maple diabetes
Introduction
Maple Diabetes Introduction Acer diabetes is a clinical syndrome caused by the oxidative decarboxylation of ketone derivatives of three branched amino acids of leucine, isoleucine and valine due to defects in branched ketoacid decarboxylase. Patients with vomiting can cause severe dehydration and lead to acidosis. Also known as maple diabetes. basic knowledge Sickness ratio: 0.0001% Susceptible population: newborn Mode of infection: non-infectious Complications: dehydration
Cause
Maple diabetes cause
Cause:
The disease is autosomal recessive. It is classified into 5 types by a group of branched -keto acid dehydrogenase activities (or lack of keto acid decarboxylase) or deficiency, and is classified into 5 types: classical type, intermittent type, intermediate type, vitamin B type and E3 type. The enzyme activity is 0% to 2%, 2% to 40%, 5% to 25%, 20% to 40%, and 5% to 10%, respectively, of normal humans. Patients with vomiting can cause severe dehydration and lead to acidosis.
Pathogenesis:
Deletion of the branched--ketoacid dehydrogenase results in a toxic reaction in which the branched--keto acid accumulates in the body. Autosomal recessive inheritance.
The -branched keto acid (KICKMVKIV) formed by the branched chain amino acid after amino transfer must be further catalytically decarboxylated by the branched -keto acid dehydrogenase in the mitochondria. The enzyme is a complex enzyme system (BCKAD complex) from the decarboxylase. (E1 includes two subunits of E1E1) dihydrolipoamide acyl transfer and dihydrolipoyl dehydrogenase E3, etc. The four coding genes are located at 19q13.1-q13.26p21-p221p2l-31 And 7q3l; wherein E3 is also a component of pyruvate dehydrogenase and -ketoglutarate dehydrogenase in human body. This enzyme system also requires pyrophosphoryl thiamine as a coenzyme to participate in the mutation of any of the above listed genes. Defects in this enzyme complex cause various types of maple glucosuria.
Defects of branched ketoacid dehydrogenase cause the corresponding ketoacid to be oxidatively decarboxylated and retained in the body and produce a special odor of branched chain amino acid metabolism disorder in the urine to increase the branched chain amino acids in the nervous system; glutamic acid glutamine and - Aminobutyric acid and the like are obviously decreased; medullary lipids such as cerebroside lipids and cerebroside sulfate are not considered to be toxic to the brain by accumulation of branched amino acids and ketoacid derivatives in the body, such as inhibition of myelination into the brain. Protein synthesis inhibits neurotransmitter function and enzyme activity, causing severe damage to developing brain tissue. In addition to typical genetic defects, there are three variants of the white matter caused by spongiform changes and myelination disorders in the cerebral hemisphere. The corpus callosum around the nucleus and the pyramidal tract are most prominent; cerebral edema is common in children with death due to acute metabolic disorders.
Prevention
Maple diabetes prevention Avoiding 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, and the enzyme activity is normal. The 0 to 2% intermittent type is 8% to 16%. Between the two, the effective form of B1 is 25% of normal, and the enzymatic activity of the above heterozygote is 50% of normal. The enzyme activity can be determined by cultured amniotic cells to make prenatal diagnosis and terminate pregnancy if necessary. Balance the diet to achieve adequate nutrition. Avoid high sugar foods such as various sweets and sweets. Reduce fat intake, in addition to limiting animal fat, daily cooking oil below 20 grams. Avoid greasy and high-fat foods such as fried foods, melon seeds, and peanuts. Avoid foods high in cholesterol, such as animal internal organs. Choose high-fiber foods such as coarse grains and vegetables with high fiber content. Regular meals can be eaten in small quantities. To ensure protein intake, 1.2 grams of protein per kilogram of body weight, but not too much. Drink more water.
Complication
Maple diabetes complications Complications dehydration
Patients with vomiting can cause severe dehydration, leading to acidosis, and should actively treat the primary disease and promptly treat dehydration acidosis.
