title: Selective screening for inborn errors of metabolism and secondary methylmalonic aciduria in pregnancy at high risk district of neural tube defects: a human metabolome study by GC-MS in China.
abstract: OBJECTIVE
  Urease pretreatment-gas chromatography-mass spectrometry (UP-GC-MS) has become a valuable tool in the field of metabolome research, including analysis of inborn errors of metabolism (IEMs) and acquired metabolic disturbances secondary to nutrition or drugs. This research aims to screen IEMs in Chinese patients and to explore the cause of neural tube defects (NTDs), a congenital malformation very common in North China.
  
  
  METHODS
  Urine samples from 618 patients at high risk of IEMs in China were collected, and UP-GC-MS was performed in the selective screening. Urinary methylmalonate (MMA) levels in pregnancy with and without NTDs fetus, respectively, at Luliang district, a countryside region with NTDs incidence 227/10,000, Shanxi Province, North China, were analyzed by GC-MS-selective ion monitoring, and compared with that from control region.
  
  
  RESULTS
  Among the 618 patients, 22 kinds and 59 cases of IEM were found. Methylmalonic aciduria (MMAuria) is on top of the list, followed by neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), phenylketonuria (PKU), multiple carboxylase deficiency (MCD), etc. Satisfactory therapeutic effects have been achieved in patients such as NICCD, MCD, and galactosemia. At Luliang district, urinary MMA levels in pregnancy, no matter NTDs-affected or unaffected, are both significantly (P<0.01) higher than that in normal control, while serum B(12) levels in NTDs-affected pregnancy are significantly lower than that both in NTDs-unaffected group (P<0.01) and in normal control (P<0.01). Furthermore, B(12) <52.5 pmol/L is associated with a 7.78-fold increased NTDs risk (P<0.01) at Luliang district.
  
  
  CONCLUSIONS
  Selective screening for IEMs by UP-GC-MS provides valuable evidences for the diagnosis of IEMs. MMAuria secondary to B(12) deficiency is quite common at Luliang district, suggesting B(12) deficiency is involved in the development of NTDs in the specific population. This metabolome research by UP-GC-MS provides valuable epidemiological information that helps to understand the prevalence and the possible intervention strategy of NTDs and IEMs, especially in Chinese population.
authors.affiliation: Department of Pediatrics, First Affiliated Hospital, Jinan University, Guangzhou 510630, China. songyuanzong@tom.com
authors.forename: Yuan-Zong
authors.initials: YZ
authors.lastname: Song
authors.forename: Bing-Xiao
authors.initials: BX
authors.lastname: Li
authors.forename: Hu
authors.initials: H
authors.lastname: Hao
authors.forename: Ruo-Lei
authors.initials: RL
authors.lastname: Xin
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Zhang
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Zi-Neng
authors.initials: ZN
authors.lastname: Wang
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Zheng
mesh_terms: D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000175:diagnosis / Q000652:urine*; D002648:Child; D002675:Child, Preschool; D002681:China / Q000453:epidemiology; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008403:Mass Screening; D026901:Membrane Transport Proteins / Q000652:urine*; D008764:Methylmalonic Acid / Q000652:urine; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000652:urine*; D015997:Neonatal Screening / Q000379:methods*; D009436:Neural Tube Defects / Q000175:diagnosis / Q000453:epidemiology / Q000652:urine*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000175:diagnosis / Q000652:urine*; D012307:Risk Factors
chemical_list: C497512:MMAA protein, human; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D008764:Methylmalonic Acid