Background: Lipid storage myopathy (LSM) is a genetically heterogeneous group with variable clinical phenotypes. Late-onset multiple acyl-coenzyme A dehydrogenation deficiency (MADD) is a rather common form of LS...Background: Lipid storage myopathy (LSM) is a genetically heterogeneous group with variable clinical phenotypes. Late-onset multiple acyl-coenzyme A dehydrogenation deficiency (MADD) is a rather common form of LSM in China. Diagnosis and clinical management of it remain challenging, especially without robust muscle biopsy result and genetic detection. As the noninvasion and convenience, muscle magnetic resonance imaging (MRI) is a helpful assistant, diagnostic tool for neuromuscular disorders. However, the disease-specific MRI patterns of muscle involved and its diagnostic value in late-onset MADD have not been systematic analyzed. Methods: We assessed the MRI pattern and fat infiltration degree of the lower limb muscles in 28 late-onset MADD patients, combined with detailed clinical features and gene spectrum. Fat infiltration degree of the thigh muscle was scored while that ofgluteus was described as obvious or not. Associated muscular atrophy was defined as obvious muscle bulk reduction. Results: The mean scores were significantly different among the anterior, medial, and posterior thigh muscle groups. The mean of fat infiltration scores on posterior thigh muscle group was significantly higher than either anterior or medial thigh muscle group (P 〈 0.00 l). Moreover, the mean score on medial thigh muscle group was significantly higher than that of anterior thigh muscle group (P 〈 0.01). About half of the patients displayed fat infiltration and atrophy in gluteus muscles. Of 28 patients, 12 exhibited atrophy in medial and/ or posterior thigh muscle groups, especially in posterior thigh muscle group. Muscle edema pattern was not found in all the patients. Conclusions: Late-onset MADD patients show a typical muscular imaging pattern of fat infiltration and atrophy on anterior, posterior, and medial thigh muscle groups, with major involvement of posterior thigh muscle group and gluteus muscles and a sparing involvement of anterior thigh compartment. Our findings also suggest that muscle MRI of lower limbs is a helpful tool in guiding clinical evaluation on late-onset MADD.展开更多
BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is a disease of rare autosomal recessive disorder.There are three types of MADD.Type I is a neonatalonset form with congenital anomalies.Type II is a neonatal...BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is a disease of rare autosomal recessive disorder.There are three types of MADD.Type I is a neonatalonset form with congenital anomalies.Type II is a neonatal-onset form without congenital anomalies.Type III is considered to a milder form and usually responds to riboflavin.However,late-onset form could also be fatal and not responsive to treatments.CASE SUMMARY We report a severe case of a young man with onset type III MADD induced by drugs and strenuous exercise characterized by rhabdomyolysis and liver dysfunction.Urine analysis indicated 12 out of 70 kinds of organic acids like glutaric acid-2 were detected.Serum analysis in genetic metabolic diseases revealed 24 out of 43 tested items were abnormal,revealing the elevation of several acylcarnitines and the reduction of carnitine in the patient.By next generation sequencing technology for gene sequencing related to fatty acid oxidation and carnitine cycle defects,a rare ETFDH gene variant was identified:NM_004453:4:C.1448C>T(p.Pro483 Leu).The patient was diagnosed with lateonset GAII.He was not responsive to riboflavin and progressively worsened into multiple organ failure that finally led to death.CONCLUSION Type III MADD can also be fatal and not responsive to treatments.展开更多
