Reduced cancer incidence in Huntington's disease: analysis in the Registry study

We dedicate this paper to the memory of Raviram Ramesh. BACKGROUND People with Huntington’s disease have been observed to have lower rates of cancers. OBJECTIVE To investigate the relationship between age of onset of HD, CAG repeat length and cancer diagnosis. METHODS Data were obtained from the European Huntington’s disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. RESULTS 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p<0.001). CONCLUSIONS Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis

How to Capitalize on the Retest Effect in Future Trials on Huntington's Disease.

The retest effect-improvement of performance on second exposure to a task-may impede the detection of cognitive decline in clinical trials for neurodegenerative diseases. We assessed the impact of the retest effect in Huntington's disease trials, and investigated its possible neutralization. We enrolled 54 patients in the Multicentric Intracerebral Grafting in Huntington's Disease (MIG-HD) trial and 39 in the placebo arm of the Riluzole trial in Huntington's Disease (RIL-HD). All were assessed with the Unified Huntington's Disease Rating Scale (UHDRS) plus additional cognitive tasks at baseline (A1), shortly after baseline (A2) and one year later (A3). We used paired t-tests to analyze the retest effect between A1 and A2. For each task of the MIG-HD study, we used a stepwise algorithm to design models predictive of patient performance at A3, which we applied to the RIL-HD trial for external validation. We observed a retest effect in most cognitive tasks. A decline in performance at one year was detected in 3 of the 15 cognitive tasks with A1 as the baseline, and 9 of the 15 cognitive tasks with A2 as the baseline. We also included the retest effect in performance modeling and showed that it facilitated performance prediction one year later for 14 of the 15 cognitive tasks. The retest effect may mask cognitive decline in patients with neurodegenerative diseases. The dual baseline can improve clinical trial design, and better prediction should homogenize patient groups, resulting in smaller numbers of participants being required

A locus-specific database for mutations in GDAP1 allows analysis of genotype-phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K

<p>Abstract</p> <p>Background</p> <p>The ganglioside-induced differentiation-associated protein 1 gene (<it>GDAP1</it>), which is involved in the Charcot-Marie-Tooth disease (CMT), the most commonly inherited peripheral neuropathy, encodes a protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying <it>GDAP1 </it>mutations are heterogeneous, making it difficult to determine genotype-phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB) established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases.</p> <p>Methods and Results</p> <p>We report the development of a publicly accessible LSDB for the <it>GDAP1 </it>gene. The <it>GDAP1</it> LSDB has adopted the Leiden Open-source Variation Database (LOVD) software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the <it>GDAP1 </it>database is illustrated by the finding that <it>GDAP1 </it>mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease.</p> <p>Conclusion</p> <p>Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the <it>GDAP1 </it>LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases.</p

Dominant ACO2 mutations are a frequent cause of isolated optic atrophy.

Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells

Container shipping on the Northern Sea Route

Since the beginning of the 20th century, the principal commercial maritime routes have changed very little. With global warming, the Northern Sea Route (NSR) has opened up as a possible avenue of trade in containerized products between Asia and Europe. This paper verifies the technical and economic feasibility of regular container transport along the NSR. By adopting a model schedule between Shanghai and Hamburg, we are able to analyze the relative costs of various axes in the Asia–Europe transport network, including the NSR. While shipping through the Suez Canal is still by far the least expensive option, the NSR and Trans-Siberian Railway appear to be roughly equivalent second-tier alternatives

Variations phénotypiques des maladies de Charcot-Marie-Tooth liées aux mutations du gène de la mitofusine 2

ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Etude d une population atteinte de céphalées chroniques quotidiennes (à propos de 16 cas)

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Génétique moléculaire et corrélations phénotype génotype des formes autosomiques récessives de maladie de Charcot Marie Tooth démyélinisante

La maladie de Charcot-Marie-Tooth (CMT) est une neuropathie sensitivomotrice héréditaire très hétérogène. Dans ce travail, nous nous sommes intéressés aux formes autosomiques récessives démyélinisantes de CMT (CMTAR). Dans un premier temps, nous avons montré l importance du phénotypage. Par la suite, avec une étude portant sur 34 familles avec un CMTAR démyélinisant et une consanguinité, nous avons recherché la fréquence des loci/gènes connus. Ceci nous a permis d élargir le spectre mutationnel des gènes testés et de montrer que plus de 50% des familles ne sont pas associées à ces gènes. Nous avons aussi étudié la répartition géographique des mutations identifiées. Ce travail nous a permis d établir ensuite des corrélations phénotypes génotypes. Nous avons participé à l'identification d'un nouveau gène, la Periaxine pour le CMT4F. Enfin, nous avons réalisé une cartographie primaire impliquant 26 familles et avons identifié plusieurs régions candidates qui sont en cours d'exploration.Charcot Marie Tooth (CMT) disease is a very heterogeneous inherited peripheral neuropathy. In this work, we were interested in autosomal recessive and demyelinating CMT. A linkage and sequencing study with known loci/genes was carried out in 34 families with demyelinating ARCMT and consanguineous marriages. In this study we enlarged the mutation spectrum in the know genes and observed geographic repartition of each locus/mutation. Loci frequencies were estimated and phenotype genotype correlations were established. We also showed that more than 50% of these families were not associated to one of the known loci/genes. Another part of this work was devoted to the gene identification strategies and allowed us to incriminate Periaxin (PRX) as the responsible gene for the CMT4F. Finally, we performed a genome scan in 26 families without linkage to the known loci and identified several regions of interest. The study of these loci is in progress.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF