Screening of 58 neonatal metabolic disorders in Iran (Part III - Urea Production Cycle Disorders)

Screening of 58 neonatal metabolic disorders in Iran (Part III - Urea Production Cycle Disorders)

Urea production cycle disorders

- A group of genetic disorders that occur due to deficiency or deficiency of enzymes that affect the urea cycle.

All of these diseases are inherited autosomal recessively (except for OTC, whose gene is located on the X chromosome), meaning that a copy of the defective gene is required for each parent to develop the disease, and in girls and boys The ratio is observed.

People with these diseases have difficulty expelling ammonia from the body.

The estimated prevalence of the disease is about 1 in 8,000, but this is not a true prevalence, as many cases of the disease remain undiagnosed and the baby may even die without a definitive diagnosis.

For example, it is said that the cause of 20% of sudden infant death syndrome (SIDS) is due to neonatal metabolic disorders, especially urea cycle disorders. Some children who show different types of autism or behavioral disorders (such as hyperactivity with screaming and screaming, self-harm, delirium) may actually be undiagnosed with urea cycle disorders.

Ammonia is a highly toxic substance that is formed from the breakdown of proteins and amino acids, so it is converted to urea before excretion. Urea is a non-toxic substance and is easily excreted in the urine.

If ammonia is not converted to urea, its concentration in the blood will increase, causing a condition called hyperemia. Elevated blood ammonia levels for a long time will cause irreversible brain damage, coma and eventually death.

Therefore, the urea cycle detoxifies the ammonia and removes excess nitrogen from the body. It is worth noting that about 80% of the nitrogen produced in the body is excreted through the liver synthesis of urea.

- In the urea production cycle, 5 enzymes are involved and defects in each of them lead to the accumulation of ammonia in the body and include 8 different diseases.

Urea is composed of two nitrogen atoms (NH2-CO-NH2).

- These two atoms originate from the free ammonia and the amine group aspartate, respectively.

- Technically, the enzyme Carbamyl Phosphate Synthetase (CPS) is not part of the urea cycle but is essential for urea synthesis.
Carbamyl phosphate itself is produced by the CPS enzyme from ammonium (NH4 +) (after combining with bicarbonate in the presence of N-acetyl glutamate substrate), thereby inoculating the ammonium ion into the urea cycle.

- Ornithine, with the help of the enzyme ornithine trans carbamylase, forms a molecule with carbamyl phosphate and citrulline. (This reaction takes place in the mitochondrial matrix and then citrulline is transported out of the mitochondria and into the cytosol).

Citrulline, in the presence of the enzyme arginine oxytocin synthase and an aspartic acid molecule and the use of an ATP and ammonia molecule (NH4 +), produces arginine oxytocin.

Arginine oxytocin is produced by the enzyme arginine oxytocinase (lysine) and produces arginine and fumarate.
- Arginine is converted to urea and ornithine under the influence of arginase. Ornitine re-enters the mitochondrial matrix for the next round (via citrulline-ornithine transporter) and urea is excreted in the urine as the carrier of the remaining two nitrogen.

Arginine is the most important mediator in the excretion of ammonia in the form of urea. All of these processes take place in the liver.

Arginine also activates the enzyme N-acetylglutamate synthase (several times).

Inadequate arginine intake (for example, during intravenous feeding) or defects in the transport of amino acids (such as two groups of amino acids such as arginine and lysine) lead to a deficiency of ornithine in mitochondria, accumulation of carbamyl phosphate, and increased blood ammonia.

Ammonia (low-capacity) hepatic metabolism is additionally mediated by the action of the enzyme glutamine synthase in the areas around the intravenous lobules of the liver.

- This enzyme binds to ammonia in the presence of an ATP molecule and magnesium ions to glutamate, leading to the production of glutamine.
In the kidneys, glutamine is converted to glutamic acid and ammonia under the influence of glutaminease, and ammonia is excreted in the urine.

Therefore, increasing the plasma concentration of glutamine is the most sensitive indicator of insufficient urea production.



Prevalence

This group is the most common inherited errors of metabolism.
The cumulative incidence of this disease is about 1 in 8000 and occurs at all ages. But this is not true, because in many cases the disease remains undiagnosed and the baby may even die without a definitive diagnosis.

