Introduction Leber hereditary optic neuropathy (LHON), an inherited mitochondriopathy, can result in progressive degeneration of retinal ganglial cells and thus in worsening and even loss of vision. ...Smoking is probably the most important risk factor for the onset and progression of the disease. Objectives/Aims To assess the smoking history and status of LHON patients to determine the need for tobacco cessation programmes in this collective. Methods From November 2011 to January 2012, 27 LHON patients completed a standardised questionnaire including Fagerström Test for Nicotine Dependence (FTND), age when smoking started and quit attempts. Smoking history was confirmed by measuring expired carbon monoxide and saliva levels of nicotine and cotinine. Results Twenty men (74%) and 7 women (26%) were evaluated. The average age at disease onset was 29 years. Fifteen (56%) of the participants were smokers at the time of the evaluation, 3 (11%) had quit smoking after diagnosis of LHON and 9 (33%) had never smoked. Saliva nicotine and cotinine concentration correlated significantly with the degree of physical dependence (p<0.05), but carbon monoxide did not. Conclusions Even after being informed of the probability of blindness if they continued to smoke, only 3 of 18 patients quit smoking. Further studies need to assess the effects of integrating smoking cessation programmes into the treatment offered to patients with manifest LHON. Also, the role of smoking in the onset and progression of the disease needs to be validated to optimise prevention and treatment measures for carriers and LHON patients.
Leber's hereditary optic neuropathy is a rare genetic disorder affecting the retinal ganglion cells leading to a persistent severe bilateral loss of visual acuity within weeks or months. Males are ...much more likely to be affected than females, disease onset in most cases takes place between age 15 and 35 years. The disease is caused by point mutations in the mitochondrial DNA. The penetrance of the disease is incomplete, i.e., not all mutation carriers develop clinical symptoms. The phenotype is relatively uniform, but age at onset, severity and prognosis may vary even within the same family. Environmental and endocrine factors, optic disc anatomy as well as mitochondrial and nuclear genetic factors are discussed to influence penetrance as well as interindividual and intrafamilial variability. However, only cigarette smoking and excessive alcohol consumption have been shown to trigger disease onset. The disease is characterised by a central visual field defect, impaired colour vision and fundoscopically a peripapillary microangiopathy in the acute phase. Most patients end up after some months with a severe visual loss below 0.1 and in most cases there is no significant improvement of visual acuity in the course. In rare cases patients experience a mostly partial visual recovery which depends on the type of mutation. For confirmation of the diagnosis a detailed ophthalmological examination with fundoscopy, family history and genetic analysis of the mitochondrial DNA is needed. To date, there is no proven causal therapy, but at early disease stages treatment with idebenone can be tried.
Purpose LHON is an orphan mitochondrial disorder affecting the retinal ganglion cells leading to permanent blindness from which recovery is rare. Here we report visual acuity outcomes for patients ...with recent onset who received Raxone® (idebenone) under an ongoing global Expanded Access Program (EAP).
Methods Visual acuity was measured in 3‐monthly intervals. Clinically relevant recovery was defined as (i) improvement from nadir by at least 10 letters on the ETDRS chart or (ii) improvement from “off‐chart” at nadir to being able to read at least 5 letters on‐chart.
Results Currently there are 61 LHON patients enrolled, of which 48 patients have been treated for an average of 11 months. So far, 24 of 48 patients (50%) have experienced a clinically relevant and stable recovery in VA (89% for T14484C, 70% for G3460A and 31% for G11778A). The average treatment effect size in patients with recovery was 29 letters and 84 % recovered within 12 months of the initiation of the EAP.
Conclusion A high proportion of LHON patients treated with idebenone under a global EAP experienced a clinically meaningful recovery of vision, further demonstrating the therapeutic potential of idebenone in the treatment of LHON.
Commercial interest
Purpose
LHON is an orphan mitochondrial disorder affecting the retinal ganglion cells leading to permanent blindness from which recovery is rare. An increasing body of evidence indicates that ...idebenone has therapeutic potential for the treatment of LHON. Data from a randomized placebo‐controlled study (RHODOS), from a number of case reports and retrospective cohort studies demonstrate that patients with established vision loss may benefit from idebenone treatment and recover visual acuity (VA).
This study reports VA outcomes for patients with recent onset of vision loss who received idebenone treatment under an ongoing global Expanded Access Program (EAP) where currently 82 patients are enrolled and have been treated for an average of 15 months. The outcomes will be compared with findings of the RHODOS study and a Case Record Survey collecting VA data from untreated patients.
Methods
Analyses are performed to assess recovery from the VA nadir. Clinically relevant recovery was defined as (i) improvement from nadir by at least 10 letters on the ETDRS chart or (ii) improvement from “off‐chart” at nadir to being able to read at least 5 letters on‐chart. Furthermore, the prevention of vision loss for patients with residual vision below 1.0 logMAR (20/200) at start of therapy was analysed.
Results
A high proportion of patients (about 50% at submission of the ) treated with idebenone under this global EAP experienced a clinically meaningful recovery of vision. In addition, in patients with residual vision below 1.0 logMAR at start of therapy, loss of VA to above this level could be prevented in a large number of patients (about 60% at submission of the ).
