丙酮酸脱氢酶复合物缺陷Leigh综合征2例临床及PDHA1基因分析
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摘要
目的探讨PDHA1基因突变所致丙酮酸脱氢酶复合物E1α亚单位缺陷Leigh综合征的临床特点及诊断和治疗。方法回顾分析2例因发育落后就诊,磁共振扫描提示Leigh综合征,并经生化代谢及基因检测确诊患儿的临床资料。结果 2例男性患儿分别于1岁1个月、4个月就诊,发育落后,肌张力障碍,肌力低下;头颅磁共振检查发现双侧基底节区对称性损害;血清丙酮酸、乳酸明显增高,血氨基酸及酯酰肉碱谱无异常。基因分析发现2例患儿X染色体PDHA1基因分别存在c.615C>G、c.605A>G错义突变,均为未报道的新突变,证实为丙酮酸脱氢酶复合物E1α亚单位缺陷所致Leigh综合征。结论 PDHA1基因突变患儿临床表现复杂多样,对于不明原因的发育落后儿童,应注意线粒体病的可能,基因检测有助于诊断、治疗及遗传咨询。
Objective To explore the clinical characteristics, diagnosis and treatment of Leigh syndrome with pyruvate dehydrogenase complex E1 α subunit deficiency caused by PDHA1 gene mutation. Method Two boys visited doctors because of psychomotor retardation. Leigh syndrome was suggested by magnetic resonance imaging(MRI) and confirmed by biochemical metabolism and genetic tests. The clinical data were retrospectively analyzed. Results Two boys visited a doctor at the age of 13 month and 4 months respectively for mental retardation, dystonia and muscle weakness at the age of 13 months and 4 months respectively. Brain MRI revealed symmetrical lesions in bilateral basal ganglia. Serum pyruvic acid and lactic acid levels increased significantly, while blood amino acid and acylcarnitine profiles were normal. Genetic analysis revealed missense mutations in the X chromosome PDHA1 gene, c.615 C>G and c.605 A>G, in the two boys respectively, which were new mutations never reported. Therefore, the two boys were diagnosed with Leigh syndrome caused by pyruvate dehydrogenase complex E1 α subunit deficiency. Conclusion The clinical manifestations of PDHA1 gene mutation in children are complex and varied. The possibility of mitochondrial disease should be considered in children with developmental retardation of unknown cause. Gene detection is helpful for diagnosis, treatment and genetic counseling.
Objective To explore the clinical characteristics, diagnosis and treatment of Leigh syndrome with pyruvate dehydrogenase complex E1 α subunit deficiency caused by PDHA1 gene mutation. Method Two boys visited doctors because of psychomotor retardation. Leigh syndrome was suggested by magnetic resonance imaging(MRI) and confirmed by biochemical metabolism and genetic tests. The clinical data were retrospectively analyzed. Results Two boys visited a doctor at the age of 13 month and 4 months respectively for mental retardation, dystonia and muscle weakness at the age of 13 months and 4 months respectively. Brain MRI revealed symmetrical lesions in bilateral basal ganglia. Serum pyruvic acid and lactic acid levels increased significantly, while blood amino acid and acylcarnitine profiles were normal. Genetic analysis revealed missense mutations in the X chromosome PDHA1 gene, c.615 C>G and c.605 A>G, in the two boys respectively, which were new mutations never reported. Therefore, the two boys were diagnosed with Leigh syndrome caused by pyruvate dehydrogenase complex E1 α subunit deficiency. Conclusion The clinical manifestations of PDHA1 gene mutation in children are complex and varied. The possibility of mitochondrial disease should be considered in children with developmental retardation of unknown cause. Gene detection is helpful for diagnosis, treatment and genetic counseling.
引文
[1]Baertling F,Rodenburg RJ,Schaper J,et al.A guide to diagnosis and treatment of Leigh syndrome[J].J Neurol Neurosurg Psychiatry,2014,85(3):257-265.
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[3]Yang YL,Sun F,Zhang Y,et al.Clinical and laboratory survey of 65 Chinese patients with Leigh syndrome[J].Chin Med J(Engl),2006,119(5):373-377.
[4]Zhang Y,Yang YL,Sun F,et al.Clinical and molecular survey in 124 Chinese patients with Leigh or Leigh-like syndrome[J].J Inherit Metab Dis,2007,30(2):265.
