NEUROLOGICAL REVIEW Genetic Testing in Spinocerebellar Ataxias Defining a Clinical Role Eng-King Tan, MD; Tetsuo Ashizawa, MD lthough genetic tests for known spinocerebellar ataxia (SCA) genes are increasingly available, their exact clinical role has received much less attention. Currently avail- able DNA tests can define the genotypes of up to two thirds of patients with domi- nantly inherited SCAs. Certain characteristic clinical features and ethnic predilection Aof some of the SCA subtypes may help prioritize specific SCA gene testing. Available data on genotype- phenotype correlation suggest that currently available DNA tests cannot accurately predict age of onset or prognosis. Because of the mostly adult-onset symptoms and the absence of effective treat- ment, genetic counseling is essential for addressing ethical, social, legal, and psychological issues associated with SCA DNA testing. Arch Neurol. 2001;58:191-195 GENETIC CLASSIFICATION lated region of the SCA8 gene that produces antisense messenger RNA to the Spinocerebellar ataxias (SCAs) are a group KLHL1 gene on the complementary of neurodegenerative diseases character- strand.6 In SCA10, the disease-causing ex- ized by cerebellar dysfunction alone or in pansion occurs in the ATTCT penta- combination with other neurological ab- nucleotide repeat of intron 9 of SCA10, a normalities. Spinocerebellar ataxias have gene of unknown function widely ex- become a focus of human genetics re- pressed in the brain.7 Five additional SCA search since expansions of coded CAG tri- loci have been mapped: SCA4 to 16q24- nucleotide repeats were shown to cause qter,8 SCA5 to 11q13,9 SCA11 to 15q1- several dominantly inherited SCAs (SCAs q21.3,10 SCA13 to 19q13.3-q13.4,11 and 1, 2, 3, 6, and 7) and dentatorubral pal- SCA14 to 19q13.4-qter.12 Episodic ataxia lidoluysian atrophy (DRPLA).1-3 Another types 1 and 2 are also dominantly inher- dominant ataxia with an expanded CAG ited cerebellar ataxias; they are caused by repeat in the TATA box binding protein point mutations within a voltage-gated po- (TBP) gene has been added recently to this tassium channel gene (KCNA1) and the ce- group of disorders.4 In these disorders, the rebral P/Q-type calcium channel a 1 sub- CAG triple repeat expansion gives rise to unit gene (CACNL1A4), respectively.13,14 an elongated polyglutamine tract in the re- The most common recessively inherited spective proteins, leading to a gain in func- ataxia is Friedreich ataxia (FRDA), which tion that is toxic to neurons. However, un- is caused by an expansion of the GAA re- translated repeat expansions also cause peat in intron 1 of the FRDA gene.15 Other dominantly inherited ataxic disorders. Spi- recessive ataxias include vitamin E defi- nocerebellar ataxia type 12 shows an ex- ciency (due to a- tocopherol transfer pro- panded CAG repeat in the 59 untrans- tein deficiency or abetalipoproteinemia), lated region of PPP2R2B, a gene coding for ataxia telangiectasia, infantile-onset a brain-specific regulatory subunit of the spinocerebellar ataxia (IOSCA), Mari- protein phosphatase PP2A.5 Spinocerebel- nesco-Sjo¨gren syndrome, spastic ataxia lar ataxia type 8 is associated with an ex- of Charlevoix-Saguenay, Refsum disease, pansion of a CTG repeat in the 39 untrans- carbohydrate-deficiency ataxia, and Cay- man Island ataxia, among others3 (also see From the Departments of Neurology, Baylor College of Medicine (Drs Tan and the Washington University ataxia clas- Ashizawa), and the Veterans Affairs Medical Center (Dr Ashizawa), Houston, Tex. sification16). Wilson disease may mimic (REPRINTED) ARCH NEUROL / VOL 58, FEB 2001 WWW.ARCHNEUROL.COM 191 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Inherited Spinocerebellar Ataxias (SCAs) for Which Commercial DNA Testing Is Available* Age at Pattern of Gene (Repeat) Disease Main Target Main Clinical Features Onset Range, y Inheritence Gene and Product Location SCA1 Cerebellum, brainstem ADCAI 5-70 AD with anticipation SCA1, ataxin 1 6p22-p23 (exon) SCA2 Cerebellum, brainstem ADCAI with slow saccade, 9-44 AD with anticipation SCA2, ataxin 2 12q24.1 (exon) areflexia MJD/SCA3 Cerebellum, brainstem ADCAI wih dystonia, rigidity, 17-72 AD with anticipation SCA3, ataxin 3 14q32.1 (exon) bulged eyes in MJD 2+ SCA6 Cerebellum ADCAIII with occasional 28-50 AD with anticipation? CACNAIA, a1A-Ca 19p13 (exon) dyskinesia and abnormal channel reflex SCA7 Cerebellum, brainstem, ADCAII 28-50 AD with anticipation SCA7, ataxin 7 3p21.1-p12 (exon) retina SCA8 Cerebellum ADCAIII 28-50 AD SCA8 19p13 (39 UTR) SCA10 Cerebellum, cerebral cortex Ataxia, seizure 12-45 AD with anticipation SCA10, E46 22q13.3 (intron 9) SCA12 Cerebellum, cerebral cortex Ataxia, upper body tremor, 8-55 AD PPP2R2B, PP2ABb 5p31-p33 (59 UTR) hyperreflexia, paucity of movements, dementia DRPLA Dentatorubral pallidoluysian Progressive myoclonus, seizure, 10-70 AD with anticipation DRPLA, atrophin 1 12p12 (exon) systems ataxia, and dementia FRDA DRG, spinal cord, Progressive ataxia and ,20 AR FRDA, frataxin 9p13 (intron 