Chapter 15 Sporadic adult-onset ataxia of unknown etiology THOMAS KLOCKGETHER* Department of Neurology, University Hospital Bonn, Bonn, Germany DEFINITION Sporadic adult-onset ataxia of unknown etiology (SAOA) is a recently introduced term that denotes the non-hereditary degenerative adult-onset ataxia disor- ders that are distinct from multiple system atrophy (MSA) (Abele et al., 2002). SAOA is defined by the fol- lowing criteria: (1) Progressive ataxia, (2) disease onset after the age of 20 years, (3) no acute or subacute disease onset, (4) no evidence of a causative gene mutation, (5) no established symptomatic cause, (6) no possible or probable MSA according to established clinical criteria (Quinn, 1989; Gilman et al., 1999, 2008). By these criteria, SAOA is distinguishable from the hereditary ataxias, the acquired ataxias, such as alcoholic cerebellar degeneration or paraneoplastic cerebellar degeneration, and MSA. As the etiology of SAOA is unknown and there are no known biochemical or ultrastructural markers of SAOA, SAOA cannot be considered as a distinct disease entity. It rather designates a heterogeneous group of disorders of unknown etiology that are defined by a characteristic clinical syndrome and exclusion of known disease causes. Idiopathic late-onset cerebellar ataxia (IDLOCA) is often used to denote the same group of disorders. The term IDLOCA was introduced by Harding (1981) and defines all non-hereditary progressive ataxias without exogenous cause. Thus, the definition of IDLOCA is broader than that of SAOA as it includes the cerebellar variant of MSA. As MSA is considered a distinct neuropathologically defined disease entity, it does not appear reasonable to sub- sume the cerebellar variant of MSA under the head- ing of IDLOCA and thereby separate the cerebellar and the parkinsonian variant of MSA (Lantos and Papp, 1994). ETIOLOGYAND PATHOGENESIS By definition, SAOA is an adult-onset degenerative disorder of unknown etiology. Consequently, a correct diagnosis of SAOA implies that all known genetic and acquired causes of ataxia have been ruled out. Never- theless, a number of hypotheses have been put forward to account for the etiology of SAOA. Genetic causes One possibility is that SAOA is an unrecognized monogenic hereditary disease, either a late-onset auto- somal recessive, an X-linked, or an autosomal dominant disease caused by mutations of single genes. Harding et al. (1991) reported monozygous triplets who were dis- cordant for SAOA. While this observation rules out the possibility that SAOA in general is an unrecognized monogenic disease, it is still conceivable that a subset of SAOA cases are due to mutations of single genes. In contrast to earlier assumptions, recessive ataxias such as Friedreich ataxia (FRDA) or ataxia–telangiectasia (AT) may start in adult age (Klockgether et al., 1993; De Michele et al., 1994; Du ¨rr et al., 1996; Sutton et al., 2004). Three large studies looking for underlying muta- tions in adult-onset sporadic ataxia patients found homozygous FRDA mutations in 5% to 8% of the patients (Moseley et al., 1998; Scho ¨ls et al., 2000; Abele et al., 2002). On the other hand, a study of 34 sporadic cerebellar ataxia patients aged 3 to 77 years failed to find abnormal levels of a-fetoprotein or mutations in the coding region of the ATM gene (Hassin et al., 1999). In addition to FRDA and AT, there is an increasing number of geneti- cally defined recessive ataxias each of which might manifest as an adult-onset sporadic disease. However, it is unlikely that one of the genetically defined recessive ataxias accounts for a considerable fraction of SAOA *Correspondence to: Thomas Klockgether, MD, Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany. Tel: þ 49-228-2871-5736. E-mail: klockgether@uni-bonn.de Handbook of Clinical Neurology, Vol. 103 (3rd series) Ataxic Disorders S.H. Subramony and A. Du ¨rr, Editors # 2012 Elsevier B.V. All rights reserved