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Genetic Testing in Spinocerebellar Ataxias
Defining a Clinical Role
Eng-King Tan, MD;
Tetsuo Ashizawa, MD
Arch Neurol. 2001;58:191-195.
ABSTRACT
Although 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 of 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.
GENETIC CLASSIFICATION
Spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases
characterized by cerebellar dysfunction alone or in combination with other
neurological abnormalities. Spinocerebellar ataxias have become a focus of
human genetics research since expansions of coded CAG trinucleotide repeats
were shown to cause several dominantly inherited SCAs (SCAs 1, 2, 3, 6, and
7) and dentatorubral pallidoluysian atrophy (DRPLA).1, 2, 3
Another dominant ataxia with an expanded CAG repeat in the TATA box binding protein (TBP) gene has been
added recently to this group of disorders.4
In these disorders, the CAG triple repeat expansion gives rise to an elongated
polyglutamine tract in the respective proteins, leading to a gain in function
that is toxic to neurons. However, untranslated repeat expansions also cause
dominantly inherited ataxic disorders. Spinocerebellar ataxia type 12 shows
an expanded CAG repeat in the 5' untranslated region of PPP2R2B, a gene coding for a brain-specific regulatory subunit of the
protein phosphatase PP2A.5 Spinocerebellar
ataxia type 8 is associated with an expansion of a CTG repeat in the 3'
untranslated region of the SCA8 gene that produces
antisense messenger RNA to the KLHL1 gene on the
complementary strand.6 In SCA10, the disease-causing
expansion occurs in the ATTCT pentanucleotide repeat of intron 9 of SCA10, a gene of unknown function widely expressed in the
brain.7 Five additional SCA loci have been
mapped: SCA4 to 16q24-qter,8 SCA5 to 11q13,9 SCA11 to 15q1-q21.3,10
SCA13 to 19q13.3-q13.4,11 and SCA14 to 19q13.4-qter.12 Episodic ataxia types 1 and 2 are also dominantly
inherited cerebellar ataxias; they are caused by point mutations within a
voltage-gated potassium channel gene (KCNA1) and
the cerebral P/Q-type calcium channel  1 subunit gene (CACNL1A4), respectively.13, 14
The most common recessively inherited ataxia is Friedreich ataxia (FRDA),
which is caused by an expansion of the GAA repeat in intron 1 of the FRDA gene.15 Other recessive
ataxias include vitamin E deficiency (due to - to copherol transfer
protein deficiency or abetalipoproteinemia), ataxia telangiectasia, infantile-onset
spinocerebellar ataxia (IOSCA), Marinesco-Sjögren syndrome, spastic ataxia
of Charlevoix-Saguenay, Refsum disease, carbohydrate-deficiency ataxia, and
Cayman Island ataxia, among others3 (also see
the Washington University ataxia classification16).
Wilson disease may mimic features of SCAs. Genetic testing is a powerful way
of confirming the diagnosis and distinguishing various SCA subtypes, although
there have been previous attempts to classify them according to their clinical
presentations.17
TYPES OF GENETIC TESTS
Although genetic testing for known SCA genes are increasingly available,
their exact clinical role has received much less attention. Currently available
commercial DNA tests can define the genotypes of up to two thirds of patients
with dominantly inherited SCAs10 (Table 1; see also Web site
http://www.genetests.org,18 which catalogs genetic testing).
As the list of these DNA tests grows, the variable and overlapping phenotypic
manifestations of the SCA subtypes make it difficult to choose which specific
SCA DNA test to order initially. Although a positive DNA test result provides
the unequivocal diagnosis at a cost comparable to magnetic resonance imaging
studies, a negative test result has little diagnostic value other than exclusion
of certain diseases. It might not be cost-effective to order blanket genetic
tests for all patients with SCA, especially with the availability of an increasing
number of DNA tests for ataxic disorders (a single SCA diagnostic test costs
approximately $300). Some laboratories offer less expensive rates when many
SCA DNA tests are done at the same time, and such a battery might be useful
in cases in which there are few clues for prioritization of the SCA DNA testing.
