|Year : 2022 | Volume
| Issue : 6 | Page : 1104-1108
Phenotypic pleiotropy in arginase deficiency: A single center cohort
Narmadham K Bharathi1, Maya Mary Thomas1, Sangeetha Yoganathan1, Mahalakshmi Chandran2, Rekha Aaron3, Sumita Danda3
1 Paediatric Neurology Unit, Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India
2 Neurochemistry Laboratory, Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||14-Jul-2022|
|Date of Acceptance||05-Aug-2022|
|Date of Web Publication||3-Dec-2022|
Narmadham K Bharathi
Paediatric Neurology Unit, Department of Neurological Sciences, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Arginase deficiency is considered a masquerader of diplegic cerebral palsy. The rarity of hyperammonemic crisis and the slowly progressive course has made it a unique entity among the urea cycle defects. Objectives: The aim of our study is to describe the varied phenotypic spectrum of children with arginase deficiency. Methodology: This retrospective study included children and adolescents aged <18 years with a biochemical or genetic diagnosis of arginase deficiency from May 2011 to May 2022. Data were collected from the hospital's electronic database. The clinical presentation, laboratory parameters at baseline and during metabolic decompensation, neuroimaging, electroencephalography findings, and molecular studies were analyzed. Results: About 11 children from nine families with biochemically or genetically proven arginase deficiency were analyzed. The male: female ratio was 2.7:1. Consanguineous parentage was observed in all children. The median age at presentation was 36 months (Range: 5 months-18 years). All children with onset of symptoms in early childhood had a predominant delay in motor milestones of varying severity. Metabolic decompensation with encephalopathy occurred in all except two children (n = 9, 81.8%). Pyramidal signs were present in all patients and additional extrapyramidal signs in two children. Positive family history was present in four probands. Seizures occurred in all children. Epilepsy with electrical status in slow wave sleep and West syndrome was noted in three children. All children had elevated ammonia and arginine at the time of metabolic crisis. The spectrum of neuroimaging findings includes periventricular, subcortical, and deep white matter signal changes and diffusion restriction. The mean duration of follow-up was 38.6 ± 34.08 months. All patients were managed with an arginine-restricted diet and sodium benzoate with or without ornithine supplementation. Conclusion: Spastic diparesis, recurrent encephalopathy, presence of family history, and elevated serum arginine levels must alert the clinician to suspect arginase deficiency. Atypical presentations in our cohort include frequent metabolic crises and epileptic encephalopathy. Early identification and management will ensure a better neurodevelopmental outcome.
Keywords: ARG1 deficiency, arginase deficiency, argininemia, hyperargininemia
|How to cite this article:|
Bharathi NK, Thomas MM, Yoganathan S, Chandran M, Aaron R, Danda S. Phenotypic pleiotropy in arginase deficiency: A single center cohort. Ann Indian Acad Neurol 2022;25:1104-8
|How to cite this URL:|
Bharathi NK, Thomas MM, Yoganathan S, Chandran M, Aaron R, Danda S. Phenotypic pleiotropy in arginase deficiency: A single center cohort. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 29];25:1104-8. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1104/361568
| Introduction|| |
The urea cycle is the final common pathway of degradation of amino acids wherein waste nitrogen in the form of ammonia is converted to urea. This pathway occurs exclusively in the liver and the resultant urea is excreted via the kidneys. The mitochondria and cytoplasm are the subcellular compartments that are involved in the pathway. A defect in the urea cycle may occur as a result of deficiency of one of the six enzymes implicated in the cycle or due to a defect in one of the two transporters across the mitochondria and cytoplasm. Arginase is an enzyme of the distal urea cycle.
Arginase deficiency is an autosomal recessive disease with an estimated incidence between 1:350,000 and 1,000,000 births. Arginase occurs in both the cytoplasmic compartment (in liver and erythrocytes) and in the mitochondrial compartment of the brain and kidney which are encoded by ARG1 and ARG2, respectively. Hyperargininemia occurs due to mutation of ARG1 which is located on chromosome 6q23.2. Urea cycle defects typically present as hyperammonemic encephalopathy in the neonatal period. Arginase deficiency is distinct from the other disorders of the urea cycle due to its insidious clinical course with the rare occurrence of acute metabolic decompensation and hyperammonemic crisis.
