Diabetes in Friedreich Ataxia

Abstract

© 2017 S. Karger AG, Basel. All rights reserved. Friedreich ataxia (FRDA) is the most common hereditary ataxia. It is a progressive autosomal recessive neurodegenerative disorder associated with an increased risk of impaired glucose tolerance and overt diabetes mellitus. FRDA is caused by a genetic mutation inserting a GAA (guanine-adenineadenine) repeat expansion within intron 1 of the FXN gene, resulting in its transcriptional silencing. The FXN gene encodes for frataxin, a protein ubiquitously expressed and located in the inner mitochondrial membrane. Frataxin is involved in the biogenesis of iron-sulphur clusters (ISCs). The progressive lack of frataxin leads to iron accumulation and decreased activity of those proteins that contain ISCs, such as complex I, II, and III of the mitochondrial electron transport chain, and aconitase, a crucial enzyme of the Krebs cycle (TCA). As a result, FRDA has been linked to mitochondrial dysfunction due to increased reactive oxidative species generation and decreased ATP production. Mitochondria of pancreatic β-cells are central to stimulus-secretion coupling, which is responsible for triggering and amplifying insulin secretion. Furthermore, the intrinsic pathway of apoptosis occurs in the mitochondria and has also been implicated in the pathogenesis of diabetes in FRDA. This chapter focuses on what is currently known about the pathophysiology of diabetes mellitus in the context of frataxin deficiency and its clinical management.