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 with MMA, including HCFC1, ACSF3, ALDH6A1, TCblR, CD320, LMBRD1, ABCD4, SUCLG1, SUCLG2, etc.

      Among them, the MMACHC gene is located at 1p34.1, contains 5 exons, encodes 282 amino acids, and has more than 70 known mutations. The most common mutations in Chinese are c.609G＞A and c.658_660delAAG.

Pathogenesis

Methylmalonic acid is a metabolite of methylmalonyl-CoA in the catabolic pathways 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.

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. , C3/C0 ratio increased, C3/acetylcarnitine C2 ratio increased, or accompanied by a decrease in free carnitine C0; urine organic acid analysis showed a significant increase in methylmalonic acid and methylcitric acid, which can be clinically diagnosed as MMA . Genetic diagnosis options include high-throughput sequencing analysis such as MMACHC, MUT, MMAA, MMAB, MCEE, and MMADHC gene panels or whole-exome sequencing. Detection of pathogenic mutations in both alleles is of diagnostic significance.

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.

MMA standard products use ddPCR method to accurately calibrate mutation frequency. 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.