At present, DNA testing that can directly detect mutations is commercially
available for SCAs 1, 2, 3, 6, 7, and 8; FRDA; and DRPLA and may become available
for SCAs 10 and 12 and the ataxia with the TBP CAG expansion in the near future.
DNA testing for point mutations may also be available on a research basis
for ataxia telangiectasia, ataxia of vitamin E deficiency, mitochondrial disorders,
Wilson disease, Refsum disease, and episodic ataxia types 1 and 2. However,
screening of point mutations in these diseases are generally not cost-effective
because each family can carry a different mutation, and their diagnoses should
be based on clinical and other laboratory findings at present (Figure 1). New technologies, such as DNA microchip arrays,19 may make DNA testing for these diseases commercially
feasible in the near future.
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Inherited Spinocerebellar Ataxias (SCAs) for Which Commercial DNA Testing
Is Available*
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Clinical algorithm for genetic testing for spinocerebellar ataxia
(SCA). If the family history suggests an autosomal recessive or uncertain
inheritance pattern, consider recessive diseases that can be tested. If test
results for these diseases are negative, consider other recessive diseases
by clinical phenotype and, if feasible, examine linkage for known recessive
ataxia loci, which may lead to a specific diagnosis. Then, the patient can
undergo DNA testing for the dominant ataxias after assessing the possibility
of dominant inheritance with incomplete family history, reduced penetrance,
and de novo mutation. In patients with no family history it is important to
exclude various secondary causes because specific treatment may be available.
When these are excluded, consider the recessive diseases, such as Friedreich
ataxia (FDRA), and then the certain autosomal dominant SCAs if the clinical
suspicion is strong. Prioritize the tests for dominant ataxias based on the
ethnic origin and the clinical phenotype. At present, there are no direct
DNA tests for detection of the mutations for SCAs 4, 5, 11, 13, and 14. AVED
indicates ataxia of vitamin E deficiency; AT, ataxia telangiectasia; and DRPLA,
dentatorubral pallidoluysian atrophy.
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CHOICE OF GENETIC TEST
In general, these tests should be done in SCAs that demonstrate a clear
mode of inheritance (Figure 1).
For those without family history, secondary causes, especially treatable ones,
should be excluded first. However, testing in apparent "sporadic" cases might
be worthwhile if the family history is unreliable or ambiguous because about
5% of sporadic cases have been found to be autosomal dominant.20
A positive family history may not always be available for patients with SCA6
and recessive ataxias such as FRDA. A de novo mutation, ie, an expansion of
an intermediate allele into a full mutant allele, may cause the disease with
clearly negative family history. Early parental deaths, nonpaternity, and
adoption should also be taken into consideration. By the same reasons, dominant
ataxias may mimic recessive inheritance. Although it is not easy to prioritize
the screening order of SCA subtypes on clinical grounds alone, the ethnic
origin and the presence of certain suggestive clinical signs may provide some
guidance.1, 2, 3 Machado-Joseph
disease (MJD) was originally described in 1972 in 2 families of Azorean descent.1, 2, 3 However, the CAG repeat
expansion that causes MJD/SCA3, has been found in different ethnic populations
with SCA3 around the world. Spinocerebellar ataxia type 3 seems to be most
common in countries such as the United States, China, and Germany; SCAs 1
and 2 in the United Kingdom and Italy; SCA2 in India and Cuba; and SCAs 3
and 6 in Japan. Spinocerebellar ataxia type 10 has been seen only in Mexicans.7 Dentatorubral pallidoluysian atrophy is rare outside
Japan. Spinocerebellar ataxia types 12, 13, and 14 have been reported in German
American, French, and Japanese families, respectively.10, 11, 12
Friedreich ataxia has never been reported in northeast Asia. Presence of a
founder effect could possibly create different prevalences within the same
ethnic population. For instance, this might in part explain why SCA1 is more
common in northern Italy and SCA2 is more frequent in southern parts of the
country.
