Screening for glutaric acidemia type I in newborns and analysis of clinical phenotypes and genetic variants
Li Panpan, Sun Meng, Li Yulin, etal.
Newborn Disease Screening Center, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250000, China
Objective To clarify the epidemiological characteristics of glutaric acidemia type 1 (GA-1) based on newborn population screening in Jinan City, and to analyze the clinical manifestations, imaging findings and GCDH gene variant characteristics in all children diagnosed with GA-1. Methods A retrospective study was conducted. All newborn screening data collected from Newborn Disease Screening Center, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University from January 2011 to January 2024 were included to calculate the incidence rate. Meanwhile, a total of 17 children diagnosed with GA-1 during the same period were enrolled as research subjects. Cases P1–P13 were identified
through newborn screening (screening confirmed group, n=13), while cases P14–P17 were diagnosed based on clinical manifestations (clinically confirmed group, n=4). P2 and P14 were siblings. Clinical phenotypes, biochemical indicators, imaging findings, and genetic detection results were summarized and analyzed. Urinary glutaric acid was detected using gas chromatography-mass spectrometry. Sanger sequencing was performed to detect compound heterozygous mutations in the GCDH gene. Statistical analysis was performed using paired sample t-test, Wilcoxon signed-rank test. Results A total of 425 624 newborns were screened, and 7 cases of GA-1 were diagnosed. The incidence of GA-1 was approximately 1：60 803. Among the 17 cases diagnosed with GA-1 during the same period, 92.3% (12/13) of the screening confirmed group were asymptomatic at diagnosis, whereas all cases in the clinically confirmed group presented with muscle weakness 100% (4/4). The overall incidence of acute encephalopathic crisis was 52.9% (9/17), with rates of 100% (4/4) in the clinically confirmed group and 38.5% (5/13) in the screening confirmed group. All children developed movement disorders after the acute encephalopathic crisis. At the last follow-up (October 2024), the overall incidences of motor/language impairment, macrocephaly, and epileptic seizures were 58.8% (10/17), 52.9% (9/17), and 35.3% (6/17), respectively. Moreover, 30.8% (4/13) of the screening confirmed group remained free of any clinical manifestations. Biochemical tests revealed differences in the abnormal levels of glutarylcarnitine/acetylcarnitine (C5DC/C2) and urinary glutaric acid between the two groups of children, P12 and P16 were low-excretor GA-1. After treatment, the C5DC/C2 and urinary glutaric acid decreased significantly (with Z values of -2.581 and -3.337, respectively, all P<0.05). The results of cranial magnetic resonance imaging for 11 children showed that 62.5% (5/8) of children in the screening confirmed group presented with bilateral temporal lobe atrophy and abnormal signals in the basal ganglia, while the incidence of the above abnormalities reached 100% (3/3) in the clinically confirmed group. Abnormal signals in the basal ganglia were detected after the onset of acute encephalopathy crisis in 75% (6/8) of cases. A total of 34 mutation loci were identified via genetic testing, among which c.1057C > T was a novel mutation. Conclusions The incidence of GA-1 in newborns in Jinan City, Shandong Province is approximately 1:60 803, which is slightly higher than that in some regions of China, highlighting the significance of newborn screening. Early screening and intervention can improve prognosis; however, attention should still be paid to the prevention and control of acute encephalopathic crises and the need for long-term follow-up. Blood C5DC/C2 and urinary glutaric acid are more valuable for monitoring. Children with the low-excretor form of GA-1 are at risk of being missed in screening, necessitating the combined use of biochemical and genetic testing to improve detection rates. The newly identified GCDH gene variants enrich the mutation spectrum of the Chinese population, providing a basis for molecular diagnosis and genetic counseling of GA-1.
2026, Vol. 14 
