Genetic Testing in Inherited Ataxias Martha A. Nance Many genetic conditions can result in ataxia. Careful clinical, radiologic, and genetic evaluation permits the specific diagnosis of many of these conditions, which in turn facilitates medical care for the patient and genetic counseling for the patient and family. Predictive, prenatal, and carrier testing are possible for some conditions, but the use of gene tests in these clinical situations requires detailed genetic counseling that may be best left to genetics specialists. © 2003 Elsevier Inc. All rights reserved. A RECENT search of “ataxia” in the genetic encyclopedia Online Mendelian Inheritance in Man (OMIM) (www.ncbi.nlm.nih.gov), yielded no fewer than 535 entries. 1 It is evident that the symptom of ataxia can be a final common reflec- tion of many structural, metabolic, and degenera- tive insults. Here we present a strategy to help physicians identify categories of genetic ataxia- causing conditions, along with general recommen- dations for identifying conditions within the cate- gories. We view genetic testing as not simply the performance of a DNA test, but rather more broadly as the performance of tests that lead to the diagnosis of a genetic condition. Physicians who diagnose genetic conditions must be aware of the potential psychosocial and medical implications of the results for the patient, as well as their genetic implications for other family members. We also review the possibility of genetic testing for indi- viduals who have no neurologic symptoms (as in predictive, prenatal, and carrier testing). GENERAL CATEGORIES OF GENETIC ATAXIAS The diverse etiologies of ataxia lend themselves nicely to the neurologist’s skills in logical deduc- tion. Five aspects of the initial history and evalu- ation are particularly helpful in refining the differ- ential diagnosis and informing the genetic assessment: (1) onset and course of the disease; (2) age of onset; (3) family history; (4) presence or absence of additional medical, neurologic, or so- matic features; and (5) brain imaging results (Fig 1). Table 1 lists a number of genetic entities that can lead to ataxia, broken down roughly into cat- egories that the neurologist may recognize by com- mon historical, physical, laboratory, genetic, imag- ing, or neurologic features. An exhaustive description of each condition is not given here, but can easily be obtained through OMIM. Disease Onset and Course An abrupt onset of symptoms would tend to point away from a genetic cause (with the excep- tion of the episodic or metabolic ataxias), whereas an insidious onset or gradual progression might be more consistent with a genetic degenerative disor- der. A static condition would suggest a congenital structural abnormality of the cerebellum. Age of Onset The genetic forms of ataxia can be grouped loosely into those that typically have onset in infancy, those beginning in childhood or adoles- cence, and those that usually begin in adulthood. Structural anomalies of cerebellar development would be expected to produce symptoms in in- fancy or early childhood, and most metabolic dis- orders, genetic syndromes, leukodystrophies, and storage disorders present during childhood or ad- olescence (although adult-onset versions of several of these are well described). Although Friedreich’s ataxia (FA) is the most common childhood- or adolescent-onset ataxia, and the spinocerebellar ataxias account for most adult-onset ataxias, im- portant exceptions to these general patterns can occur. The advent of genetic testing for FA brought with it the revelation that this disorder, previously defined to have onset before age 21, can in fact begin in adulthood. 2-4 Moreover, at least two of the adult-onset spinocerebellar ataxias (SCAs), SCA2 and SCA7, can present with severe early symptoms From the Department of Neurology, University of Minnesota, Minneapolis, MN and The Struthers Parkinson’s Center, Golden Valley, MN 55426. Address reprint requests to Dr. Martha A. Nance, Struthers Parkinson’s Center, 6701 Country Club Drive, Golden Valley, MN 55426. © 2003 Elsevier Inc. All rights reserved. 1071-9091/03/1003-0000$30.00/0 doi:10.1016/S1071-9091(03)00031-7 223 Seminars in Pediatric Neurology, Vol 10, No 3 (September), 2003: pp 223-231