Screening of 58 neonatal metabolic disorders in Iran (Part 9 - Galactosomia)

Screening of 58 neonatal metabolic disorders in Iran (Part 9 - Galactosomia)

In the following discussion, we will examine another disorder that is being screened in this test, namely the increase in blood galactose levels and (galactosomia).


Galactosemia

Classic galactosemia is caused by a defect in carbohydrate metabolism (sugar) that is inherited by the pattern of autosomal recessive inheritance and is seen in girls and boys equally.

 For this reason, it is more common in consanguineous marriages. Carriers of this disease have no symptoms.

This condition is caused by a lack of enzymes that naturally convert galactose to glucose.

Classical galactosemia is caused by a deficiency of the enzyme galactose, a ureyl transferase phosphate, or GALT.

In 95% of cases of galactosemia, a defect in the GALT enzyme and in the remaining 5% due to other disorders such as galactokinase deficiency (GALK or rarely uracil diphosphate galactose epimerase (GALE) deficiency.

Galactose is produced in the intestines by lactose hydrolysis (milk sugar) and is easily converted to glucose in the liver during the following reactions:

ا Galactose is influenced by the enzyme galactose kinase (GALK) by consuming an ATP molecule (phosphodiesterase) and galactose-1 produces phosphate.

ا Galactose 1 - The resulting phosphate, under the influence of the enzyme galactose, reacts with the ureyl transferase (GALT) phosphate with uridine diphosphate glucose and releases glucose 1. Phosphate and uridine diphosphate galactose (UDPGal).

حاصل The resulting ureidine diphosphate galactose (UDPGal) is also converted to uridine diphosphate glucose (UDPGal) under the influence of the enzyme uridil diphosphate galactose epimerase (GALE) (the final part of the conversion of galactose to glucose takes place at this stage).

Therefore, in the normal state, galactose is converted to glucose in the liver. In the absence of converting enzymes, galactose and its metabolites accumulate in the blood and urine.

Molecular galactosemia is a heterogeneous disease, and various genetic mutations can contribute to the disease.

The GALT gene is located on the short arm of chromosome 9 in the p13 region. This gene contains 11 exons and Kbp is 4.3 in length.

 So far, more than 160 different polymorphisms have been identified in the GALT gene, most of which are pathogenic.

The most popular mutations in galactosemia are the L195P-X380R-Q169K-K285N-Q188R mutations, the most common of which is the Q188R mutation.

- The Q188R mutation is located in Exon 6 and is converted to 563 by adenine to guanine, leading to the replacement of arginine amino acid with glutamine at amino acid 188.

 Although the Q188R mutation is the most common mutation in galactosemia in the world, its frequency varies among different races and ethnicities. Among European whites, the mutation accounts for 64% of mutated alleles.

The K285N mutation is the second most common mutation in the white population, located in Exon 9, and is caused by a change in guanine to thymine at 855. The K285N mutation is less common than the Q188R mutation, with a total prevalence of 8% in Europe but high in Central Europe.

Lack of galactokinase enzyme is another cause of galactosemia, the gene for which is located on chromosome 17.


The prevalence of galactosemia

One case per 55 to 60 thousand live births. The prevalence of this disease in Iran has not yet been precisely determined.


Clinical signs

The clinical symptoms of the disease in different periods are as follows:


● Birth time: normal (asymptomatic)

● Infancy: Children with galactosemia appear healthy at birth, but after breastfeeding several times, gradually the effects of enzymatic defects on the third and fourth days of life (after several breastfeeding times containing high lactose) It appears and the symptoms of the disease appear.

Lactose is chemically a two-sugar compound that is converted to glucose and galactose in the small intestine under the influence of the enzyme lactase.

 The presence of this enzyme is essential for the digestion and absorption of milk lactose, because only simple sugars are able to cross the wall of the small intestine and enter the bloodstream.

Symptoms include diarrhea, severe vomiting that diagnoses pyloric stenosis and the need for surgery, anorexia, liver dysfunction that leads to jaundice and hepatomegaly, growth retardation, weight loss, and neonatal infection. With Escherichia coli bacteria. Galactosomal disease, if left untreated, can be a very threatening disease in the first days and weeks after birth.

In classical galactosemia, GALT deficiency causes the accumulation of galactose, a phosphate, and galactose in tissues. The accumulation of galactose in these patients involves several organs.

In galactokinase deficiency, galactose accumulates in the blood and tissues. In the lens of the eye, galactose is converted to galactitol by aldose reductase.

But the lens of the eye is impermeable to this sugar, so a lot of water collects in the lens and together with glutathione causes cataracts.

 Breastfeeding and infancy: cataracts (typically occurring at two months), cirrhosis, ascites, edema, bleeding, spleen enlargement, mental retardation, hyperactivity, renal laryngeal syndrome, neurological disorders (brain damage usually with symptoms Lethargy and hypotension appear), speech delay, and tumor tumor prognosis.

Adolescence and adulthood: mental retardation, ovarian failure, neurological disorders such as decreased muscle tone, imbalance and tremor (tremor).

Screening

During the screening of metabolic diseases, the level of activity of galactose and the activity of effective enzymes in this disease are examined on the samples of dried blood stains on filtered paper (Dried Blood Spot = DBS).