In addition to the wide phenotypic overlap among the SCAs, significant
interfamilial and intrafamilial phenotypic variability exists even for each
SCA subtype. However, it is worthwhile noting characteristic features of some
SCAs.1, 2, 3 Markedly
reduced velocity of saccadic eye movements, areflexia, and changes similar
to those seen in olivopontocerebellar atrophy on magnetic resonance images
of the brain suggest SCA2. Spinocerebellar ataxia type 7 is characterized
by macular degeneration. Combinations of protruded eyes, muscle fasciculations,
spasticity, chorea, gaze-evoked nystagmus, parkinsonism, and peripheral neuropathy
favor MJD/SCA3, but SCA1 and SCA12 also share some of these features. Spinocerebellar
ataxia types 5, 6, 10, and 11 should be considered in patients with relatively
pure cerebellar signs. Patients with SCA13 characteristically show slowly
progressive cerebellar ataxia of early childhood onset, with mild mental retardation
and motor developmental delay. There are some overlapping clinical features
between SCA6 and episodic ataxia type 2 and familial hemiplegic migraine.1, 2, 3, 14 This
is not surprising because the CAG expansion in SCA6 is located in the alpha-1A
voltage-dependent calcium channel gene, and episodic ataxia type 2 is caused
by a point mutation in the same gene. If there is a history of seizures with
ataxia, DRPLA and SCA10 need to be considered; in the latter, seizures are
accompanied by relatively pure cerebellar ataxia. Spinocerebellar ataxia type
3 and DRPLA need to be considered in patients with suspected Huntington disease
(HD) whose HD DNA test results were normal because of some shared features.
Some patients with SCA3 may show a pure parkinsonian phenotype. Most families
with SCAs that are caused by polyglutamine-coding CAG expansions show anticipation,
ie, earlier disease onset with increasingly severe disease phenotype in succeeding
generations.1, 2, 3
Spinocerebellar ataxia types 5, 10, and probably 14 also show anticipation,7, 9, 12 whereas SCAs 8, 12,
and 13 do not.4, 5, 10
Our experience suggests that the predictive value of some of these characteristic
clinical features may increase when applied to a particular ethnic population
in which the most common SCA subtypes are known. Further studies may make
it possible to compute the probabilities of SCA subtypes based on these factors
for each patient.
LIMITATIONS
Cautious interpretation of an SCA test result and understanding of its
implication are vital in genetic counseling and patient care. Anticipation
observed in most SCAs accompanies progressive increases of expanded CAG repeats
in successive generations, often depending on paternal transmission. Patients
with larger CAG repeats generally show earlier ages of onset, with greater
disease severity than those with relatively smaller repeats. A similar mechanism
involving the ATTCT repeat seems to explain anticipation in SCA10 families.
However, because the repeat size accounts for only up to 60% of the variability
of age of onset, we cannot predict the exact age of onset for a given size
of a disease allele of any SCA subtype.1, 2, 3
Although individuals undergoing predictive testing frequently ask for prediction
of age of onset and prognosis, further research regarding other genetic and
environmental determinants are required before we can answer this question.
There seems to be a critical size of repeat for most of the SCAs above which
the disease would manifest. However, this is not absolute in some SCAs in
which disease and normal allele sizes overlap in an intermediate range. Alleles
in the intermediate range show reduced penetrance in SCA2. In SCA7, the intermediate
alleles do not cause disease but can give rise to de novo expansion to the
disease-causing allele in subsequent generations (Table 1). Further studies are needed in SCA8 to address the observation
that fully expanded alleles show reduced penetrance in affected families and
are also found in controls and other patients without SCA.3, 6
Defining the risk of developing the disease in such instances is a difficult
task. Effects of parental origin on repeat size instability may become an
important subject in genetic counseling because paternal transmission of many
SCAs (eg, SCAs 1, 2, and 3) may result in a severe, rapidly progressive phenotype
at a young age. In SCA7, this phenomenon may be the most prominent in which
increased embryonic lethality in paternal transmission has been postulated.21
NONMEDICAL ISSUES
Despite the great advances in molecular genetics of SCAs, the phenotypic
