Screening of 58 neonatal metabolic disorders in Iran (Part 12 - Review of Urinary Tract Urinary Disease or MSUD)
Screening of 58 neonatal metabolic disorders in Iran (Part 12 - Review of Urinary Tract Urinary Disease or MSUD)
In the following, we will explain a relatively common disease in Iran that is screened during this process.
Cause of illness:
In this disease, the body of an infected person cannot consume some "amino acids" (amino acids are obtained from the breakdown of proteins in the body).
These amino acids are leucine, isoleucine, and valine, which are classified as branched chain amino acids (BCAAs).
These three amino acids are found in abundance in protein foods such as milk, meat, and eggs, and are less common in regular flour, cereals, nuts (such as peanuts), and some vegetables and fruits.
The main cause of this disease is the lack or reduction of an enzyme called "branched-chain alpha-ketoacid dehydrogenase" (BCKDH).
This enzyme is needed to consume the above amino acids and provide energy and growth for the child, otherwise these substances accumulate in the body and cause damage to various parts, especially the brain (and thus the nervous system, encephalopathy and mental retardation).
The enzyme is made up of four subunits, and mutations or mutations in the genes involved in making these subunits cause MSUD. The gene for this enzyme is located on chromosome 19.
The specific sign of the disease is that the urine of patients with the disease smells like maple syrup (the smell of candy or burnt sugar), so it is called "urinary disease with the smell of maple syrup".
Normally, catabolism (= breakdown) of "branched-chain amino acids" occurs in the liver, kidneys, muscles, heart, and adipose tissue.
The natural catabolism of these amino acids is involved in the growth and energy supply of the body.
MSUD is divided into five groups according to classification.
1- Classic
2- Intermediate
3- Intermittent
4- Thiamine Responsive
5- LipoAmid Dehydrogenase Deficiency
1- Classic type: This type occurs due to the lack of the enzyme complex "alpha-keto acid dehydrogenase mitochondrial" and its prevalence is 1 in 200,000 births.
It is the most common type of disease in which enzyme activity is zero or low (enzyme activity is usually less than 2% of normal).
In the first few days of life, children with this condition develop symptoms such as not breastfeeding and vomiting, and are usually unable to tolerate BCAAs.
Therefore, their diet should be free of these amino acids.
2- Intermediate: Unlike the classic form, the level of enzymatic activity is slightly higher (about 8-3% of normal). This group usually tolerates higher amounts of leucine.
Of course, in the case of illness and hunger, the child's condition will be similar to the classic condition and the type of treatment will be the same.
3- Intermittent: It is a mild form of the disease in which the rate of enzymatic activity is about 8-15% of normal.
In this group, children often have no symptoms until the age of 12 to 24 months, but during illness, starvation, or after stress such as BCAAs, their level rises, the child has a metabolic crisis.
Symptoms of a metabolic crisis include excessive sleepiness, sluggishness, vomiting, mood swings, and, if left untreated, can lead to muscle stiffness, seizures, coma, and even death.
Thiamine (Responsive) in this type of supplement supplementation with thiamine leads to increased enzyme activity and thus helps in the use of leucine, isoleucine and valine.
In most cases, only moderate protein restriction is required. This type is actually a rarer form of MSUD.
5 - LipoAmid Dehydrogenase Deficiency: A very rare form of the disease that is associated with nerve damage, muscle weakness, growth disorders and mobility problems, and in some cases the death of the child.
Usually, the baby does not have symptoms until 6-8 months of age, but after that, following a condition called "lactic acidosis" (due to the intense accumulation of lactic acid in the body), symptoms such as vomiting, heartburn and shortness of breath appear (if not). Treatment can kill the child.
In this form, in addition to lactic acid, other substances accumulate in the body, including branched-chain amino acids.
Genetics and inheritance: MSUD
A person who has a defective (mutated) gene is called a carrier of that gene. In order for a person to have MSUD, both parents must carry the defective gene, because the inherited disease is autosomal recessive.
Normally, each person has two genes involved in making the alpha-ketoacid dehydrogenase enzyme, one of which is given to them by the father and the other by the mother.
If one of those genes has normal function and the other has abnormal function, the person carrying the gene is considered MSUD, and if the person has both defective genes, he or she is considered "infected" with MSUD.
When both parents are "carriers" of the MSUD gene:
n any pregnancy, there is a 25% chance that the fetus will receive both defective genes and be "infected" with MSUD.
The probability that the fetus is the only "carrier" of a gene for MSUD (ie, like its parents) is 50%.
The probability that the fetus will receive healthy genes from its parents and be normal is 25%.
It should be noted that the chances of getting the disease in boys and girls are the same.
Prevalence:
The global prevalence of this disease is 1 in 185,000. In Portugal, 1 in 86,800, and in high-marital societies (intra-marital coefficients, it is possible for an individual to inherit a pair of alleles from their ancestor through their parents) such as Mennonites in Pennsylvania, USA 1 to 200 have been reported.
In a 10-year study by Dr. Zahed Pasha et al., Published in 1992, out of a total of 3154 infants admitted to Amirkalay Babylon Children's Hospital in Babol, 16 MSUD cases were diagnosed. The report was based on the high rate of consanguineous marriages (38.6%) and the high average marital coefficient of 0.0188 (in this study, 87.5% of the parents of these children were related).
In this report, the prevalence of the disease is 7 times higher than the global statistics.
Symptoms:
Children with the classic form of the disease look normal at birth and within 3 to 7 days.
Children with intermediate forms have milder symptoms and do not develop the disease quickly.
