Introduction
Isovalerate Isovaleric acldemla The amount of isovaleric acid in the blood is increased due to the innate lack of the leucine-metabolizing enzyme (isopropionate coenzyme Aiso-valeril CoA) or the isovaleric acid glycine (isoamylate glycine complex) is often excreted from the urine.
Isovaleric acid isolavalic acldemla due to the innate lack of leucine-metabolizing enzyme (isovalerate coenzyme Aiso-valeril CoA) caused by an increase in the amount of isovaleric acid in the blood or frequent excretion of isovaleric acid glycine from the urine (isovalerate glycine containing Compound). Severe vomiting, severe ketoacidosis with intermittent seizures and lethargy. And because of the accumulation of isovaleric acid, both exhaled and body surface have bad odor. Isovaleric acid can be experimentally induced by hypoglycemia A (hypoglycin A) obstruction (ia-maica vomiting).
Historical records
Tanaka and colleagues reported the first case of isovaleric acid in 1966, the first hereditary organic acid disease diagnosed by gas chromatography-mass spectrometry. More than 60 cases have been reported so far. Isovaleric acid is named for its elevated isotonic acid concentration in patients. The normal plasma isovaleric acid concentration is lower than 10μM. The plasma isovaleric acid concentration in patients with isovaleric acid may be normal or have a 10-fold increase (10-450μM), but the concentration in acute attack is 100-400 times higher than normal ( 600 to 5000 μM). Isovaleric acid has a "sweaty foot" odor, which is generally not obvious during the remission period, but is very significant during the acute attack period. The concentration of isovaleric acid in urine was significantly lower than that of plasma, and the excretion amount was 8 to 300 μmol/d (normally less than 2 μmol/d).
Cause
The cause of isovaleric acid is the lack of isovaleryl-CoA dehydrogenase, resulting in the accumulation of isovaleryl-CoA and its metabolites. The enzymatic activity of mitochondria in patients with fibroblasts is about 0% to 43% of normal, and residual enzyme activity is not related to clinical severity. Isovaleric acid is autosomal recessive, and the gene of isovaleryl-CoA dehydrogenase is localized to human chromosome 15q14~q 15. In the same family, there may be acute neonatal or chronic intermittent patients, suggesting that the clinical phenotype is different, and some are caused by non-genetic factors.
Clinical manifestation
Two different clinical types have been reported, with approximately half of the patients presenting with acute severe neonatal disease and the other half with chronic intermittent seizures. In vitro enzymatic tests are all the same biochemical defects, namely the lack of isovaleryl-CoA dehydrogenase activity.
Acute infants are normal at birth, and within a few days (usually 3 to 4 days, but as early as the first day after birth or as late as the 14th day), milking and vomiting occur, followed by dehydration, burnout and lethargy. Many have low body temperature, tremor or twitching, and convulsions. Often accompanied by an unpleasant "sweaty foot" odor caused by increased isovaleric acid. Metabolic acidosis with mild to moderate ketouria, lactateemia, significant hyperammonemia (200 ~ 1200 μM), and hypocalcemia are more common. The typical course of disease is the rapid appearance of bruising, followed by coma and death. The cause of death may be severe metabolic acidosis, cerebral edema, hemorrhage or secondary infection. More than half of the acute cases reported have died. With the improvement of diagnostic techniques and the improvement of treatment methods, such as the use of glycine and carnitine, the prognosis is improved. If the patient survives in the neonatal period, then the course of the disease can be converted to a chronic intermittent type, and subsequent development may be normal.