Symptom
Maple Diabetes Symptoms Common Symptoms Coma hypokalemia Angle bowel tension hypertonic convulsion Metabolic acidosis ataxia
According to the clinical manifestations, maple diabetes can be divided into classic type, intermittent type, intermediate type, thiamine reaction type and E3 deficiency type, among which the most common type is classic type, accounting for 75%, and intermediate type and intermittent type of thiamine treatment are also available. reaction.
The clinical manifestations of this disease are not uniform, mainly related to the degree of decreased BCKD complex activity, and the BCKD complex activity is determined by the mutation of E1, E2 and E3 genes, which can be diagnosed after birth, the patient's urine, sweat and phlegm. There is a special maple odor, and the clinical manifestations range from typical performance to only mild symptoms.
1. Classical type (neonatal type) Infants are normal within 24 hours after birth, and symptoms of ketoacidosis appear after 1 week, manifested as difficulty in feeding, vomiting, metabolic acidosis and neurological damage, such as Convulsion, increased muscle tone, even muscle rigidity, angulation, or alternating muscle tension and relaxation, lethargy or coma, patients may have hypoglycemia, but convulsions and coma are not caused by hypoglycemia, because of low blood sugar After correction, these symptoms did not improve. If not diagnosed and treated correctly, the patient often died within weeks or months. This type is the most serious and the most common type of maple diabetes, even after treatment. Survival can also have sequelae of mental retardation and impaired nervous system, which is common in the Mennonite population.
2. Intermittent type This type of patient is often induced under stress, such as surgery, infection and frequent vomiting, the clinical manifestations of the attack are similar to the classic type, and there is ataxia, but this type of patient BCKD complex Residual activity is higher than typical type, 8% to 10% of patients can be close to normal, so the symptoms are mild, severe cases can also die after the attack, intermittent blood and urine branched chain amino acid concentration increased, accompanied by hypoglycemia , hypokalemia, hyperammonemia, ketosis and acidosis, M2 examination of the bilateral globus pallidus showed a high signal change.
3. intermediate type (intermediate type) In the neonatal period, there are also maple odor and mild symptoms in the urine, and later induced maple diabetes in other diseases, mainly the symptoms and signs of nervous system involvement, the same as the classic type, but Light, respond to treatment with large doses of vitamin B1.
4. Vitamin B (thiamine)-reactive vitamin B1 is a coenzyme of the BCKD complex. When the BCKD complex is reduced in activity due to mutations in the E1, E2 and E3 genes, a large amount of thiamine pyrophosphate is required. Coenzyme, clinical manifestations are also relatively light, the treatment of large doses (200mg / 24h) of vitamin B1 for 3 weeks showed efficacy, but also infants with vitamin B1 10mg is effective.
5. Dihydrogenacyl dehydrogenase (E3) deficiency type This type is shared by all -keto acid dehydrogenase complexes due to the lack of BCKD complex-specific kinase, so the activity of BCKD complex is reduced. Also, pyruvate dehydrogenase and -ketoglutarate dehydrogenase function are impaired, causing organic acidosis in newborns. The child is normal at birth, then has systemic relaxation, low muscle tone, progressive ataxia And severe neurological symptoms and signs can die in childhood.
Examine
Maple diabetes check
Urine check
(1) In the urine of patients, due to the release of -keto acid produced by the metabolism of branched-chain amino acids, there is a smell of maple syrup. Podebrad et al. used a mutual selective gas chromatography-mass spectrometry method for urine samples from 7 patients. (enautio-MD GC-MS), the odorous substance in the urine is 4,5-dimethyl-3-hydroxy-2(5H)-furanone [4,5 dimethyl-3-hydroxy-2(5H)- Furanone], also known as Sotolone.
