Arginase Deficiency (Argininemia)


Article Author:
Jose Morales


Article Editor:
Kristin Sticco


Editors In Chief:
Jon Parham
Jon Sivoravong


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
4/8/2019 11:18:46 PM

Introduction

Arginase deficiency (Arginininemia) is an autosomal recessive metabolic disorder characterized by hyperammonemia secondary to arginine accumulation. Ammonia levels can vary according to patient’s current age and status, presenting initially with reduction of growth, and moving to milestone development and cognition. Sometimes when not treated the disorder leads to regression. 

Often diagnosed at birth through newborn screening (NBS), affected newborns are found to have elevated levels (up to 4 times) of arginine. Its management corresponds classically as another urea cycle defect, with mild or absent hyperammonemia and, if present, responds adequately to reductive ammonia actions. Chronic treatment consists of protein restriction along with nitrogen-scavenging medications.[1]

Etiology

Mutations in ARG1 lead to an unstable arginase enzyme, a protein found in the cytosol and responsible for the final step of the urea cycle. This results in the hydrolysis of arginine to urea and ornithine.

Another gene responsible for arginase can be found (ARG2); however, it is not translated in enough quantities to compensate the primary defect.[2]

Epidemiology

Arginase deficiency is the most uncommon urea cycle disorder. The estimated incidence is around 1 per 1,000,000. No particular genotype-phenotype correlations have been postulated to date, meaning there is no accurate method to indicate a particularly affected population.[1][3]

Pathophysiology

Arginase, commonly found in liver, erythrocytes, and salivary glands, catalyzes the fifth and last reaction of the urea cycle, hydrolyzing L-arginine into ornithine and urea. 

Its inactivation or absence, causes accumulation of arginine, reversibly translating into ammonia overproduction at different levels and expressions after 1 to 3 years of life; although, a few cases have been reported in early infancy. 

Orotic acid accumulation can often be found, given that reduction of ornithine impairs ornithine transcarbamylase activity, creating a backup or overflow of carbamyl phosphate which is subsequently shunted to the pyrimidine synthetic path.[4][3]

Histopathology

Brain lesions found on the histopathology of patients with chronic hyperammonemia on infancy have often been correlated to those of hypoxic-ischemic events.

Late manifestations of the liver include fibrosis, cirrhosis, and hepatocellular carcinoma.[5]

Toxicokinetics

The substantial toxic effect of ammonia accumulation causes brain damage through cerebral edema. Affected regions include parietal, occipital, and frontal.[5]

History and Physical

Arginase deficiency (arginininemia) rarely presents in the newborn/infant period. Hyperammonemia may still present, but it is not life endangering. After 1 to 3 years of life, patients develop intermittent episodic hyperammonemia which can be induced by catabolic states (infections), high dietary protein intake, or medications (valproate). This status can only be recognized while the patient is presenting the acute injury.[6]

While developing, patients progressively present reduction of linear growth (100%) and spastic diplegia while cognitive development stagnates or regresses. Particular long-term cognitive manifestations evidenced on recent studies include intellectual disability, ADHD, aggressive behaviors, pervasive development disorder, memory recollection, and fine motor skills impairment. The last 2 are remarkable in the adult population.

If no treatment is provided, patients will develop severe complications of the abnormalities stated above. Objective neurologic findings discovered through brain imaging studies consist of seizures, microcephaly, and cortical atrophy.[7][5]

Evaluation

Newborn screening programs around the nation can successfully detect high arginine levels. However, it is not universal as of yet, around 12 states do not include it in their analysis, therefore, in individuals with no such opportunity, a high index of suspicion should rise if they present with regression of development milestones. [6]

Following elevated arginine levels (which can rise 4-fold), ammonia levels in acute states (if present, above 200 micrograms/dL). Subsequent arginase enzyme analysis on red blood cells (less than 1%) or sequence analysis of ARG1 confirm the diagnosis; however, the latter is considered the first confirmatory step due to feasibility to perform.[8]

Treatment / Management

Initial workup after diagnosis consists of plasma ammonia concentration, plasma arginine levels, and cognitive and neurologic evaluation. This stage is critical, as there are particular managements for other types of urea cycle disorders, where arginine administration is provided to reduce ammonia levels by being catalyzed and indirectly increasing citrulline levels.

For acute states, most of the time, hyperammonemia requires no more than conservative treatment, for example, intravenous (IV) fluids. If severe hyperammonemia, clinicians should consider reduction by dialysis, either through ECMO or hemodialysis. These should be stopped once ammonia levels reach 250 micrograms/dL or lower. The use of nitrogen scavengers like sodium phenylacetate or sodium benzoate for severe or moderate cases, along with restriction of protein intake, and the introduction of non-protein calorie sources like fats and carbohydrates should be considered. When using carbohydrates with intravenous fluids, use dextrose 10% and one-quarter normal saline. Avoid overhydration as cerebral edema can show up. Abstinence from protein should not last more than 48 hours, as further catabolism can present from essential amino acids. Should seizures present, use phenobarbital or carbamazepine. Valproate is contraindicated since it induces hyperammonemia.[6]

For maintenance, protein restriction should be on the minimal protein intake range to help basic functions and development. With half of the dietary protein free of arginine, a total absence of this amino acid cannot be accepted given its essential role for T cell and endothelial function. Ideal protein intake in infants ranges from 1 to 1.5 gm/kg. As the child grows, the restriction can be tolerated on lower levels. Daily administration of nitrogen scavengers on maintenance dosing is sodium phenylbutyrate 350 to 600 mg/kg per day.

Liver transplantation can be considered as an ultimate treatment to reduce recurrent hyperammonemia.

Monthly visits during infancy, with progressively increased intervals between visits as the patient grows. Monitor liver function, arginine levels, spasticity, and development.

