Methylmalonic Aciduria

- Feb 06, 2019-

Methylmalonic aciduria or methylmalonic acidemia is the most common congenital disorder of organic acid metabolism. It is a general term for the accumulation of methylmalonic acid in vivo caused by various reasons. It was first reported in 1967. In recent years, the etiology, diagnosis, treatment and genetic mechanism of the disease have been gradually clarified. With the popularization of mass spectrometry, the epidemiological data of the disease have been constantly updated. It is reported that the incidence in Japan is 2/9780, 2/102200 to 2/16246, Italy is 1/61775, and the incidence in China is unknown.


The etiology of methylmalonate Uria is complex. Hereditary methylmalonic aciduria, including methylmalonyl coenzyme A mutase protein (mut) deficiency and cobalamin coenzyme (vitamin B12) metabolic deficiency, is autosomal recessive inheritance. The coding gene of methylmalonyl coenzyme A mutase is located at 6p21. So far, 10 mutations have been found, most of which are missense mutations leading to amino acid exchange. The complete defect of mut0 was mut-type, and part of the defect was mut-type. Cobalamin metabolic disorders include five types: two are deficiencies in the synthesis of adenosylcobalamin (AdoCbl), i.e. mitochondrial cobalamin reductase (CblA) deficiency, which is localized at 4q31.21 and mitochondrial cobalamin adenosyltransferase (CblA).


B) Lack of adenosylcobalamin and methylcobalamin (CblC, CblD, CblF) due to abnormal metabolism of cobalamin in cytoplasm and lysosome. The clinical manifestations of mut 0, mut-, CblA and CblB were similar, with only methylmalonate uria. The biochemical characteristics of CblC, CblD and CblF patients were methylmalonate Uria with homocysteinemia. According to the treatment response of patients to vitamin B12, it can be divided into two types: vitamin B12 reactive type and non-reactive type. Most of the patients with vitamin B12 reactive type were deficient in coenzyme synthesis. Most of the patients with Cb1A, CblC, CblD and CblF reactive type were vitamin B12 reactive type. Vitamin B12 was effective in half of the patients with Cb1B reactive type. The unresponsive type of vitamin B12 was mostly mutase deficiency.


In addition to the above genetic defects, cobalamin II deficiency, chronic gastrointestinal and hepatobiliary diseases, long-term vegetarian diet and special drug treatment can lead to vitamin B12 deficiency and methylmalonate uria. Long-term inadequate intake of vitamin B12 by mothers causes vitamin B12 deficiency in the fetus, which not only causes pernicious anemia in mothers, but also leads to secondary methylmalonate uria, hematopoietic dysfunction and abnormal development of nervous system in infants.


The plasma levels of vitamin B12 and homocysteine in 173 neonates and their mothers were investigated. It was proved that the plasma levels of vitamin B12 in neonates within 6 weeks of birth were negatively correlated with those in mothers and positively correlated with those in mothers.


In the acute stage of the disease, fluid replacement and acidosis correction should be the main treatment. If necessary, abdominal dialysis or hemodialysis should be carried out. At the same time, calorie and liquid supply should be guaranteed to reduce protein decomposition. Small amounts of insulin should be given when necessary to limit the intake of natural protein. In view of the extremely high mortality rate of severe children or acute episode of metabolic acidosis, it is highly suspected that treatment can be carried out before diagnosis, such as discontinuation of protein intake, intravenous fluid infusion, and intramuscular injection of large doses of vitamin B12.


All patients with methylmalonate Uria should be treated with high-dose vitamin B12 test, intramuscular injection of 1 mg/d for 3-5 days. The responsiveness to vitamin B12 should be judged by comparing the concentration of methylmalonate in urine before and after treatment. High-dose vitamin B12 test therapy can not only strive for the opportunity of treatment, save vitamin B12 reactive patients, but also contribute to the diagnosis of disease type and guide long-term treatment.


The ineffective type of vitamin B12 is mainly dietary therapy. The ideal way is to limit the natural protein, supplement the special therapeutic milk powder which removes isoleucine, valine, methionine and threonine. The daily intake of natural protein in infants and young children should be controlled at 1.0-1.2 g/kg. The long-term maintenance dose of vitamin B12 is 1 mg per week to monthly intramuscular injection or oral methylcobalamin 500-1000 UG per day. The medium protein intake keeps the concentration of blood and urine methylmalonic acid in an ideal range.


Due to the accumulation of organic acids such as methylmalonic acid and propionic acid, corresponding ester acylated carnitine is produced, which leads to increased consumption of carnitine. Supplementation of carnitine can promote the excretion of ester acyl carnitine and increase the tolerance of the body to natural proteins. It is not only helpful to the control of acute disease, but also can effectively improve the prognosis. Carnitine can be injected intravenously or intramuscularly in acute phase, 100-200 mg/kg per day, and 30-60 mg/kg per day in remission period, which can be maintained for a long time. For patients with homocysteinemia, betaine should be given supplementary therapy (1000-3000mg/d) to reduce blood homocysteine concentration and improve the nervous system of children.