Defects in enzymes, cofactors, or transporters of metabolic pathways cause inherited metabolic disorders (IMDs), a group of genetic disorders (Scala et al., 2012; Scaturro et al., 2013). Several IMDs have serious consequences in affected neonates, including drowsiness, irreversible intellectual disability, physical disability, coma, and even death (Saudubray et al., 2002; Wasant et al., 2002). The genealogy and incidence of genetic metabolic diseases vary greatly among different regions and ethnic groups (Chace et al., 2003). Mass spectrometry is characterized by high throughput, efficiency, and sensitivity, and can simultaneously detect several metabolites (Millington et al., 1990; Rinaldo et al., 2006; Fernandez-Lainez et al., 2012). It is widely used in screening neonatal genetic metabolic diseases and is crucial in the early diagnosis of amino acid metabolic (Wilcken et al., 2003; Shi et al., 2012), organic acid metabolic, and fatty acid oxidation diseases. Tandem mass spectrometry (MS/MS)-based NBS was launched in 2004 in China, and the average incidence of IMDs in a preliminary study was 1/3,795 (Shi et al., 2012). In recent years, proteomics has been applied to the study of IMDs, and tandem mass spectrometry (MS/MS) technology has made key advances achieved in this field. This technology enables the analysis of large numbers of proteins in different body fluids (serum, plasma, urine, saliva, tears) with a single analysis of each sample, and can even be applied to dried samples (Chantada-Vazquez et al., 2022). Meanwhile, with the introduction of next-generation sequencing (NGS) for newborn screening (NBS), more inherited metabolic disorders (IMDs) can technically be included (Veldman et al., 2023). In this study, we retrospectively analyzed the screening results of various genetic metabolic diseases of 90,829 neonates born in Women and Children Healthcare Hospital of Zhuzhou from 2019 to 2022 based on 4 years of experience in MS/MS to understand the disease spectrum, incidence, and clinical phenotype characteristics of amino acid metabolic, organic acid metabolic, and fatty acid oxidation diseases.

MS/MS has become the main means to expand the screening of newborn IMDs. It can screen 40 to 50 disease types, including amino acid metabolism, organic acid metabolism, and fatty acid oxidation disorders (Schulze et al., 1999; Lindner et al., 2011; Ombrone et al., 2016). Newborn screening is an effective disease prevention measure, which can prevent children’s intellectual disability and improve the quality of the birth population (Chace et al., 1999; American College of Medical Genetics Newborn Screening Expert, 2006). The data used in this study were obtained from the counties and districts of the city, covering the city’s urban and suburban towns. From 2019 to 2022, 90,829 newborns were screened for 48 IMDs using MS/MS, and 11 diseases of four types (amino acid metabolic, organic acid, fatty acid oxidation, and urea cycle disorders) were detected. The total incidence rate was approximately 1/3,027. The incidence rates of neonatal amino acid metabolic, organic acid metabolic, and fatty acid oxidation diseases were approximately 1/11,831, 1/16,007, and 1/6,977, respectively. China is a large population, and according to the overall incidence of neonatal IMDs published by the state, about 3,000 patients accumulate every year. If these children are diagnosed and treated promptly, intellectual disability can be avoided. This has significant social and economic benefits.

The incidence rate of amino acid disorders in our study was lower (1/8,257) than that in Germany (26.3/100,000), the United Kingdom (26.7/100,000), and China (17.1/100,000) (Sanderson et al., 2006; Huang et al., 2022) and was even lower than that in neighboring Guangzhou (1/11,831) (Tang et al., 2021). Four amino acid disorders types were detected in our study, and PAHD accounted for the highest proportion of amino acid metabolic diseases. Some were mild cases, indicating that the incidence rate of amino acid metabolic diseases in this region is relatively low. In the future, primary prevention is expected to reduce such diseases to a lower level to improve the quality of the birth population.

Five types of organic acid metabolic diseases (short/branched chain acyl-CoA dehydrogenase deficiency (SCADD), methylmalonic cademia (MMA), middle/branched chain acyl-CoA dehydrogenase deficiency (MCADD), holocarboxylase synthetase (HCSD), and glutaric cademia type I (GA-I) were detected. The incidence of organic acid metabolic diseases in our study was 1/18,165, which was lower than the national average (1/8,071) (Deng et al., 2021). Notably, this study reported three unreported mutations in three genes (ACADM, ACADS, and HLCS) [c.893G>A (p.R298K), c.482G>A (p.S161N), and c.1544G>A (p.S515)] (Table 5) The three genes were derived from three diseases (SCADD, MCADD, and HCSD), and all of them were compound heterozygous mutations. These newly discovered mutations are convenient for providing further genetic counseling and enriching the database information of organic acid metabolism diseases. Most of the five diseases were inherited from parents. The results of this study suggest that although the incidence of organic acid metabolic diseases is low in this region, the proportion of people carrying the gene mutations for organic acid metabolic diseases is relatively high.

The combined FAOD incidence is 1/9,300 in reports from Australia, Germany, and the United States; however, it is rarely identified in Asian countries. In this study, the incidence of FAOD was 1/7,569. This was higher than that in Zhejiang Province (1/32,354) (Huang et al., 2011), Suzhou City (1/10,041) (Luo et al., 2018), Shanxi Province (1/9,015) (Dai et al., 2021) and the national average level of 1/10,917 (Lindner et al., 2010; Deng et al., 2021; Pereira et al., 2021). Furthermore, only one fatty acid metabolic disease was found in this region. The common gene mutations was SLC22A5 c.1400C>G (p.S467C), with 90% of patients with PCD having this gene mutation, of which two patients maternally inherited PCD. Notably, the incidence of fatty acid metabolism in the Zhuzhou area was higher than that in other areas, and only one disease (PCD) was found, and its incidence is much higher than that of the Chinese population. This suggests a regionally high incidence of IMDs in this area.

Thus, by analyzing the screening and genetic diagnosis results of 90,829 newborns with IMDs in Zhuzhou, the disease spectrum, incidence, and clinical phenotype characteristics of amino acid metabolic, organic acid, and fatty acid oxidation disorders in newborns were determined. However, this study provides a different perspective. The incidence of fatty acid oxidation disorders in the Zhuzhou was relatively high, and the incidence of PCD was higher than that of other IMDs, suggesting a high regional incidence of fatty acid oxidation disorders in this area. The prevalence of organic acid metabolic diseases is high, and most patients with organic acid metabolism are inherited from their parents. Scientifically screening and diagnosing IMD the cases using biochemical methods and second-generation sequencing are required to achieve early screening and diagnosis and to provide strong support for reducing neonatal birth defects.

We have provided the most comprehensive mutation spectrum for IMDs. Additionally, we provided intensive genetic counseling and methods for early diagnosis and treatment. Our study may provide a baseline for genetic counseling, public education, and a reference for improving the prevention of IMDs.