Yiming Lin1, Dongmei Chen2, Weilin Peng1, Kunyi Wang3, Weihua Lin1, Jianlong Zhuang4, Zhenzhu Zheng1, Min Li5, Qingliu Fu6. 1. Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China. 2. Department of Neonatal Intensive Care Unit, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China. 3. Integrated Technical Service Center, Quanzhou Customs, Quanzhou, Fujian Province 362000, China. 4. Prenatal Diagnosis Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China. 5. Hangzhou Genuine Clinical Laboratory Co. Ltd, Hangzhou, Zhejiang Province 310007, China. Electronic address: limin@biosan.cn. 6. Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China. Electronic address: wrightlym@sina.com.
Abstract
BACKGROUND: Isovaleric acidemia (IVA) is a rare autosomal recessive disorder of leucine metabolism caused by a defective isovaleryl-CoA dehydrogenase (IVD) gene. Reports of IVA diagnoses following newborn screening (NBS) in the Chinese population are few. METHODS: We investigated the biochemical, clinical, and molecular profiles of 5 patients with IVA in China. The estimated incidence of IVA in Quanzhou, China is 1 in 1:84,469. RESULTS: Initial NBS revealed mild to markedly increased isovalerylcarnitine (C5) concentrations in all 5 patients, and differential diagnosis revealed increased urinary isovaleryglycine concentrations in 2 patients. One patient presented with acute neonatal symptoms, whereas the other 4 remained asymptomatic. Eight distinct IVD gene variants were identified. The most common variant was c.1208A > G (p.Y403C), with an allele frequency of 30%. Five variants were previously unreported, namely, c.499A > G (p.M167V), c.640A > G (p.T214A), c.740G > A (p.G247E), c.832G > C (p.V278L), and c.1195G > C (p.D399H). Different in silico prediction analyses suggested that these previously unreported missense variants are pathogenic. Protein modelling analyses also showed that these missense variants may cause structural damage and dysfunction in IVD. CONCLUSIONS: Patients with IVA may have C5 concentrations approaching the cut-off values, highlighting the need for stringent recall criteria and second-tier tests to improve screening performance.
BACKGROUND:Isovaleric acidemia (IVA) is a rare autosomal recessive disorder of leucine metabolism caused by a defective isovaleryl-CoA dehydrogenase (IVD) gene. Reports of IVA diagnoses following newborn screening (NBS) in the Chinese population are few. METHODS: We investigated the biochemical, clinical, and molecular profiles of 5 patients with IVA in China. The estimated incidence of IVA in Quanzhou, China is 1 in 1:84,469. RESULTS: Initial NBS revealed mild to markedly increased isovalerylcarnitine (C5) concentrations in all 5 patients, and differential diagnosis revealed increased urinary isovaleryglycine concentrations in 2 patients. One patient presented with acute neonatal symptoms, whereas the other 4 remained asymptomatic. Eight distinct IVD gene variants were identified. The most common variant was c.1208A > G (p.Y403C), with an allele frequency of 30%. Five variants were previously unreported, namely, c.499A > G (p.M167V), c.640A > G (p.T214A), c.740G > A (p.G247E), c.832G > C (p.V278L), and c.1195G > C (p.D399H). Different in silico prediction analyses suggested that these previously unreported missense variants are pathogenic. Protein modelling analyses also showed that these missense variants may cause structural damage and dysfunction in IVD. CONCLUSIONS:Patients with IVA may have C5 concentrations approaching the cut-off values, highlighting the need for stringent recall criteria and second-tier tests to improve screening performance.