Screening of 58 neonatal metabolic disorders in Iran (Part IV - Amino Acid Disorders)

Screening of 58 neonatal metabolic disorders in Iran (Part IV - Amino Acid Disorders)

In the following, we will discuss one of the most important disorders that is screened during this process, namely amino acid disorders.

Disorders of amino acids

Amino acids are the building blocks of proteins and perform a variety of functions in the body. In addition, plasma is the second most important non-protein plasma nitrogen compound after urea.

- The hereditary pattern of these disorders is the autosomal recessive pattern and is observed in girls and boys equally. For this reason, the prevalence of these diseases is higher in consanguineous marriages.

Although more than 150 different types of amino acids are known biologically, only 20 of them are important components of proteins in the body.

- In general, when after consuming protein, these substances are first broken down into their building blocks (amino acids) and then used in the body's metabolism to make the proteins needed by the body. This is very important in the process of developing a baby. They can also be used as a source of energy.

Biologically, amino acids are divided into two groups: essential and non-essential amino acids. Essential amino acids are those that, unlike other groups, are not produced in the body and must be absorbed through food. The group includes nine amino acids, including leucine, isoleucine, valine, phenylalanine, threonine, methionine, tryptophan, and lysine. In addition, histidine amino acids are essential for humans and arginine for animals.

Eleven amino acids are made by the body itself from the beginning, which are called unnecessary amino acids and are produced from intermediate compounds that are readily available. These amino acids include alanine, arginine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine and tyrosine.

- Normally, the amount of protein we receive daily is much higher than we need, and as a result, a very small percentage of it is used to make new proteins. For example, less than 5% of dietary phenylalanine amino acids used in the diet are used to make new proteins and thus grow the body, and the rest are used to produce other amino acids, including tyrosine and other amino acids involved in brain activity. Takes.

When a baby's body is unable to burn amino acids, this can have several consequences: first, the amino acids increase before this process and turn into other compounds that can be toxic, and second, the lack of production of some compounds ( It is made up of amino acids, some of which are especially important for brain function.

The early stages of amino acid metabolism include the following:

- Convert one amino acid to another amino acid

- Removal of amine group from amino acid

If a disorder occurs in the enzymes of this stage, it leads to an increase in blood amino acids, and as a result, these disorders are considered as a class of amino acid disorders.

Many inherited metabolic disorders are caused by an increase in amino acids in the blood. An inherited disorder of an amino acid is usually directly related to a lack of an enzyme involved in the metabolism of one or more amino acids, so that its degradation process is impaired, resulting in very high plasma concentrations of these amino acids and urinary excretion.

- Sometimes these disorders are caused by the body's inability to transfer these amino acids into the cells.

- In these cases, the concentration of amino acids is clearly 3-4 times the normal limit, but may increase up to 10 times normal.

Increased levels of amino acids are found in certain amino acids such as phenylketonuria (PKU), maple syrup (MSUD), and certain amino acids such as glutaric acid. Decreased levels of amino acids are also seen in nephritis, nephrotic syndromes, and Hartnup's disease.

For example, in phenylketonuria, a defect in the enzyme converting phenylalanine to tyrosine (phenylalanine hydroxylase I and II) is seen. Phenylalanine is normally converted to a small amount in the presence of an enzyme called transaminase.

 The excess phenylalanine in this process is converted to tyrosine and is easily excreted by the kidneys. Phenylprovic acid is also converted to other ketone bodies in the body's metabolism and excreted in the urine.

Lack of the enzyme phenylalanine hydroxylase I causes classic phenylketonuria. In the absence of phenylalanine hydroxylase enzymes, phenylalanine levels and phenylpyroic acid increase, leaving toxic and destructive effects on nerve cells. These babies do not have many symptoms at birth, but most parents complain of drowsiness or lack of breastfeeding.

 If not diagnosed and treated in time, the disorder can lead to severe muscle cramps, impaired physical development, decreased IQ, seizures, nausea, vomiting, eczema-like skin rashes, and the conversion of sweat and urine odor to a mouse-like odor. The color of the skin and hair increases compared to other members of the family. In addition, behavioral disorders, hyperactivity, and devastation are seen in older children.

