Molecular Genetic And Clinical Study Of Chinese Leber Hereditary Optic Neuropathy

Molecular genetic study of a Chinese pedigree of Leber hereditary optic neuropathyPurpose:Clinical and genetic study of a four-generation Han Chinese family with Leber hereditary optic neuropathy(LHON) lacking the common primary mutations,and analyze the possible mitochondrial DNA(mtDNA) mutations associated with LHON in this family.Methods:Ophthalmic examinations of patients in the Chinese LHON family were conducted.Genomic DNA was isolated from the whole blood of participants,sequence analysis of the complete mitochondrial genome was performed,and compared with control subjects and the latest updated revised Cambridge Reference Sequence.Results:Patients in this Chinese LHON family showed typical clinical features of LHON.Routine genetic analysis did not found any reported primary LHON mutations. Sequence analysis of the entire mtDNA found the secondary mutation T4216C in the ND₁ gene,which also determines the Caucasian haplogroup J;the mutation A13651G in the ND₅ gene,leading to a moderately conserved threonine changed by alanine;the reported mutation A15951G in the tRNA^Thr gene was also found in this family. Conclusions:This is the first report that the secondary mutation T4216C occurred independently from primary mutations in a Chinese LHON pedigree,and it is the first report that the concomitant mutations T4216C/ND₁ and the A 13651G/ND₅ occur in the context of the Asian haplogroup D4b1,the co-inheritance of T4216C,A13651G and A15951G mutations increase the probability of LHON.However,as none of primary mutations has been identified,mtDNA variants alone can not explain the pathogenic mechanism of this special LHON pedigree,it is strongly suggested that nuclear modifier genes most likely paly an important role on the penetrance of the disease.PARTâ…¡Evaluation of the serum levels of SOD and MDA in patients with Leber hereditary optic neuropathy carrying the mitochondrial DNA G11778A mutationPurpose:To determine the serum levels of total superoxide dismutase(SOD) activity and malondialdehyde(MDA),and evaluate the oxidant-antioxidant status in patients with Leber hereditary optic neuropathy(LHON) carrying the mitochondrial G11778A mutation.Methods:19 patients and 12 carriers from three Chinese G11778A LHON families were enrolled in this study,and 30 age-matched healthy volunteers were recruited as normal controls.The serum levels of total SOD activity and MDA in all subjects were measured by Xanthine oxidase test and Thiobarbituric acid technique,respectively.Results:The serum level of total SOD activity in LHON patients was significantly less than those in carders and normal controls(q=7.085 and 8.351,respectively,both P＜0.01),however,there was no significant difference between the carriers and normal controls(q=0.269,P＞0.05).The serum level of MDA in patients and carders was significantly higher than that in normal controls(q=9.069 and 4.748,respectively,both P＜0.01),and it was also significantly higher in patients than that in carriers(q=3.618, P＜0.05).Conclusions:Antioxidant capacity decreased evidently in patients with LHON,which supported that the onset of LHON was related with oxidation-antioxidation imbalance.PARTâ…¢Retinal nerve fiber layer analysis by optical coherence tomography in different stages of Leber hereditary optic neuropathyPurpose:To study the retinal nerve fiber layer(RNFL) thickness in different clinical stages of Leber hereditary optic neuropathy(LHON) by optical coherence tomography (StratusOCT),and discuss the classification of LHON.Methods:21 maternal family members(41 eyes) from three Chinese LHON families and 136 age-matched healthy controls(209 eyes) were invited to the study.The fast RNFL thickness(3.4) scan acquisition protocol was used to assess the thickness of RNFL by StratusOCT.Results:Eyes with unaffected carriers showed normal fundus and normal RNFL thickness;eyes with the presymptomatic and the early LHON showed a thicker RNFL in the temporal,superior,inferior quadrants and the 360°average measuremen;eyes with progressive LHON showed a thinner RNFL in the temporal quadrant only;eyes with atrophy LHON revealed a thinner RNFL in all quadrants.Conclusions:According to clinical features and verified by StratusOCT,maternal family memebers were divided into five subgroups:the unaffected carrier,and the presymptomatic,early,progressive,atrophic LHON.RNFL thickness analysis by StratusOCT is helpfor to detect the pathogenic changes of LHON,such classification of LHON may be the best description of the natural pathologic process of LHON,and may be helpful for further study of LHON.