Screening of 58 neonatal metabolic disorders in Iran (Part 11 - Review of Phenylketonuria)

Screening of 58 neonatal metabolic disorders in Iran (Part 11 - Review of Phenylketonuria)
In the following, we will explain a relatively common disease in Iran that is screened during this process.
Phenylketonuria (PKU)
Cause of illness:
Phenylketonuria (PKU, Phenylketonuria) is an inherited metabolic disease in which the amount of a chemical (amino acid) in the blood increases.
The substance is called phenylalanine and is involved in the production of proteins along with food.
It is found in protein foods (such as dairy, eggs, meat and legumes) and some artificial sweeteners (called aspartame).
In patients with PKU, the body cannot consume this amino acid.
Therefore, the level of phenylalanine in the blood and body increases and if left untreated, it can cause serious problems such as mental retardation.
The gene responsible for making the enzyme phenylalanine dehydrogenase, PAH, is located on chromosome 11 and has a problem with mutations.
Therefore, the enzyme is not made enough or is made abnormally, and the person cannot take phenylalanine (this enzyme is needed to convert phenylalanine to another amino acid called tyrosine).
Obviously, the increase in phenylalanine in the body is toxic and causes damage to various parts.
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.
In the conversion of phenylalanine to tyrosine, two enzymes, phenylalanine hydroxylase I and II, are involved. The enzyme cofactor I is the bioptrin (one of the derivatives of folic acid) and is involved in the transfer of hydrogen, and the enzyme cofactor II is NADPH.
It is worth noting that phenylalanine is normally converted to small amounts in the presence of an enzyme (transaminase) and alpha-ketoglutaric acid to phenylpyroic acid.
Excess phenylalanine in this process is converted to tyrosine and is easily excreted by the kidneys. Phenylprovic acid is converted to phenylacetic acid by an enzyme (decarboxylase) or is regenerated by an enzyme (dehydrogenase) to produce phenyl lactic acid.
These three acids are called ketone bodies [1] and are excreted by the kidneys. Lack of the enzyme phenylalanine hydroxylase I causes classic phenylketonuria.
Therefore, based on the location of the defect in this metabolic pathway, PKU disease is divided into the following three subgroups:
1- Classic phenylketonuria disease: due to lack of phenylalanine hydroxylase I enzyme
2- Biopterin defect in cofactor biosynthesis (BIOPT-BS or Biopterin Cofactor biosynthesis or Pyruvoyl tetrahydropterin Synthase Deficiency) which is a very rare disease and its prevalence is 1 to 1 million.
3. Biopterin Defects in Cofactor Regeneration (BIOPT-REG or Dihydriopteridine Reductase Deficiency), which is a very rare disease with a prevalence of 1 to 1 million.
Genetics and PKU inheritance
The disease is inherited as autosomal recessive.
This means that in order for a baby to have the disease, he must have received a defective gene from each of his parents (in other words, the parents of each of these babies each have a copy of the defective gene, but because they also have a copy of a healthy gene, so Do not show any symptoms).
Prevalence:
In the United States, one in every 10,000 to 15,000 babies born has the disease, but because all babies have been screened for PKU since the 1960s, we are less likely to have symptoms.
The highest prevalence of the disease in Turkey is reported to be 1 in 2600, Ireland 1 in 4500 and Scotland 1 in 5300. The prevalence of PKU in Iran is 1: 5000 (ie between 300 and 400 infants with PKU are born in Iran annually).
Clinical signs:
The disease may be mild to severe. Its extreme form is called Classical PKU. Babies with this form look normal for the first few months of life.
But if left untreated, they can cause mental retardation and behavioral problems.
Girls and boys with PKU may have eczema and blue eyes, and their skin and hair may be lighter than those of other family members (because they do not produce enough melanin).
An interesting thing about these people is that when they increase phenylalanine, for example, in cases where they have not been treated or have eaten foods containing phenylalanine, the smell of urine, breath, skin and wax in their ears smells of mice or molds.
In people with moderate to mild forms of the disease, the severity of mental retardation is lower unless they are fed formula.
People with very mild forms (hyperphenylanemia, hyperphenylalaninemia) may not need to follow a special diet.
In the absence of phenylalanine hydroxylase enzymes, the levels of phenylalanine and phenylpyroic acid increase and have toxic effects on nerve cells.
These babies do not have many symptoms at birth, but most parents complain of drowsiness or lack of breastfeeding.
In the absence of diagnosis and treatment or failure to follow a special and timely diet, the following symptoms are seen in patients:
- Severe muscle spasm,
- Significant growth disorder,
- Decreased IQ,
- Seizures,
- Nausea,
- Vomit,
- Eczema-like skin rashes,
- Inhalation of mousy body odor from the body and urine, which is caused by the secretion of phenyl acetic acid in patients' sweat and urine.
