BACKGROUND Isovaleric acidemia(IVA)is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase(IVD).Its morbidity is low,but mortality is high.There is no ef...BACKGROUND Isovaleric acidemia(IVA)is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase(IVD).Its morbidity is low,but mortality is high.There is no effective cure for this disease.Early identification of IVA using clinical features can significantly slow disease progression and reduce mortality.Here we report a Chinese neonate with two mutations of IVD and share valuable information on this disease.CASE SUMMARY A 12-day-old male neonate with“poor response for 1 d and repeated convulsions accompanied by high muscle tension for 6 h”was hospitalized.The patient was the first child of nonconsanguineous ethnic Chinese parents.He was delivered by cesarean section due to breech position at 39+1 wk of gestation with a birth weight of 3.27 kg.Initially,he suffered from dyspnea and rhinobyon,and at 10 d after birth the patient suddenly developed poor feeding,low response,lethargy and seizures.Organic acid analysis of blood and urine by tandem mass spectrometry and gas chromatography mass spectrometry showed extremely high concentrations of isovaleryl glycine.The patient had an acute episode of IVA causing severe metabolic stress and eventually died.CONCLUSION A new case of an IVA patient carrying c.1193G>A(p.Arg398Gln)and c.1208A>G(p.Try403Cys)mutations is reported in China.展开更多
Isovaleryl-CoA(coenzyme A)dehydrogenase(IVD)plays a pivotal role in the catabolism of leucine,converting isovaleryl-CoA to 3-methylcrotonyl-CoA.Dysfunction of IVD is linked to isovaleric acidemia(IVA),a rare metabolic...Isovaleryl-CoA(coenzyme A)dehydrogenase(IVD)plays a pivotal role in the catabolism of leucine,converting isovaleryl-CoA to 3-methylcrotonyl-CoA.Dysfunction of IVD is linked to isovaleric acidemia(IVA),a rare metabolic disorder characterized by the accumulation of toxic metabolites.In this study,we present the cryo-electron microscopy structures of human IVD,resolved both in its apo form and in complex with its substrates,isovaleryl-CoA and butyryl-CoA.Our findings reveal a tetrameric architecture with distinct substrate-binding pockets that facilitate the enzyme’s preference for short branched-chain acyl-CoAs.Key residues involved in FAD binding and substrate interaction were identified,elucidating the catalytic mechanism of IVD.Additionally,we investigated the impact of various disease-associated hotspot mutations derived from different regions,demonstrating their effects on enzyme stability and activity.Notably,mutations such as A314V,S281G/F382V,and E411K resulted in substantial loss of function,while others exhibited milder effects,which is consistent with our structural analyses.These insights enhance our understanding of IVD’s enzymatic properties and provide a foundation for developing targeted therapies for IVA.展开更多
文摘BACKGROUND Isovaleric acidemia(IVA)is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase(IVD).Its morbidity is low,but mortality is high.There is no effective cure for this disease.Early identification of IVA using clinical features can significantly slow disease progression and reduce mortality.Here we report a Chinese neonate with two mutations of IVD and share valuable information on this disease.CASE SUMMARY A 12-day-old male neonate with“poor response for 1 d and repeated convulsions accompanied by high muscle tension for 6 h”was hospitalized.The patient was the first child of nonconsanguineous ethnic Chinese parents.He was delivered by cesarean section due to breech position at 39+1 wk of gestation with a birth weight of 3.27 kg.Initially,he suffered from dyspnea and rhinobyon,and at 10 d after birth the patient suddenly developed poor feeding,low response,lethargy and seizures.Organic acid analysis of blood and urine by tandem mass spectrometry and gas chromatography mass spectrometry showed extremely high concentrations of isovaleryl glycine.The patient had an acute episode of IVA causing severe metabolic stress and eventually died.CONCLUSION A new case of an IVA patient carrying c.1193G>A(p.Arg398Gln)and c.1208A>G(p.Try403Cys)mutations is reported in China.
基金supported by the National Key Research and Development Program of China(2022YFC2703100 and 2023YFC3605504)the Chinese Academy of Medical Sciences Initiative for Innovative Medicine(2021-I2M-1-003)+1 种基金the National High Level Hospital Clinical Research Funding(2022-PUMCH-D-002 and 2022-PUMCH-B-098)the National Natural Science Foundation of China(82225007,92149305,and 82030017).
文摘Isovaleryl-CoA(coenzyme A)dehydrogenase(IVD)plays a pivotal role in the catabolism of leucine,converting isovaleryl-CoA to 3-methylcrotonyl-CoA.Dysfunction of IVD is linked to isovaleric acidemia(IVA),a rare metabolic disorder characterized by the accumulation of toxic metabolites.In this study,we present the cryo-electron microscopy structures of human IVD,resolved both in its apo form and in complex with its substrates,isovaleryl-CoA and butyryl-CoA.Our findings reveal a tetrameric architecture with distinct substrate-binding pockets that facilitate the enzyme’s preference for short branched-chain acyl-CoAs.Key residues involved in FAD binding and substrate interaction were identified,elucidating the catalytic mechanism of IVD.Additionally,we investigated the impact of various disease-associated hotspot mutations derived from different regions,demonstrating their effects on enzyme stability and activity.Notably,mutations such as A314V,S281G/F382V,and E411K resulted in substantial loss of function,while others exhibited milder effects,which is consistent with our structural analyses.These insights enhance our understanding of IVD’s enzymatic properties and provide a foundation for developing targeted therapies for IVA.
