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Year : 2019  |  Volume : 14  |  Issue : 1  |  Page : 2-6

Hyperargininemia experiences over last 7 years from a tertiary care center

1 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Web Publication18-Jun-2019

Correspondence Address:
Dr. Sadanandavalli Retnaswami Chandra
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru 560029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JPN.JPN_1_19

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Context: Several Enzymes carry out chemical reactions for the production of energy and carrying out normal functioning of the organism. Disorders of these functions can result in permanent damage to the child affecting multiple systems. Most metabolic disorders are at least controllable and therefore it is important to recognize them early for ensuring optimum growth and development. This involves proper pattern recognition by the clinician. Aims: In this study we are discussing a rare treatable metabolic disorder namely Hyperargininemia seen by the authors in the last seven years. Settings and Design: Various parameters of confirmed hyperargininemia patients were analysed. Methods and Material: It is a descriptive study where all patients were confirmed cases with red blood cell arginase levels <10. Statistical Analysis used: Descriptive statistical analysis, Mann-whitney test, spearman’s rho. Results: In this study we found consanguinity in 30 % of patients. At least one sibling was affected in 13 % of patients. Females were more in this group though the pattern remains AR. Symptom onset showed variability from less than 1 year to up to 17 years. Commonest clinical feature was cognitive dysfunction, spasticity, seizures, microcephaly and lesser number with extrapyramidal and cerebellar features. Failure to thrive and dysmorphic features were also seen. Conclusion: Hyperargininemia commonly manifests as regression, failure to thrive, spasticity, seizures with or without microcephaly. When the above phenotype is seen, it is mandatory to screen for urea cycle disorders.

Keywords: Arginase 1 deficiency, hyperargininemia, treatable inborn error of metabolism

How to cite this article:
Chandra SR, Christopher R, Ramanujam CN, Harikrishna GV. Hyperargininemia experiences over last 7 years from a tertiary care center. J Pediatr Neurosci 2019;14:2-6

How to cite this URL:
Chandra SR, Christopher R, Ramanujam CN, Harikrishna GV. Hyperargininemia experiences over last 7 years from a tertiary care center. J Pediatr Neurosci [serial online] 2019 [cited 2023 Sep 29];14:2-6. Available from: https://www.pediatricneurosciences.com/text.asp?2019/14/1/2/260610

   Introduction Top

Ammonia is the product of deamination reactions of nitrogenous compounds and is highly toxic to tissues. Urea cycle involves conversion of ammonia to urea. These reactions mainly happen in liver and later transported to kidney for excretion. Urea cycle (Krebs–Henseleit cycle) disorders are a group of inborn errors of metabolism involved in hepatic metabolism of nitrogen to urea. Biosynthesis of urea takes place as follows.[1] To produce one molecule of urea, 3ATP are required, that is, 2 (NH3) + CO2 + 3ATP = Urea + H2O + 3ADP. Ornithine is converted to citrulline catalyzed by carbamoyl phosphate synthase, an enzyme present in hepatic mitochondria. Citrulline ornithine translocase causes entry of ornithine to mitochondria and exit of citrulline. Subsequent reactions take place in cytosol. Argininosuccinate synthetase acts on citrulline and aspartate, and generates argininosuccinate. The enzyme argininosuccinase cleaves this to l-arginine and fumarate. Enzyme arginase acts on arginine, and hydrolytically breaks and yields urea and regenerates ornithine that diffuses back to mitochondria.[2],[3] Hyperargininemia is a relatively rare autosomal-recessive disease due to defect in the arginase I enzyme resulting in high plasma arginine and ammonia levels. The urea cycle carries six enzymatic reactions involved in converting nitrogen to urea, and arginase is the last enzyme in the cycle. Most of these disorders become symptomatic in infancy with encephalopathy due to hyperammonemia and hyperglutaminemia. The enzymes involved are N-acetyl glutamine synthase deficiency, carbamoyl phosphate synthetase 1 deficiency, argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency, and arginase 1 deficiency, which are autosomal recessive, and ornithine transcarbamylase deficiency that is X linked, ([Figure 1] shows the urea cycle).
Figure 1: Urea cycle. ARG = Arginase, ASL = Argininosuccinate lyase, ASS = Argininosuccinate synthetase, CPS1 = Carbamoyl phosphate synthetase 1, OTC = Ornithine transcarbamylase

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The incidence of hyperargininemia is 1 in 2,000,000 live births.[4] The clinical features are as follows. They do not present generally at birth, but usual symptoms start by 2–4 years as seizures, spasticity, and cognitive decline.[5] Early recognition and initiation of treatment pave a huge way in improving the quality of life of these children as it is a treatable metabolic disorder.