Conclusions
The therapeutic potential of idebenone in the treatment of LHON is further demonstrated by the clinical experience in a large cohort of patients under a global EAP.
Purpose To establish the long term benefit of oral idebenone 900mg/day in the treatment of Leber's Hereditary Optic Neuropathy (LHON).
Methods Patients who participated in a 24‐week, multi‐centre (3 ...sites), double‐masked, randomized, placebo controlled trial (RHODOS) were re‐assessed at a single visit by means of Visual Acuity (VA) using ETDRS charts.
Results Eighty‐five patients were enrolled in the RHODOS study: 55 treated with idebenone (900mg/day) and 30 with placebo. At the end of the 24 week treatment period, the VA for patients randomized to placebo deteriorated. In contrast, in patients treated with 900mg/day idebenone, VA was preserved. In addition, in severely affected patients with off‐chart vision at Baseline, only idebenone treated patients improved sufficiently to read at least 1 full line on the ETDRS chart (Klopstock et al., 2011). VA was repeated at a follow‐up visit conducted 2.5 years (median) after treatment discontinuation. The difference in VA between placebo and idebenone treated patients was maintained. Specifically, in patients who during RHODOS received idebenone and who on average were protected from vision loss, VA did not deteriorate upon discontinuation of treatment.
Conclusion These findings support the original conclusion that in selected patients with LHON, idebenone has significant therapeutic potential in preventing further vision loss and facilitating vision recovery.
Commercial interest
Das mitoNET wurde als interdisziplinäres, deutschlandweites Netzwerk mit dem Ziel konzipiert, eine Verbesserung der Patientenversorgung auf dem Gebiet der mitochondrialen Erkrankungen zu erreichen. ...Das horizontale klinische Netzwerk des mitoNET umfasst 8 neurologische und 13 pädiatrische Kliniken, die für die Patientenrekrutierung, deren Phänotypisierung und die Erfassung des natürlichen Verlaufs im Rahmen von jährlichen Kontrolluntersuchungen zuständig sind. Die Speicherung der erhobenen Daten erfolgt in einer eigens entwickelten webbasierten Registerdatenbank. Das Netzwerk betreibt 2 Biobanken zur Asservierung von DNA, RNA, Plasma sowie von diagnostisch gewonnenen Fibro- und Myoblasten. Vier Forschungsprojekte zielen auf eine Verbesserung des diagnostischen Spektrums durch Etablierung neuer Methoden, und ein Teilprojekt beschäftigt sich mit der Überprüfung neuer Therapiemöglichkeiten. Das mitoNET wird seit Anfang 2009 vom Bundesministerium für Bildung und Forschung (BMBF, Förderkennzeichen 01GM1113A) gefördert.
Zusammenfassung
Das mitoNET wurde als interdisziplinäres, deutschlandweites Netzwerk mit dem Ziel konzipiert, eine Verbesserung der Patientenversorgung auf dem Gebiet der mitochondrialen Erkrankungen ...zu erreichen. Das horizontale klinische Netzwerk des mitoNET umfasst 8 neurologische und 13 pädiatrische Kliniken, die für die Patientenrekrutierung, deren Phänotypisierung und die Erfassung des natürlichen Verlaufs im Rahmen von jährlichen Kontrolluntersuchungen zuständig sind. Die Speicherung der erhobenen Daten erfolgt in einer eigens entwickelten webbasierten Registerdatenbank. Das Netzwerk betreibt 2 Biobanken zur Asservierung von DNA, RNA, Plasma sowie von diagnostisch gewonnenen Fibro- und Myoblasten. Vier Forschungsprojekte zielen auf eine Verbesserung des diagnostischen Spektrums durch Etablierung neuer Methoden, und ein Teilprojekt beschäftigt sich mit der Überprüfung neuer Therapiemöglichkeiten. Das mitoNET wird seit Anfang 2009 vom Bundesministerium für Bildung und Forschung (BMBF, Förderkennzeichen 01GM1113A) gefördert.
Episodic ataxia type 1 (EA1) is an autosomal dominant K(+) channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be ...triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K(+) channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K(+) channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1.
Within Rosa section Caninae (dogroses) two different growth types exist, arching (L-type) and erect (D-type). Due to the specific mode of chromosome allocation during meiosis, character inheritance ...in dogroses is maternally skewed. In this paper we try to assess the mode of inheritance of the 'growth form' in reciprocal hybrids of R. canina L. and R. rubiginosa L. to predict possible ecological niches and radiation processes of hybridogenic offspring. A quantitative analysis of mechanical properties indicates that neither an expected parentally skewed nor an intermediate habit was expressed by the hybrids, but a dominant L-type as in R. canina, regardless of the parental relationship (pollen-parent or seed-parent). Our results implicate two possible scenarios to be further tested: (a) R. canina acts as a species with a dominant allele for the growth form character. If so, this would be the first evidence of a Mendelian character inheritance in the dogroses. (b) 'Growth form' in the dogroses is not a Mendelian character, but a syndrom which realises as an emergent functional property with underlying phenotypic structural differences in stem and wood anatomy.PUBLICATION ABSTRACT
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