounds and elevated glutamine levels, as well as the hyperammonemia...

More Information

Publications62

  1. Lee E, Hu C, Bhargava R, Rozengurt N, Stout D, Grody W, et al. Long-term survival of the juvenile lethal arginase-deficient mouse with AAV gene therapy. Mol Ther. 2012;20:1844-51 pubmed publisher
    Arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia. Human patients suffer from neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation...
  2. Picker J, Puga A, Levy H, Marsden D, Shih V, Degirolami U, et al. Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema. J Pediatr. 2003;142:349-52 pubmed
    ..The levels of glutamine and arginine but not ammonia were markedly elevated, lending support to the "glutamine hypothesis" as the mechanism of cerebral edema in urea cycle defects...
  3. Lee E, Hu C, Bhargava R, Ponnusamy R, Park H, Novicoff S, et al. AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse. Gene Ther. 2013;20:785-96 pubmed publisher
    Complete arginase I deficiency is the least severe urea cycle disorder, characterized by hyperargininemia and infrequent episodes of hyperammonemia...
  4. Gau C, Rosenblatt R, Cerullo V, Lay F, Dow A, Livesay J, et al. Short-term correction of arginase deficiency in a neonatal murine model with a helper-dependent adenoviral vector. Mol Ther. 2009;17:1155-63 pubmed publisher
    ..These studies demonstrate that the AI deficient newborn mouse can be temporarily corrected and rescued using a HDV...
  5. Marescau B, De Deyn P, Lowenthal A, Qureshi I, Antonozzi I, Bachmann C, et al. Guanidino compound analysis as a complementary diagnostic parameter for hyperargininemia: follow-up of guanidino compound levels during therapy. Pediatr Res. 1990;27:297-303 pubmed
    ..guanidino compound analyses in the biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients ..
  6. Iyer R, Yoo P, Kern R, Rozengurt N, Tsoa R, O Brien W, et al. Mouse model for human arginase deficiency. Mol Cell Biol. 2002;22:4491-8 pubmed
    Deficiency of liver arginase (AI) causes hyperargininemia (OMIM 207800), a disorder characterized by progressive mental impairment, growth retardation, and spasticity and punctuated by sometimes fatal episodes of hyperammonemia...
  7. 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 pubmed publisher
    ..In this patient, low-protein diet successfully reduced hyperammonemia, but hyperargininemia persisted...
  8. Boles R, Stone M. A patient with arginase deficiency and episodic hyperammonemia successfully treated with menses cessation. Mol Genet Metab. 2006;89:390-1 pubmed
    ..A similar case was previously reported. A catamenial trigger should be considered in adolescent female arginase-deficient patients with episodes of hyperammonemia...
  9. Yu H, Iyer R, Yoo P, Kern R, Grody W, Cederbaum S. Arginase expression in mouse embryonic development. Mech Dev. 2002;115:151-5 pubmed
    ..The strong AI expression in the peripheral nervous system suggests that the pathogenesis of the neurological retardation in AI deficiency may be conditioned by AI deficiency in the nervous system during embryonic development...
  10. Muleme H, Reguera R, Berard A, Azinwi R, Jia P, Okwor I, et al. Infection with arginase-deficient Leishmania major reveals a parasite number-dependent and cytokine-independent regulation of host cellular arginase activity and disease pathogenesis. J Immunol. 2009;183:8068-76 pubmed publisher
  11. Gomes Martins E, Santos Silva E, Vilarinho S, Saudubray J, Vilarinho L. Neonatal cholestasis: an uncommon presentation of hyperargininemia. J Inherit Metab Dis. 2010;33 Suppl 3:S503-6 pubmed publisher
    b>Hyperargininemia is a rare inborn error of metabolism due to arginase deficiency, which is inherited in an autossomal recessive manner...