   Patients and Methods Top

We analyzed the confirmed patients seen by us in the last 7 years. Demographic, phenotypic, and biochemical parameters and course of illness were evaluated. H/o consanguinity in parents, H/O similar illness in family, if so their clinical features which included problems from birth, age at recognition of symptom, global delay, seizures, spasticity, extrapyramidal signs, cerebellar signs encephalopathy, skeletal changes, dysmorphism, other system changes, morbidity, mortality as well as laboratory biochemical parameters were evaluated. Biochemical parameters include complete hemogram, glucose (F), glucose (R), urea, creatinine, lipid profile, serum electrolytes, arterial blood gas analysis, liver function test, creatinine phosphokinase, uric acid, osmolality, thyroid function test, ammonia, and lactate. Tandem mass spectrometry (TMS) include arginine levels (3–130), ornithine levels (10–220), free carnitine, CO (9–65), citrulline (10–40), leucine/isoleucine (44–220), valine (54–250), and alanine (112–480). Patient’s urine were evaluated for screening of abnormal excretion of products of metabolism. All patients underwent computed tomography/magnetic resonance imaging or both in some cases.

   Result Top

Total of 15 patients (10 females [67.7%] and 5 males [33.3%]) were included in the study. The age of symptom onset was less than 2 years in two patients, at 2 years in two patients, 3 years in two patients, 5 years in one patient, 6 years in two patients, 7 years in two patients, and 17 years in one patient [Figure 2]. Short stature in two patients, mongoloid eyes in one patient, hallux valgus in one patient, microcephaly in five patients, facial dysmorphism in four patients, and bony abnormalities in one patient (scoliosis) were the common associations [Figure 3]. Cognitive decline was seen in all cases. Seizures were present in 11 cases (73.7%) of children of which two had typical generalised tonic clonic seizures type. It correlated with a mean arginine level of 518.9275 µmol with a standard error of 79.67919 µmol. Delayed milestones were present in eight cases (53.3%). Regression of acquired milestones was seen in three cases (33.3%). Consanguinity was present in 33.3% (five cases) and attention deficit hyperactivity syndrome in one patient. Spasticity was seen in 87.4% (13 patients) of children and it was correlated with mean arginine level of 512.7167 µmol with a standard error of 57.44132 µmol. Ataxia and chorea were present in one patient [Figure 4]. All children had poor growth and development [Figure 5] and [Figure 6].
Figure 2: Age distribution of onset of disease

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Figure 3: Dysmorphic features. X-axis indicates clinical features. Y-axis indicates number of patients

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Figure 4: Neurological features

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Figure 5: Severe failure to thrive with spasticity

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Figure 6: Blood ammonia 300micmol/dL and 56 gms/dl after protein load

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Biochemical evaluation showed the following: mean arginine level in males was 486.2040 µmol with a standard error of 63.35667 µmol. In females, it was 491.2670 µmol with a standard error of 58.15679 µmol. The mean with both genders put together was 489.5793 µmol with a standard error of 42.80442 µmol. The mean ammonia level was 452 and it was elevated in 87.5% patients. The diagnosis was confirmed by red cell arginase assay, which was <10% in all the 15 cases. Urine arginine was elevated in four cases [Figure 7]. High arginine levels positively correlated with spasticity and seizures.
Figure 7: Biochemical parameters in blood. X-axis indicates level of various aminoacids; Y-axis indicates number of patients

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Imaging showed cerebellar atrophy [Figure 8] and [Figure 9] in three patients, diffuse atrophy in one patient, frontal and temporal atrophy in one patient, white matter hypodensity in one patient, and bulky cortex in one patient [Figure 10].
Figure 8: Imaging features. X-axis indicates clinical features; Y-axis indicates number of patients

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Figure 9: Cerebellar atrophy