[5]Rahman S,Thorburn D.Nuclear gene-encoded Leigh syndrome overview[M]//Adam MP,Ardinger HH,Pagon RA,et al.Gene Reviews?[Internet].Seattle(WA):University of Washington,Seattle;1993-2016.2015 Oct 1.
[6]张尧,杨艳玲,秦炯.丙酮酸脱氢酶复合物缺陷与疾病[J].临床儿科杂志,2006,24(12):956-958.
[7]Lissens W,De Meirleir L,Seneca S,et al.Mutations in the X-linked pyruvate dehydrogenase(E1)alpha subunit gene(PDHA1)in patients with a pyruvate dehydrogenase complex deficiency[J].Hum Mutat,2000,15(3):209-219.
[8]Finsterer J.Leigh and leigh-like syndrome in children and adults[J].Pediatr Neurol,2008,39(4):223-235.
[9]Gerards M,Sallevelt SC,Smeets HJ.Leigh syndrome:resolving the clinical and genetic heterogeneity paves the way for treatment options[J].Mol Genet Metab,2016,117(3):300-312.
[10]Lake NJ,Bird MJ,Isohanni P,et al.Leigh syndrome:neuropathology and pathogenesis[J].J Neuropathol Exp Neurol,2015,74(6):482-492.
[11]Lake N,Compton AG,Rahman S,et al.Leigh syndrome:one disorder,more than 75 monogenic causes[J].Ann.Neurol,2016,79(2):190-203.
[12]Steller J,Gargus JJ,Gibbs LH,et al.Mild phenotype in a male with pyruvate dehydrogenase complex deficiency associated with novel hemizygous in-frame duplication of the E1αsubunit gene(PDHA1)[J].Neuropediatrics,2014,45(1):56-60.
[13]吴莫龄,刘丽,蔡燕娜,等.丙酮酸脱氢酶复合物缺乏症一例的临床特点及基因检测[J].中华儿科杂志,2014,52(11):863-866.
[14]张尧,孙芳,杨艳玲,等.丙酮酸脱氢酶E1 a亚单位缺陷导致Leigh综合征[J].中国当代儿科杂志,2007,9(3):216-219.
[15]潘英,黄高展,连楚南,等.丙酮酸脱氢酶复合物缺乏症一例并文献复习[J].国际儿科学杂志,2017,44(6):437-439.
[16]刘舒,梁金群,欧阳海梅,等.利用新一代测序技术对1例丙酮酸脱氢酶复合体缺乏症患儿基因突变检测[J].中华实用儿科临床杂志,2016,31(20):1575-1577.
[17]Imbard A,Boutron A,Vequaud C,et al.Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency.Structural implications of novel amino acid substitutions in E1 protein[J].Mol Genet Metab,2011,104(4):507-516.
[18]Deeb KK,Bedoyan JK,Wang R,et al.Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency[J].Mol Genet Metab Rep,2014,1:362-367.
[19]Shin HK,Grahame G,McCandless SE,et al.Enzymatic testing sensitivity,variability and practical diagnostic algorithm for pyruvate dehydrogenase complex(PDC)deficiency[J].Mol Genet Metab,2017,122(3):61-66.
[20]Quintana E,Gort L,Busquets C,et al.Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency[J].Clin Genet,2010,77(5):474-482.
[21]吴莫龄.丙酮酸脱氢酶复合物缺乏症的研究现状[J].国际儿科学杂志,2014,41(6):610-613.
[22]Castiglioni C,Verrigni D,Okuma C,et al.Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation.Case report and mini-review[J].Eur JPaediatr Neurol,2015,19(5):497-503.
[23]Sata S,Ioi H,Kashiwagi Y,et al.Novel mutation(R263X)of the E-1alpha subunit in pyruvate dehydrogenase complex deficiency[J].Pediatr Int,2010,52(4):e181-e183.
[24]Wang HS,Lin KL.Ketogenic diet:an early option for epilepsy treatment,instead of a last choice only[J].Biomed J,2013,36(1):16-17.
[2]Piekutowska-Abramczuk D.The molecular background of Leigh syndrome[J].Neurol Neurochir Pol,2008,42(3):238-250.
[3]Yang YL,Sun F,Zhang Y,et al.Clinical and laboratory survey of 65 Chinese patients with Leigh syndrome[J].Chin Med J(Engl),2006,119(5):373-377.
