How Common Is Maple Syrup Urine Disease?

Maple glycosuria (MSUD), also known as maple diabetes and branched-chain ketoaciduria, is an autosomal recessive disease. Due to a congenital defect of the branched keto acid decarboxylase, the catabolism of branched amino acids is blocked. A large amount of -keto--methylvaleric acid is discharged from the liquid, which is named after the sweet smell of maple syrup.

Basic Information

nickname

Maple diabetes, branched-chain ketoaciduria

English name

English alias

Visiting department

Pediatrics

Common causes

Heredity

Common symptoms

Symptoms of progressive brain damage, severe convulsions, paralysis or severe metabolic disorders

Causes of maple syrup

This disease is an autosomal recessive genetic disease. Defects in branch ketoacid decarboxylase cause catabolism of branch amino acids.

Clinical manifestations of maple syrup

It mainly invades the nervous system and shows symptoms of progressive brain damage. It is an important cause of children's mental retardation. In severe cases, convulsions, paralysis, or severe metabolic disorders may occur. Clinically, this disease can be divided into 5 types.

Typical maple syrup

The most common and most severe type. At birth, he is in good condition, and generally presents symptoms such as drowsiness or irritability, difficulty in breastfeeding, weight loss, etc. from the 4th to 7th day after birth; decreased and increased muscle tone occurs frequently, and debrain-like spastic paralysis, convulsions, and coma are common. Breathing becomes shallow with intermittent cyanosis. The urine of the children has a smell of maple syrup; some children may be accompanied by hypoglycemia, ketoacidosis, and fullness of the front palate. Most children die of recurrent metabolic disorders or neurological dysfunction within a few months of life, and a few survivors also have neurological disabilities such as mental retardation, spastic paralysis, and cortical blindness.

2. Light (or middle) type

Enzyme activity is 3% to 30% of normal people. The branched chain amino acids and branched chain ketoacids in the blood are only slightly increased; the urine has excessive branched chain ketoacids excreted. A few may have acute metabolic disorders such as ketoacidosis. Presented as mental retardation, but without other typical neurological symptoms and signs, and without the characteristics of intermittent attacks.

3. Intermittent

Enzyme activity is 5% to 20% of normal people. It usually develops in late infancy or childhood, but also late in adulthood. Anorexia, vomiting, indifferent expression, drowsiness, ataxia, behavioral changes, gait instability, severe convulsions, coma, and even death may occur in the severe cases, and the urine presents a taste of maple syrup. A few have low intelligence. The duration of the disease varies, and there can be multiple ups and downs, and some children die of acute ketosis.

4.Thiamine effective type

Enzyme activity is 30% to 40% of normal people (its clinical manifestations are similar to those of intermediate-type children) with only mild mental retardation and no typical or intermittent symptoms of nerve damage. Only the content of branched keto acid in the blood is slightly higher than normal children. Children with this type have a good effect on vitamin B1, and blood biochemical abnormalities can be significantly improved.

5. Dihydrolipoamidoacyl dehydrogenase (E3) deficiency

Rare, the clinical manifestations are similar to the intermediate type, but due to the deficiency of the E3 subunit, in addition to the low activity of branched chain -keto acid dehydrogenase, children also have pyruvate dehydrogenase and -ketoglutarate dehydrogenase functions. Damaged, so accompanied by severe lactic acidosis. It usually develops within a few months of birth, and progressive neurological symptoms such as decreased muscle tone, dyskinesias, and developmental retardation gradually appear. Large amounts of lactic acid, pyruvate, -ketoglutarate, -hydroxyisovalerate, and -hydroxyketoglutarate are excreted in the urine; due to the large accumulation of pyruvate, the blood alanine concentration also increased. Restriction of protein and fat intake in children with this type of treatment, such as treatment with large doses of VB ₁ are not effective.

Maple syrup urine test

Newborn screening

Guthrie's bacterial growth inhibition method is mostly used to screen for this disease. When the blood leucine concentration is> 4 mg / dl (305 µmol / L), the urinary branched-chain keto acid excretion should be further detected. Prevents mental retardation.

2. Biochemical detection

Electrolyte and blood gas analysis should be performed on the clinically diagnosed children. If metabolic acidosis and anion gap widening, blood and urine amino acid and organic acid analysis should be performed. Some children may have hypoglycemia in the acute phase.