Symptoms generally include tingling, lethargy, poor breastfeeding, weight loss, hypotension (muscle relaxation), hypertension (muscle stiffness), vomiting, screaming, sudden onset of illness, and inhaling the distinctive odor of "maple syrup." From the urine, when the baby is replaced after drying, the smell becomes even more intense.
Acidosis, ketosis and dehydration are other symptoms of the disease.
As mentioned earlier, the most obvious feature of this disease is the smell of urine, which is similar to the smell of maple syrup or burnt candy.
In this disease, the amount of leucine, isoleucine, valine and alpha-keto acids related to these compounds in the plasma and urine of the patients increases.
However, small amounts of branched-chain alpha-hydroxy acids, which are formed by the reduction of alpha-keto acids, are also present in the urine of patients.
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 leucine, isoleucine, and valine, which are the primary markers of MSUD screening.
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 leucine / phenylalanine ratios (more than 4.7), leucine / alanine (more than 1.5),
Isoleucine / phenylalanine, isoleucine / alanine and valine / phenylalanine (more than 2.5).
If you notice an increase in the above ratios and the presence of these changes 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 MSUD). Confirmation or diagnosis is recommended to confirm the diagnosis.
Diagnosis:
Plasma amino acid profile test: Lucin, isoleucine, valine, alloisolusin are shown to increase.
Alanine is also reduced in these patients. Increased L-alloisolusin in MSUD is considered a diagnostic marker.
Urinary amino acid profile test: It is characterized by increased urinary excretion of branched-chain amino acids.
Perform an organic acid profile test in the urine: which shows itself in the form of an increase in alpha keto acids and hydroxy acids.
Positive urinary ketone positive
Screening test 2,4-dihydrophenyl hydrazine in an acidic environment: which determines the presence of alpha keto acids in the urine. However, this test is also positive in cases such as phenylketonuria (phenolic pyruvic acid), histidineemia (imidazole pyruvic acid), and methionine malabsorption (Oasthouse syndrome).
Inhaling a scent similar to the smell of maple syrup or burnt candy from urine
Genetic testing: Today, there are specific genetic tests (DNA tests) that can be used to determine whether a fetus carries MSUD genes in the fetus or the person in question (including prenatal diagnosis and screening methods). The defect in the activity of the enzyme "alpha ketoacid dehydrogenase in the peripheral chain" can be investigated with the help of coronal villi or amniotic fluid.
Genetic testing of mutations in the genes BCKDHA, BCKDHB and DBT.
With the start of treatment in the first week of life, the serious consequences of the disease can be largely prevented.
Treatment options include replacing dietary proteins with a mixture of amino acids without leucine, isoleucine, and valine.
When plasma levels of these amino acids return to normal, some of these compounds are re-added to milk and other foods so that they never exceed the required metabolic rate.
Dialysis alone is not a reference method for reducing high levels of branched-chain amino acids (BCAAs) except in emergencies where the child's nervous system is compromised.
A more effective treatment is the administration of serums containing amino acids, free of BCAAs, which enter the body along with glucose.
Leucine, valine, and isoleucine are used to produce protein in the body after injection of a specially prescribed solution (thus reducing the amount of these three branched-chain amino acids BCAAs).
Insulin or similar compounds are sometimes prescribed separately to speed up BCAAs.
Supplementation with isoleucine and valine supplements is helpful in relieving deficiency of these two amino acids when their serum levels are rapidly reduced compared to leucine, as very low levels of isoleucine and valine can cause severe skin rashes in children.
Long-term MSUD treatment involves strict permanent control and strict dietary restrictions on protein intake to prevent the accumulation of BCAAs in the blood.
The main ingredient in the diet (low in protein, high in carbohydrates) is milk powder for children with MSUD (such as Enfamil and Similac powders).
This special formula contains all the vitamins, minerals and amino acids needed to provide calories and growth for a child, but it also includes restrictions on the consumption of these three amino acids.
Thiamine and carnitine are also helpful.
After consuming this formula, it is necessary to strictly control the blood levels of amino acids and perform other tests to possibly adjust the composition of the formula so that all three BCAAs branched-chain amino acids are kept in balance in the baby's body. When a child with MSUD develops, he or she should continue to consume his or her own formula and be given a balanced diet based on his or her daily leucine levels.
It is worth noting that the MSUD diet cannot include high-protein foods such as meat, grains, eggs, and to a lesser extent dairy products, seeds (peanuts). Consumption of more fruits and vegetables under a doctor's supervision is not prohibited.
In addition, the child should be given enough carbohydrates and fluids to prevent illness during an illness.
Liver transplantation: It is also considered as a treatment method (the enzyme responsible for the breakdown of branched-chain amino acids is made in the liver, which is solved by liver transplantation).
Prognosis
The prognosis of the disease is only promising when the relevant defect in the baby is diagnosed before 5 days of age and treatment is started. Unfortunately, most newborns have not yet shown signs of the disease during screening tests.
In addition, the methods used in most centers are old and have incorrect calculations. Therefore, most infants are followed up only after the onset of symptoms.
The prognosis of the disease can be determined by the results of the analysis of BCAAs and the blood test, which shows the amount of 20 amino acids and their relationship with each other.
In general, rapid treatment of the baby (which should last a lifetime) is often associated with normal development, which can prevent his mental retardation. However, for unknown reasons, these children are more likely to develop ADHD, anxiety, and depression than other children.
Some children later develop encephalitis or a metabolic crisis, even with timely treatment (children who have experienced multiple seizures are more likely to have brain damage and mental retardation).
References:
http://www.newbornscreening.info/Parents/aminoaciddisorders/MSUD.pdf
http://emedicine.medscape.com/article/946234-overview#a5
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Screening of 58 neonatal metabolic disorders in Iran (Part 11 - Review of Phenylketonuria)
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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)