Introduction
Glutaric acidemiaCan be divided into two types. The first type is mainly characterized by neurological symptoms, which were previously found in patients with cerebral palsy. The second type is a very serious metabolic disease, and treatment is difficult. For the early detection of newborn screening, treatment technology is currently being developed, but its effectiveness will take some time to evaluate.
Disease classification editor
In general, patients may be normal before the age of two, may have asymptomatic giant brain, present symptoms in the late stages of infancy, including neurological symptoms such as difficulty in movement, progressive hand-foot chorea, muscle hypotony to stiffness , paralysis, angular arch reversal (opistdotonis, limbs flipped outward, the body is arched), etc., there may beepilepsyOr an acute episode of slumbering coma. During the first acute illness, it is generally considered to be epilepsy, encephalitis or Reye syndrome. Patients may suffer from severe brain damage but are mistaken for cerebral palsy. After the first symptoms of the disease, they may not be awake or I have been slumbering for hours. Symptoms of acute metabolism include restlessness, loss of appetite, lethargy, and low tension, but after physical discomfort, the brain may begin to get hurt quickly. Brain poisoning will precede the obvious chemical abnormalities in the blood. Generally, symptoms such as hypoglycemia, moderate to severe acidosis, and high blood ammonia, which are severely abnormal in metabolic function, will appear in the late stage of the disease. Considered to be a very urgent situation.
diagnosis
The amount of organic acid in the urine or blood of the patient can be detected by mass spectrometry or gas chromatographic analysis. Generally, the glutaric acid excretion in the urine of the patient is higher than that of the average person (1 gm/day), and 3-hydroxyglutaric acid Will also improve. Glutaric acid in the blood also rises, especially after ingesting large amounts of lysine. In the case of an acute attack, there may be hypoglycemia, high blood ammonia, elevated blood transamination, and metabolic acidosis. However, the amino acid in the blood is usually normal. To accurately diagnose the white blood cells or skin fibroblasts, the dehydrogenation activity of the glutarylene A is mainly tested. The diagnosis of the fetus can be detected by culture of chorionic or amniotic fluid cells, and the amount of glutaric acid in the amniotic fluid may also increase.
treatment
The first type of glutarate is still incurable, and treatment is needed to avoid acute attacks and symptom control. Long-term diet control: patients need to limit the intake of lysine and tryptophan, so as not to cause excessive accumulation of intermediate toxic products, although diet restrictions, it is necessary to pay attention to maintain adequate energy and protein intake, excessive restrictions may Will cause growth retardation, please contact the dietitian. At present, there is a special milk powder for the first type of glutaric acid.
RiboflavinversusCarnitineSupplement: Daily supplementation of riboflavin (vitamin B2) about 200-300mg can improve the efficiency of the action of defective enzymes. While supplementing 50-100 mg of carnitine daily, it can accelerate the combination of glutaric acid and carnitine to accelerate the metabolism of glutaric acid and reduce the accumulation of toxic substances.
Treatment at an acute attack: An acute episode may result in death, so proper treatment is important. It is necessary to supplement water, electrolytes and nutrients in a timely manner to improve the phenomenon of dehydration and metabolic acidosis. If blood ammonia is elevated, blood ammonia should be lowered immediately. If the disease can be diagnosed early, it can be treated correctly to prevent neurological symptoms. If it is not treated early, many sports disorders will lead to progressive disability, and intelligence may be affected. Once the injury is caused, it cannot be recovered.
Second type introduction
Pathogenesis Hereditary ETF-QO or ETF deficiency leads to glutaric acid type II, and ETF-QO deficiency is more common in patients with congenital malformations. ETF-QQ antigen deficiency was first detected in the liver mitochondria of a baby girl with polycystic kidney disease and other congenital malformations. The enzyme deficiency was also confirmed in fibroblasts, and the enzyme activity in the patient cells was completely lacking. Enzyme activity is between the patient and normal, suggesting that the disease is autosomal recessive. Patients with mild or delayed hair deficiency have a milder degree of enzyme deficiency. The lack of ETF was first found in two newborn patients with no congenital malformations. In one case, both ETFa and b subunits were deficient, and the other case had only a subunit defect. Some delayed cases have different levels of ETF deficiency. A small number of patients with glutaric acid type II have normal ETF and ETF-QO activity, which may be related to flavin adenosine nucleoside (FAD) biosynthesis or transport disorders. The gene encoding ETF-QO is initially located on chromosome 4, and the genes encoding ETFa and b subunits are located on chromosomes 15q23-25 and chromosome 19, respectively.
