Abstract Friedreich’s ataxia (FRDA), the most-common form of autosomal recessive ataxia, is inherited in most cases by a large expansion of a GAA triplet repeat in the first intron of the frataxin (X25) gene. Genetic heteroge- neity in FRDA has been previously reported in typical FRDA families that do not link to the FRDA locus on chromosome 9q13. We report localization of a second FRDA locus (FRDA2) to chromosome 9p23–9p11, and we provide evidence for further genetic heterogeneity of the disease, in a family with the classic FRDA phenotype. Keywords Friedreich’s ataxia · FRDA2 · Chromosome 9p23-p11 · Genetic heterogeneity Introduction Friedreich’s ataxia (FRDA) is an autosomal recessive ataxia with a frequency of 2×10 –5 . The typical primary clinical features of FRDA include onset of the disease before the age of 25 years with progressive limb and gait ataxia and areflexia in the lower limbs. Within 5 years of onset, pyramidal weakness of the legs, areflexia in the upper limbs, loss of position and vibration sense, and dysarthria develop. Cardiomyopathy in most patients and diabetes in 10% of patients are also observed. Secondary features include scoliosis, optic atrophy, nystagmus, and sensorineural deafness [1, 2]. Atypical forms of FRDA have been reported, which include late-onset Friedreich’s ataxia [3], Friedreich’s ataxia with retained reflexes [4], and Acadian FRDA that has a milder course than classi- cal FRDA [5, 6]. The FRDA gene, called X25, is located on chromo- some 9q13 [7, 8] and encodes a 210-amino acid protein called frataxin [9]. Frataxin is localized in the mitochon- dria [10] and is thought to be involved in iron homeosta- sis, based on the involvement of the yeast homologue of frataxin (YFH1) in iron homeostasis [11]. Iron deposits were observed in myocardial cells from FRDA patients [12] and more recently, a dysfunction of iron-sulfur cen- ter-containing respiratory enzymes in endomyocardial biopsies from FRDA patients has been reported [13]. The function of frataxin is still unknown, and its role in mitochondrial iron homeostasis remains to be elucidated. More than 95% of FRDA cases are caused by a homo- zygous expansion of a large GAA triplet repeat in the first intron of X25 [9]. The size of the GAA triplet repeat cor- relates with the age of onset and the severity of the disease [14, 15]. Rare point mutations have also been identified in patients, which include missense, nonsense, and splice site mutations [9, 16, 17, 18]. No patient homozygous for a point mutation in X25 has been reported to date. Most pa- tients with a point mutation have a severe course of the disease, although severity cannot be predicted [18]. Two large consanguineous families with the FRDA phenotype were reported in 1993 that did not link to the FRDA locus on chromosome 9 [19]. The phenotype in these families is associated with vitamin E deficiency and it was subsequently linked to chromosome 8q [20]. Mutations in the α-tocopherol transfer protein were iden- tified in these patients [21]. This FRDA-like phenotype has been classified as a different disease entity called au- K. Christodoulou ( ✉ ) · D.-M. Georgiou · M. Tsingis · E. Zamba L.T. Middleton The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus e-mail: roula@mdrtc.cing.ac.cy Tel.: +357-2-392649, Fax: +357-2-358238 F. Deymeer · P. Serdarog ˘ lu · C. Özdemir Department of Neurology, Istanbul University, Istanbul, Turkey M. Poda Department of Genetics, DETAE, Istanbul University, Istanbul, Turkey P. Ioannou The Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia L.T. Middleton Clinical Discovery Genetics, Glaxo Smith Kline R&D, London, UK Neurogenetics (2001) 3:127–132 DOI 10.1007/s100480100112 ORIGINAL ARTICLE Kyproula Christodoulou · Feza Deymeer Piraye Serdaro ˘ glu · Cos ¸kun Özdemir · Mehves ¸ Poda Domna-Maria Georgiou · Panos Ioannou Marios Tsingis · Eleni Zamba · Lefkos T. Middleton Mapping of the second Friedreich’s ataxia (FRDA2) locus to chromosome 9p23-p11: evidence for further locus heterogeneity Received: 10 December 2000 / Accepted: 5 March 2000 / Published online: 21 April 2001 © Springer-Verlag 2001