A membrane-bound protein was purified from rat liver mitochondria.After being di-gested with V8 protease,two peptides containing identical 14 amino acid residue sequences were obtained.Using the 14 amino acid peptide ...A membrane-bound protein was purified from rat liver mitochondria.After being di-gested with V8 protease,two peptides containing identical 14 amino acid residue sequences were obtained.Using the 14 amino acid peptide derived DNA sequence as gene specific primer,the cDNA of correspondent gene 5′-terminal and 3′-terminal were obtained by RACE technique.The full-length cDNA that encoded a protein of 616 amino acids was thus cloned,which included the above mentioned peptide sequence.The full length cDNA was highly homologous to that of human ETF-QO,indicating that it may be the cDNA of rat ETF-QO.ETF-QO is an iron sulfur protein located in mitochondria inner membrane containing two kinds of redox center:FAD and[4Fe-4S]center.After comparing the sequence from the cDNA of the 616 amino acids protein with that of the mature protein of rat liver mitochondria,it was found that the N terminal 32 amino acid residues did not exist in the mature protein,indicating that the cDNA was that of ETF-QOp.When the cDNA was expressed in Saccharomyces cerevisiae with inducible vectors,the protein product was enriched in mitochondrial fraction and exhibited electron transfer activity(NBT re-ductase activity)of ETF-QO.Results demonstrated that the 32 amino acid peptide was a mito-chondrial targeting peptide,and both FAD and iron-sulfur cluster were inserted properly into the expressed ETF-QO.ETF-QO had a high level expression in rat heart,liver and kidney.The fu-sion protein of GFP-ETF-QO co-localized with mitochondria in COS-7 cells.展开更多
多种酰基辅酶A脱氢酶缺陷(Multiple acyl CoA dehydrogenase deficiency,MADD)是一种罕见的脂肪酸、氨基酸和胆碱代谢异常的常染色体隐性遗传病,由电子转移黄素蛋白或电子转移黄素蛋白脱氢酶的基因缺陷引起。迟发型MADD患者大多具有ETFD...多种酰基辅酶A脱氢酶缺陷(Multiple acyl CoA dehydrogenase deficiency,MADD)是一种罕见的脂肪酸、氨基酸和胆碱代谢异常的常染色体隐性遗传病,由电子转移黄素蛋白或电子转移黄素蛋白脱氢酶的基因缺陷引起。迟发型MADD患者大多具有ETFDH突变,可出现近端肌肉无力和远端感觉神经病变,对核黄素治疗反应较好。主要机制可能是ETFDH突变导致线粒体中的电子传递链异常,从而无法在线粒体膜中产生能量。核黄素可以减少ETF/ETF-QO蛋白的异常表达,改善患者的发病状况,是理想的治疗方案。但目前对核黄素无反应的MADD患者的发病机制和治疗方案尚不清楚。展开更多
基金grants from the National Natural Science Foundation of China,the National Key Clinical Specialty Discipline Construction Program,and Fujian Key Clinical Specialty Discipline Construction Program
文摘Background: Lipid storage myopathy (LSM) is a genetically heterogeneous group with variable clinical phenotypes. Late-onset multiple acyl-coenzyme A dehydrogenation deficiency (MADD) is a rather common form of LSM in China. Diagnosis and clinical management of it remain challenging, especially without robust muscle biopsy result and genetic detection. As the noninvasion and convenience, muscle magnetic resonance imaging (MRI) is a helpful assistant, diagnostic tool for neuromuscular disorders. However, the disease-specific MRI patterns of muscle involved and its diagnostic value in late-onset MADD have not been systematic analyzed. Methods: We assessed the MRI pattern and fat infiltration degree of the lower limb muscles in 28 late-onset MADD patients, combined with detailed clinical features and gene spectrum. Fat infiltration degree of the thigh muscle was scored while that ofgluteus was described as obvious or not. Associated muscular atrophy was defined as obvious muscle bulk reduction. Results: The mean scores were significantly different among the anterior, medial, and posterior thigh muscle groups. The mean of fat infiltration scores on posterior thigh muscle group was significantly higher than either anterior or medial thigh muscle group (P 〈 0.00 l). Moreover, the mean score on medial thigh muscle group was significantly higher than that of anterior thigh muscle group (P 〈 0.01). About half of the patients displayed fat infiltration and atrophy in gluteus muscles. Of 28 patients, 12 exhibited atrophy in medial and/ or posterior thigh muscle groups, especially in posterior thigh muscle group. Muscle edema pattern was not found in all the patients. Conclusions: Late-onset MADD patients show a typical muscular imaging pattern of fat infiltration and atrophy on anterior, posterior, and medial thigh muscle groups, with major involvement of posterior thigh muscle group and gluteus muscles and a sparing involvement of anterior thigh compartment. Our findings also suggest that muscle MRI of lower limbs is a helpful tool in guiding clinical evaluation on late-onset MADD.
