According to the survey on BDs in China, it has become the second highest cause of infant death and a major cause of child disability. Congenital heart disease, polydactyly, cleft lip and palate, neural tube defects, congenital hydrocephalus, limb shortening, equinovarus foot, hypospadias, syndactyly, and microtia being the 10 most high-risk BDs in Chinese neonates. BDs in high-altitude areas revealed that the three main types of BDs were cleft lip and palate, polydactyly, and deformed feet, which are consistent with BDs prevalence patterns reported in China. The incidence rate of polydactyly was similar to that reported by other Chinese researchers[10, 11], but it had higher rate than the studies by Tomoyuki and Boris. The incidence rate of cleft lip and palate we found was different from some domestic studies[14, 15] and abroad studies [12, 13], and the incidence rate of deformed feet was similar to that reported by Tomoyuki. Previous researches had shown that about 25% of BDs are caused by genetic factors, about 10% are due to environmental factors, and the remaining 65% may be caused by a combined effect of genetic and environmental factors or other unknown reasons. The study found that fetal age (less than 37 weeks), low birth weight, mother pregnancy age (more than 30 years old), and abnormal birth childbearing were risk factors for BDs.
Heredity metabolic diseases, as a main manifestation of BDs, were often overlooked or misdiagnosed as miscellaneous diseases due to their complexity. Nevertheless, the diseases, caused by aberrant metabolism, have drawn considerable attention due their severity and high incidence rate among neonates. Furthermore, amino acids not only play a central role in building proteins, but also participate in metabolism functioning as an intermediate. The corresponding disorders can lead to clinical signs and symptoms, even serious diseases, in metabolism, immunity and the cardiovascular and nervous systems. It was reported that the concentration of amino acid in children’s blood varies with BD-associated factors, such as birth weight and embryonic age, as revealed in the study. Domestic studies have shown that there are differences in the distribution of amino acids and ester carnitine in newborns from different regions. This study found there was a significant difference in the levels of both Met and Arg between the plain normal neonates and the high-altitude normal neonates, and the levels of these two types of amino acids were similar between the high-altitude normal and BDs neonates. It suggests that a higher level in plain areas is essential but not insufficient for normal neonates in high-altitude. There were significant different levels of C5OH\C4DC, C6DC, C8, C14, and C14:2 in the plain normal neonates and the high-altitude normal neonates, and the levels of C0, C6DC, C8:1, C14, C14:2, and C16:1 were significantly different between the high-altitude normal and BDs neonates. These results reveal a difference in multiple ester carnitines between the normal neonates in the plain and the high-altitude normal and BDs neonates. It was speculated that the metabolic status of short, medium, and long chain fatty acids might be related to disease state and high-altitude environment factors such as high altitude and oxygen deficit.
Inherited metabolic diseases are a type of disease that can cause BDs, with an overall incidence about 1/3000-1/5000. In China, the increasing incidence of phenylketonuria, which caused 1200 to 1500 new cases each year, has become a main cause of fetal and neonatal mortality. This study found two amino acid metabolic diseases (hyperphenylalaninemia and hypermethioninemia) and one organic aciduria (methylmalonic aciduria with homocysteinemia). There were no fatty acid metabolic diseases, which may be related to the low incidence rate of fatty acid oxidative metabolic disorders and few screening cases. Two amino acid metabolic disease were observed during the neonatal period and did not produce clinical symptoms.
Phenylalanine is one of the essential amino acids. Phenylalanine hydroxylase (PAH) and tetrahydrobiopterin take part in the conversion of phenylalanine into tyrosine. Mutations in the gene encoding of phenylalanine hydroxylase may cause defects in enzyme activity, leading to hyperphenylalaninemia, which is also known as phenylketonuria. It has been reported that 44 pathogenic genotypes of phenylketonuria in Shenzhen were detected, and the mutation rate was 81.48%, which was lower than the 92.65% in the Tai'an area and the same as the 80.8% in the Qinghai area. This study found PAH c.728 G > A (p.r243q), which is a common pathogenic variant genotype.
Hypermethioninemia is a genetic metabolic disease, and the deficiency of methionine adenosine transferase activity is one of the main etiologies. The genetic pattern of methionine adenosyltransferase deficiency is usually autosomal recessive inheritance, but few studies showed autosomal dominant inheritance[19, 20]. In this study, methionine was abnormally elevated in children with hypermethioninemia by LC-MS/MS without any symptoms. Gene analysis confirmed the mutation of exon 3 C. 274T > C and exon 7 C. 895C > T of a complex inherited pathogenic MAT1A variant. Core family gene analysis showed that parents carried the two pathogenic variants, which corresponded to autosomal recessive inheritance.
Methylmalonic aciduria is the most common organic aciduria in China, and 10 kinds of gene defects have been found to cause hereditary methylmalonic aciduria. Specifically, they are single-gene hereditary diseases and most are autosomal recessive heredity. Methylmalonate aciduria with homocysteinemia may be the main clinical phenotype in Chinese patients with methylmalonate aciduria. Previous studies have found that cblC and MMACHC are common enzyme deficiencies in Chinese patients[21, 22]. The clinical manifestations of methylmalonate aciduria with homocysteinemia are complex and varied, including psychomotor retardation, anemia, visual impairment, skin lesions, and the liver and kidneys damagements. A case of methylmalonate aciduria with homocysteinemia was found to present with low response, poor appetite, and aggravated jaundice after birth. Biochemical examination indicated hypoglycemia, metabolic acidosis, and hyperammonemia. Blood amino acid ester acyl carnitine spectrum analysis showed that C3 and C3/C2 levels increased, suggesting that it may be methylmalonic acidemia or propionic acidemia. Urine organic acid analysis showed that methylmalonic acid levels also increased significantly, while gene analysis revealed an MMACHC c.482G > A (p.R161Q) pathogenic variant. Core pedigree analysis showed that the parents were carriers of the pathogenic variant. Finally, the neonates were diagnosed with methylmalonate aciduria.
Testing of amino acids, fatty acids and gene analysis in blood is helpful for finding amino acids and fatty acids metabolism disorders, clinical diagnosis and treatment.