Sudden Infant Death Syndrome (SIDS) is the cause of 20% of neonatal metabolic disorders, especially those with urea cycle disorders.

Clinical signs

In general, the onset and severity of an attack on urea cycle disorders vary greatly, depending on the type of gene mutation in the enzyme and its rate of action in the urea cycle. As a result, based on the type of mutation, urea cycle disorders are seen in three forms: severe, moderate, and mild.

The most severe form of the disorder is usually fatal in children. But adults have been found to have a relative deficiency of one of the enzymes in the urea cycle.
Moderate to mild forms of the disease are not normal unless stressful (such as infections, especially viral infections), excessive protein intake - especially during the holidays -, strenuous exercise, surgery, prolonged starvation and consumption. There are medications such as valproic acid, prednisolone, and other corticosteroid compounds, which increase protein metabolism and thus increase ammonia production, and the patient develops symptoms of ammonia poisoning.

 

- Birth time: normal.

Neonatal period: In the severe form, after a short period of asymptomatic symptoms, rapidly progressive symptoms appear within the first few days of life (36 to 48 hours after birth), which include drowsiness, poor breastfeeding, rapid or slow breathing. Temperature instability (especially low body temperature), seizures, brain damage, deep coma, loss of normal neonatal reactions, and intracranial hemorrhage (caused by a defective coagulation system). All of these conditions are signs of an increase in blood ammonia.

Infancy and childhood: Physical impairment, nutritional problems, vomiting, brain damage, seizures, imbalance, and seizures.

Adolescence and adulthood: It is more common in mild to moderate forms. Behavioral problems, sleep apnea attacks, drowsiness, mental health problems (such as psychosis or psychosis, schizophrenia, and bipolar disorder), and recurrent brain damage that usually result from high protein intake or stress. Adults with a mild form of the disease remain largely unrecognized, and sometimes go to the hospital emergency department with symptoms such as dizziness, confusion, aggression, and lack of consciousness, which are confused with drug or alcohol intoxication.

 

Urea cycle disorders are the most common cause of severe ammonia increase, manifesting as recurrent, progressive, or chronic neurological disorders caused by cerebral edema. Due to the short time from the onset of the first symptoms to the irreversible brain damage, rapid and effective diagnosis and treatment are very important. The prognosis is good in terms of neurological complications and psychomotor, provided that the coma is less than 36 hours before starting treatment.

Metabolic crises usually appear during infancy, late childhood, and adulthood. In the meantime, the children's condition is relatively good, but their physical development may be poor.

 

Neonatal screening:

During screening for metabolic diseases in infants 2 to 7 days of age, MS / MS markers are tested for amino acid markers.
Among the markers measured during this screening are the amino acids arginine, citrulline, arginocinoxic acid, ornithine, and hemocytrolin, which are the primary screening markers for urea production cycle disorders. If the result of the above tests is higher than normal in Western surgery, the MS / MS test should be repeated 1 to 2 days later with re-blood sampling. Obviously, if there is an enzymatic problem, the amount of these markers will increase further in the second sample.
Secondary markers: After confirming the increase of primary markers during the above two sampling stages, the changes of secondary markers during the two sampling stages are also checked by calculating the following ratios:
Increased Arginosuccinic Acid / Arginine and Citrulline / Arginine Ratios (More than 5.95)

If you see an increase in the above ratios and the presence of these changes in the secondary markers, the individual's response is considered "outside the normal range" and is reported as a "suspicious" test for urea production cycle disorders and confirmatory or diagnostic tests are performed. Confirmation of the diagnosis is recommended.

 

Diagnosis:

HPLC Plasma Amino Acids Profile Test: Increases or decreases the amino acids arginine, citrulline, arginosuccinic acid, ornithine, glutamine, and hemocytrolin.
Urinary amino acid profile test: This is characterized by increased urinary excretion of the above amino acids.
Increased levels of ammonia and sometimes blood lactate while normal blood sugar levels.
Performing organic acid profile tests such as uric acid uric acid
Genetic testing: Today, there are specific genetic tests (DNA tests) that can be used to determine if a fetus is carrying a defective gene.