  12. Lee B, Jin H, Kim G, Choi J, Yoo H. Argininemia presenting with progressive spastic diplegia. Pediatr Neurol. 2011;44:218-20 pubmed publisher
  13. Delwing de Lima D, Delwing Dal Magro D, Vieira C, Grola G, Fischer D, de Souza Wyse A. Hyperargininemia and renal oxidative stress: Prevention by antioxidants and NG -nitro-l-arginine methyl ester. J Biochem Mol Toxicol. 2017;31:1-7 pubmed publisher
    ..Data indicate that Arg causes an oxidative imbalance in the renal tissues studied; however, in the presence of antioxidants and l-NAME, some of these alterations in oxidative stress were prevented...
  14. Delwing D, Delwing D, Gonçalves M, Sarkis J, Wyse A. NTPDase and 5'-nucleotidase activities of synaptosomes from hippocampus of rats subjected to hyperargininemia. Neurochem Res. 2007;32:1209-16 pubmed
    ..In conclusion, according to our results it seems reasonable to postulate that arginine alters the cascade involved in the extracellular degradation of ATP to adenosine...
  15. Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta Paediatr. 2008;97:1412-9 pubmed publisher
    ..To estimate the incidence of urea cycle diseases (UCDs) in Finland and determine the course of the various disorders as well as the outcome...
  16. Gungor S, Akinci A, Firat A, Tabel Y, Alkan A. Neuroimaging findings in hyperargininemia. J Neuroimaging. 2008;18:457-62 pubmed publisher
    ..Though the pathogenesis of neuronal damage in hyperargininemia is not clear, high serum and cerebrospinal fluid arginine levels can be directly related with neuronal damage...
  17. Lim H, Lim H, Ryoo S, Benjo A, Shuleri K, Miriel V, et al. Mitochondrial arginase II constrains endothelial NOS-3 activity. Am J Physiol Heart Circ Physiol. 2007;293:H3317-24 pubmed
    ..These data suggest that arginase II is predominantly confined to the mitochondria and that this mitochondrial arginase II regulates NO production, vascular endothelial function, and vascular stiffness by modulating NOS-3 activity...
  18. Wu T, Liu Y, Li X, Wang Q, DING Y, Ma Y, et al. Five novel mutations in ARG1 gene in Chinese patients of argininemia. Pediatr Neurol. 2013;49:119-23 pubmed publisher
    ..The clinical manifestations in patients are similar to cerebral palsy so the diagnosis is usually much delayed. Reports of argininemia from mainland China are few, and genetic analyses have not been reported...
  19. Wyse A, Bavaresco C, Hagen M, Delwing D, Wannmacher C, Severo Dutra Filho C, et al. In vitro stimulation of oxidative stress in cerebral cortex of rats by the guanidino compounds accumulating in hyperargininemia. Brain Res. 2001;923:50-7 pubmed
    b>Hyperargininemia is a metabolic disorder biochemically characterized by tissue accumulation of arginine and other guanidino compounds...
  20. Grody W, Klein D, Dodson A, Kern R, Wissmann P, Goodman B, et al. Molecular genetic study of human arginase deficiency. Am J Hum Genet. 1992;50:1281-90 pubmed
    ..explored the molecular pathology in 28 individuals homozygous or heterozygous for liver arginase deficiency (hyperargininemia) by a combination of Southern analysis, western blotting, DNA sequencing, and PCR...
  21. Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis. 1998;21 Suppl 1:151-9 pubmed
    ..Our data point to the importance of early diagnosis and aggressive treatment...
  22. Delwing D, Delwing D, Dutra Filho C, Wannmacher C, Wajner M, Wyse A. Arginine administration reduces catalase activity in midbrain of rats. Neuroreport. 2002;13:1301-4 pubmed
    b>Hyperargininemia is an inherited neurometabolic disorder biochemically characterized by tissue accumulation of arginine and clinically by severe neurological symptoms whose pathophysiology is poorly understood...