and genetic variability, the mostly adult-onset symptoms, and the absence
of effective treatment make formulation of specific guidelines in genetic
counseling of SCA a daunting task. Although at present there are no proposed
guidelines for SCA testing, we must address the numerous ethical, social,
legal, and psychological issues similar to those raised previously for HD
(another trinucleotide repeat disorder with no effective treatment), including
confirmatory testing, prenatal diagnosis, predictive testing and asymptomatic
testing for children, confidentiality, insurability, finances, employment,
disability, and marriage.22 With increasing
availability of DNA testing for a growing number of SCAs, physicians will
be confronted with many of these problems. Geneticists and experienced genetic
counselors should shoulder this burden. However, physicians at tertiary and
primary levels should also participate and, in some cases, may need to play
a major role in this task. Testing in at-risk asymptomatic children has been
generally discouraged. Prenatal testing of SCAs has been available, but few
parents seem to be electing it. Issues such as termination of pregnancy in
the event of a detectable mutation in the fetus and follow-up care for psychological
problems require careful management by a team of physicians, genetic counselors,
psychologists, and social workers. Great effort should be accorded to predictive
testing, which usually creates the most distress in those tested. A study
conducted by Nance and colleagues23 before
the discovery of the SCA1 gene revealed that about
two thirds of 117 patients, spouses, and at-risk individuals of 2 SCA1 kindreds
wanted predictive testing immediately and 42% thought prenatal testing should
be made available. Members of one kindred demonstrated a significantly higher
level of anticipated adverse psychological responses such as depression, anger,
and suicidal thoughts. Cooperative efforts to establish guidelines for this
issue are needed. Experiences in HD are invaluable in this process; however,
keep in mind that there are important differences between each SCA subtype
and HD, especially in their psychological and social needs.
FUTURE CHALLENGES
Increasing understanding of the pathogenic mechanisms in SCAs caused
by polyglutamine expansions and FRDA may lead to exploitation of new effective
therapeutic drugs in the near future.24, 25
Today, experimental neuroprotective drugs (such as N-methyl-D-aspartate
antagonists) are already available for trials.26
Developing a reliable ataxia rating scale to monitor disease progression and
treatment response has been initiated.27 The
future availability of therapeutic interventions would drastically change
the indications of DNA testing and its psychological and social impacts. Analyses
of cost-effectiveness of DNA testing and its potential social implications
are also important. Cloning of genes of SCAs 4, 5, 11, 13, and 14 and other
unclassified hereditary SCAs, further understanding of genotypic-phenotypic
correlations, and studies of susceptibility loci and disease-modifying genes
would be translated into more comprehensive genetic testing programs.
AUTHOR INFORMATION
Accepted for publication September 26, 2000.
From the Departments of Neurology, Baylor College of Medicine (Drs
Tan and Ashizawa), and the Veterans Affairs Medical Center (Dr Ashizawa),
Houston, Tex.
Corresponding author and reprints: Tetsuo Ashizawa, MD, Department
of Neurology, Baylor College of Medicine, 6550 Fannin Dr, Smith 1801, Houston,
TX 77030 (e-mail: tetsuoa{at}bcm.tmc.edu).
REFERENCES
| |
1. Ashizawa T, Zoghbi HY. Diseases with trinucleotide repeat expansions. In: Appel S, ed. Current Neurology. Amsterdam,
the Netherlands: IOS Press; 1997:79-135.
2. Wells RD, Warren ST. Genetic Instabilities and Hereditary Neurological
Diseases. Orlando, Fla: Academic Press Inc; 1998.
3. Evidente VG, Gwinn-Hardy KA, Caviness JN, Gilman S. Hereditary ataxias. Mayo Clin Proc. 2000;75:475-490.
ISI
| PUBMED
4. Nakamura K, Jeong S-Y, Ichikawa Y. SCA13, a novel autosomal dominant cerebellar ataxia caused by the expanded
polyglutamine in TATA-binding protein identified with 1C2 antibody immunoscreening
[abstract]. Am J Hum Genet. 2000;67:389.
5. Holmes SE, O'Hearn EE, McInnis MG, et al. Expansion of a novel CAG trinucleotide repeat in the 5' region
of PPP2R2B is associated with SCA12. Nat Genet. 1999;23:391-392.
FULL TEXT
|
ISI
| PUBMED
6. Koob MD, Moseley ML, Schut LJ, et al. An untranslated CTG repeat expansion causes a novel form of spinocerebellar
ataxia (SCA8). Nat Genet. 1999;21:379-384.