However, there have been several reports of children with arginase deficiency who presented with metabolic decompensation and hyperammonemia.,, In view of the expanding phenotypic diversity seen in this disease, we have studied the clinical pleiotropy of this condition based on our experience in treating these children at our center.
| Materials and Methods|| |
This is a retrospective study from a tertiary care center in South India. The medical records of children and adolescents aged <18 years attending the Paediatric Neurology clinic and admitted to wards from May 2011 to May 2022 were analyzed. Arginase deficiency was established by biochemical evidence of hyperargininemia on serum amino acid testing or genetic defect in the ARG1 gene. Data were collected from the hospital's electronic database. The data were extracted in a predesigned proforma. Details of the initial clinical symptomatology, presence of consanguinity or family history, physical examination findings, laboratory parameters such as ammonia, serum amino acid profile including arginine and ornithine at baseline and/or during metabolic decompensation, urine orotic acid, Magnetic Resonance Imaging, electroencephalography findings, and molecular studies with targeted sequencing/exome testing were analyzed.
For the quantification of serum amino acid extraction, plasma samples were deproteinized with equal volumes of 5% TCA for 1 h at 25°C and centrifuged at 450 g for 10 min. The deproteinized supernatants were diluted 5-fold with 67 mM sodium citrate buffer pH 2.2, filtered through 0.22 μm Millipore filters. Amino acids were analyzed in 30 μl of the filtrate by HPLC by adsorption to a strong cation exchanger and elution according to their isoelectric pH over the pH range 3.2 to 10.0 as given by Ishida et al. The HPLC system used was Shimadzu LC-20AD. Orotic acids were measured colorimetrically. Standard graphs for each amino acid and orotic acid were constructed with different concentrations and used to quantify amino acids and orotic acid in the samples.
| Results|| |
A total of 11 children from nine families with biochemically or genetically proven arginase deficiency were analyzed. The male:female ratio was 2.7:1. All children had second- or third-degree consanguineous parentage. The median age at presentation was 36 months (Range: 5 months-18 years). All children with onset of symptoms in early childhood had a predominant delay in motor milestones of varying severity. Metabolic decompensation with encephalopathy occurred in all except two children (n = 9, 81.8%). There were recurrent episodes of encephalopathy in three children. One child who presented at the age of 18 years had history of normal premorbid development and recurrent episodes of altered sensorium, diminished vision, and vomiting since the age of 11 years, and these episodes were followed by gradual recovery over few weeks. These episodes were managed with adequate hydration, dextrose infusion, sodium benzoate administration, and protein-restricted diet. In view of poor compliance with the prescribed diet, he had frequent episodes and progressive pyramidal signs. In the latest episode, he presented with hyperammonemic encephalopathy and his ammonia levels had declined to the normal range only after three cycles of hemodialysis. Pyramidal signs were present in all patients and additional extrapyramidal signs in two children. Positive family history was present in four probands. All children had seizures. Two children presented in infancy with cryptogenic west syndrome and the workup done revealed argininemia. Epilepsy with electrical status epilepticus in sleep (ESES) was noted in one child who had polymorphic seizures including generalized tonic, atypical absence seizures, and negative myoclonus. All children had elevated ammonia at the time of metabolic crisis ranging from 215 to 814 μg/dL (normal lab reference: 27–102 μg/dL). Baseline ammonia levels ranged from 60 to 164 μg/dL. The median value of serum arginine at baseline was 347 μM (normal lab reference: 10-140 μM; range in our cohort: 30-771 μM). The median serum arginine at episodes of the crisis was 436 μM ranging from 178 to 613 μM. Urine orotic acid levels were elevated in three out of the six tested individuals. Hepatic involvement with transaminitis and coagulopathy was noted in nine children (81.8%). The spectrum of neuroimaging findings includes periventricular, subcortical, and deep white matter signal changes and diffusion restriction. The mean duration of follow-up was 38.6 ± 34.08 months. All patients were managed with an arginine-restricted diet and sodium benzoate with or without ornithine supplementation. Out of the 11 patients, one was lost to follow-up and one child succumbed at 8 years of age. The clinical presentation, notable lab parameters, imaging findings, and genetic mutations are depicted in [Table 1]. The levels of ammonia, arginine, and ornithine at baseline and/or during metabolic decompensation are depicted in [Figure 1], [Figure 2], and [Figure 3], respectively.