  23. Wu G, Jaeger L, Bazer F, Rhoads J. Arginine deficiency in preterm infants: biochemical mechanisms and nutritional implications. J Nutr Biochem. 2004;15:442-51 pubmed
    ..This new knowledge will be beneficial for designing the next generation of enteral and parenteral amino acid solutions to optimize nutrition and health in this compromised population...
  24. Scaglia F, Brunetti Pierri N, Kleppe S, Marini J, Carter S, Garlick P, et al. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr. 2004;134:2775S-2782S; discussion 2796S-2797S pubmed publisher
    ..In contrast, hyperargininemia found in patients with arginase 1 deficiency is associated with pyramidal tract findings and spasticity, ..
  25. Haraguchi Y, Aparicio J, Takiguchi M, Akaboshi I, Yoshino M, Mori M, et al. Molecular basis of argininemia. Identification of two discrete frame-shift deletions in the liver-type arginase gene. J Clin Invest. 1990;86:347-50 pubmed
    ..These data seem to be the first evidence of a case of argininemia caused by two different deletion mutations...
  26. Chadefaux B, Rabier D, Kamoun P. [Prenatal diagnosis of enzymopathies of the urea cycle]. Ann Biol Clin (Paris). 1988;46:471-6 pubmed
    ..A new method for measuring ornithine transcarbamylase and carbamylphosphate synthetase-I was used for prenatal diagnosis of the related enzymopathies in chorionic villi...
  27. Kaminsky Y, Kosenko E. Argocytes containing enzyme nanoparticles reduce toxic concentrations of arginine in the blood. Bull Exp Biol Med. 2012;153:406-8 pubmed
    ..has been developed and the possibility of reducing blood arginine concentration in animals with experimental hyperargininemia with arginase-loaded erythrocytes (argocytes) has been studied...
  28. Grody W, Chang R, Panagiotis N, Matz D, Cederbaum S. Menstrual cycle and gonadal steroid effects on symptomatic hyperammonaemia of urea-cycle-based and idiopathic aetiologies. J Inherit Metab Dis. 1994;17:566-74 pubmed
    ..These studies suggest a new therapeutic approach to defective ureagenesis in female patients and a relationship between ammonia production or disposal and the menstrual cycle...
  29. Landsverk M, Wang J, Schmitt E, Pursley A, Wong L. Utilization of targeted array comparative genomic hybridization, MitoMet, in prenatal diagnosis of metabolic disorders. Mol Genet Metab. 2011;103:148-52 pubmed publisher
    ..These data highlight the importance of targeted array CGH in patients with suspected metabolic disorders and incomplete or negative sequencing results, as well as its emerging role in prenatal diagnosis...
  30. Matsuda I, Matsuura T, Hoshide R, Uchino T, Matsubasa T. [Molecular basis of urea cycle disorders]. Nihon Rinsho. 1993;51:520-4 pubmed
    ..Alleles are extremely heterogeneous in all enzyme deficiencies, in sharp difference from other inborn errors of metabolism, such as cystic fibrosis and hemoglobinopathies...
  31. Munder M, Mollinedo F, Calafat J, Canchado J, Gil Lamaignere C, Fuentes J, et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood. 2005;105:2549-56 pubmed
    ..Our findings demonstrate important differences between murine and human leukocytes with respect to regulation and function of arginine metabolism via arginase...
  32. Christopher R, Rajivnath V, Shetty K. Arginase deficiency. Indian J Pediatr. 1997;64:266-9 pubmed
    b>Hyperargininemia due to arginase deficiency is a rare, inherited, urea cycle disorder. We report a case of arginase deficiency in a 5-year old boy presenting with mild hyperammonemia, hyperargininemia, and dibasic aminoaciduria.
  33. Oldham M, VanMeter J, Shattuck K, Cederbaum S, Gropman A. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol. 2010;42:49-52 pubmed publisher
    ..This finding confirms the hypothesis that the mechanism of injury in arginase deficiency, although still unknown, is unlikely to be similar to that causing ornithine transcarbamylase deficiency...
