Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria

Abstract

The cblC type of combined methylmalonic aciduria (MMA) and homocystinuria (HC) is the most common inborn error of vitamin B 12 metabolism and is caused by mutations in the MMACHC gene. To elucidate the spectrum of mutations that causes combined MMA and HC in Chinese patients, the MMACHC gene was sequenced in 79 unrelated Chinese patients. Sequence analysis identified 98.1% of disease alleles and found that all patients had at least one MMACHC mutation. A total of 24 mutations were identified. Out of the 24 mutations identified, 9 were novel ones, including missense mutations (c.365A4T and c.452A4G), nonsense mutations (c.315C4G and c.615C4A), deletions (c.99delA and c.277-3_c.303del30), duplications (c.248dupT and c.626dupT) and an insertion (c.445_446insA). The c.609G4A, c.658_660delAAG, c.482G4A, c.394C4T and c.80A4G mutations were the most common mutations and accounted for 80% of disease alleles. Haplotype analysis suggests that the spread of the c.80A4G, c.609G4A and c.658_660delAAG mutations in Chinese patients were caused by a founder effect. The results indicate that defects occurring in the MMACHC gene are the major cause of this disease in Chinese patients with combined MMA and HC, and direct mutation analysis can therefore be used as a rapid confirmatory diagnosis among these Chinese patients.

Do not Miss Rare and Treatable Cause of Early-Onset Hemolytic Uremic Syndrome: Cobalamin C Deficiency

“…The identification of the gene defect does not always predict the time and severity of disease, as indicated by Nogueira et al [11]. However, MMACHC transcript levels may provide a clue in terms of onset of the disease [10]. Patients with cobalamin deficiency secondary to these 2 mutations (c.481C>T and c.271dupA) with renal involvement were summarized in Table 2.…”

“…The frequency of the mutations varies in different parts of the world. Liu et al [10] investigated mutation spectrum of 71 Chinese patients with cblC defect according to the age of onset. They found that mutations other than c.271dupA accounted for 80% of disease alleles.…”

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

“…The late onset form of the cblC disorder has been reported in a smaller number of cases and is associated with a better response to treatment (10). So far, Ͼ75 mutations have been identified in the gene encoding CblC, and Ͼ700 affected alleles have been sequenced (8,11,12).…”

Cobalamin C Deficiency in an Adolescent With Altered Mental Status and Anorexia

“…12 However, compound heterozygosity of this mutation with a missense mutation, such as c.482G.A on exon 4 (predicted protein p.Arg161Gln), tends to result in late-onset disease, which may be due to higher expression of the late-onset allele compared with the early-onset allele. 12,13,[19][20][21][22] Two other case reports have described patients who were also compound heterozygotes for c.271dupA and c.482G.A (Table 2). 20,23 Both patients presented with neuropsychiatric, hematologic, genitourinary, and musculoskeletal complaints, similar to our patient.…”