Abstract：Objective To analyze mutation types, clinical features, and treatment outcomes of cobalamin C (cblC) type combined methylmalonic aciduria and homocystinuria (MMA-HC) and to investigate the relationship of genotypes with clinical phenotypes and outcomes. Methods The clinical data of 16 Chinese children diagnosed with cblC type MMA-HC by gene analysis were retrospectively analyzed. According to the onset age, the patients were classified into early onset (≤1 year) and late onset (> 1 year). According to the clinical phenotype, the patients were classified into mild, moderate, and severe groups. All the patients were treated with vitamin B12 (cyanocobalamin) or hydroxocobalamin, betaine, folate, vitamin B6, and L-carnitine. Results Fifteen patients belonged to the early onset type, including 11 in the severe group and 4 in the moderate group. The remaining one belonged to the late onset type. Seven reported mutations and two novel mutations (c.445_446delTG and c.349G> c) were detected. The c.609G> A and c.658_660delAAG were the most common mutations detected in 13 (81%) out of 16 patients. The genotype caused by compound heterozygous mutations of these two alleles (c.609 G> A/c.658_660delAAG) was the most common in the patients, detected in 4 (25%) out of 16 patients. Patients with this genotype had severe microcephaly and eye diseases and these clinical manifestations were not improved after the treatment. The patient with late-onset cblC type MMA-HC had normal clinical phenotypes after treatment. In the 15 early onset patients, the more severe the clinical phenotype, the worse the treatment outcome. Conclusions The cblC type MMA-HC mainly manifests as early onset in China and c.609G > A and c.658_660delAAG are the most common mutations causing this disease. The clinical phenotypes are associated with the outcomes in children with cblC type MMA-HC.
YU Ya-Fen,LI Fang,MA Hong-Wei. Relationship of genotypes with clinical phenotypes and outcomes in children with cobalamin C type combined methylmalonic aciduria and homocystinuria[J]. CJCP, 2015, 17(8): 769-774.
Fowler B, Leonard JV, Baumgartner MR. Causes of and diagnostic approach to methylmalonic acidurias[J]. J Inherit Metab Dis, 2008, 31(3): 350-360.
[2]
Liu MY, Yang YL, Chang YC, et al. Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria[J]. J Hum Genet, 2010, 55(9): 621-626.
Lerner-Ellis JP, Tirone JC, Pawelek PD, et al. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type[J]. Nat Genet, 2006, 38(1): 93-100.
[5]
Fischer S, Huemer M, Baumgartner M, et al. Clinical presentation and outcome in a series of 88 patients with the cblC defect[J]. J Inherit Metab Dis, 2014, 37(5): 831-840.
Wang F, Han LH, Yang YL, et al. Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China[J]. J Inherit Metab Dis, 2010, 33 (Suppl 3): S435-S442.
Morel CF, Lerner-Ellis JP, Rosenblatt DS, et al. Combined methylm alonic aciduria and homocystinuria (cblC): phenotype-genotype correla tions and ethnic-specific observations[J]. Mol Genet Metab, 2006, 88(4): 315-321.
[12]
Fischer S, Huemer M, Baumgartner M, et al. Clinical presentation and outcome in a series of 88 patients with the cblC defect[J]. J Inherit Metab Dis, 2014, 37(5): 831-840.
[13]
Martina Huemer, Sabine Scholl-Bürgi, et al. Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy[J]. Orphanet J Rare Diseases, 2014, 9: 161.
[14]
Debray FG, Boulanger Y, Khiat A, et al. Reduced brain choline in homocystinuria due to remethylation defects[J]. Neurology, 2008, 71(1): 44-49.
Bodamer OA, Sahoo T, Beaudet AL, et al. Creatine metabolism in combined methylmalonic aciduria and homocystinuria[J]. Ann Neurol, 2005, 57(4): 557-560.
[17]
Roehrs C, Garrido-Sanabria ER, Silive AC, et a1. Succinate in creases neuronal post-synaptic excitatory potentials in vitro an d induces convulsive behavior through N-methyl-D-aspartated mediated mechanism[J].Neuroscience, 2004, 125(4): 965-971.
[18]
Malfatti CR, Perry ML, Schweigert D, et al. Convulsions in-duced by methylmalonic acid are associated with glutamic acid deearboxylase inhibition in rats: a role for GABA in the seizuyes presented by methylmalonic acidemic patients?[J]. Neuroscience, 2007, 146(4): 1879-1887.
[19]
Martinelli D, Deodato F, Dionisi-Vici C. Cobalamin C defect: natural history, pathophysiology, and treatment[J]. J Inherit Metab Dis, 2011, 34(1): 127-135.
[20]
Froese DS, Zhang J, Healy S, et al. Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria[J]. Mol Genet Metab, 2009, 98(4): 338-343.
[21]
Matos IV, Castejón E, Meavilla S. Clinical and biochemical outcome after hydroxocobalamin dose escalation in a series of patients with cobalamin C deficiency[J]. Mol Genet Metab, 2013, 109(4): 360-365.
[22]
Pastore A, Martinelli D, Piemonte F. Glutathione metabolism in cobalamin deficiency type C (cblC)[J]. J Inherit Metab Dis, 2014, 37(1): 125-1299.