[4]Zhang Y,Yang YL,Sun F,et al.Clinical and molecular survey in 124 Chinese patients with Leigh or Leigh-like syndrome[J].J Inherit Metab Dis,2007,30(2):265.
[5]Rahman S,Thorburn D.Nuclear gene-encoded Leigh syndrome overview[M]//Adam MP,Ardinger HH,Pagon RA,et al.Gene Reviews?[Internet].Seattle(WA):University of Washington,Seattle;1993-2016.2015 Oct 1.
[6]张尧,杨艳玲,秦炯.丙酮酸脱氢酶复合物缺陷与疾病[J].临床儿科杂志,2006,24(12):956-958.
[7]Lissens W,De Meirleir L,Seneca S,et al.Mutations in the X-linked pyruvate dehydrogenase(E1)alpha subunit gene(PDHA1)in patients with a pyruvate dehydrogenase complex deficiency[J].Hum Mutat,2000,15(3):209-219.
[8]Finsterer J.Leigh and leigh-like syndrome in children and adults[J].Pediatr Neurol,2008,39(4):223-235.
[9]Gerards M,Sallevelt SC,Smeets HJ.Leigh syndrome:resolving the clinical and genetic heterogeneity paves the way for treatment options[J].Mol Genet Metab,2016,117(3):300-312.
[10]Lake NJ,Bird MJ,Isohanni P,et al.Leigh syndrome:neuropathology and pathogenesis[J].J Neuropathol Exp Neurol,2015,74(6):482-492.
[11]Lake N,Compton AG,Rahman S,et al.Leigh syndrome:one disorder,more than 75 monogenic causes[J].Ann.Neurol,2016,79(2):190-203.
[12]Steller J,Gargus JJ,Gibbs LH,et al.Mild phenotype in a male with pyruvate dehydrogenase complex deficiency associated with novel hemizygous in-frame duplication of the E1αsubunit gene(PDHA1)[J].Neuropediatrics,2014,45(1):56-60.
[13]吴莫龄,刘丽,蔡燕娜,等.丙酮酸脱氢酶复合物缺乏症一例的临床特点及基因检测[J].中华儿科杂志,2014,52(11):863-866.
[14]张尧,孙芳,杨艳玲,等.丙酮酸脱氢酶E1 a亚单位缺陷导致Leigh综合征[J].中国当代儿科杂志,2007,9(3):216-219.
[15]潘英,黄高展,连楚南,等.丙酮酸脱氢酶复合物缺乏症一例并文献复习[J].国际儿科学杂志,2017,44(6):437-439.
[16]刘舒,梁金群,欧阳海梅,等.利用新一代测序技术对1例丙酮酸脱氢酶复合体缺乏症患儿基因突变检测[J].中华实用儿科临床杂志,2016,31(20):1575-1577.
[17]Imbard A,Boutron A,Vequaud C,et al.Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency.Structural implications of novel amino acid substitutions in E1 protein[J].Mol Genet Metab,2011,104(4):507-516.
[18]Deeb KK,Bedoyan JK,Wang R,et al.Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency[J].Mol Genet Metab Rep,2014,1:362-367.
[19]Shin HK,Grahame G,McCandless SE,et al.Enzymatic testing sensitivity,variability and practical diagnostic algorithm for pyruvate dehydrogenase complex(PDC)deficiency[J].Mol Genet Metab,2017,122(3):61-66.
[20]Quintana E,Gort L,Busquets C,et al.Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency[J].Clin Genet,2010,77(5):474-482.
[21]吴莫龄.丙酮酸脱氢酶复合物缺乏症的研究现状[J].国际儿科学杂志,2014,41(6):610-613.
[22]Castiglioni C,Verrigni D,Okuma C,et al.Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation.Case report and mini-review[J].Eur JPaediatr Neurol,2015,19(5):497-503.
[23]Sata S,Ioi H,Kashiwagi Y,et al.Novel mutation(R263X)of the E-1alpha subunit in pyruvate dehydrogenase complex deficiency[J].Pediatr Int,2010,52(4):e181-e183.
[24]Wang HS,Lin KL.Ketogenic diet:an early option for epilepsy treatment,instead of a last choice only[J].Biomed J,2013,36(1):16-17.
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