Genetic Testing in Spinocerebellar Ataxias Defining a Clinical Role

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 available DNA tests can define the genotypes of up to two thirds of patients with dominantly 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 treatment, 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 ␣ 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 ␣- tocopherol transfer pro- panded CAG repeat in the 5Ј 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 3Ј 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

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, ␣1A-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 (3Ј 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, PP2AB␤ 5p31-p33 (5Ј 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 Ͻ20 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

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-Ͼ300

CTG (complex) 16-34 . . . 100-250‡ Negative Positive Positive ATTCT (none) 10-22 . . . Ͼ1000 CAG (none) 7-28 . . . 66-78 Consider Other Recessive Ataxias (see the “Choice of Genetic Test” Section)

CAG (none) 3-36 . . . 49-88 Consider Incomplete Family History, De Novo Mutation, Reduced Penetrance, etc, for Autosomal Dominant Ataxias GAA (none) 7-28 . . . 120-Ͼ1700 DNA Testing for the Dominant Ataxias (SCAs 1, 2, 3, 6, 7, Specific Specific 8, 10, and 12 and DRPLA) With Prioritization: Positive Diagnosis Diagnosis (1) Based on Ethnic Origin and Geographical Location of Inherited of Sporadic (see the “Choice of Genetic Test” Section) Ataxia Ataxia (2) Based on Clinical Phenotype (see the Table and the “Choice of Genetic Test” Section) Further Genetic Counseling Negative

Consider Other Ataxic Symptomatic Specific Disorders Treatment Management

was originally described in 1972 in 2 families of Azorean Clinical algorithm for genetic testing for spinocerebellar ataxia (SCA). If the descent.1-3 However, the CAG repeat expansion that causes family history suggests an autosomal recessive or uncertain inheritance MJD/SCA3, has been found in different ethnic popula- pattern, consider recessive diseases that can be tested. If test results for these diseases are negative, consider other recessive diseases by clinical tions with SCA3 around the world. Spinocerebellar ataxia phenotype and, if feasible, examine linkage for known recessive ataxia loci, type 3 seems to be most common in countries such as which may lead to a specific diagnosis. Then, the patient can undergo DNA the United States, China, and Germany; SCAs 1 and 2 in testing for the dominant ataxias after assessing the possibility of dominant inheritance with incomplete family history, reduced penetrance, and de novo the United Kingdom and Italy; SCA2 in India and Cuba; mutation. In patients with no family history it is important to exclude various and SCAs 3 and 6 in Japan. Spinocerebellar ataxia type secondary causes because specific treatment may be available. When these 10 has been seen only in Mexicans.7 Dentatorubral are excluded, consider the recessive diseases, such as Friedreich ataxia pallidoluysian atrophy is rare outside Japan. Spinocer- (FDRA), and then the certain autosomal dominant SCAs if the clinical suspicion is strong. Prioritize the tests for dominant ataxias based on the ebellar ataxia types 12, 13, and 14 have been reported in ethnic origin and the clinical phenotype. At present, there are no direct DNA German American, French, and Japanese families, re- tests for detection of the mutations for SCAs 4, 5, 11, 13, and 14. spectively.10-12 Friedreich ataxia has never been re- AVED indicates ataxia of vitamin E deficiency; AT, ataxia telangiectasia; and ported in northeast Asia. Presence of a founder effect could DRPLA, dentatorubral pallidoluysian atrophy. possibly create different prevalences within the same ethnic population. For instance, this might in part explain SCA13 characteristically show slowly progressive cer- why SCA1 is more common in northern Italy and SCA2 ebellar ataxia of early childhood onset, with mild men- is more frequent in southern parts of the country. tal retardation and motor developmental delay. There In addition to the wide phenotypic overlap among are some overlapping clinical features between SCA6 the SCAs, significant interfamilial and intrafamilial phe- and episodic ataxia type 2 and familial hemiplegic mi- notypic variability exists even for each SCA subtype. How- graine.1-3,14 This is not surprising because the CAG ex- ever, it is worthwhile noting characteristic features of some pansion in SCA6 is located in the alpha-1A voltage- SCAs.1-3 Markedly reduced velocity of saccadic eye move- dependent calcium channel gene, and episodic ataxia type ments, areflexia, and changes similar to those seen in ol- 2 is caused by a point mutation in the same gene. If there ivopontocerebellar atrophy on magnetic resonance im- is a history of seizures with ataxia, DRPLA and SCA10 ages of the brain suggest SCA2. Spinocerebellar ataxia need to be considered; in the latter, seizures are accom- type 7 is characterized by macular degeneration. Com- panied by relatively pure cerebellar ataxia. Spinocerebel- binations of protruded eyes, muscle fasciculations, spas- lar ataxia type 3 and DRPLA need to be considered in ticity, chorea, gaze-evoked nystagmus, parkinsonism, and patients with suspected Huntington disease (HD) whose peripheral neuropathy favor MJD/SCA3, but SCA1 and HD DNA test results were normal because of some shared SCA12 also share some of these features. Spinocerebel- features. Some patients with SCA3 may show a pure par- lar ataxia types 5, 6, 10, and 11 should be considered in kinsonian phenotype. Most families with SCAs that are patients with relatively pure cerebellar signs. Patients with caused by polyglutamine-coding CAG expansions show

