Clinical and molecular analysis of cobalamin C type methylmalonic aciduria with homocystinuria in a Chinese family

Abstract

Background Researches determined that c.365A＞T and c.658_66 0delAAG variant is rare type of MMACHC gene mutation in the patients with cobalamin C (CblC) type methylmalonic aciduria and homocystinuria (cblC disease).What is more,the cblC disease family with the same mutation has not been reported up to now.Objective This study was to detect and analyze the mutations in MMACHC gene in a Chinese family with cblC disease.Methods This protocol complied with Helsinki declaration,and all the medical examination were performed under the informed consent of custodian.The Chinese family was composed of four members of the two generations,including a 14-year male proband,his 4-year sister,their mother and father.All members of the family underwent complete ophthalmologic examinations covered with the ocular anterior segment and posterior segment.The peripheral blood as collected for the families for the extraction of DNA.All exons of MMACHC gene were screened for sequence alterations by PCR and direct DNA sequencing.Results The cblC disease family was verified to be anautosomal recessive inheritance.The proband and his sister appeared to be the cblC disease children and their parents were phenotypic normal.The sickened children were diagnosed and managed at 10 years old and 1 year old,respectively.No obvious abnormal finding was seen in the anterior ocular segment,but different degrees of macular atrophies were seen in both eyes of the children.In addition,nystagmus was found in the proband.The compound heterozygote mutations in the MMACHC gene were identified in two affected children,which included a deletion mutation (c.658_660delAAG,p.KdelLys) in exon 4 and a missense mutation (c.365A＞T,p.H122L) in exon 3,both of them were respectively inherited from their unaffected parents.However,c.365A＞T variant was sequenced in the phenotypica normal mother,and c.658_660delAAG variant was found in the phenotypica normal father.Conclusions A rare compound heterozygote mutation of MMACHC is identified in this Chinese family,indicating MMACHC may play a critical role in the development of cblC disease. Key words: Homocystinuria/genetics; Methylmalonic acid/metabolism; Heterozygote; DNA mutational analysis; Complication; Eye; cblC disease; Chinese