Advancements in the pathophysiology of Friedreich's Ataxia and new prospects for treatments.

On November 9-12, 2006, the Friedreich's Ataxia Research Alliance (FARA) and the National Institutes of Health (NIH) hosted the Third International Friedreich's Ataxia (FRDA) Scientific Conference at the NIH in Bethesda, Maryland, highlighting the exciting research leading now to a variety of clinical trials that show promise of effective treatments for this devastating disorder. Nearly 150 leading FRDA scientists from around the world discussed their new insights and findings. The presence of six pharmaceutical and biotechnology companies underscored the importance of the public-private partnership that has grown in the past years. Some of these companies are already involved in advancing promising drug compounds into clinical trials, while others are eager to help take newer discoveries through drug development and into subsequent clinical trials. National Institute of Neurological Disorders and Stroke (NINDS) Director Dr. Story Landis noted in her opening remarks for the conference that there was a "palpable sense of energy, excitement, and enthusiasm" over the scientific progress made since the FRDA gene was discovered over 10 years ago.

Friedreich ataxia mouse models with progressive cerebellar and sensory ataxia reveal autophagic neurodegeneration in dorsal root ganglia.

Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by degeneration of the large sensory neurons of the spinal cord and cardiomyopathy. It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biosynthesis. Through a spatiotemporally controlled conditional gene-targeting approach, we have generated two mouse models for FRDA that specifically develop progressive mixed cerebellar and sensory ataxia, the most prominent neurological features of FRDA. Histological studies showed both spinal cord and dorsal root ganglia (DRG) anomalies with absence of motor neuropathy, a hallmark of the human disease. In addition, one line revealed a cerebellar granule cell loss, whereas both lines had Purkinje cell arborization defects. These lines represent the first FRDA models with a slowly progressive neurological degeneration. We identified an autophagic process as the causative pathological mechanism in the DRG, leading to removal of mitochondrial debris and apparition of lipofuscin deposits. These mice therefore represent excellent models for FRDA to unravel the pathological cascade and to test compounds that interfere with the degenerative process.

Dystrophinopathy caused by mid-intronic substitutions activating cryptic exons in the DMD gene.

In the course of a mutation search performed by muscle dystrophin transcript analysis in 72 Duchenne and Becker Muscular Dystrophies (DMD/BMD) patients without gross gene defect, we encountered four unrelated cases with additional out-of-frame sequences precisely intercalated between two intact exons of the mature muscle dystrophin mRNA. An in silico search of the whole dystrophin genomic sequence revealed that these inserts correspond to cryptic exons flanked by one strong and one weak consensus splice site and located in the mid-part of large introns (introns 60, 9, 1M, and 62, respectively). In each case we identified an intronic point mutation activating the cryptic donor or acceptor splice site. The patients exhibited a BMD/intermediate phenotype consistent with the presence of reduced amounts of normally spliced transcript and normal dystrophin. The frequency of this new type of mutation is not negligible (6% of our series of 65 patients with 'small' mutations). It would be missed if the exploration of the DMD gene is exclusively performed on exons and flanking sequences of genomic DNA.

Changing patient perceptions of the side effects of cancer chemotherapy.

BACKGROUND: Quality-of-life (QoL) issues have become increasingly important as the number of newly diagnosed patients with cancer increases and survival improves. In 1983, Coates et al. reported a survey of patient perceptions of the side effects of cancer chemotherapy and showed the importance of including patient feedback for the accurate assessment of QoL (Eur J Cancer Clin Oncol. 1983;19:203-208.). The authors carried out a similar survey in 100 patients with cancer with the objectives of 1) investigating the changes in patient perceptions that have occurred and 2) evaluating the impact of new treatments on the profile of chemotherapy side effects among patients receiving anticancer drugs. METHODS: One hundred patients attending the outpatient Medical Oncology Department of the Pitié Salpêtrière Hospital Group were surveyed between August 1998 and February 2000 by trained interviewers who were blinded to the patients' treatment. Patients identified all side effects associated with their treatment using a set of 45 cards that named physical side effects (Group A) and a set of 27 cards that named nonphysical side effects (Group B), and the patients ranked these side effects according to severity. The top 5 cards from each group were then combined, and the resulting 10 cards were rated again by severity, regardless of group. Results were analyzed for the entire cohort and for demographic, social, and clinical subgroups. RESULTS: The participants included 65 women and 35 men; the most common malignancies were breast carcinoma (40 patients), gastrointestinal carcinoma (19 patients), lung carcinoma (7 patients), and ovarian carcinoma (9 patients). Patients rated affects my family or partner as the most severe side effect, alopecia was second, and fatigue was the third most severe. Effects on work or home responsibilities, effects on social activities, and loss of interest in sex were ranked fourth, fifth, and sixth, respectively. The results contrasted with those of Coates et al., in which affects my family or partner was ranked 10th, and fatigue was ranked 8th. CONCLUSIONS: Patient perceptions of the side effects of cancer chemotherapy have changed markedly. In the current study, fatigue and psychosocial QoL concerns predominated, compared with emesis, nausea, and negative reactions to the treatment visit in the original survey. The current findings are consistent with the progress that has been made in reducing certain chemotherapy-associated toxicities. Fatigue, however, although it often is related to anemia and is treatable with recombinant human erythropoietin, remains a major concern. The emotional, social, and sexual consequences of cancer treatment present continuing challenges in efforts to optimize QoL and to develop effective supportive care.