Inherited Metabolic Disease Laboratory

David Taylor
February 2012
Argininaemia

Defect: Argininaemia deficiency results from deficiency of the enzyme arginase. It is

thought to be the least common of the urea cycle disorders.

Pathway: Arginase catalyses the fifth step in the urea cycle, in which arginine is
hydrolysed into ornithine and urea (Figure 1). The urea cycle performs a number of
roles: it is the sole source of endogenous arginine, ornithine, and citrulline
production; it is the dominant mechanism for the removal of waste nitrogen form
protein turnover; it is the principal mechanism for metabolism of other nitrogenous
metabolic compounds like adenosine monophosphate; it incorporates enzymes
which overlap with the nitric oxide production pathway (ASS and ASL).

Figure 1: The urea cycle. The enzyme block (arginase) in argininaemia is indicated by the red line.

Genetics:
Argininaemia is inherited in an autosomal recessive manner. The arginase enzyme is
encoded by the ARG1 gene.
Inherited Metabolic Disease Laboratory
David Taylor
February 2012
Clinical Presentation:
In contrast to the other eight urea cycle disorders, arginase deficiency rarely results
in elevated plasma ammonia concentration in the newborn period, even in
individuals whom lack enzyme expression entirely. Episodic hyperammonaemia of
varying concentration can occur, but is rarely severe enough to be life threatening.
Hyperammonaemia is often only detected if measured during an acute illness. It is
thought that 75% of individuals with arginase deficiency survive their disease, living
long, albeit handicapped lives.

In most cases birth and early childhood pass entirely normally. However, from the
ages of 1-3 growth is seen to slow and spasticity (most commonly spastic diplegia)
begins to be observed. Soon after, normal neurological development slows or stops
altogether and the child does not achieve developmental milestones. If the disorder
remains untreated, children progress to severe spasticity, loss of the ability to walk,
loss of bowel and bladder control and severe intellectual disability.

There is a spectrum of affectedness in children ranging from those in whom the

primary manifestation is severe spasticity through to those whom are more affected
neurologically. All affected individuals have growth deficiency, whilst the seizures that
are commonplace can usually be controlled easily.

Older individuals have been known to present with arginase deficiency with
postoperative encephalopathy.

Age of onset:
Age of onset of symptoms is typically at 1-3 months following an unremarkable birth
and early infancy.

Biochemistry:
Hyperammonaemia with respiratory alkalosis are common to all urea cycle defects
during periods of metabolic decompensation.

Plasma amino acids: An elevation of plasma arginine concentration 3-4x the upper
limit of normal is highly suggestive of a diagnosis. Note: Up to 2x elevations in
arginine can be seen in infants whom are otherwise normal. In all other urea cycle
defects, arginine concentrations are low.

Plasma ammonia. Elevated plasma ammonia concentrations may occur

intermittently, however acute presentation with ammonia >150 mol/L is
uncommon.

Urinary orotic acid concentration. Urinary orotic acid concentration is often elevated;
however its measurement is not a primary screen for the disorder.
Inherited Metabolic Disease Laboratory
David Taylor
February 2012
Confirmatory tests:
Enzyme studies using erythrocytes can be used to confirm the diagnosis.

Prenatal Diagnosis:
Genetic prenatal diagnosis is potentially possible where the disease causing mutation
is known, although it does not appear to be currently offered within the UK as a test.

Treatment:
The management of individuals with arginase deficiency closely mirrors those
described for other urea cycle disorders with one caveat: individuals with arginase
deficiency are less prone to episodes of hyperammonaemia. Moreover, when
hyperammonemia is present it is more likely to respond to conservative management
such as intravenous fluid administration. Arginine supplementation is
contraindicated. In infants feeding of 1-1.5 g protein/kg body weight with 50% as
essential amino acids. Older children require lower protein intake.

However, if plasma ammonia concentrations need to be lowered rapidly dialysis is

recommended. Dialysis can be discontinued in most cases when the plasma
ammonia falls below 200 mol/L. Sodium phenylbutyrate and sodium benzoate can
then be administered to provide an alternative route for nitrogen excretion.

The seizures which are associated with the disorder are readily treated by
phenobarbital or carbamazepine. Sodium valproate should be avoided, as this is
known to exacerbate hyperammonaemia.

Acute intercurrent illnesses should be treated promptly with special dietary

intervention or hospitalization to minimize the effect of catabolism.

Most individuals with arginase deficiency have persistent hepatic synthetic function
abnormalities, particularly, elevated prothrombin time. In some circumstances
hepatic fibrosis and cirrhosis have developed and have either been fatal or required a
liver transplant.

Pathophysiology:
It is not fully understood what the consequences of persistently raised
concentrations of arginine are.

High concentrations of ammonia (when present) are speculated to have the follwing
consequences. The target of ammonia toxicity in the brain appears to be the
astrocyte, with development of Alzheimer type II astrocytosis being a probable
histopathologic consequence of ammonia toxicity.

One proposed mechanism for ammonia-induced neurologic dysfunction is cerebral

oedema. Glutamine, produced by the metabolism of ammonia via glutamine
Inherited Metabolic Disease Laboratory
David Taylor
February 2012
synthetase within astrocytes, acts as an intracellular osmole and attracts water into
the astrocytes, which leads to swelling and appears to induce oxidative dysfunction
of the mitochondria.

In another mechanism of astrocyte toxicity, ammonia appears to directly trigger

oxidative and nitrosative stress in the astrocyte by increasing intracellular calcium,
leading to mitochondrial dysfunction and cellular energy failure via opening of the
mitochondrial transition pore.

Additional proposed mechanisms of neuronal dysfunction include ammonia-induced

RNA oxidation, activation of mitogen-activated protein kinases, and activation of
nuclear factor-B, all of which can lead to enhanced cytokine activity and an
inflammatory response, as well as impaired intracellular signaling