Introduction
Maple diabetesMaple diabetes(maple syrup urine disease, MSUD) is an autosomal recessive disorder. Due to the congenital defects of branched ketoacid dehydrogenase, the catabolism of branched amino acids is blocked, because a large amount of α-keto-β is excreted in the urine of children. - Methyl valeric acid, hence the name of the sweet smell of maple syrup.
Cause
(1) Causes of the disease
The disease belongs to autosomal recessive genetic disease, and the defect of branched ketoacid dehydrogenase causes the catabolism of branched amino acids to be blocked.
(two) pathogenesis
The α-branched ketoacid (KIC, KMV, KIV) formed by the branched chain amino acid after amino transfer must be further catalyzed by a branched α-keto acid dehydrogenase in the mitochondria, which is a complex enzyme system (BCKAD). Complex), consisting of decarboxylase (E1, including E1α, E1β two subunits), dihydrolipoyl transacetylase (E2) and dihydrolipoyl dehydrogenase (E3) Composition, their coding genes are located at 19q13.1-q13.2, 6p21-p22, 1p2l-31 and 7q31, respectively; wherein E3 is also a component of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in humans. This enzyme system also requires thiamine pyrophosphate as a coenzyme. Mutations in any of the above listed genes result in defects in this enzyme complex, resulting in various types of maple glucosuria.
Branched ketoacid dehydroxylase defects cause the corresponding ketoacids to be oxidatively decarboxylated, retained in the body, and excreted in the urine, producing a special odor. Branched-chain amino acid metabolism disorders increase the amount of branched-chain amino acids in the nervous system; glutamate, glutamine and γ-aminobutyric acid are significantly decreased; medullary lipids such as cerebroside, proteolipid and cerebroside sulfate Not enough. It is believed that the accumulation of branched amino acids and ketoacid derivatives in the body has toxic effects on the brain, such as inhibiting myelination, interfering with protein synthesis in the brain, inhibiting neurotransmitter function and enzyme activity, and causing serious development of brain tissue. damage. In addition to typical genetic defects, there are three variants. Spongiform changes and myelination disorders occur in the white matter of the child, most prominent in the cerebral hemisphere, corpus callosum, dentate nucleus and pyramidal tract; children with death due to acute metabolic disorders have cerebral edema .
symptom
The disease is divided into 5 types.
1. Typical maple diabetes This type is the most common and most serious type, and its branched α-ketoacid dehydrogenase activity is lower than 2% of normal children. On the 4th to 7th day after birth, symptoms such as drowsiness, restlessness, difficulty in breastfeeding, and weight loss gradually appeared. The muscle tension decreased and increased alternately. It was common to go to the brain-like spasm, convulsions and coma, and the disease progressed rapidly. The urine of the child has maple syrup; some children may be accompanied by hypoglycemia, ketone, acidosis, and fullness of the front and back. Most children die of recurrent metabolic disorders or neurological dysfunction within a few months after birth. A few survivors also have mental retardation such as mental retardation, spastic paralysis, and cortical blindness.
2. The light (or intermediate) type of enzyme activity is about 3% to 30% of normal people, and the blood chain branched chain amino acid and branched chain keto acid are only slightly increased; the urine has excess branched keto acid excretion. A small number of acute metabolic disorders such as ketoacidosis may occur; this type and thiamine-effective type are difficult to identify, and clinical trials can be used to assist diagnosis.
3. The intermittent enzyme activity is about 5% to 20% of normal people. The child is usually asymptomatic, with normal physical and mental development, usually in the late stage of infants or in childhood, and also late in adulthood. Most are induced by factors such as infection, surgery, and high protein diet. Drowsiness, ataxia, behavioral changes, gait instability, seizures, coma, and even death in severe cases, and the taste of maple syrup in the urine. The children had normal blood and urine biochemical tests during the interictal period, and a few had low intelligence.
4. The thiamine-efficient enzyme activity is about 30% to 40% of that of normal people, and its clinical manifestations are similar to those of intermediate children. The use of thiamine (vitamin B1) treatment can improve the clinical symptoms, blood and urine biochemical changes back to normal, the dose is generally 100 ~ 500mg / d, while limiting the daily protein intake.