文摘BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is a disease of rare autosomal recessive disorder.There are three types of MADD.Type I is a neonatalonset form with congenital anomalies.Type II is a neonatal-onset form without congenital anomalies.Type III is considered to a milder form and usually responds to riboflavin.However,late-onset form could also be fatal and not responsive to treatments.CASE SUMMARY We report a severe case of a young man with onset type III MADD induced by drugs and strenuous exercise characterized by rhabdomyolysis and liver dysfunction.Urine analysis indicated 12 out of 70 kinds of organic acids like glutaric acid-2 were detected.Serum analysis in genetic metabolic diseases revealed 24 out of 43 tested items were abnormal,revealing the elevation of several acylcarnitines and the reduction of carnitine in the patient.By next generation sequencing technology for gene sequencing related to fatty acid oxidation and carnitine cycle defects,a rare ETFDH gene variant was identified:NM_004453:4:C.1448C>T(p.Pro483 Leu).The patient was diagnosed with lateonset GAII.He was not responsive to riboflavin and progressively worsened into multiple organ failure that finally led to death.CONCLUSION Type III MADD can also be fatal and not responsive to treatments.
基金This project was supported by the Knowledge Innovation Program of the Chinese Academy of Sciences.
文摘A membrane-bound protein was purified from rat liver mitochondria.After being di-gested with V8 protease,two peptides containing identical 14 amino acid residue sequences were obtained.Using the 14 amino acid peptide derived DNA sequence as gene specific primer,the cDNA of correspondent gene 5′-terminal and 3′-terminal were obtained by RACE technique.The full-length cDNA that encoded a protein of 616 amino acids was thus cloned,which included the above mentioned peptide sequence.The full length cDNA was highly homologous to that of human ETF-QO,indicating that it may be the cDNA of rat ETF-QO.ETF-QO is an iron sulfur protein located in mitochondria inner membrane containing two kinds of redox center:FAD and[4Fe-4S]center.After comparing the sequence from the cDNA of the 616 amino acids protein with that of the mature protein of rat liver mitochondria,it was found that the N terminal 32 amino acid residues did not exist in the mature protein,indicating that the cDNA was that of ETF-QOp.When the cDNA was expressed in Saccharomyces cerevisiae with inducible vectors,the protein product was enriched in mitochondrial fraction and exhibited electron transfer activity(NBT re-ductase activity)of ETF-QO.Results demonstrated that the 32 amino acid peptide was a mito-chondrial targeting peptide,and both FAD and iron-sulfur cluster were inserted properly into the expressed ETF-QO.ETF-QO had a high level expression in rat heart,liver and kidney.The fu-sion protein of GFP-ETF-QO co-localized with mitochondria in COS-7 cells.
文摘多种酰基辅酶A脱氢酶缺陷(Multiple acyl CoA dehydrogenase deficiency,MADD)是一种罕见的脂肪酸、氨基酸和胆碱代谢异常的常染色体隐性遗传病,由电子转移黄素蛋白或电子转移黄素蛋白脱氢酶的基因缺陷引起。迟发型MADD患者大多具有ETFDH突变,可出现近端肌肉无力和远端感觉神经病变,对核黄素治疗反应较好。主要机制可能是ETFDH突变导致线粒体中的电子传递链异常,从而无法在线粒体膜中产生能量。核黄素可以减少ETF/ETF-QO蛋白的异常表达,改善患者的发病状况,是理想的治疗方案。但目前对核黄素无反应的MADD患者的发病机制和治疗方案尚不清楚。