3. Analysis of amino acids and organic acids

Quantitative detection of amino acids and organic acids in children's blood, urine, or cerebrospinal fluid using GC-MS can confirm the diagnosis: elevated levels of branched chain amino acids and branched chain organic acids in the blood; in the acute phase, the concentration of -ketoisovalerate in the blood Increased, -hydroxyisovaleric acid in urine increased; L-Isoisoleucine unique to this disease can be detected in blood.

4. Enzymatic test

Can detect the activity of cultured fibroblasts and lymphoblasts branched-chain keto acid dehydrogenase complex.

5. DNA analysis

For family members of known mutation types, PCR can be used to amplify DNA and detect with labeled oligonucleotide probes.

6. Routine brain examination

The level of intelligence examination has been reduced, abnormal brain waveforms can be seen on EEG examination, and brain CT examination can reveal cerebral edema caused by acute metabolic disorders.

Maple syrup diagnosis

The screening test for branched keto acids in urine can be tested with ferric chloride (green-gray positive) and dinitrophenylhydrazine test (yellow precipitation is positive). Paper or column chromatography was used to determine the increase in branched amino acids in blood and urine. Determination of keto acids by thin layer chromatography or gas chromatography. Enzyme activity can be measured using leukocytes or skin fibroblasts. In typical cases, C-labeled leucine cannot be changed to CO _{2. The} enzyme activity is normal 0% to 2%, the intermittent type is 8% to 16%, and the light type is between Between the two, the B ₁ effective type is more than 25% of normal. The heterozygous enzyme activity is 50% of normal. Prenatal diagnosis can be made by measuring enzyme activity with cultured amniotic fluid cells.

Amniotic fluid puncture, amniotic fluid cell culture, and enzyme activity determination can be used for prenatal diagnosis of certain amino acid metabolic disorders to determine whether to terminate pregnancy.

Differential diagnosis of maple syrup

Patients with neurological symptoms should be distinguished from other central nervous system diseases. The children's urine and sweat have a maple-like odor and laboratory tests can help identify them.

Complications of maple syrup

Most children die from recurrent metabolic disorders or neurological dysfunction within a few months of life. A few survivors also have mental retardation, spastic paralysis, and blindness of the nervous system such as cortical blindness. Some treatments can be accompanied by spastic paralysis, convulsions and coma, which can be accompanied by hypoglycemia, acidosis, mental retardation, ataxia, dyskinesia, developmental delay, behavior changes, etc.

Maple Diabetes Treatment

Maple urination can be treated with a low-protein diet; limit the amount of branched amino acids; pay attention to vitamin supplements.

Diet therapy

Start early and stick to it for life. If it starts before severe neurological symptoms (within 1 week after birth), normal development is expected. Consumption of branched chain amino acids in food must be limited. Since hyperleucineemia has the greatest damage to the nervous system, and the content of the three branched-chain amino acids in natural foods is the highest, leucine is the highest. Therefore, it is generally recommended to consume 300-600mg of protein containing leucine every day. Only give 1/2 to 2/3 of the recommended amount. Blood amino acid analysis and adjustment should be performed every week.

2. Treatment of acute metabolic crisis

Acute metabolic disorders of MSUD lead to a large accumulation of branched chain amino acids and ketoacids in the blood, severe ketosis, acidosis, and rapid decline of nervous system function. Active measures must be taken to save the lives of children.

3. Principles of treatment

Quickly reduce the accumulation of toxic metabolites in the body; provide sufficient nutrients; promote the body's anabolic metabolism and inhibit catabolism. Available measures:

(1) For total intravenous nutrition, a standard total intravenous nutrition solution can be used to remove branched chain amino acids.

(2) Treatment with insulin and glucose requires several days to keep blood branched chain amino acids and their keto acids at low levels.

(3) Subcutaneous injection of recombinant human growth hormone (r-hGH) can reduce tissue protein breakdown.

(4) Vitamin B1 (thiamine) effective type can be given vitamin B1.

(5) Do peritoneal or hemodialysis regularly.

4. Liver transplant

Typical children with MSUD can be considered for liver transplantation as soon as they are diagnosed.

Prognosis of maple syrup

Dietary therapies that control the intake of branched amino acids have been successfully used to stop the development of disease in patients with typical maple syrup urine disease, but the varying degrees of central nervous system damage that may have been incurred before treatment may continue.

Maple syrup prevention

To avoid close marriage, the enzyme activity can be measured using leukocytes or skin fibroblasts, and the cultured amniotic fluid cells can be used to determine the enzyme activity to make a prenatal diagnosis and terminate the pregnancy if necessary.