Arginase Deficiency

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.

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 the image below). 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.[2] 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. A 2016 study suggests an adverse effect of arginase-1 deficiency on level 5 cortical motor neurons, as well as diminished synaptic transmission in a neonatal mouse model, recoverable by gene therapy.[3]

Frequency

United States

The incidence of arginase deficiency  cannot be cited because of the absence of any population screening data.

Mortality/Morbidity

The morbidity associated with arginase deficiency 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, arginase deficiency equally affects both genders.[4]

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.[5]

With heightened awareness of arginase deficiency, more affected individuals are surviving into adolescence and adulthood; hence, the natural history of arginase deficiency, with and without treatment, is emerging.[6, 7]

In view of the relatively subtle and progressive presentation, patient rarely escape irreversible damage to the CNS. Nonetheless, early diagnosis in the clinical course allows for improved outcome.

Even in patients who receive a late diagnosis, treatment from birth in a subsequent infant of an affected family should prevent the developmental delay and the spasticity, based on more recent experience.

Advise parents of an affected child of their obligate heterozygote status.

Adherence to a low-protein diet is imperative; stress the importance to long-term outcome.

Seek early medical attention for intercurrent illnesses because hyperammonemic crisis, although uncommon in this disease, can occur.

Prenatal diagnosis is possible with an enzyme assay using fetal RBCs; arginase mutations have been identified in skin fibroblasts from amniotic fluid and specimens from chorionic villus biopsies.

A history of delayed development, protein intolerance, and spasticity is suggestive of arginase deficiency.[8]

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.

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

See the list below:

• 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

See the list below:

• 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

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 40 mutational variants have been identified.[9]

Beyond the inherent problems in diagnosis of any urea cycle disorder, arginase deficiency is somewhat difficult to diagnose.

The typical crisis associated with hyperammonemia is rare, and random measurement of blood ammonia levels during periods of clinical stability is not helpful.

Arginine excretion in urine is not usually massively increased because of isozyme induction; however, a urinary amino acid excretion pattern can be observed. The excretion pattern is similar to that found in cystinuria, with increased arginine, ornithine, lysine, and, possibly, cystine. It can be observed because of competitive inhibition of dibasic amino acid reabsorption by elevated arginine in the renal proximal tubule.

Plasma arginine levels may not be greatly increased in cases of self-restriction of protein intake; therefore, even experienced clinicians may fail to diagnose the disease. Urine orotic acid is usually mildly increased.[10] Plasma ammonia levels may be mildly increased or normal.

When mild-to-moderate elevated plasma arginine levels are observed in association with developmental delay and spasticity, a red cell arginase assay is indicated for definitive biochemical diagnosis.

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings in a relatively large group of patients with arginase deficiency have been reported recently.[11] As in the vast majority of inherited biochemical disorders, and the urea cycle defects specifically, the results are not in any way unique to the disease. Hence, MRI as a part of the initial diagnostic evaluation contributes little, if anything.

Protein intake is restricted in patients with arginase deficiency. A carefully monitored diet plan is necessary.

Because severe hyperammonemia is unusual, the need for intravenous therapy or hemodialysis is unlikely. In the event that intravenous therapy or hemodialysis is required, the need to omit intravenous arginine from the treatment regimen should be obvious.

Long-term therapy rests on provision of a low-protein diet and, possibly, oral sodium benzoate or sodium phenylbutyrate. A recent report suggests that glycerol phenylbutyrate supplies a more extended scavenger effect[12] ; this deserves further evaluation, as it could provide for an improvement in quality of life for affected individuals. A metabolic disease expert should guide the treatment of this rare condition.

A 2016 demonstration of arginase-1 activity restoration via gene manipulation to patient-specific arginase-1–deficient pluripotent stem cells offers the possibility of correction of the hepatic defect in humans. However, clinical trials have yet to be reported.[13]

As has been the case for several years with all urea cycle disorders, orthoptic liver transplantation has been advocated as a definitive cure for arginase deficiency. In a recent report of long-term follow-up of 2 arginase-deficient patients, Silva et al claim the arrest of neurological progression without dietary restrictions.[14] Since the disorder is so uncommon, it is difficult to verify such claims based on a large patient series.

See the list below:

• Medical geneticist

• Metabolic disease specialist

• Dietitian

Prenatal diagnosis can be performed using DNA analysis.

Recent experience with tandem mass spectrometric newborn screening technique has permitted early identification and treatment. Infants treated in this fashion have thus far done well and remained healthy.

A biochemical geneticist, a metabolic disease specialist, or both should guide the management of arginase deficiency, as with all urea cycle disorders.[15]

Nutritional management is the mainstay of treatment and should be carried out under the scrutiny of a highly trained nutritionist.

Closely monitor affected individuals for growth and plasma amino acid levels; under no circumstances should a child with arginase deficiency be cared for by a primary care provider alone.

Long-term treatment of arginase deficiency is based on a low-protein diet and, possibly, administration of oral sodium benzoate or sodium phenylbutyrate.

Class Summary

The use of benzoate and phenylacetate is based on the need to provide alternate routes for disposition of waste nitrogen. Benzoate is transaminated to form hippuric acid, which is rapidly cleared by the kidney. Phenylacetate is converted to phenylacetyl coenzyme A (CoA) and then conjugated with glutamine to form phenylacetylglutamine. These 2 pathways result in disposition of 1 and 2 molecules of ammonia, respectively. Phenylbutyrate is more acceptable as a form of oral therapy because of a diminished odor but is not available for intravenous use.

Sodium benzoate and sodium phenylacetate (Ucephan, Ammonul)

Sodium benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol nitrogen. Sodium phenylacetate converted to phenylacetylglutamine, thereby taking up 1 mol per mol of free ammonia. The PO (Ucephan) and IV (Ammonul) products contain a combination of sodium benzoate 10 g/100 mL and sodium phenylacetate 10 g/100 mL (100 mg of each/mL).

Sodium phenylbutyrate (Buphenyl)

Prodrug rapidly converted PO to phenylacetylglutamine, which serves as substitute for urea and is excreted in the urine carrying 2 mol of nitrogen per mol of phenylacetylglutamine, assisting in clearance of nitrogenous waste.

Glycerol phenylbutyrate (Ravicti)

Glycerol phenylbutyrate is a nitrogen-binding agent for long-term management of adult and pediatric patients (including newborns) with urea cycle disorders who cannot be managed with dietary protein restriction and/or amino acid supplementation alone. It is a pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate and then by beta oxidation to phenylacetate. Glutamine is conjugated with phenylacetate to form phenylacetylglutamine, a nitrogen waste product that is excreted in the urine. It is not indicated for the treatment of hyperammonemia.