title: Clinical presentation, gene analysis and outcomes in young patients with early-treated combined methylmalonic acidemia and homocysteinemia (cblC type) in Shandong province, China.
abstract: OBJECTIVE
  To estimate the incidence of MMA on newborn screening in Shandong province from May 2011 to May 2014 and summarize the clinical presentation, biochemical features, mutation analysis, and treatment regime of early-treated patients with cblC disease.
  
  
  METHODS
  Between May 2011 and May 2014, 35,291 newborns were screened for MMA in Jinan maternal and Child Care Hospital, Shandong province. The levels of C3, C3/C2, methionine and tHcy were measured. Most patients received treatment with intramuscular hydroxocobalamin after diagnosis. Metabolic parameters, clinical presentation and mental development were followed up.
  
  
  RESULTS
  Nine patients were identified among 35,291 by newborn screening, giving an estimated incidence of 1:3920 live births for MMA, and all were classified as cblC disease. Among them, five patients received treatment with intramuscular hydroxocobalamin and two patients did not receive any treatment. One patient died of metabolic crises triggered by infection at the age of 38 days. Seven different mutations (c.609G>A, c.455_457delCCC, c.394C>T, c.445_446insA, c.658_660delAAG, c.452A>G and IVS1+1G>A) were detected. The mutations (c.455_457delCCC and IVS1+1G>A) are novel. Five patients who received treatment had favorable metabolic response, with both reduction of urine MMA and tHcy and increase of methionine. We obtained 7 records of DQ assessment. The five patients who received treatment presented with developmental delay and obvious neurological manifestations. In two patients who did not receive any treatment, case 8 presented with severe mental retardation and developmental delay, while case 9 had nearly normal DQ values at the age of 1(1/12)years.
  
  
  CONCLUSIONS
  Our study characterized variable phenotypes of neurodevelopment in early-treated cblC patients diagnosed on newborn screening. The long-term outcomes of cblC disease are unsatisfactory in spite of conventional treatment and improvement of biochemical abnormalities. Although the number of patients is too small, the information provided in this work is of value in highlighting possible genotype-phenotype correlation that influences outcomes in cblC disease by future studies.
authors.affiliation: Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, Shandong Province, China; Jinan Maternal and Child Care Hospital, Jinan 250001, Shandong Province, China.
authors.forename: Bingjuan
authors.initials: B
authors.lastname: Han
authors.affiliation: The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, Jiangsu Province, China.
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Jinan Maternal and Child Care Hospital, Jinan 250001, Shandong Province, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Tian
authors.affiliation: Jinan Maternal and Child Care Hospital, Jinan 250001, Shandong Province, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zou
authors.affiliation: The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, Jiangsu Province, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Yang
authors.affiliation: Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, Shandong Province, China. Electronic address: weweikeyan@163.com.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, Shandong Province, China; Jinan Maternal and Child Care Hospital, Jinan 250001, Shandong Province, China; Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. Electronic address: liuyingxia@njmu.edu.cn.
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors; D002352:Carrier Proteins / Q000235:genetics; D002681:China; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D006712:Homocystinuria / Q000175:diagnosis / Q000453:epidemiology* / Q000209:etiology* / Q000235:genetics; D006801:Humans; D020138:Hyperhomocysteinemia; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008764:Methylmalonic Acid; D015997:Neonatal Screening / Q000706:statistics & numerical data; D014806:Vitamin B 12 Deficiency / Q000151:congenital* / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D008764:Methylmalonic Acid
keywords: Follow-up; MMACHC; Methylmalonic acidemia; Newborn screening; cblC disease