Urea Cycle Disorders

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Disorders of the urea cycle (small Krebs cycle, ornithine, ureosynthetic cycle) form a group of enzymatic disorders, which result in the accumulation of nitrogen in the form of ammonia, which is very toxic to the body and causes irreversible brain damage.

The clinical manifestation of these diseases is usually the first days of life. Hyperammonaemia causes cramps, vomiting and coma. In older children, these disorders are most often manifested by psychomotor retardation, failure to thrive, vomiting, behavioral disorders, recurrent cerebral ataxias, and headaches.

It is necessary to monitor the level of ammonia in the blood in every patient with neurological symptoms of unknown origin. The frequency of urea cycle disorders is approximately 1:30,000.

Pathogenesis

The urea cycle serves to excrete excess nitrogen (ammonia) in the form of urea. Urea is non-toxic, freely soluble in water and diffusible. Urea is the main organic component of urine.

If the urea cycle is disrupted due to an enzymatic defect, hyperammonemia develops, amino acids accumulate in front of the enzyme block and, conversely, the concentration of amino acids behind the enzyme block decreases.

Plasma glutamine levels are also usually elevated. This is due to the fact that in this case an alternative route of ammonia conversion is used, which is converted to glutamine by means of glutamine synthetase and glutamate substrate. Increased glutamine content in astrocytes leads to an osmotic effect of their swelling and brain edema.

During the accumulation of carbamoyl phosphate, orotic acid is formed, which is an important diagnostic marker. It is increased in disorders of all enzymes except CPS1, when even carbamoyl phosphate is not formed, so conversion is not possible.

Distribution

Includes 5 inherited disorders:

	damaged enzyme	location	type of inheritance	incidence	OMIM	links
Hyperammonemia I	carbamoyl phosphate synthetase (CPS1)	mitochondria	AR hereditary	rare (about 24 cases)	#237300	[1]
Hyperammonemia II	ornithine carbamoyltransferase (OTC)	mitochondria	X bound, manifestations may also be present in heterozygous girls		#311250	[2]
Citrullinemia	arginine succinate synthetase (ASS)	cytosol	AR hereditary	1:70 000–1:100 000	#215700	[3]
Arginine succinaturia	arginine succinate lyase (ASL)	cytosol	AR hereditary	1:70 000–1:100 000	#207900	[4]
Argininemia	arginase (ARG1)	cytosol	AR hereditary	rare (50 cases)	#207800	[5]

Clinical picture

Urea cycle

Urea cycle disorders usually occur in 2 forms - early and late.

Early forms manifest shortly after birth with hyperammonaemic coma, metabolic acidosis, liver failure, convulsions, and cerebral edema.

Late forms are manifested by anorexia, vomiting, failure to thrive, hypotension and disorders of psychomotor development.

Hyperammonemia (type I)

It is a carbamoyl phosphate synthetase defect that occurs in two forms: severe (lethal neonatal) and milder with later onset.

The lethal neonatal form is manifested by severe brain damage, hyperammonemic coma and ketoacidosis. In the milder form, hyperammonemic coma, Reye-like syndrome, vomiting, hypotension, failure to thrive, and psychomotor retardation may occur.

In the analysis of the laboratory examination, we find low concentrations of arginine and citrulline and high concentrations of glutamine. In contrast, uracil and orotic acid are normal.

Citrulinaemia (type I)

It is an arginine succinate synthase defect occurring in two forms. The first is neonatal, manifested by hyperammonemic coma and lactic acidosis. The second form is chronic juvenile, whose symptoms are anorexia, vomiting, hypotension, growth and psychomotor retardation and convulsions.

We distinguish two more types of citrulinaemia. Type II is characterized by a deficiency of the mitochondrial transporter aspartate and glutamate (citrine), resulting in an intramitochondrial aspartate deficiency. Type III is characterized by a partial arginine succinate synthetase deficiency with high residual enzyme activity

In the laboratory, we find low concentrations of arginine, but high concentrations of citrulline and glutamine, uracil and orotic acid are increased.

Arginine succinaturia

It is an arginine succinate lyase defect that occurs in two forms, early and late. The early form manifests as a severe hyperammonemic coma shortly after birth and is often fatal. In late form, we can observe hypotension, failure, loss of appetite, chronic vomiting and behavioral disorders during childhood. Other manifestations may include hepatomegaly and brittle hair (trichorrhexis nodosa).

In the laboratory, we find a low concentration of arginine and increased concentrations of glutamine and citrulline, and we show an increase in the concentration of orotic acid and uracil in the urine.

Argininemia

It is an arginase I defect, the symptoms of which include spastic diplegia, epilepsy, psychomotor retardation, hyperactivity, irritability, inconsolable crying, anorexia, vomiting, and rare symptomatic hyperammonaemia progressing to coma.

We show hyperargininemia in the laboratory and increased urinary excretion of orotic acid. The leading symptom is hyperammonemia.

If we look at ABR, we first find respiratory alkalosis and later metabolic acidosis.

Another important indicator is amino acids in plasma (chromatography), where in the results we find increased concentration of glutamine and glutamic acid and little arginine (except argininaemia), further increased amino acid concentration before enzymatic defect and decreased amino acid concentrations after defect (eg little citrulline and a lot of arginine). orotate → OTC - as with each enzyme block).

Orotic acid in the urine is elevated in disorders of all enzymes except CPS1.

We perform determination of enzymatic activity from liver tissue and analysis of mutations.

Differential diagnosis of hyperammonaemia

Disorders can be divided into congenital and acquired.

Congenital defects include urea cycle disorders, organic aciduria, fatty acid transport or oxidation disorders, hyperinsulinism, and hyperammonemic syndrome.

We include Reye's syndrome, liver failure of other etiology, transient hyperammonemia of the newborn (it is mainly in NNPH). The treatment is performed with the help of valproate em.

Therapy

First aid consists of converting catabolism into anabolism (i.v. high doses of glucose with insulin, high-calorie parenteral nutrition) and detoxification. Sodium benzoate activates alternative pathways of nitrogen excretion. Phenylbutyrate, which is metabolized to phenylacetate, ensures the binding of glutamine and allows it to be excreted by the kidneys. In case of impaired consciousness, an elimination method (hemodialysis, hemodiafiltration) must be used to reduce ammonia. We also substitute amino acids (usually arginine and citrulline - valid only in selected defects).

Lifetime protein intake must be reduced to 0-1.2 g / kg / day and must be substituted with essential AMK mixtures. Liver transplantation is required for severe metabolic disorders.

Prognosis

With early therapy (except severe forms of OTC) may be good, with the development of severe hyperammonic coma (usually over 300 μmol / l ammonia at a standard around 50 to 70 μmol / l) in neonatal age there is a high risk of disability.