FULL TEXT
|
ISI
| PUBMED
7. Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of ATTCT pentanucleotide repeat in spinocerebellar
ataxia type 10. Nat Genet. 2000;26:191-194.
FULL TEXT
|
ISI
| PUBMED
8. Flanigan K, Gardner K, Alderson K, et al. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy
(SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet. 1996;59:392-399.
ISI
| PUBMED
9. Ranum LP, Schut LJ, Lundgren JK, Orr HT, Livingston DM. Spinocerebellar ataxia type 5 in a family descended from the grandparents
of President Lincoln maps to chromosome 11. Nat Genet. 1994;8:280-284.
FULL TEXT
|
ISI
| PUBMED
10. Worth PF, Giunti P, Gardner-Thorpe C, Dixon PH, Davis MB, Wood NW. Autosomal dominant cerebellar ataxia type III: linkage in a large British
family to a 7.6cM region on chromosome 15q14-21.3. Am J Hum Genet. 1999;65:420-426.
FULL TEXT
|
ISI
| PUBMED
11. Herman-Bert A, Stevanin G, Netter J-C, et al. Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 in
a family with autosomal dominant cerebellar ataxia and mental retardation. Am J Hum Genet. 2000;67:229-235.
FULL TEXT
|
ISI
| PUBMED
12. Yamashita I, Sasaki H, Yabe I, et al. A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM
interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter. Ann Neurol. 2000;48:156-163.
FULL TEXT
|
ISI
| PUBMED
13. Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is associated with point mutations
in the human potassium channel gene, KCNA1. Nat Genet. 1994;8:136-140.
FULL TEXT
|
ISI
| PUBMED
14. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused
by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996;87:543-552.
FULL TEXT
|
ISI
| PUBMED
15. Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic
GAA triplet repeat expansion. Science. 1996;271:1423-1427.
ABSTRACT
16. Washington University ataxia classification. Available at: http://www.neuro.wustl.edu/neuromuscular/ataxia/aindex.html. Accessed November 16, 2000.
17. Harding AE. Clinical features and classification of inherited ataxias. Adv Neurol. 1993;61:1-14.
PUBMED
18. GeneTests. Available at: http://www.genetests.org. Accessed November
16, 2000.
19. Harrington CA, Rosenow C, Retief J. Monitoring gene expression using microarrays. Curr Opin Microbiol. 2000;3:285-291.
FULL TEXT
|
ISI
| PUBMED
20. Moseley ML, Benzow KA, Schut LJ, et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats
among 361 ataxia families. Neurology. 1998;51:1666-1667.
FREE FULL TEXT
21. Monckton DG, Cayuela ML, Gould FK, Brock GJ, Silva R, Ashizawa T. Very large (CAG)(n) DNA repeat expansions in the sperm of two spinocerebellar
ataxia type 7 males. Hum Mol Genet. 1999;8:2473-2478.
FREE FULL TEXT
22. International Huntington Association (IHA) and the World Federation
of Neurology (WFN) Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's
disease. Neurology. 1994;44:1533-1536.
FREE FULL TEXT
23. Nance MA, Sevenich EA, Schut LJ. Knowledge of genetics and attitudes toward genetic testing in two hereditary
ataxia (SCA1) kindreds. Am J Med Genet. 1994;54:242-248.
FULL TEXT
|
ISI
| PUBMED
24. Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays
mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000;6:797-801.
FULL TEXT
|
ISI
| PUBMED
25. Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A. Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary
study. Lancet. 1999;354:477-479.
FULL TEXT
|
ISI
| PUBMED
26. Botez MI, Botez-Marquard T, Mayer P, Marchand L, Lalonde R, Reader TA. The treatment of spinocerebellar ataxias: facts and hypotheses. Med Hypotheses. 1998;51:381-384.
FULL TEXT
|
ISI
| PUBMED
27. Trouillas P, Takayanagi T, Hallett M, et al for the Ataxia Neuropharmacology Committee of the World Federation
of Neurology. International Cooperative Ataxia Rating Scale for pharmacological assessment
of the cerebellar syndrome. J Neurol Sci. 1997;145:205-211.
FULL TEXT
|
ISI
| PUBMED
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