(REPRINTED) ARCH NEUROL / VOL 58, FEB 2001 WWW.ARCHNEUROL.COM 193

©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 anticipation, ie, earlier disease onset with increasingly se- ously for HD (another trinucleotide repeat disorder vere disease phenotype in succeeding generations.1-3 Spi- with no effective treatment), including confirmatory nocerebellar ataxia types 5, 10, and probably 14 also show testing, prenatal diagnosis, predictive testing and anticipation,7,9,12 whereas SCAs 8, 12, and 13 do not.4,5,10 asymptomatic testing for children, confidentiality, Our experience suggests that the predictive value of some insurability, finances, employment, disability, and mar- of these characteristic clinical features may increase when riage.22 With increasing availability of DNA testing for a applied to a particular ethnic population in which the most growing number of SCAs, physicians will be confronted common SCA subtypes are known. Further studies may with many of these problems. Geneticists and experi- make it possible to compute the probabilities of SCA sub- enced genetic counselors should shoulder this burden. types based on these factors for each patient. However, physicians at tertiary and primary levels should also participate and, in some cases, may need to LIMITATIONS play a major role in this task. Testing in at-risk asymptomatic children has been generally discouraged. Prena- Cautious interpretation of an SCA test result and under- tal testing of SCAs has been available, but few parents standing of its implication are vital in genetic counsel- seem to be electing it. Issues such as termination of ing and patient care. Anticipation observed in most SCAs pregnancy in the event of a detectable mutation in the accompanies progressive increases of expanded CAG re- fetus and follow-up care for psychological problems peats in successive generations, often depending on pa- require careful management by a team of physicians, ternal transmission. Patients with larger CAG repeats gen- genetic counselors, psychologists, and social workers. erally show earlier ages of onset, with greater disease Great effort should be accorded to predictive testing, severity than those with relatively smaller repeats. A simi- which usually creates the most distress in those tested. lar mechanism involving the ATTCT repeat seems to ex- A study conducted by Nance and colleagues23 before plain anticipation in SCA10 families. However, because the discovery of the SCA1 gene revealed that about two the repeat size accounts for only up to 60% of the vari- thirds of 117 patients, spouses, and at-risk individuals ability of age of onset, we cannot predict the exact age of of 2 SCA1 kindreds wanted predictive testing immedi- onset for a given size of a disease allele of any SCA sub- ately and 42% thought prenatal testing should be type.1-3 Although individuals undergoing predictive test- made available. Members of one kindred demonstrated ing frequently ask for prediction of age of onset and prog- a significantly higher level of anticipated adverse psy- nosis, further research regarding other genetic and chological responses such as depression, anger, and environmental determinants are required before we can suicidal thoughts. Cooperative efforts to establish guide- answer this question. There seems to be a critical size of lines for this issue are needed. Experiences in HD are repeat for most of the SCAs above which the disease would invaluable in this process; however, keep in mind that manifest. However, this is not absolute in some SCAs in there are important differences between each SCA sub- which disease and normal allele sizes overlap in an in- type and HD, especially in their psychological and termediate range. Alleles in the intermediate range show social needs. reduced penetrance in SCA2. In SCA7, the intermediate alleles do not cause disease but can give rise to de novo FUTURE CHALLENGES expansion to the disease-causing allele in subsequent generations (Table). Further studies are needed in SCA8 to Increasing understanding of the pathogenic mechanisms address the observation that fully expanded alleles show in SCAs caused by polyglutamine expansions and FRDA reduced penetrance in affected families and are also found may lead to exploitation of new effective therapeutic drugs in controls and other patients without SCA.3,6 Defining in the near future.24,25 Today, experimental neuroprotec- the risk of developing the disease in such instances is a tive drugs (such as N-methyl-D-aspartate antagonists) are difficult task. Effects of parental origin on repeat size in- already available for trials.26 Developing a reliable ataxia rat- stability may become an important subject in genetic coun- ing scale to monitor disease progression and treatment re- seling because paternal transmission of many SCAs (eg, sponse has been initiated.27 The future availability of thera- SCAs 1, 2, and 3) may result in a severe, rapidly progres- peutic interventions would drastically change the indications sive phenotype at a young age. In SCA7, this phenom- of DNA testing and its psychological and social impacts. enon may be the most prominent in which increased em- Analyses of cost-effectiveness of DNA testing and its po- bryonic lethality in paternal transmission has been tential social implications are also important. Cloning of postulated.21 genes of SCAs 4, 5, 11, 13, and 14 and other unclassified hereditary SCAs, further understanding of genotypic- NONMEDICAL ISSUES phenotypic correlations, and studies of susceptibility loci and disease-modifying genes would be translated into more Despite the great advances in molecular genetics of comprehensive genetic testing programs. SCAs, the phenotypic and genetic variability, the mostly adult-onset symptoms, and the absence of effective treatment make formulation of specific guidelines in Accepted for publication September 26, 2000. genetic counseling of SCA a daunting task. Although at Corresponding author and reprints: Tetsuo Ashi- present there are no proposed guidelines for SCA test- zawa, MD, Department of Neurology, Baylor College of ing, we must address the numerous ethical, social, legal, Medicine, 6550 Fannin Dr, Smith 1801, Houston, TX 77030 and psychological issues similar to those raised previ- (e-mail: [email protected]).