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Figure 10: Bulky cortex

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   Discussion Top

In last 7 years, the total number of cases seen by us was 15. The onset of symptom varied from <1 to 17 years. Apart from cognitive decline and regression, the unique clinical feature found in these patient groups is spasticity.[6] This correlates with the observation reported in the literature. Once the diagnosis is confirmed, treatment options consist of protein restriction and using alternate techniques to remove nitrogenous wastes as well as supplementing essential amino acids.[7],[8] With the aforementioned treatment, the arginine levels can be brought to normal in cerebrospinal fluid and plasma.[9] This results in improvement in spasticity, encephalopathy, and seizures, and improves growth. For ammonia scavenging, sodium benzoate and sodium phenyl butyrate can be used, which excretes nitrogen as hippuric acid and phenyl acetyl glutamine.[10] It has been reported that if patients are treated as early as possible, complete normality can be achieved even though strict adherence to protein restriction and amino acid supplementation is not always easy. Other symptom-modifying treatment options are antispasticity agents and botulinum toxin injections for spasticity.[11] With reference to management of seizures, sodium valproate must be avoided. Whenever an affected sibling is identified, it is mandatory to look for the same in the subsequent pregnancies. Arginase 1 is expressed in red blood cells of fetuses by 16–20 weeks of gestation.[12] Percutaneous umbilical blood sampling as well as ARG1 mutation should be performed. Newborn screening is indicated for all children even though the disease is relatively rare. This can be carried out by using TMS.[13] A direct enzyme assay has not yielded the expected results.[3]

   Conclusion Top

Hyperargininemia is a rare metabolic disease belonging to the urea cycle disorders. The onset of symptoms varies from neonatal period to the second decade. Apart from the common features of neurometabolic disorders, the unique combination of spasticity and seizures should raise the suspicion of arginase 1 deficiency. Early diagnosis and appropriate treatment give excellent prognosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


We sincerely thank the Director, NIMHANS, Prof Rita Christopher, Dept of neurochemistry and all our patients and caregivers for help and co-operation.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Nassogne MC, Héron B, Touati G, Rabier D, Saudubray JM. Urea cycle defects: management and outcome. J Inherit Metab Dis 2005;28:407-14.  Back to cited text no. 1
Christopher R, Rajivnath V, Shetty KT. Arginase deficiency. Indian J Pediatr 1997;64:266-9.  Back to cited text no. 2
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.  Back to cited text no. 3
Kido J, Nakamura K, Mitsubuchi H, Ohura T, Takayanagi M, Matsuo M, et al. Long-term outcome and intervention of urea cycle disorders in Japan. J Inherit Metab Dis 2012;35: 777-85.  Back to cited text no. 4
Iyer R, Jenkinson CP, Vockley JG, Kern RM, Grody WW, Cederbaum S. The human arginases and arginase deficiency. J Inherit Metab Dis 1998;21:86-100.  Back to cited text no. 5
Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996;43: 127-70.  Back to cited text no. 6
Cederbaum SD, Moedjono SJ, Shaw KN, Carter M, Naylor E, Walzer M. Treatment of hyperargininaemia due to arginase deficiency with a chemically defined diet. J Inherit Metab Dis 1982;5:95-9.  Back to cited text no. 7
Snyderman SE, Sansaricq C, Norton PM, Goldstein F. Argininemia treated from birth. J Pediatr 1979;95:61-3.  Back to cited text no. 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 DeynPP, editor. Guanidino compounds in biology and medicine. London: John Libbey & Company Ltd.,Vol. 2. 1997. pp. 53-69.  Back to cited text no. 9
Batshaw ML, Brusilow S, Waber L, Blom W, Brubakk AM, Burton BK, et al. Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion. N Engl J Med 1982;306:1387-92.  Back to cited text no. 10
Kelle B, Yavuz F. Argininemia is not a contraindication for botulinum toxin injection. J Pediatr Orthop B 2016;25:86-7.  Back to cited text no. 11
Spector EB, Kiernan M, Bernard B, Cederbaum SD. Properties of fetal and adult red blood cell arginase: a possible prenatal diagnostic test for arginase deficiency. Am J Hum Genet 1980;32:79-87.  Back to cited text no. 12
Picker JD, Puga AC, Levy HL, Marsden D, Shih VE, Degirolami U, et al. Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema. J Pediatr 2003;142:349-52.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]

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