(2) Determination of branched chain amino acids (including leucine, valine, isoleucine and other isoleucine): the corresponding keto acid excreted from the urine [ie 2-keto acid 4-methyl-2 ketone) 2-oxo acid 4-methyl-2-oxopentenoate (KIC), 3-methyl-2-oxobutanoate (KIV), (S)-(SKMV), and R)-3-methyl-2-ketovaleric acid [(R)-3-methyl-2-oxopantanoate, R-KMV], Schadewaldt et al. Determination of blood and urine in 10 patients with typical maple diabetes According to the concentration, the results showed that the corresponding metabolites from the urine of the above-mentioned branched-chain amino acids were KIC (0.1% to 25%), KIV (0.14% to 21.3%), and SKMV (0.26% to 24.6%). And R-KMV (0.1% to 35.9%), the free branched chain amino acids excreted in the urine are few.
(3) Qualitative determination of urinary ketone: fresh urine samples were positive by adding a few drops of dinitrophenylhydrazine and 0.1 NHCl to produce yellow diphenyl hydrazine precipitate.
2. Blood test
(1) Determination of branched-chain amino acids in blood: The concentration of branched-chain amino acids in blood can be directly determined by automatic amino acid analyzer or ion exchange chromatography or tandem mass spectrometry, including leucine, isoleucine, etc. Isoleucine (alloisoleucine) and proline, due to the reduced or absent activity of the BCKD complex, these branched-chain amino acids are elevated in blood, especially the increase in leucine is higher than the other three branched-chain amino acids. Obviously, the amount of leucine in the normal human blood is very small, and it is elevated in this disease. Therefore, it is diagnostic to determine the level of lysine in blood.
(2) Determination of plasma branched-chain amino acid metabolites: 5- and 3-methyl-2-ketovaleric acid in the plasma of the disease is elevated to the aggregate.
3. Plasma amino acid diurnal changes
In this disease, the non-branched amino acids in the fasted state have higher rate of amino acid oxidation than the rate of protein cleavage, and the branched chain amino acids are blocked by specific metabolism, so the branched chain amino acids are net and the blood levels are increased. This is in fasting and The diurnal variation of plasma amino acids in the fed state is the metabolic characteristic of this disease.
4. CT examination of this disease CT examination has a low density of white matter, especially the deep white matter of the cerebellum, brain stem, cerebral peduncle, thalamus and posterior branch of the internal capsule. These neurological changes have progressed after diet treatment, and at the same time, edema disappears. This phenomenon can be distinguished from other brain organic diseases.
5. Brain MRI can have bilateral globus pallidus with high signal in T2 phase, but these CT and MRI findings can not be used as a basis for diagnosis of this disease.
6. Determination of oxidative dehydroxylation of cultured amniotic fluid cells by radionuclide technique can be used for prenatal diagnosis.
Diagnosis
Diagnosis and diagnosis of maple diabetes
diagnosis
The disease often occurs in infancy, and the clinical manifestations are extremely heterogeneous, from asymptomatic to severe clinical manifestations, so the diagnosis is not easy. If you can use the tandem spectrometer for screening in newborns, you can get early diagnosis. Although the disease is a hereditary disease, but the genetic pattern is autosomal recessive inheritance, family history does not help the diagnosis.
Newborn urine, sweaty maple odor or metabolic acidosis of unknown origin should be highly suspected.
Classical type is common, the main clinical manifestations are central nervous system damage, such as increased muscle tone, convulsions, lethargy and coma, as well as metabolic acidosis.
Clinical diagnosis depends on the increase of plasma branched-chain amino acids and their metabolite 2-oxo acid, especially the increase in the concentration of different leucine that does not participate in protein synthesis in vivo, or determination The metabolites of urinary branched-chain amino acids are also helpful for clinical diagnosis. However, it is necessary to confirm the mutation of E1, E2 or E3 by molecular biotechnology. DNA of these enzyme genes extracted from peripheral blood leukocytes and skin fibroblasts can be used. Molecular biology techniques are used for mutation testing.
Differential diagnosis
Hypoglycemia: hypoglycemia is common in children with classic MSUD. However, correcting hypoglycemia does not improve the clinical situation. The diagnosis depends on amino acid analysis, showing plasma levels of leucine, isoleucine, proline and other isoleucine. Significantly elevated, while alanine levels decreased.
