Grafakou Olga, Oexle Konrad, van den Heuvel Lambert, Smeets Roel, Trijbels Frans, Goebel Hans H, Bosshard Nils, Superti-Furga Andrea, Steinmann Beat, Smeitink Jan
Nijmegen Centrer for Mitochondrial Disorders, University Medical Centre Nijmegen, Department of Paediatrics, Geert Grooteplein 10, 9101, 6500HB Nijmegen, The Netherlands.
Eur J Pediatr. 2003 Oct;162(10):714-8. doi: 10.1007/s00431-003-1282-z. Epub 2003 Aug 19.
A boy with recurrent episodes of hypoglycaemia and ataxia, microcephaly, mental retardation, permanent lactic acidaemia, intermittent 2-oxoglutaric aciduria as well as elevation of serum branched chain amino acids was diagnosed with dihydrolipoamide dehydrogenase (E3) deficiency. Analysis of genomic DNA revealed compound heterozygosity for two novel mutations: I393T in exon 11, located at the interface domain of the protein and possibly interfering with its dimerisation, and IVS9+1G>A located at a consensus splice site. A heterozygous polymorphism was also detected. In the patient's cDNA the I393T mutation and the polymorphism appeared to be homozygous, indicating that the mRNA coming from the IVS9+1G>A mutant allele is not stable.
as opposed to the non-neurological phenotype of patients with a homozygous G229C mutation, this patient developed Leigh syndrome. Dihydrolipoamide dehydrogenase and pyruvate dehydrogenase complex activities in muscle were 29% and 14% of the lowest control values, respectively. Pyruvate dehydrogenase complex activity in fibroblasts was normal, however, indicating that the biochemical examination of defects in energy metabolism should be performed in a more energy demanding tissue.
一名患有反复低血糖发作、共济失调、小头畸形、智力发育迟缓、持续性乳酸性酸中毒、间歇性2 - 氧代戊二酸尿症以及血清支链氨基酸升高的男孩被诊断为二氢硫辛酰胺脱氢酶（E3）缺乏症。对基因组DNA的分析揭示了两个新突变的复合杂合性：外显子11中的I393T，位于蛋白质的界面结构域，可能干扰其二聚化；以及位于共有剪接位点的IVS9 + 1G>A。还检测到一个杂合多态性。在患者的cDNA中，I393T突变和多态性似乎是纯合的，表明来自IVS9 + 1G>A突变等位基因的mRNA不稳定。
与具有纯合G229C突变患者的非神经学表型不同，该患者发展为Leigh综合征。肌肉中二氢硫辛酰胺脱氢酶和丙酮酸脱氢酶复合物活性分别为最低对照值的29%和14%。然而，成纤维细胞中的丙酮酸脱氢酶复合物活性正常，这表明能量代谢缺陷的生化检查应在对能量需求更高的组织中进行。