- Fourteen diseases are in this group.

Clinical signs:

In general, the age of onset of symptoms and the type of symptoms vary greatly depending on the type of disease. Most of these babies are healthy at birth and have no symptoms. Some children develop physical retardation and mental retardation if left untreated.

 Some also have symptoms such as drowsiness, tingling, not breastfeeding, vomiting, and irritability. If left untreated, more serious problems such as respiratory problems, seizures, encephalitis, coma and death can occur.

Most amino acid disorders are associated with a series of pathological changes in the myelin membrane of the central nervous system called spongy myelinopathy = SM.

 Depending on the type of amino acid that is increased, disorders specific to each disease occur. The smell of mice in PKU, the smell of burnt caramel or the smell of maple syrup in MSUD, and the smell of cabbage in tyrosinoma of type I are the specific clinical signs of amino acid disorders.

In homocysteine ​​disease, cardiovascular disorders, cerebral infarction, eye disorders, and learning disabilities are seen.

 

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 methionine, glycine, leucine, isoleucine, valine, phenylalanine, and tyrosine, which are the primary markers for screening for amino acid 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 in primary markers during the above two sampling stages, the changes of the secondary markers during the two sampling stages are also calculated.

Secondary markers include:

- Phenylalanine / tyrosine ratio (normally less than 1.9) in PKU disease,

- Leucine / phenylalanine ratio (normally less than 4.7) Leucine / alanine ratio (normally less than 1.5) Valine / phenylalanine ratio (normally less than 5.2) in MSUD,

Methionine / phenylalanine ratio (normally between 0.17 and 1.2) in homocysteineuria and hyperthyroidism

- Tyrosine / citrolin ratio in tyrosinemia,

- Glycine / Alanine ratio in non-ketotic hyperglycemia,

If these changes are observed in secondary markers, the individual's response is considered "outside the normal range" and is reported as a "suspicious" test for amino acid disorders, and confirmatory or diagnostic tests are recommended to confirm the diagnosis.

 

Diagnosis:

HPLC Plasma Acid Acid Profile Test: Increases or decreases the amino acids methionine, glycine, leucine, isoleucine, valine, phenylalanine, and tyrosine.

Urinary amino acid profile test: This is characterized by increased urinary excretion of the above amino acids.

Increased levels of ketones in the urine.
Perform profiling of organic acids in urine.
Measurement of urine biopsy.
Measurement of enzyme levels in fibroblasts
In cases suspected of non-ketotic hyperglycemia, measurement of Glycine CSF to Glycine Plasma ratio
Genetic testing: Today, there are specific genetic tests (DNA tests) that can be used to determine if a fetus is carrying a defective gene.
 

treatment:

The main purpose of treatment in these diseases is the following:

Try to prevent the accumulation of toxic metabolites as well as compensate for the metabolic substance that is deficient
Withdrawal of toxins accumulated in the body by methods such as fluid administration (to compensate for the lack of breastfeeding, increase fluid flow and ensure effective excretion of toxic metabolites)
Vitamin therapy (as therapeutic cofactors in cases of deficiency and deficiency of related groups and increased metabolism)
 

- There is no 100% cure for these disorders and you should only try to prevent the complications of these diseases as much as possible by using special diets.

- The main goal of treatment in amino acid disorders is to get enough amino acids or protein to maintain the growth process, but it should not be exceeded to the extent that it causes damage to the body due to increased amino acids.

Diets in each of these disorders are designed to contain the required amount of a specific amino acid in which the disease increases and thus prevents a large amount of toxic amino acids from reaching the body. For this reason, most of these disorders use special formulas.

- Because these formulas are not considered a complete treatment, the level of these amino acids must be strictly controlled during the treatment process. Nervous symptoms caused by a deficiency or increase in toxic substances should also be monitored regularly.

- For example, in the treatment of PKU, the disease can be managed by eliminating foods containing phenylalanine. In these patients, artificial sweeteners such as L-aspartylphenylalanine, which is used as a substitute for sucrose in many pediatric therapies, should be avoided.

Prescribing high doses of vitamin B6, folate, and other vitamins to patients with homocystinuria reduces the level of homocysteine.