Friedreich ataxia – From clinics to pathophysiology via genetics

Seminar

This seminar is part of the INTERBIO Seminar Series

Title: Friedreich ataxia – From clinics to pathophysiology via genetics

Speaker: Francesc Palau

Affiliation: Institute of Biomedicine, CSIC, and CIBER de Enfermedades Raras (CIBERER), Valencia, Spain

Host: INTERBIO

Abstract

Friedreich ataxia (FRDA; OMIM 22390) is an autosomal recessive neurodegenerative disorder characterized by early onset and progressive limb and gait ataxia, dysarthria, deep tendon areflexia especially of the lower extremities, and presence of a sensory axonal neuropathy with motor conduction velocities greater than 40 m/s. In addition, most patients show hypertrophic cardiomyopathy. Additional non-neurological features are skeletal deformities and glucose intolerance or diabetes mellitus. It is named after Nicholaus Friedreich, professor of medicine in Heidelberg in the second half of the nineteenth century, who first described the condition. Though a rare disease, FRDA is the most common of the inherited ataxias in most of Europe. Its prevalence is highest in Western Europe, with more than 1 case in 30,000 reported in Northwest and East Spain and Ireland. A survey in France detected 11 carriers of this recessive disorder per 1,000 tested from the general population. Prevalence appears to decrease in Eastern Europe. The disease is caused by GAA triplet expansions and point mutations in the FXN gene mapped to human chromosome 9q13. FXN encodes frataxin, a small protein of 210 amino acids expressed in the mitochondrial matrix. Frataxin seems to act as a iron donor to other proteins for their utilization in different biochemical pathways, such as biogenesis of iron-sulfur clusters (ISC) and activation of aconitase. Thus, the pathogenic consequences of frataxin deficiency have been related with defects of ISC biogenesis but also with iron deposits, oxidative stress  and regulation of the mitochondrial respiratory chain. Based on cell and mitochondrial effects of the lack of frataxin, several pharmacological approaches have been proposed. These include the use of antioxidants to reduce radical oxidative species such as idebenone or coenzyme Q10 (CoQ), chelators that mobilize the iron deposits observed in patients or more recently histone deacetylase (HDAC) inhibitors to reverse FXN silencing caused by expansion of the GAA trinucleotide reduces transcription of FXN gene, which in turn leads to frataxin deficiency. 

In the present lecture I will addressed a whole vision of the disease from the clinical aspects to the pathogenesis and cell pathophysiology of frataxin deficiency, including some points related to current therapies and clinical trials.
 

About the speaker

Francesc Palau, MD, PhD
Profesor de Investigación
Instituto de Biomedicina, CSIC
Director de la Unidad de Genética y Medicina Molecular, Instituto de Biomedicina de Valencia 

Director Científico, CIBER de Enfermedades Raras (CIBERER)

National Coordinator (SP) Orphanet (the portal for rare diseases and orphan drugs - EU)

Premio Reina Sofía 2004 de Prevención de Deficiencias 

Research Profile at biomedexperts