Preference should be given to medications that bypass liver metabolism over other medications. Examples are ibuprofen over acetaminophen or another antiepileptic over valproate.

Research has been implemented to provide a better response or an ultimate cure for this pathology. Approaches like adeno-associated viral vectors, CRISPR-associated protein nine genome editing, and induced pluripotent stem cells have shown a successful response to their target goal. However, these results have not been translated to a clinical setting due to their early stages.[4][8]

Differential Diagnosis

Despite elevated levels of arginine in comparison to other amino acids that may even be encountered as normal on newborn screening or amino acid profile, suggest a strong diagnosis of arginase deficiency. Other urea cycle disorders should be considered, particularly in the event of hyperammonemia without a strong amino acid profile.[4][8]

Pearls and Other Issues

Given the broad phenotype and variable presentation, an initial, thorough investigation of proband can later expand to siblings or other relatives should they present with similar symptomatology.[9] 

For prenatal testing, gene sequencing should be the first diagnostic step, as chorionic villus sampling and amniocytes lack arginase become unsuitable procedures.[10]

Enhancing Healthcare Team Outcomes

Arginase deficiency (Arginininemia) is an autosomal recessive metabolic disorder characterized by hyperammonemia secondary to arginine accumulation. The disorder is rare and is best managed by a pediatrician, geneticist, endocrinologist and a dietitian. The disorder is sometimes identified during screening of the newborn. The Ammonia levels can vary according to the patient’s age and status, presenting initially with reduction of growth, and moving to milestone development and cognition. Sometimes when not treated the disorder leads to regression. 

Often diagnosed at birth through newborn screening (NBS), affected newborns are found to have elevated levels (up to 4 times) of arginine. Its management corresponds classically as another urea cycle defect, with mild or absent hyperammonemia and, if present, responds adequately to reductive ammonia actions. Chronic treatment consists of protein restriction along with nitrogen-scavenging medications.[1]

The pharmacist should educate the caregiver on the need for compliance with medication and the importance of low protein diet.

 


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Arginase Deficiency (Argininemia) - Questions

Take a quiz of the questions on this article.

Take Quiz
A 6-year-old female is brought to the emergency department by emergency medical service due to seizures. Currently, her status is post-ictal. The parents arrive a few minutes later stating the patient has a metabolic disorder they can't name at the moment. On her current list of medications are valproate for seizure disorder and sodium benzoate to reduce ammonia. A serum amino acid panel reveals elevated arginine. Which of the following antiseizure medications is contraindicated?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 2-year-old male is admitted to the pediatric floor due to altered mental status. The parents report the patient was developing well until 6 months ago when they noticed patient reduced babbling and has not progressed on his vocabulary. They also have noticed his legs turn a bit stiff at times and after heavy meals patient's mental status turns into obnubilation. Blood workup reveals hyperammonemia and quantitative plasma amino acids revealing high amounts of an amino acid involved in the last step of the urea cycle. What is the primary diagnosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 29-year-old female is being followed for arginase deficiency. Which symptoms are expected to be worse than any other at her age?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
An 8-year-old male is admitted to the critical care unit due to severe hyperammonemia. The baseline diagnosis is arginase deficiency. Which of the following would be the first step in management?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A couple comes to the clinic for prenatal care. They are concerned their new child will have arginase deficiency as their 3-year-old has the condition. They ask for advice regarding testing at week 12 of gestation. Which of the following options is the more suitable at this point?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Arginase Deficiency (Argininemia) - References

References

Arginases and arginine deficiency syndromes., Morris SM Jr,, Current opinion in clinical nutrition and metabolic care, 2012 Jan     [PubMed]
Arginases I and II: do their functions overlap?, Cederbaum SD,Yu H,Grody WW,Kern RM,Yoo P,Iyer RK,, Molecular genetics and metabolism, 2004 Apr     [PubMed]
The human arginases and arginase deficiency., Iyer R,Jenkinson CP,Vockley JG,Kern RM,Grody WW,Cederbaum S,, Journal of inherited metabolic disease, 1998     [PubMed]
A Case of Hyperargininaemia Presenting at Unusually Low Age., Lal V,Khera D,Gupta G,Singh K,Sharma P,, Journal of clinical and diagnostic research : JCDR, 2017 Jul     [PubMed]
Newborn screening for hyperargininemia due to arginase 1 deficiency., Therrell BL,Currier R,Lapidus D,Grimm M,Cederbaum SD,, Molecular genetics and metabolism, 2017 Aug     [PubMed]
Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium., Waisbren SE,Gropman AL,Batshaw ML,, Journal of inherited metabolic disease, 2016 Jul     [PubMed]
Yahyaoui R,Blasco-Alonso J,Benito C,Rodríguez-García E,Andrade F,Aldámiz-Echevarría L,Muñoz-Hernández MC,Vega AI,Pérez-Cerdá C,García-Martín ML,Pérez B, A new metabolic disorder in human cationic amino acid transporter-2 that mimics arginase 1 deficiency in newborn screening. Journal of inherited metabolic disease. 2019 Jan 22;     [PubMed]
Asrani KH,Cheng L,Cheng CJ,Subramanian RR, Arginase I mRNA therapy - a novel approach to rescue arginase 1 enzyme deficiency. RNA biology. 2018;     [PubMed]
Morales JA,Bhimji SS, Arginase Deficiency (Argininemia) 2018 Jan;     [PubMed]
Diez-Fernandez C,Rüfenacht V,Gemperle C,Fingerhut R,Häberle J, Mutations and common variants in the human arginase 1 (ARG1) gene: Impact on patients, diagnostics, and protein structure considerations. Human mutation. 2018 Aug;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Family Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Family Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Family Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Family Medicine. When it is time for the Family Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Family Medicine.