Diagnosis and treatment of Friedreich ataxia: a European perspective.
Friedreich ataxia is the most frequent hereditary ataxia, with an estimated prevalence of 3-4 cases per 100,000 individuals. This autosomal-recessive neurodegenerative disease is characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, decreased vibration sense, muscular weakness in the legs, and a positive extensor plantar response. Non-neurological signs include hypertrophic cardiomyopathy and diabetes mellitus. Symptom onset typically occurs around puberty, and life expectancy is 40-50 years. Friedreich ataxia is usually caused by a large GAA-triplet-repeat expansion within the first intron of the frataxin (FXN) gene. FXN mutations cause deficiencies of the iron-sulfur cluster-containing subunits of the mitochondrial electron transport complexes I, II, and III, and of the iron-sulfur protein aconitase. Mitochondrial dysfunction has been addressed in several open-label, non-placebo-controlled trials, which indicated that treatment with idebenone might ameliorate hypertrophic cardiomyopathy; a well-designed phase II trial suggested concentration-dependent functional improvements in non-wheelchair-bound children and adolescents. Other current experimental approaches address iron-mediated toxicity, or aim to increase FXN expression through the use of erythropoietin and histone deacetylase inhibitors. This Review provides guidelines, from a European perspective, for the diagnosis of Friedreich ataxia, differential diagnosis of ataxias and genetic counseling, and treatment of neurological and non-neurological symptoms.
Department of Neurology, University Hospital, RWTH Aachen, Pauwelsstrasse 30, Aachen, Germany. jschulz@ukaachen.de
Jörg B
JB
Schulz
Sylvia
S
Boesch
Katrin
K
Bürk
Alexandra
A
Dürr
Paola
P
Giunti
Caterina
C
Mariotti
Francoise
F
Pousset
Ludger
L
Schöls
Pierre
P
Vankan
Massimo
M
Pandolfo
D000975:Antioxidants / Q000627:therapeutic use; D003937:Diagnosis, Differential; D003952:Diagnostic Imaging; D005060:Europe / Q000453:epidemiology; D005621:Friedreich Ataxia / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics / Q000628:therapy*; D006801:Humans; D018482:Muscle, Skeletal / Q000503:physiopathology; D009482:Neurophysiology / Q000379:methods
D000975:Antioxidants