Spinocerebellar ataxias (SCAs) are a group of more than 20 genetically based neurodegenerative diseases characterized by progressive cerebellar dysfunction.1 Because of their relative low prevalence, identifying mutations in two different SCA genes in the same family is exceedingly rare.2, 3 Here, we describe a patient who carries a mutation in both the spinocerebellar ataxia type 3 (SCA3) and spinocerebellar ataxia type 8 (SCA8) alleles, and we discuss the impact of these findings on patient management and genetic counseling.
The patient is a 31-year-old Caucasian man who presented at an age of 29 with the chief complaint of balance problems. The patient's father died at an age of 47 with a progressive neurodegenerative condition that was suspected at the time to have been Machado–Joseph disease (now known as SCA3) based purely on the clinical presentation. No other family member was known to have had a neurodegenerative syndrome. Neurological examination of our patient revealed mild limb ataxia with mild decrease in rapid alternating movements and slight clumsiness on finger-nose testing. Cranial nerve examination showed only slow saccades and slight horizontal gaze-evoked nystagmus. Routine blood tests and brain imaging were normal. Because of the patient's positive family history, a complete ataxia genetic evaluation was obtained. Results showed that the patient carried a single SCA3 repeat expansion in the full mutation range (abnormal allele 74 repeats, normal allele 28 repeats; normal values ≤40). In addition, an expansion of the repeat associated with SCA8 (CTA/CTG) was detected (abnormal allele 1010 repeats, normal allele 25 repeats; normal values ≤50). Because of these results, genetic tests were performed on the patient's asymptomatic mother, who tested positive for the SCA8 mutation (abnormal allele 508 repeats, normal allele 26 repeats), but not for the SCA3 expansion. During the two years of clinical follow-up, the patient's ataxic symptoms have not progressed and neurological examination has remained unchanged.
SCA3, the most common form of SCA, is a high-penetrance disease caused by the expansion of a CAG trinucleotide repeat.1, 4 In contrast, SCA8 is a rare low-penetrance CTA/CTG repeat disorder.5, 6 The exact pathogenic size range of the SCA8 expansion is still under debate. Most SCA8 patients carry 110 to 250 repeats, while expansions that are somewhat smaller (71–110) or larger (250–800) are suggestive of having reduced penetrance.5–7 A few patients carrying larger expansion tracts have been described, but large expansions are also observed in healthy controls.8 There is marked variability in disease severity and penetrance even within the same family, and the CTA/CTG expansion is highly unstable between generations.5–7 Since the consequences of carrying an SCA8 mutation are not completely clear, some authors have even questioned the validity of including SCA8 in the commercially available panels that are widely used for the genetic diagnosis of ataxia.8 If a result comes back positive for a mutation with uncertain clinical manifestations, physicians and genetic counselors are faced with the difficulty of explaining these complicated and indeterminate results to patients. In addition, these panels can include tests that are not even desired, and the health care provider must decide if and how to relay these results.
The implications of finding an SCA8 mutation become even more complex when patients also have a mutation in another ataxia gene. For instance, in our patient, the first issue of clinical and prognostic relevance is determining which SCA mutation is responsible for the major aspects of his ataxic phenotype. Several lines of evidence support SCA3 as the most likely pathogenic factor of ataxia in this case. First, the patient carries an SCA3 repeat expansion in the full mutation range.1 Second, the patient's SCA3 mutation is assumed to be inherited from the patient's symptomatic father, while his SCA8 expansion is inherited from his asymptomatic mother. Third, the patient's SCA8 mutation is very long and consequently characterized by low penetrance.7
Another important issue in the management of our patient concerns genetic counseling for relatives and offspring. The proband's siblings and offspring were each at risk for either SCA3 alone, SCA8 alone, inheritance of both SCA3 and SCA8, or neither. While the inheritance risks of SCA3 repeat expansions are well established, reliable information regarding the length of the SCA8 repeat and the occurrence of disease is lacking. The implications for future generations are even more difficult to assess due to the tendency of SCA8 mutations to contract when transmitted paternally and expand when transmitted maternally.7 Specific to this case, transmission of the SCA8 mutation from our patient to his children might generate shorter alleles which fall within the range that constitutes a higher degree of penetrance, thus potentially causing the expression of clinical features. Further, the presence of an SCA8 repeat with an additional SCA repeat complicates counseling for the phenotype of the affected individual because of the current uncertainty about the interplay between multiple ataxia gene expansions, which might affect the individual's prognosis.
Health care providers should be aware that the increasing use of genetic testing panels for the molecular diagnosis of hereditary forms of ataxias has the potential to uncover more than one mutation in the same patient. The implications of such results may be uncertain, but should be explained to patients and family members. Alternatively, physicians and patients may opt to initially request focused screening for specific SCA mutations based on the patient's phenotype and family history.