Real-world clinical experience with Idebenone in the treatment of Leber hereditary optic neuropathy

Background: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. Methods: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed. Results: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor. Conclusions: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings indicate that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. Safety results were consistent with the known safety profile of idebenone

High-resolution mtDNA evidence for the late-glacial resettlement of Europe from an Iberian refugium

The advent of complete mitochondrial DNA (mtDNA) sequence data has ushered in a new phase of human evolutionary studies. Even quite limited volumes of complete mtDNA sequence data can now be used to identify the critical polymorphisms that define sub-clades within an mtDNA haplogroup, providing a springboard for large-scale high-resolution screening of human mtDNAs. This strategy has in the past been applied to mtDNA haplogroup V, which represents <5% of European mtDNAs. Here we adopted a similar approach to haplogroup H, by far the most common European haplogroup, which at lower resolution displayed a rather uninformative frequency distribution within Europe. Using polymorphism information derived from the growing complete mtDNA sequence database, we sequenced 1580 base pairs of targeted coding-region segments of the mtDNA genome in 649 individuals harboring mtDNA haplogroup H from populations throughout Europe, the Caucasus, and the Near East. The enhanced genealogical resolution clearly shows that sub-clades of haplogroup H have highly distinctive geographical distributions. The patterns of frequency and diversity suggest that haplogroup H entered Europe from the Near East ∼20,000–25,000 years ago, around the time of the Last Glacial Maximum (LGM), and some sub-clades re-expanded from an Iberian refugium when the glaciers retreated ∼15,000 years ago. This shows that a large fraction of the maternal ancestry of modern Europeans traces back to the expansion of hunter-gatherer populations at the end of the last Ice Age

The Genetic Heritage of the Earliest Settlers Persists Both in Indian Tribal and Caste Populations

Two tribal groups from southern India—the Chenchus and Koyas—were analyzed for variation in mitochondrial DNA (mtDNA), the Y chromosome, and one autosomal locus and were compared with six caste groups from different parts of India, as well as with western and central Asians. In mtDNA phylogenetic analyses, the Chenchus and Koyas coalesce at Indian-specific branches of haplogroups M and N that cover populations of different social rank from all over the subcontinent. Coalescence times suggest early late Pleistocene settlement of southern Asia and suggest that there has not been total replacement of these settlers by later migrations. H, L, and R2 are the major Indian Y-chromosomal haplogroups that occur both in castes and in tribal populations and are rarely found outside the subcontinent. Haplogroup R1a, previously associated with the putative Indo-Aryan invasion, was found at its highest frequency in Punjab but also at a relatively high frequency (26%) in the Chenchu tribe. This finding, together with the higher R1a-associated short tandem repeat diversity in India and Iran compared with Europe and central Asia, suggests that southern and western Asia might be the source of this haplogroup. Haplotype frequencies of the MX1 locus of chromosome 21 distinguish Koyas and Chenchus, along with Indian caste groups, from European and eastern Asian populations. Taken together, these results show that Indian tribal and caste populations derive largely from the same genetic heritage of Pleistocene southern and western Asians and have received limited gene flow from external regions since the Holocene. The phylogeography of the primal mtDNA and Y-chromosome founders suggests that these southern Asian Pleistocene coastal settlers from Africa would have provided the inocula for the subsequent differentiation of the distinctive eastern and western Eurasian gene pools