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

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. Design and 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 B12 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, B12< 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 B12 deficiency is quite common at Luliang district, suggesting B12 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.