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

[homocystinuria without methylmalonic aciduria]

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 (C 3 ), free carnitine (C 3 /C 0 ), and acetylcarnitine (C 3 /C 2 ) 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 Â C >G (p .Y 105 X ) and c .470 Â G >C (p .W 157 S ). In terms of genotype-phenotype correlation , the c .609 Â G >A mutation was associated with early -onset disease when homozygous . Unlike previous reports from other populations , c .609 Â G >A (p .W 203 X ) 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 .

Diseases
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Diseases presenting "early-onset disease when homozygous" symptom

homocystinuria without methylmalonic aciduria

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