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.

Combining data from epidemiological studies in Friedreich's Ataxia (FRDA) and patient organization membership lists, shows that FRDA prevalence exhibits large regional differences in Europe with a prevalence gradient from west to east. Highest levels are observed in northern Spain, south of France and Ireland, lowest levels in Scandinavia and Russia. The observed distribution of FRDA in Europe co-localizes with the gradient of the chromosomal R1b marker as detected within west Europe. This gradient is either derived from Palaeolithic migrations out of the Franco-Cantabrian Ice age refuge or from Neolithic migrations entering west Europe with the advance of agriculture. FRDA prevalence may have been increased in this population anytime after its separation from the closely related R1a carrying group. East European populations with a high frequency of the R1a marker show 10 fold lower prevalence of FRDA, indicating that the FRDA mutation was present in the common ancestor and was increased in the R1b carrying group. The FRDA carrying population went through a Palaeolithic population bottleneck supporting the view that the observed FRDA distribution and potentially the R1b distribution are derived from Palaeolithic migrations out of the FrancoCantabrian ice age refuge.

Idebenone exhibited dose-dependent pharmacokinetics in daily doses up to 2,250 mg. In 6/14 subjects, adverse events of mild to moderate severity were observed.

Four phase 1 studies were conducted to assess the pharmacokinetics and metabolism of idebenone (including parent drug and inactive metabolites QS10, QS6, and QS4) and to evaluate the safety of a wide range of idebenone doses and regimens in healthy adult men. After a single oral dose of idebenone 150 mg, 750 mg, or 1050 mg in fasted or fed subjects, blood samples were taken for up to 72 hours. In one study, after a single oral dose and a 7-day washout period, subjects received repeated doses of idebenone 150 mg or 750 mg every 8 hours for 14 days. In the repeated-dose study, urine samples also were taken. Plasma and urine samples were analysed with the use of liquid chromatography with tandem mass spectrometry. Non-compartmental standard pharmacokinetic methods were used. In these studies, a total of 69 subjects ranging in age from 19 to 41 years (body weight, 57-94.6 kg) were included. Plasma concentrations of parent idebenone were low but increased in proportion to dose and increased approximately five-fold in the presence of food. Total QS4 was the main metabolite in plasma and urine. The most common adverse events were loose stool, fatigue, headache, and disturbances in attention. Idebenone was well tolerated in single oral doses up to 1050 mg and in repeated daily doses up to 2250 mg. Idebenone showed linear pharmacokinetics after single and repeated oral dosing. Administration after a meal resulted in the highest exposure to parent idebenone.

SUMMARYIntraperitoneal injection of the non-phorbol tumor promoter anthralin (l,%dihydroxy-9-anthrone) in male rats resulted in an increase of hepatic ornithine decarboxylase (ODC) activity. Maximal activity was observed 8 h after promoter administration reaching levels about 30 times over control. The kinetics of anthralin dependent ODC induction differed markedly from that by either 12-0-tetradecanoylphorbol-13-acetate (TPA) or phenobarbital (PB) (Bisschop et al., Carcinogenesis 2 (1981) 1282). With anthralin a slow decrease of ODC back to control level is observed approximately within 22 h. In contrast, ODC induction mediated by other tumor promoters like TPA and PB decreased to control levels within 4-6 hours. Administration of a second dose of anthralin 8 h after the first dose prevented the activity decrease as normally observed after a single dose of a tumor promoter. This effect lasted at least 10 h. ODC activity induction occurred in a dosedependent manner being linear from 10-2000 pg anthralin/kg body wt. Pretreatment of the animals either with actinomycin D or with cycloheximide completely blocked anthralin mediated ODC induction suggesting that de novo ODC-mRNA synthesis and subsequent translation is involved in this process.