eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Arginase Deficiency

Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
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Updated: Mar 2, 2009

Introduction

Background

Arginase deficiency is thought to be the least common of the urea cycle disorders. This entity also manifests itself in a fashion somewhat different from other disorders in the group (see Physical). Two separate isozymes of the enzyme arginase have been reported.¹ Type I is found in the liver and contributes the vast majority of hepatic arginase activity, whereas type II is inducible and found in extrahepatic tissues. The disease is caused by a deficiency of arginase type I in the liver.

Pathophysiology

The hepatic urea cycle is the major route for waste nitrogen disposal, which is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle takes place in mitochondria; mitochondrial dysfunction may impair urea production and result in hyperammonemia (see Hyperammonemia). Overall, the rate of synthesis of N -acetylglutamate, the enzyme activator that initiates incorporation of ammonia into the cycle, regulates the activity of the cycle.

The reaction normally mediated by arginase is the terminal step in the urea cycle, which liberates urea with regeneration of ornithine (see Media file 1). Consequently, as in argininosuccinic aciduria, both waste nitrogen molecules normally eliminated by the urea cycle are incorporated into the arginine substrate molecule in the reaction.

The severe hyperammonemia observed in other urea cycle defects is rarely observed in patients with arginase deficiency for at least 2 identifiable reasons. The first reason is that formed arginine, which contains 2 waste nitrogen molecules, can be released from the hepatocyte and excreted in urine. The second reason may be attributed to the inducibility of the type II isozyme in peripheral tissues, which can attack the arginine released by the hepatocyte and produce urea and ornithine. The ornithine returns to the liver for use in the urea cycle, while the urea is excreted. A 4-fold increase in renal type II arginase has been demonstrated in an affected patient.

The distinct tendency to develop spastic diplegia in patients with arginase deficiency, as compared with patients with other urea cycle disorders, suggests a specific pathogenic mechanism at the CNS level, apart from the generalized toxicity of hyperammonemia. The nature of this mechanism remains unelucidated, but some workers have pointed to an accumulation of guanidino compounds that could interfere with GABAergic transmission. These compounds have also been shown to inhibit the cerebral cortical sodium-potassium adenosine triphosphatase (ATPase) of rats at concentrations comparable with those seen in affected humans. The ATPase is essential to maintenance of the electrochemical gradient of neurons, and its inhibition may be involved in the pathogenesis of the seizure disorder associated with this disease. 

Frequency

United States

Incidence cannot be cited because of the absence of any population screening data.

Mortality/Morbidity

Morbidity is high, but the rarity of the condition makes citing statistics impossible. Death from arginase deficiency appears to be relatively infrequent, but reliable statistics are not available.

Sex

As an autosomal recessive trait, the disease equally affects both genders.²

Age

As an inherited disorder, the age of onset is typically during the neonatal period. Because of its atypical manifestation, the disease may easily be missed in the neonatal period and only recognized in later infancy or early childhood. Some cases likely go undiagnosed, with clinical symptomatology attributed to cerebral palsy.³

Clinical

History

• A history of delayed development, protein intolerance, and spasticity is suggestive of arginase deficiency.
  • Although a catastrophic neonatal presentation is uncommon in patients with arginase deficiency, surmising that onset is at birth and that progression is relatively slow compared with other urea cycle disorders is reasonable. Specifically, dietary protein intolerance is an early sign and should not be overlooked.
  • The typical presentation is that of an older infant whose development is delayed, who has occasional episodes of vomiting and somnolence without apparent cause, who is protein intolerant, and who shows evidence of long-tract neurological impairment.
  • A common clinical feature in this disorder is spasticity, and the disease is likely underdiagnosed because many affected children are diagnosed with cerebral palsy without effort to diagnose arginase deficiency.
• The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in presentation, diagnostic features, and treatment. For these reasons, disorders in the urea cycle defect family are individually considered in this article; however, hyperammonemia is a common denominator and can present with some or all of the following symptoms:
  • Anorexia
  • Irritability
  • Heavy or rapid breathing
  • Lethargy
  • Vomiting
  • Disorientation
  • Somnolence
  • Asterixis (rare)
  • Combativeness
  • Obtundation
  • Coma
  • Cerebral edema
  • Death (if treatment is not forthcoming or effective)
• As a consequence, the most striking clinical findings of each individual urea cycle disorder relate to the constellation of symptoms of hyperammonemia and rough temporal sequence of events.
• Arginase deficiency may have a somewhat different manifestation for reasons cited above.

Physical

• General
  
  
  • Signs of severe hyperammonemia may be present.
  • Poor growth may be observed.
• Head, ears, eyes, nose, and throat (HEENT): Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.
• Pulmonary
  
  
  • Tachypnea or hyperpnea may be present.
  • Apnea and respiratory failure may occur in latter stages.
• Abdominal: Hepatomegaly may be present and is usually mild.
• Neurologic
  
  
  • Poor coordination and spasticity
  • Hyperreflexia
  • Dysdiadochokinesia
  • Hypotonia or hypertonia
  • Ataxia
  • Tremor
  • Seizures and hypothermia
  • Lethargy progressing to combativeness to obtundation to coma; decorticate or decerebrate posturing if profound hyperammonemia present

Causes

• The gene for liver arginase has been cloned and is located on chromosome 6. It has been mapped to locus 6q23, consists of 11.5 kilobases, and comprises 8 exons. A mouse "knockout" model for arginase I deficiency has been produced. These animals die within 10-12 days of birth of severe hyperammonemia, whereas animals deficient in arginase II have no identifiable phenotype, except for impaired fertility in the male.
• Approximately 20 mutational variants have been identified.

• Search for CME/CE on This Topic »

• N-Acetylglutamate Synthetase Deficiency (Pediatrics: Genetics and Metabolic Disease)
• Hyperammonemia (Neurology)
• Hyperammonemia (Pediatrics: Genetics and Metabolic Disease)