212 BARRIENTOS ET AL. HUMAN MUTATION 10:212216 (1997) © 1997 WILEY-LISS, INC. HUMU 797 RESEARCH ARTICLE Sporadic Heteroplasmic Single 5.5 Kb Mitochondrial DNA Deletion Associated With Cerebellar Ataxia, Hypogonadotropic Hypogonadism, Choroidal Dystrophy, and Mitochondrial Respiratory Chain Complex I Deficiency Antoni Barrientos, 1,2 Jordi Casademont, 1 David Genís, 3 Francesc Cardellach, 1 José Manuel Fernández-Real, 4 José María Grau, 1 Alvaro Urbano-Márquez, 1 Xavier Estivill, 2 and Virginia Nunes 2 * 1 Muscle Research Unit, Department of General Internal Medicine, Hospital Clínic i Provincial, University of Barcelona, Spain 2 Department of Molecular Genetics, Institut de Recerca Oncològica (IRO), Barcelona, Spain 3 Neurology Unit, Hospital Josep Trueta, Girona, Spain 4 Endocrinology Unit, Hospital Josep Trueta, Girona, Spain Communicated by Leena Peltonen This report describes a patient with cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy, associated with mitochondrial respiratory chain complex I deficiency and a 5.5 kb mtDNA single deletion in skeletal muscle. Hum Mutat 10:212–216, 1997. © 1997 Wiley-Liss, Inc. KEY WORDS: ataxia; hypogonadism; choroidal dystrophy; single mtDNA deletion INTRODUCTION The association of cerebellar ataxia with hypogo- nadism is well known (Harding, 1984; Neuhauser and Opitz, 1975). When choroidal dystrophy is also present, it has been considered a specific syndrome (Limber et al., 1989; Baroncini et al., 1991; Erdem et al., 1994). Patients usually develop other neuro- logical signs (Harding, 1984). The association of these clinical manifestations has been explained as a pleiotropic effect caused by the homozygous state of an autosomal recessive gene (Neuhauser and Opitz, 1975). However, the dysfunction of organs and tissues not related either embryologically or functionally is characteristic of mitochondrial diseases. Further- more, a mitochondrial respiratory chain complex III deficiency has recently been described in a patient with early-onset cerebellar ataxia, myoclonus, and hypogonadism, although mitochondrial DNA (mtDNA) mutations could not be detected (Toscano et al., 1995). MATERIALS AND METHODS The family of the patient originated from Spain and was nonconsanguineous (see family tree in Fig. 1). The proband, a 39-year-old female, suffered from primary amenorrhea. She developed ataxia at age 31 and severe progressive loss of visual acuity at 36. Investigations showed normal blood levels of lac- tic and pyruvic acids and absence of both anemia and leukopenia. The plasmatic concentrations of es- tradiol, luteinizing hormone (LH), and follicle-stimu- lating hormone (FSH) were low, without response after repetitive stimulation with luteinizing hormone- releasing hormone (LH-RH), suggesting a hypophy- seal origin of the endocrinological disorder. Magnetic resonance imaging showed marked at- rophy of cerebellar hemispheres and vermis, without brainstem atrophy. The father, mother, and two sis- ters of the patient were clinically normal. A muscle biopsy from the vastus lateralis was per- formed. Cryostat sections on frozen muscle tissue were routinely processed for histochemistry as previ- ously reported (Grau et al., 1993). Mitochondrial Received 11 October 1996; accepted 8 December 1996. *Correspondence to: Dep. of Molecular Genetics (IRO), Av. de Castelldefels, km 2,7, 08907 Hospitalet del Llobregat, Barce- lona, Spain. Contract grant sponsor: DGICYT; Contract grant number: PB93-0019; Contract grant sponsor: CICYT; Contract grant num- ber: SAF 915/95; Contract grant number: SAF 96-0227.