Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China

Abstract

The most common inborn error of cobalamin (cbl) metabolism in China is the cblC type characterized by combined methylmalonic acidemia and hyperhomocysteinemia. The clinical presentation is relatively nonspecific, such as feeding difficulty, recurrent vomiting, hypotonia, lethargy, seizures, progressive developmental delay, and mental retardation, together with anemia and metabolic acidosis. More specific biochemical findings include high levels of propionylcarnitine (C3), free carnitine (C3/C0), and acetylcarnitine (C3/C2) measured by tandem mass spectrometry (MS/MS), elevation of methylmalonic acid (MMA) measured by gas chromatography-mass spectrometry (GC-MS), and increased total homocysteine with normal or decreased methionine. We report on 50 Chinese patients with combined methylmalonic acidemia and hyperhomocysteinemia. Forty-six belonged to the cblC complementation group. Mutation analysis of the MMACHC gene was performed to characterize the mutational spectrum of cblC deficiency, and 17 different mutations were found. Most were clustered in exons 3 and 4, accounting for 91.3% of all mutant alleles. Two mutations were novel, namely, c.315 C>G (p.Y105X) and c.470 G>C(p.W157S). In terms of genotype-phenotype correlation, the c.609 G>A mutation was associated with early-onset disease when homozygous. Unlike previous reports from other populations, c.609 G>A (p.W203X) was the most frequent cblC mutation detected in our study of Chinese patients, affecting 51 of 92 MMACHC alleles (55.4%). The high prevalence of this nonsense mutation could have potential therapeutic significance for Chinese cblC patients. Besides traditional approaches consisting of hydroxocobalamin injections, carnitine, betaine, and protein restriction, novel drugs that target premature termination codons may have a role in the future.

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

“…The c.394C>T mutation is associated mainly with late onset disease. The c.609G>A mutation accounts for 85 % of the identified alleles in Chinese patients, and even though it leads to a premature termination codon it remains predominantly associated with late onset disease in this population (Wang et al 2010) but has been observed in some early-onset cases in other populations (Weisfeld-Adams et al 2013). Other mutations have been shown to cluster according to ethnicity (Morel et al 2006; Nogueira et al 2008).…”

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

“…A similar nonsense mutation, c.609G>A, is the most common mutation in patients of Chinese descent. Severity of disease and age of onset in compound heterozygotes carrying c.609G>A depend on the severity of the other mutation (Wang et al 2010). Given our patient's compound heterozygosity for a late-and an early-onset mutation, he would be predicted to have a mild clinical presentation.…”

Combined methylmalonic acidemia and homocysteinemia presenting predominantly with late-onset diffuse lung disease: a case series of four patients

“…All 3 patients carried the c.80A > G mutation which has been reported in 4 Chinese patients with TMA or PAH [9]. The c.331C > T mutation was associated with the early-onset form mainly in the French, Canadian, Acadian and Cajun populations [10, 11], and has been reported in 1 Chinese patient [12]. The c.609G > A mutation is a hot spot mutation in Chinese patients with CblC defect [12, 13] and has been reported in 2 Chinese patients with HUS [14].…”

“…The c.331C > T mutation was associated with the early-onset form mainly in the French, Canadian, Acadian and Cajun populations [10, 11], and has been reported in 1 Chinese patient [12]. The c.609G > A mutation is a hot spot mutation in Chinese patients with CblC defect [12, 13] and has been reported in 2 Chinese patients with HUS [14]. Patient 3 and 4 carried compound heterozygous mutations (c.80A > G, c.609G > A), which have been reported in eight Chinese patients with early-onset of the condition [12, 13], and 1 late-onset Chinese patient with PAH and renal TMA [9].…”