(REPRINTED) ARCH NEUROL / VOL 58, FEB 2001 WWW.ARCHNEUROL.COM 194

©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 14. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and REFERENCES episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996;87:543-552. 1. Ashizawa T, Zoghbi HY. Diseases with trinucleotide repeat expansions. In: Appel 15. Campuzano V, Montermini L, Molto MD, et al. Friedreich’s ataxia: autosomal re- S, ed. Current Neurology. Amsterdam, the Netherlands: IOS Press; 1997:79-135. cessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996; 2. Wells RD, Warren ST. Genetic Instabilities and Hereditary Neurological Dis- 271:1423-1427. eases. Orlando, Fla: Academic Press Inc; 1998. 16. Washington University ataxia classification. Available at: http://www 3. Evidente VG, Gwinn-Hardy KA, Caviness JN, Gilman S. Hereditary ataxias. Mayo .neuro.wustl.edu/neuromuscular/ataxia/aindex.html. Accessed November 16, 2000. Clin Proc. 2000;75:475-490. 17. Harding AE. Clinical features and classification of inherited ataxias. Adv Neurol. 4. Nakamura K, Jeong S-Y, Ichikawa Y. SCA13, a novel autosomal dominant cer- 1993;61:1-14. ebellar ataxia caused by the expanded polyglutamine in TATA-binding protein 18. GeneTests. Available at: http://www.genetests.org. Accessed November 16, identified with 1C2 antibody immunoscreening [abstract]. Am J Hum Genet. 2000; 2000. 67:389. 19. Harrington CA, Rosenow C, Retief J. Monitoring gene expression using micro- 5. Holmes SE, O’Hearn EE, McInnis MG, et al. Expansion of a novel CAG trinucleo- arrays. Curr Opin Microbiol. 2000;3:285-291. tide repeat in the 5Ј region of PPP2R2B is associated with SCA12. Nat Genet. 20. Moseley ML, Benzow KA, Schut LJ, et al. Incidence of dominant spinocerebellar 1999;23:391-392. and Friedreich triplet repeats among 361 ataxia families. Neurology. 1998;51: 6. Koob MD, Moseley ML, Schut LJ, et al. An untranslated CTG repeat expansion causes 1666-1667. a novel form of spinocerebellar ataxia (SCA8). Nat Genet. 1999;21:379-384. 21. Monckton DG, Cayuela ML, Gould FK, Brock GJ, Silva R, Ashizawa T. Very large 7. Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of ATTCT penta- (CAG)(n) DNA repeat expansions in the sperm of two spinocerebellar ataxia type nucleotide repeat in spinocerebellar ataxia type 10. Nat Genet. 2000;26:191- 7 males. Hum Mol Genet. 1999;8:2473-2478. 194. 