|Table 1: Clinical profile, imaging findings, and genetic tests of Arginase deficiency patients|
Click here to view
|Figure 1: Graph depicting ammonia levels at baseline and/or crises in children with arginase deficiency. (Normal lab reference of ammonia cited with brackets)|
Click here to view
|Figure 2: Graph depicting the arginine levels at baseline and/or crisis. (Normal lab reference cited within brackets)|
Click here to view
|Figure 3: Graph depicting serum arginine vs ornithine levels at baseline. (Normal lab reference cited within brackets)|
Click here to view
Seven different mutations were identified in this cohort. In two families, a genetic test was done only on one of the affected siblings. Two unrelated families had the same mutation in exon 3 (c.319G>A; p.Gly107Arg). A novel variant was identified in two other unrelated families in exon 4 (c.428A>G; p.Gln143Arg, Clinvar accession ID: VCV000996071.3). All variants are missense except one which revealed the acceptor splice variant in intron 4. Two other novel variants were identified in exon 4 (c.452A>G; p.Glu151Gly) and in exon 8 (c.899C>G; p.Thr300Ser) and they were classified as likely pathogenic.
| Discussion|| |
Hyperargininemia occurs due to the deficiency of arginase, which is the last enzyme in the urea cycle pathway that involves the cleavage of arginine to urea and ornithine. Mutation in the ARG1 gene on chromosome 6q23.2 causes deficiency of arginase 1 which is the isoform produced in the cytoplasmic component of the liver and erythrocytes. It is also expressed in the gastrointestinal tract, thymus, skin, uterus, and sympathetic ganglion. Arginase II is produced in the mitochondria of the kidney and prostate and to a lesser extent in the brain, gastrointestinal tract, and lactating mammary gland. It is seemingly upregulated in patients with argininemia but this has no protective effect. Deficient activity of arginase results in the accumulation of waste nitrogen in the form of ammonia. The decreased incidence of hyperammonemia and the predominant pyramidal manifestations in arginase deficiency versus the increased incidence of hyperammonemic crisis with the predominant metabolic encephalopathy-like presentations in the rest of the proximal urea cycle defects makes ammonia a less likely cause in the pathogenesis of the clinical manifestations in arginase deficiency. The presence of catabolites of arginine in the form of guanidino compounds such as α-keto-δ-guanidinovaleric acid, α-N-acetylarginine, and argininic acid in the urine and plasma of patients with arginase deficiency postulates the metabolites of arginine to be a potential causative factor of neurotoxicity and the resultant spasticity. These compounds are also potent inhibitors of GABA and glycine responses in cultured mouse neurons and hence are implicated in the process of epileptogenesis.
The predominant manifestation of this disease is the insidious onset of progressive spastic diplegia with or without extrapyramidal signs and similar findings of pyramidal signs were noted in all our patients and extrapyramidal manifestations were noted in two children. The prevalence was more among males in our cohort, though a previously described case series revealed increased prevalence among females. The presence of hyperammonemic crisis in 81.8% of children in our cohort was an uncommon feature that is rarely described in this disorder. Similar occurrences have been reported in several previous case reports.,, Orotic acid was not consistently elevated among the tested individuals in our study population. However, the elevation of orotic acid has been described in disorders of arginine metabolism. Arginase deficiency results in decreased production of ornithine which is an essential substrate for ornithine transcarbamylase. The resultant relative excess of carbamyl phosphate is therefore shunted into the pyrimidine synthesis pathway resulting in orotic aciduria. However, increased urine orotic acid is not a reliable marker for diagnosing disorders of arginine metabolism owing to the fact that it can also be elevated in the impairment of pyrimidine synthesis, genetic defect in UMP synthase, or by drugs that inhibit the terminal part of pyrimidine synthesis pathway viz. allopurinol and 6-azauridine.
The consistent elevation of arginine in untreated patients and the concomitant decrease in serum ornithine were noted in our series as depicted in [Figure 3]. This finding could be exploited in the evaluation of arginine/ornithine ratio as a potential screening tool in children in whom the clinical course is suggestive of this disease. The utility of the arginine/ornithine ratio as a screening method has previously been proposed in the newborn population. However, this awaits further validation in older children and across different centers.
The treatment typically involves the use of protein-restricted diet. In a particular patient who had epilepsy with ESES, strict adherence to protein-rich diet resulted in nutritional dermatosis with a secondary infection which resulted in prolonged in-patient stay with nutritional rehabilitation. In addition to dietary management, treatment includes the use of ammonia scavenging agents such as sodium benzoate at 250 to 500 mg/kg/day in three divided doses. The other ammonia scavenging agents that could be used include sodium phenylbuyrate (≤250 mg/kg/day if <20 kg and 5 g/m2/day if >20 kg).