The patient should be further evaluated by observing an increase in galactose levels or a defect in the function of these enzymes.

Diagnosis using confirmatory tests

● Serum and red blood cells: Measurement of galactose in serum and galactose - 1- Phosphate in red blood cells.

Urine: Positive reducing agents (just note that when a child vomits or has anorexia or venous glucose, galactose may not be present in the urine and the test may be false negative).

Testing the reducing agents (Benedict's test) is helpful in diagnosing the presence of urinary sugars. Other tests, such as chromatography tests, are used to determine the type of reducing sugar available after the Benedict test.

The results of scientific studies show that with positive Benedict's experiments, even in cases of Trace and (+1), it is still possible to have sugar that is clinically important.

 Therefore, the lack of correlation between the type of reducing sugar and the severity of the positive Benedict test makes it necessary to pay attention to any degree of positiveness of the test.

آن Enzymatic studies: Measurement of GALT, GALK and GALE enzymes in white blood cells and fibroblasts. Definitive diagnosis is made by proving the deficiency or absence of the GALT enzyme in red blood cells.

. With continued damage to the renal tubules, in addition to positive test for resuscitation material, excretion of amino acids, albumin and glucose from the urine is also observed.

DNA testing and examination of the disease's mutations determine which of the enzymes GALT, GALK, and GALE are defective.

 

Note 1: Galactokinase deficiency should be considered in children with cataracts and substances other than glucose in the urine. Diagnosis is confirmed by a deficiency of galactokinase in red blood cells.

 In these patients, the level of galactose-1-phosphate in the blood decreases.

Note 2: When one or more of the symptoms listed in the patient are present, a classic galactosemia should be suspected.

Note 3: If the patient consumes milk, regenerative sugar will be found in his urine, but the reaction of glucose oxidase is negative (ie, the sugar in his urine is not glucose). Other techniques, such as chromatography, can show that this is galactose sugar.

Comparison of the results of chromatography of urinary sugars and enzymatic measurement indicates that a significant number of patients are diagnosed with galactosemia based on the results of urine tests.

In fact, they suffer from a disease other than classic galactosemia, and are deprived of vital galactose sugar (which is involved in both energy production and the structure of many parts of the body, such as cell membranes and nerves).

 Despite the invention of new diagnostic methods, simple laboratory tests, such as urine resuscitation tests and urine sugar chromatography, are still valuable because of their simplicity, cheapness, and non-need for a special device.

Diagnosis before pregnancy

By examining the enzyme in amniocentesis or umbilical cord blood.

treatment

Eliminate milk and its products from the diet and replace it with formulas containing hydrolyzed casein or soy. Treatment should begin before three months of age.

Substitute milk powder for these patients is as follows:

1- Soy lactose free milk based on soy (such as isomyl, biomyl side, etc.) is the first choice.

2- AL100 in cases of lactose above 10 mg / dl

3. Galactomin 17 at concentrations above 13 mg / dl

Prior to the launch of galactosomal diagnostic tests, many children with the disease survived only a few months, but since then it has been possible to identify and treat infected children at an early age.

 During infancy, lactose-free formulas are the nutrient of choice. Cereals for children are added to the child's diet at 4 to 6 months of age. Fruit and vegetable juices are gradually added to the child's diet at 5 to 8 months of age.

Consumption of many foods for these children is unrestricted. A person with the disease can eat meat, poultry and eggs. Also, using fats and lots of bread will not be a problem for them.

Eating a lactose-free diet will help prevent many of the symptoms of the disease. These patients should continue this diet for the rest of their lives. Existing commercial foods should be carefully evaluated, as some of them contain large amounts of galactose.

Children undergoing treatment can have normal physical development. Growth rate depends on family pattern of height and weight, as well as adequate amounts of protein and calories. Many children with the disease will have learning difficulties or speech problems, despite pursuing treatment.

Follow-up studies on children who have been treated since birth or at least during the first 2 months of life have shown that eliminating the sources of galactose alone cannot cure the disease.

Taking advantage of new treatment options such as adding transferase activity, replacing reduced metabolites, or replacing the required gene.

Prognosis

Early diagnosis and treatment of the disease prevents premature death and many serious injuries in these children. Severe and timely treatment of these patients has a good prognosis and if left untreated, it will have severe and threatening complications.

Such as: mental retardation, imbalance, tremor, ovarian failure, speech delay and cataracts (if treatment is delayed and starts at three months).

 

How to track patients after diagnosis:

Parents of such patients should be taught that they need lifelong treatment and that it is mandatory to follow the nutritional tips of these patients in order to have a growth process, health and natural development.

Long-term follow-up of the disease should be recommended to parents so that the baby's condition is always healthy.

Consultations with a group of counselors, including pediatricians, geneticists, and nutritionists, should also be consulted, and parents should be aware that the slightest violation of the diet can lead to the death of their child.

Genetic counseling is recommended for the molecular diagnosis of the disease and the risk of having the next child (if you decide to become pregnant in the future).

These patients should be monitored regularly by a metabolic specialist.

    

RelatedNews Screening of 58 neonatal metabolic disorders in Iran (Part 9 - Galactosomia)

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