- The presence of lighter skin and hair color than other family members,
- Disturbed behavior disorders,
- ADHD,
- Aattention Deficit Hyperactivity Disorder (ADHD)
- In older children, devastation (psychologically) is seen.
Neonatal screening:
The disease is usually diagnosed during postpartum screening tests (infancy).
However, this test should be considered for anyone with symptoms of mental retardation and growth retardation, regardless of age.
Because in rare cases, the result of the neonatal screening test is falsely normalized (and therefore the affected infant is not identified).
generally:
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 amino acids phenylalanine and tyrosine, which are the primary markers of PKU screening.
In the classic form of the disease, the level of phenylalanine increases and the level of tyrosine decreases, but in the other two forms of the disease, BIOPT-BS and BIOPT-REG, only the increase in phenylalanine is observed.
If the result of the above tests is abnormal in Westernization, 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 change more in the second sample.
Secondary markers: After confirming the changes of the primary markers during the above two sampling stages, the changes of the secondary marker during the two sampling stages are also checked by calculating the following ratio:
Increased phenylalanine / tyrosine ratios in all three forms of the disease (more than 1.9)
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 (especially PKU) and to perform confirmatory or diagnostic tests to confirm the diagnosis. The disease is recommended.
Diagnosis:
Performing plasma amino acid profile testing: obtaining results by increasing phenylalanine and decreasing tyrosine.
Urinary amino acid profile test: The result is an increase in urinary excretion of phenylalanine.
Performing organic acid profile tests in urine: get results by increasing alpha keto acids and hydroxy acids such as:
- phenyllactate,
- phenylpyrovate,
- 4- Hydroxy phenylacetate,
- 4- Hydroxy phenylpyrovate,
- 2- Hydroxy phenylacetate
- and mandelate.
Urine biopsy measurement
Inhaling a smell similar to the smell of a mouse or mold from urine, breath, skin and earwax
Genetic testing: Today, there are specific genetic tests (DNA tests) that can be used to determine if a person is carrying the PKU gene (including a PAH gene mutation).
It is not possible to completely cure PKU.
However, the mental retardation of these patients can be prevented by limiting protein intake (phenylalanine) and the use of special diets (low protein diet with vitamin and mineral intake + the use of special formula).
This diet should be followed for the rest of your life.
Especially in women and in the years when they are likely to have children, as well as during pregnancy (because even if the fetus is healthy, if the amount of phenylalanine in the mother's blood increases, it can cause damage to the fetus).
Foods high in phenylalanine, such as soy, egg whites, seal meat, shrimp, chicken breast, fish, snacks, tuna and turkey, are not allowed.
In contrast, starchy foods such as potatoes and corn, as well as foods such as bread and pasta, are allowed.
Prognosis:
Only 2 to 5% of people with the disease will have normal intelligence if left untreated, but people who are treated and follow a good diet usually have a good prognosis and have normal intelligence. .
Of course, it has been found that if a special diet is stopped, the IQ of these people will also decrease.
Elevated phenylalanine levels in the blood can also be associated with psychological symptoms (anxiety, depression, paranoid thoughts, obsessive-compulsive disorder, etc.) (because an increase in phenylalanine can affect the brain and lead to neuropsychological problems. ).
Women who have high blood phenylalanine levels during pregnancy are more likely to have children with mental retardation, small headaches, heart problems and growth retardation (because they have been exposed to high phenylalanine during pregnancy). .
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Screening of 58 neonatal metabolic disorders in Iran (Part 12 - Review of Urinary Tract Urinary Disease or MSUD)
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Screening of 58 neonatal metabolic disorders in Iran (Part 10 - Report of an infant with ischemic ischemia)
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Screening of 58 neonatal metabolic disorders in Iran (Part 9 - Galactosomia)
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Screening of 58 neonatal metabolic disorders in Iran (Part 8 - Congenital adrenal insufficiency)
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Screening of 58 neonatal metabolic disorders in Iran (Part 7 - Biotinidase deficiency)
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Screening for 58 neonatal metabolic disorders in Iran (Part 6 - Organic Acid Disorders)
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Screening for 58 neonatal metabolic disorders in Iran (Part 5 - Fatty Acid Disorders)
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Screening of 58 neonatal metabolic disorders in Iran (Part IV - Amino Acid Disorders)
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Screening of 58 neonatal metabolic disorders in Iran (Part III - Urea Production Cycle Disorders)
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Beginning of screening of 58 neonatal metabolic disorders in Iran (Part II - Generalities)