Early recognition of this condition can help prevent further neurological decline. Despite adequate compliance with treatment and diet, children continue to have progression in spasticity and resultant motor decline which, however, occurs at a slower rate. Epileptic encephalopathy syndromes such as West syndrome and epilepsy with ESES are unusual complications of this disease. In our cohort, the children with seizures were treated with routine antiseizure medications excluding valproate. The child with epilepsy with ESES was treated with pulse methylprednisolone followed by a tapering course of oral steroids and oral diazepam on which there was a substantial reduction in seizure frequency.
Despite the presence of the same mutations in the ARG1 gene in unrelated family members in our cohort, there was remarkable variability in age at presentation and the clinical course highlighting the phenotypic pleiotropy of this disease. There were three novel variants in our cohort. Among some variants of our cohort which were previously reported, there were no specific characteristics to suggest a phenotype-genotype correlation., However, the limited number of patients in our study and the general rarity of this condition pose difficulty in establishing such a correlation. The incorporation of multicentric data in a unified database may pave way for further detailed exploration.
The use of molecular studies will enable genetic counseling, carrier screening, and prenatal diagnosis. In our cohort, prenatal diagnosis was offered to one family which identified a carrier mutation. To the best of our knowledge, this study is the single largest series of Arginase deficiency in India with the inclusion of molecular studies.
| Conclusion|| |
The presence of motor predominant developmental delay and progressive spasticity with or without extrapyramidal features should alert the clinician to suspect arginase deficiency. The occurrence of metabolic encephalopathy with hyperammonemia in the clinical course of the disease seems to be a more common entity than previously described. Epilepsy with ESES is an uncommon complication that has been rarely reported.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest
| References|| |
Sun A, Crombez EA, Wong D. Arginase deficiency. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al
., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1159/
. [Last accessed on 2022 Jun 24].
Robert K. Nelson Textbook of Pediatrics. 21st
ed. Philadelphia, PA: Elsevier; 2020. p. 3289-90.
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.
Cornelius L, Raju V, Julin A. Arginase deficiency presenting as acute encephalopathy. J Pediatr Neurosci 2019;14:133-6.
] [Full text]
Jain-Ghai S, Nagamani SCS, 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.
Zhang Y, Landau YE, Miller DT, Marsden D, Berry GT, Kellogg MD. Recurrent unexplained hyperammonemia in an adolescent with arginase deficiency. Clin Biochem 2012;45:1583-6.
Ishida Y, Fujita T, Asai K. New detection and separation method for amino acids by high-performance liquid chromatography. J Chromatogr A 1981;204:143-8.
Deignan JI, Marescau B, Livesay JC, Iyer RK, De Dyen PP, Cederbaum SD, et al
. Increased plasma and tissue guanidino compounds in a mouse model of hyperargininemia. Mol Genet Metab 2008;93:172-8.
Marescaua B, Qureshi IA, De Deyn P, Letarte J, Ryba R, Lowenthal A. Guanidino compounds in plasma, urine and cerebrospinal fluid of hyperargininemic patients during therapy. Clin Chim Acta 1985;146:21-7.
De Deyn PP, Marescau B, Macdonald RL. Guanidino compounds that are increased in hyperargininemia inhibit GABA and glycine responses on mouse neurons in cell culture. Epilepsy Res 1991;8:134-41.
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.
] [Full text]
Brosnan ME, Brosnan JT. Orotic acid excretion and arginine metabolism. J Nutr 2007;137 (6 Suppl 2):1656S-61S.
Jay A, Seeterlin M, Stanley E, Grier R. Case report of argininemia: The utility of the arginine/ornithine ratio for newborn screening (NBS). JIMD Rep 2012;9:121-4.
Nandhagopal R, Al-Murshedi F, Al-Busaidi M, Al-Busaidi A. Encephalopathy mimicking non-convulsive status Epilepticus. Neurosci J 2018;23:52-6.
Huemer M, Carvalho DR, Brum JM, Ünal Ö, 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.
Bijarnia-Mahay S, Häberle J, Jalan AB, Puri RD, Kohli S, Kudalkar K, et al
. Urea cycle disorders in India: Clinical course, biochemical and genetic investigations, and prenatal testing. Orphanet J Rare Dis 2018;13:174.
[Figure 1], [Figure 2], [Figure 3]