1) cerebellum, peripheral proprioceptive sensory loss, 3-70 nerve areflexia, cardiomyopathy, diabetes *ADCA indicates autosomal dominant cerebellar ataxia, ADCAI; cerebellar ataxia plus other neurologic abnormalities; ADCAII, ADCA with macular degeneration; and ADCAIII, pure cerebellar ataxia17; AD, autosomal dominant; AR, autosomal recessive; MJD, Machado-Joseph disease; DRPLA, dentatorubral pallidoluysian atrophy; FRDA, Friedreich ataxia; DRG, dorsal root ganglia; UTR, untranslated region; and question mark, anticipation has been reported but not confirmed. †Normal alleles 40-44 are interrupted by 1 or 2 CATs and disease alleles 40-44 are not. Ellipses indicate intermediate alleles have not been reported in these diseases. ‡Disease alleles show reduced penetrance. features of SCAs. Genetic testing is a powerful way of con- testing for point mutations may also be available on a re- firming the diagnosis and distinguishing various SCA sub- search basis for ataxia telangiectasia, ataxia of vitamin E types, although there have been previous attempts to clas- deficiency, mitochondrial disorders, Wilson disease, Ref- sify them according to their clinical presentations.17 sum disease, and episodic ataxia types 1 and 2. How- ever, screening of point mutations in these diseases are TYPES OF GENETIC TESTS generally not cost-effective because each family can carry a different mutation, and their diagnoses should be based Although genetic testing for known SCA genes are in- on clinical and other laboratory findings at present creasingly available, their exact clinical role has re- (Figure). New technologies, such as DNA microchip ar- ceived much less attention. Currently available commer- rays,19 may make DNA testing for these diseases com- cial DNA tests can define the genotypes of up to two thirds mercially feasible in the near future. of patients with dominantly inherited SCAs10 (Table; see also Web site www.genetests.org,18 which catalogs ge- CHOICE OF GENETIC TEST netic testing). As the list of these DNA tests grows, the variable and overlapping phenotypic manifestations of In general, these tests should be done in SCAs that dem- the SCA subtypes make it difficult to choose which spe- onstrate a clear mode of inheritance (Figure). For those cific SCA DNA test to order initially. Although a posi- without family history, secondary causes, especially treat- tive DNA test result provides the unequivocal diagnosis able ones, should be excluded first. However, testing in at a cost comparable to magnetic resonance imaging stud- apparent “sporadic” cases might be worthwhile if the fam- ies, a negative test result has little diagnostic value other ily history is unreliable or ambiguous because about 5% than exclusion of certain diseases. It might not be cost- of sporadic cases have been found to be autosomal domi- effective to order blanket genetic tests for all patients with nant.20 A positive family history may not always be avail- SCA, especially with the availability of an increasing num- able for patients with SCA6 and recessive ataxias such ber of DNA tests for ataxic disorders (a single SCA di- as FRDA. A de novo mutation, ie, an expansion of an in- agnostic test costs approximately $300). Some laborato- termediate allele into a full mutant allele, may cause the ries offer less expensive rates when many SCA DNA tests disease with clearly negative family history. Early paren- are done at the same time, and such a battery might be tal deaths, nonpaternity, and adoption should also be useful in cases in which there are few clues for prioriti- taken into consideration. By the same reasons, domi- zation of the SCA DNA testing. At present, DNA testing nant ataxias may mimic recessive inheritance. Although that can directly detect mutations is commercially avail- it is not easy to prioritize the screening order of SCA sub- able for SCAs 1, 2, 3, 6, 7, and 8; FRDA; and DRPLA and types on clinical grounds alone, the ethnic origin and the may become available for SCAs 10 and 12 and the ataxia presence of certain suggestive clinical signs may pro- with the TBP CAG expansion in the near future. DNA vide some guidance.1-3 Machado-Joseph disease (MJD) (REPRINTED) ARCH NEUROL / VOL 58, FEB 2001 WWW.ARCHNEUROL.COM 192 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Patient With Cerebellar Syndrome Positive Detailed History Negative Repeat Normal Intermediate Disease Family History and Examination Family History (Cryptic Sequence) Range Range Range CAG (CAT) 6-44 . .† 40-82 Autosomal Genetic Autosomal Recessive or CAG (CAA) 14-31 34-35 34-59 Dominant Counseling Uncertain Inheritance CAG (none) 12-40 . 55-200 Testing for Recessive Disorders if Compatible Exclude Secondary With Observed Manifestations Causes, CAG (none) 4-20 . 21-33 Disease Test Disease Test Negative eg, Neuroacanthocytosis, FRDA (GAA)>120 Refsum Phytanic Acid Paraneoplastic Syndrome, AVED Vitamin E Wilson Ceruloplasmin Hypothyroidism, Alcoholism, AT α-Fetoprotein and Antigliadin Antibody CAG (none) 4-19 28-35 37-.300 CTG (complex) 16-34 .