  34. Edwards R, Moseley K, Watanabe Y, Wong L, Ottina J, Yano S. Long-term neurodevelopmental effects of early detection and treatment in a 6-year-old patient with argininaemia diagnosed by newborn screening. J Inherit Metab Dis. 2009;32 Suppl 1:S197-200 pubmed publisher
    ..The Short Sensory Profile showed some difficulty with taste and smell sensitivity. Long-term observation over 6 years in a patient with early treated argininaemia shows promising neurodevelopmental results...
  35. Delwing D, Tagliari B, Chiarani F, Wannmacher C, Wajner M, Wyse A. Alpha-tocopherol and ascorbic acid administration prevents the impairment of brain energy metabolism of hyperargininemic rats. Cell Mol Neurobiol. 2006;26:177-89 pubmed
    ..Furthermore, pretreatment with alpha-tocopherol and ascorbic acid prevented the impairment of energy metabolism caused by hyperargininemia in cerebellum and hippocampus of rats.
  36. Becker Catania S, Gregory T, Yang Y, Gau C, de Vellis J, Cederbaum S, et al. Loss of arginase I results in increased proliferation of neural stem cells. J Neurosci Res. 2006;84:735-46 pubmed
    ..The consequence of these changes may contribute to the differential phenotypes of KO vs. WT cells. It appears that AI may play an important and unanticipated role in growth and development of NSCs...
  37. Mohseni J, Boon Hock C, Abdul Razak C, Othman S, Hayati F, Peitee W, et al. Novel complex re-arrangement of ARG1 commonly shared by unrelated patients with hyperargininemia. Gene. 2014;533:240-5 pubmed publisher
    b>Hyperargininemia is a very rare progressive neurometabolic disorder caused by deficiency of hepatic cytosolic arginase I, resulting from mutations in the ARG1 gene...
  38. Brosnan M, Brosnan J. Orotic acid excretion and arginine metabolism. J Nutr. 2007;137:1656S-1661S pubmed publisher
    ..as an index of arginine deficiency because it is found in patients with arginase deficiency who exhibit hyperargininemia. Increased orotic acid excretion can also arise as a result of impairments of pyrimidine synthesis, whether ..
  39. Hewson S, Clarke J, Cederbaum S. Prenatal diagnosis for arginase deficiency: a case study. J Inherit Metab Dis. 2003;26:607-10 pubmed
    ..The result was confirmed by postnatal enzyme analysis of red cells from the newborn. On the basis of our experience, prenatal diagnosis of arginase deficiency by cord red blood cell arginase activity assay appears possible...
  40. Mumenthaler S, Rozengurt N, Livesay J, Sabaghian A, Cederbaum S, Grody W. Disruption of arginase II alters prostate tumor formation in TRAMP mice. Prostate. 2008;68:1561-9 pubmed publisher
    ..However, the biological function of arginase II in prostate cancer still remains to be elucidated. In this study, we utilized the TRAMP mouse prostate cancer model to better understand the contribution of AII on tumor development...
  41. Scholl Burgi S, Sigl S, Haberle J, Haberlandt E, Rostasy K, Ertl C, et al. Amino acids in CSF and plasma in hyperammonaemic coma due to arginase1 deficiency. J Inherit Metab Dis. 2008;31 Suppl 2:S323-8 pubmed publisher
    ..31). The CSF/plasma ratios of most neutral amino acids were elevated but not those of the imino- and of the dibasic amino acids lysine and ornithine. The mechanism leading to the increase of most neutral amino acids in brain is not known...
  42. Uchino T, Haraguchi Y, Aparicio J, Mizutani N, Higashikawa M, Naitoh H, et al. Three novel mutations in the liver-type arginase gene in three unrelated Japanese patients with argininemia. Am J Hum Genet. 1992;51:1406-12 pubmed
    ..There was no evidence of activity of the three mutant arginases expressed in E. coli. We tentatively conclude that argininemia is heterogeneous, at the molecular level...