Pathogenesis
Clinical manifestations of glutaric acidemia type 2 clinically divided into 3 types, that is, neonatal morbidity with congenital malformations, neonatal morbidity without congenital malformations, and mild and / or delayed. The first two types often have severe acyl-CoA dehydrogenation defects, the latter being mildDehydrogenation defects of various acyl-CoAOr ethylmalonic acid-dipic aciduria.
Clinical manifestation
1, the neonatal period with congenital malformations are mostly premature infants, 24 to 48 hours after birth, low muscle tone, liver, severe hypoglycemia and metabolic acidosis. Children often have a special sweaty foot smell similar to patients with isovaleric acid. Some children may have swollen kidneys or have facial abnormalities (high forehead, low ear, wide eye distance, poor dysplasia, etc.). Patients may have arched foot, anterior abdominal muscle development defects, external genital abnormalities (hypospadias and painful erections). Most of these patients died within a week after birth, and some cases showed no deformity during physical examination. Only renal cysts were found at autopsy.
2, the neonatal period without congenital malformations often occur 24 hours or days after birth, low muscle tone, increased breathing, metabolic acidosis, liver, hypoglycemia and sweaty foot odor. Some patients can survive for a long time due to timely diagnosis and treatment, but those with severe cardiomyopathy often die within a few months. A small number of cases show hypoglycemia in the neonatal period, followed by Reye-like symptoms, and patients can survive for a longer period of time.
3, delayed clinical glutaric acid type 2 or ethylmalonic acid - adipic acid uric acid patients with clinical manifestations. Patients may have intermittent episodes of vomiting, hypoglycemia, and acidosis in the weeks after birth, or have no symptoms during childhood, episodes of vomiting, hypoglycemia, hepatomegaly, and proximal myopathy in adulthood. Other manifestations may include progressive lipid deposition myopathy, carnitine deficiency, or progressive extrapyramidal dyskinesia.
Routine laboratory tests can have severe metabolic acidosis with an increase in anion clearance. Mild to moderate hyperammonemia, severe hypoglycemia without ketosis. Serum transaminase can be increased, prothrombin and partial thromboplastin time can be extended. Serum lactic acid usually increases. The chest X-ray shows a heart enlargement, and the electrocardiogram may suggest hypertrophic cardiomyopathy. Renal cysts can be seen by abdominal ultrasound or CT scan.
Urine organic acid analysis can be used in a variety of profiles, including volatile short chain organic acids (eg, isovaleric acid, isobutyric acid, 2-methylbutyric acid), glutaric acid, ethylmalonic acid, 3-hydroxyiso Valeric acid, 2-hydroxyglutaric acid, 5-hydroxycaproic acid, adipic acid, suberic acid, azelaic acid, dodecanoic acid, isovalerylGlycineAnd 2-methylbutyrylglycine. 3-hydroxybutyric acid and acetoacetic acid are only small or undetectable. Organic acids in blood and cerebrospinal fluid are also increased. In some cases, only intermittent authors were found, and urinary organic acid analysis only showed abnormalities in the acute phase.
Amino acid analysis showed total amino acidemia and total amino aciduria, and proline and hydroxyproline were significantly increased in neonatal patients, while patients with delayed type often had elevated serum and urinary creatinine.
Serum carnitine levels can be normal or low, but urinary esterified carnitine is significantly increased. After oral administration of carnitine, the patient excreted a large amount of acylcarnitine in the urine, including acetylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, hexanoylcarnitine, butyrylcarnitine and propionylcarnitine.
Diagnosis of neonatal ketosis hypoglycemia and metabolic acidosis, a characteristic urinary organic acid spectrum can diagnose glutarate type II. Delayed diagnosis of the hair is more difficult, because patients often do not have metabolic acidosis and failed to perform urinary organic acid analysis in a timely manner, and such patients with organic aciduria are not significant, only in acute attacks. In the urine, 2-hydroxyglutaric acid was found to be differentially diagnosed with glutaric acid (glutaryl coenzyme A dehydrogenase deficiency), which excreted 3-hydroxyglutarate in the urine. The clinical manifestations of some patients with mild glutaric acid type II are very similar to those of vonGierke disease. The latter is often accompanied by ketonemia and ketonuria. Liver biopsy can be identified. The deficiency of ETF or ETF-QO antigen in tissues can be detected by Western blot or radiolabeled immunoprecipitation, and ETF or ElF-QO activity can be directly determined if necessary. Prenatal diagnosis can be performed by measuring a large amount of glutaric acid or amniotic fluid cells in amniotic fluid to oxidize specific substrate disorders. An enlarged cystic kidney can be found in ETF-QO deficient fetuses.
diagnosis
Treatment of neonatal patients often die within a few months after birth.
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