22. International Huntington Association (IHA) and the World Federation of Neurol- 8. Flanigan K, Gardner K, Alderson K, et al. Autosomal dominant spinocerebellar ogy (WFN) Research Group on Huntington’s Chorea. Guidelines for the molecu- ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic lar genetics predictive test in Huntington’s disease. Neurology. 1994;44:1533- localization to chromosome 16q22.1. Am J Hum Genet. 1996;59:392-399. 1536. 9. Ranum LP, Schut LJ, Lundgren JK, Orr HT, Livingston DM. Spinocerebellar ataxia 23. Nance MA, Sevenich EA, Schut LJ. Knowledge of genetics and attitudes toward type 5 in a family descended from the grandparents of President Lincoln maps genetic testing in two hereditary ataxia (SCA1) kindreds. Am J Med Genet. 1994; to chromosome 11. Nat Genet. 1994;8:280-284. 54:242-248. 10. Worth PF, Giunti P, Gardner-Thorpe C, Dixon PH, Davis MB, Wood NW. Auto- 24. Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-1 and caspase-3 ex- somal dominant cerebellar ataxia type III: linkage in a large British family to a pression and delays mortality in a transgenic mouse model of Huntington dis- 7.6cM region on chromosome 15q14-21.3. Am J Hum Genet. 1999;65:420- ease. Nat Med. 2000;6:797-801. 426. 25. Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig 11. Herman-Bert A, Stevanin G, Netter J-C, et al. Mapping of spinocerebellar ataxia A. Effect of idebenone on cardiomyopathy in Friedreich’s ataxia: a preliminary 13 to chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebel- study. Lancet. 1999;354:477-479. lar ataxia and mental retardation. Am J Hum Genet. 2000;67:229-235. 26. Botez MI, Botez-Marquard T, Mayer P, Marchand L, Lalonde R, Reader TA. The 12. Yamashita I, Sasaki H, Yabe I, et al. A novel locus for dominant cerebellar ataxia treatment of spinocerebellar ataxias: facts and hypotheses. Med Hypotheses. 1998; (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chro- 51:381-384. mosome 19q13.4-qter. Ann Neurol. 2000;48:156-163. 27. Trouillas P, Takayanagi T, Hallett M, et al, for the Ataxia Neuropharmacology Com- 13. Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is mittee of the World Federation of Neurology. International Cooperative Ataxia associated with point mutations in the human potassium channel gene, KCNA1. Rating Scale for pharmacological assessment of the cerebellar syndrome. J Neu- Nat Genet. 1994;8:136-140. rol Sci. 1997;145:205-211.

(REPRINTED) ARCH NEUROL / VOL 58, FEB 2001 WWW.ARCHNEUROL.COM 195