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MMA Reference Standard
Background
Methylmalonic acidemia (MMA), also known as methylmalonic aciduria, is the most common autosomal recessive organic acid metabolic disease among rare diseases in my country. MMA is caused by metabolic defects of methylmalonyl CoA mutase (MCM) or its coenzyme cobalamin (Cbl; also known as vitamin B12, VitB12). Depending on whether the patient's total homocysteine in the blood is elevated, it is divided into two biochemical phenotypes: simple MMA and MMA combined with homocystinemia (referred to as combined MMA). Combined MMA accounts for about 70% of MMA patients in my country. At present, there is one gene related to combined MMA (MMACHC) and five genes related to simple MMA (MUT, MMAA, MMAB, MCEE, MMADHC). There are also some genes that can cause atypical MMA or rare diseases complicated by MMA, including HCFC1, ACSF3, ALDH6A1, TCblR, CD320, LMBRD1, ABCD4, SUCLG1, SUCLG2, etc.
Pathogenesis
Methylmalonic acid is a metabolite of methylmalonyl-CoA in the decomposition pathway of isoleucine, valine, methionine, threonine, cholesterol and odd-chain fatty acids. Under normal circumstances, it is converted into succinyl-CoA under the action of methylmalonyl-CoA mutase and adenosylcobalamin and participates in the tricarboxylic acid cycle. The specific pathogenesis is shown in the figure below:
Figure 1 Methylmalonic acid metabolic pathway
Detection Methods
In the Guidelines for the Diagnosis and Treatment of Rare Diseases (2019 Edition), when methylmalonic acidemia is suspected clinically, blood amino acid and acylcarnitine spectrum analysis shows an increase in propionylcarnitine C3, an increase in the C3/C0 ratio, an increase in the C3/acetylcarnitine C2 ratio, or a decrease in free carnitine C0; urine organic acid analysis shows a significant increase in methylmalonic acid and methylcitrate, which can be used to clinically diagnose MMA. Genetic diagnosis options include high-throughput sequencing analysis such as MMACHC, MUT, MMAA, MMAB, MCEE, and MMADHC gene panels or whole exome sequencing, and the detection of pathogenic mutations in two alleles is of diagnostic significance.
Table 1 Summary of MMA detection methods
Product Data
In the MMA detection experiment, how to judge the accuracy of the results, standard products are indispensable. Kebai now launches MMA related standard products, mainly including MMAA, MMUT, and MMACHC gene loci, and other gene loci will be launched in the future.
Some product data display
Figure 2. Results of dPCR with MMUT c.323G>A Reference Standard and MMUT c.1106G>A Reference Standard.
CB-Gene MMA standard products use ddPCR method to accurately calibrate mutation frequency. CB-Gene MMA gene mutation reference products include relatively common or high incidence mutation types in clinical practice, which can help laboratories evaluate the performance of related products better and more effectively.