The first clinical episode of a chronic intermittent patient is usually within one year of age, usually after an upper respiratory tract infection or a high protein diet. Symptoms of recurrent episodes include vomiting, lethargy, and progression to coma. There are acidosis with ketoneuria, as well as special "sweaty feet" smell. Limiting protein intake and infusion of glucose can alleviate symptoms. Other accompanying symptoms include diarrhea, thrombocytopenia, neutropenia, and complete cytopenia, and some cases have hair loss and hyperglycemia. Many cases of organic aciduria may be associated with hyperglycemia, and the same case may or may not have hyperglycemia at different episodes of attack, which may be independent of the nature of the disease itself, but due to stress hormone response. This type occurs most frequently during infancy, with reduced chances of infection and decreased protein intake as the age increases. In most chronic intermittent cases, psychomotor development is normal, but some cases may be mild or severely intelligent. Many patients have a natural aversion to high protein foods. At present, biochemical diagnosis can be performed at the first episode. Early diagnosis combined with restriction of protein intake and use of glycine and carnitine can greatly improve the possibility of normal development of patients.
Diagnostic criteria
Since the clinical manifestations of isovaleric acid are common to many organic aciduria, its diagnosis depends on organic acid analysis. The "sweaty foot" smell in the acute attack may indicate the disease, but the glutaric acid type II may have a similar smell due to the accumulation of butyric acid, isobutyric acid, 2-methylbutyric acid and isovaleric acid in the body. Perform a differential diagnosis. There is usually no odor during the remission period, and it is not always scented at the time of onset. Newborn or older infants have multiple symptoms such as refusal to milk, vomiting, lethargy, coma, metabolic acidosis, ketosis, hyperammonemia, hypocalcemia, thrombocytopenia, neutrophils and whole blood cells Reduction, etc., should take into account the disease. Analysis of plasma volatile short-chain acid showed that increased isovaleric acid and no other increase in short-chain acid should be considered for the diagnosis of isovaleric acid, but the detection is difficult and can not diagnose other organic aciduria. Because patients with isovaleric acid have elevated levels of valerated isovaleryl glycine, urinary non-volatile organic acid analysis is often used for diagnosis and differential diagnosis with other organic aciduria. The urinary organic acid profile of patients with typical isovaleric acid in the acute phase is extremely elevated with isovaleryl glycine, accompanied by significant increase in 3-hydroxyisovalerate, and other metabolites such as 4-hydroxyisovalerate, methyl succinic acid, 3-Hydroxyisoheptanoic acid, isovaleryl glutamic acid, isovaleryl glucuronic acid, isovalerylalanine and isovaleryl creearine were significantly increased. In addition, significant increases in non-specific lactic acid, 3-hydroxybutyrate, and acetoacetate are more common. The only organic acid that has diagnostic significance during remission is increased to isovalerylglycine.
High-field proton magnetic resonance (NMR) can directly detect isovaleryl glycine in a small amount of urine, which is a promising new method for rapid diagnosis of organic aciduria. NMR is particularly valuable for the diagnosis of isovaleric acid, because isovaleric acid (whether the patient is in the acute phase or in the remission phase) is the only disease in which urinary isovaleryl glycine is extremely elevated.
Analysis of urinary carnitine ester can be used as adjunctive diagnosis of isovaleric acid. The acyl-CoA product is in equilibrium with the corresponding acylcarnitine and is excreted in the urine. A small amount of isovalerylcarnitine can be detected in the urine of patients with ischemic acid during remission. Oral L-carnitine l00mg/kg can increase the release of isovalerylcarnitine to 3200mmol/mole creatinine, suggesting that carnitine can increase the reliability of the diagnosis of isovaleric acid with acylcarnitine.
The biochemical diagnosis of isovaleric acid can be confirmed by the release method or the fluorescence method for the activity of isovaleryl-CoA dehydrogenase in fibroblasts, but the method is difficult. Fluorometric determination of isovaleryl-CoA dehydrogenase activity, or culture of amniotic fluid [1-14C] isovaleric acid macromolecular markers, or determination of isovaleryl glycine content in amniotic fluid by isotope dilution method Acidemia for prenatal diagnosis.
treatment
The disease is given a low-protein or low-leucine diet and a three-branched amino acid diet. Oral glycine 250mgi (kg. d) can prevent complications, but need to pay attention to the neurotoxicity caused by hyperglycemia. Oral L-carnitine can also be taken.
简体中文