  43. Hayakawa C, Aono S, Keino H, Mizutani N, Watanabe K, Ikemoto M, et al. Absence of erythrocyte arginase protein in Japanese patients with hyperargininemia. Eur J Pediatr. 1991;150:800-3 pubmed
    In Japan, hyperargininemia has been reported in only 5 unrelated families and four patients are alive at present...
  44. Wu T, Yang Y. [Advances in clinical and molecular genetics studies on argininemia]. Zhongguo Dang Dai Er Ke Za Zhi. 2013;15:954-9 pubmed
  45. Niese K, Collier A, Hajek A, Cederbaum S, O Brien W, Wills Karp M, et al. Bone marrow cell derived arginase I is the major source of allergen-induced lung arginase but is not required for airway hyperresponsiveness, remodeling and lung inflammatory responses in mice. BMC Immunol. 2009;10:33 pubmed publisher
    ..Arginase is significantly upregulated in the lungs in murine models of asthma, as well as in human asthma, but its role in allergic airway inflammation has not been fully elucidated in mice...
  46. Sacca S, Campagna P, Ciurlo G. Congenital glaucoma associated with an arginase deficit: a case report. Eur J Ophthalmol. 1996;6:421-6 pubmed
    ..Argininemia is a rare congenital disease caused by deficiency. We present here a case in which argininemia and buphthalmos are associated...
  47. Berthe M, Darquy S, Breuillard C, Lamoudi L, Marc J, Cynober L, et al. High plasma citrulline and arginine levels ensured by sustained-release citrulline supplementation in rats. Nutrition. 2011;27:1168-71 pubmed publisher
    ..However, citrulline is very rapidly metabolized. We therefore developed a sustained-release form of citrulline and evaluated its metabolic behavior in rats...
  48. Cederbaum S, Yu H, Grody W, Kern R, Yoo P, Iyer R. Arginases I and II: do their functions overlap?. Mol Genet Metab. 2004;81 Suppl 1:S38-44 pubmed
    ..Finally, prenatal diagnosis appears to be possible as was predicted, but never proven, some years ago...
  49. Mavri Damelin D, Eaton S, Damelin L, Rees M, Hodgson H, Selden C. Ornithine transcarbamylase and arginase I deficiency are responsible for diminished urea cycle function in the human hepatoblastoma cell line HepG2. Int J Biochem Cell Biol. 2007;39:555-64 pubmed
    ..This strategy could provide a cell source capable of urea synthesis, and hence ammonia detoxificatory function, which would be useful in a bio-artificial liver...
  50. Kasten J, Hu C, Bhargava R, Park H, Tai D, Byrne J, et al. Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse. Mol Genet Metab. 2013;110:222-30 pubmed publisher
    Human arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia, which lead to neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation; ..
  51. Schiff M, Benoist J, Cardoso M, Elmaleh Berges M, Forey P, Santiago J, et al. Early-onset hyperargininaemia: a severe disorder?. J Inherit Metab Dis. 2009;32 Suppl 1:S175-8 pubmed publisher
    ..Despite appropriate but delayed treatment, our patient exhibited severe psychomotor delay at age 1 year...
  52. Dianzani U, Pileri A, Bianchi A, Camponi A, Tamponi G, Massaia M. Biochemical and immunologic abnormalities in peripheral blood T lymphocytes of patients with hemophilia A. Eur J Haematol. 1988;41:334-40 pubmed
    ..Lastly, alloreactive cytotoxicity was decreased in group B and was normal in groups A and C...
  53. Deignan J, Cederbaum S, Grody W. Contrasting features of urea cycle disorders in human patients and knockout mouse models. Mol Genet Metab. 2008;93:7-14 pubmed
    ..Consequently, all of the current mouse models are highly useful for future research into novel pharmacological and dietary treatments and gene therapy protocols for the management of urea cycle disorders...