5. Dihydrolipoic acid amide dehydrogenase (E3) deficiency is rare, clinical manifestations are similar to intermediate type, but due to defects in E3 subunit, children with low activity of branched chain α-ketoacid dehydrogenase, acetone Acid dehydrogenase and α-ketoglutarate dehydrogenase function are also impaired, so it is accompanied by severe lactic acidosis. Generally, it occurs in the months of birth, and progressive neurological symptoms such as decreased muscle tone, dyskinesia, and developmental delay occur. A large amount of lactic acid, pyruvic acid, α-ketoglutaric acid, α-hydroxyisovalerate, and α-hydroxyketoglutaric acid are discharged from the urine; the concentration of alanine in the blood is also increased due to the large accumulation of pyruvic acid.
diagnosis
When the clinical symptoms suggest this disease, a laboratory test is needed to confirm the diagnosis. Screening of the branched ketoacid in the urine can be carried out using a ferric chloride test (positive for greenish gray) and a dinitrophenylhydrazine test (positive for yellow precipitation). Check for increased amino acids in the blood and urine, which can be determined by paper chromatography or column chromatography. The keto acid can be determined by thin layer chromatography or gas chromatography. The enzyme activity can be determined by using white blood cells or skin fibroblasts. In typical cases, the 14C-labeled leucine can not be changed to 14CO2, and the enzyme activity is 0 to 2% of normal. The intermittent type is 8% to 16%, the light type is between the two, and the B1 effective type is more than 25% of the normal type. The heterozygous enzyme activity is 50% normal. Prenatal diagnosis can be made by measuring the enzyme activity using cultured amniocytes.
Identification
Children with neurological symptoms should be distinguished from other central nervous system diseases. The urine and sweat of children have maple syrup and laboratory tests can help identify.
complication
Hemorrhoids, convulsions and coma can be associated with hypoglycemia, acidosis, mental retardation, ataxia, movement disorders, developmental delay, behavioral changes, etc.
treatment
1. Diet therapy should start as soon as possible and persist for life. If it begins before the onset of severe neurological symptoms (within 1 week after birth), it is expected to reach normal development. The intake of branched-chain amino acids in food must be limited so that the concentration of branched-chain amino acids in the blood can be maintained within the normal range. Since hyperleucine has the greatest damage to the nervous system, and the content of the three branched-chain amino acids in natural foods is the highest with leucine, it is generally recommended to consume 300-600 mg of leucine per day. Only 1/2 to 2/3 of the recommended amount should be administered, and blood amino acid analysis should be performed weekly to adjust. If the exposure to bright and isoleucine is excessively restricted, skin damage such as perioral papillary rash or skin damage similar to intestinal dermatitis and diaper dermatitis may occur.
2. Treatment of acute metabolic crisis MSUD acute metabolic disorders lead to massive accumulation of branched-chain amino acids and their ketoacids in the blood, severe ketosis, acidosis and rapid decline of nervous system function, and active measures must be taken to save the lives of children. The principle of treatment is: rapidly reduce the accumulation of toxic metabolites in the body; provide sufficient nutrients; promote the body's anabolism, inhibit catabolism. Possible measures:
(1) peritoneal or hemodialysis.
(2) Total vein nutrition: A standard total intravenous nutrient solution for removing branched chain amino acids can be used.
(3)insulin: With insulin 0.3-0.4 U/kg and glucose 26 g/kg, the treatment lasts for several days to keep the blood branched-chain amino acids and their keto acids at a low level.
(4)Recombinant growth hormone(r-hGH): Subcutaneous injection reduces tissue protein breakdown.
3. Other medications for vitamin B1 (ThiamineThe effective form can be given vitamin B1 10 ~ 1000mg / d.
4. Liver transplantation A typical MSUD child can be considered for liver transplantation once diagnosed, and soon after the effect, biochemical metabolism returns to normal.
prevention
Avoid close relatives. The enzyme activity can be measured by white blood cells or skin fibroblasts. In typical cases, the 14C-labeled leucine can not be changed to 14CO2, the enzyme activity is normal 0 to 2%, the intermittent type is 8% to 16%, and the light type is between the two. Between the B1 effective type is more than 25% of normal. The heterozygous enzyme activity is 50% normal. Prenatal diagnosis can be made by measuring the enzyme activity using cultured amniocytes, and the pregnancy is terminated if necessary.
简体中文