Subramony et al. (1996) described a family segregating late-onset progressive cerebellar ataxia with onset of gait difficulties at age 50. There was no pontine atrophy at autopsy nor was there evidence of hypogonadism. The segregation appeared to be ... Subramony et al. (1996) described a family segregating late-onset progressive cerebellar ataxia with onset of gait difficulties at age 50. There was no pontine atrophy at autopsy nor was there evidence of hypogonadism. The segregation appeared to be autosomal dominant with multiple instances of male-to-male transmission. Direct DNA analysis excluded expansions at the SCA1 (164400), Machado-Joseph (607047), and DRPLA (125370) loci. Zhuchenko et al. (1997) reported 8 unrelated families who showed a very similar clinical picture consisting predominantly of mild but slowly progressive cerebellar ataxia of the limbs and gait, dysarthria, nystagmus, and mild vibratory and proprioceptive sensory loss. The disease is insidious and most patients do not realize they are affected initially but do describe a sense of momentary imbalance and 'wooziness' when they make a quick turn or a rapid movement. Typically, it is years after this initial sensation when the patients realize they have developed balance and coordination difficulties. The disease usually progresses over 20 to 30 years, leading to impairment of gait and causing the patient to become wheelchair-bound. In a few older patients, choking has been observed, suggesting involvement of the brainstem. The disease was the cause of death in several members of 2 kindreds. Magnetic resonance imaging (MRI) of the brain in affected individuals demonstrated isolated cerebellar atrophy. By genotype survey, Zhuchenko et al. (1997) found a CAG repeat expansion in the CACNA1A gene (see MOLECULAR GENETICS). The clinical and genetic features of 38 genetically confirmed cases of SCA6 from 8 families were described by Ishikawa et al. (1997). Gait ataxia was invariably the initial symptom and was the chief symptom throughout the clinical course. Other symptoms were cerebellar speech, limb ataxia, decreased muscle tonus, and horizontal gaze nystagmus. Tendon reflexes were normal or slightly increased. Extracerebellar symptoms, such as pyramidal or extrapyramidal tract signs, ophthalmoparesis, or decreased sensation, were not seen. None of the patients complained of migraine. Magnetic resonance imaging demonstrated atrophy restricted to the cerebellum. The age at onset ranged from 20 to 66 years, and the average age at onset was 45 years. Gomez et al. (1997) described clinical, genetic, neuroimaging, neuropathologic, and quantitative oculomotor studies in 4 kindreds with genotypically confirmed SCA6. The age of onset of ataxia ranged from 24 to 63 years among affected individuals. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of oculomotor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibuloocular reflex. In 2 of the kindreds, they found strong linkage to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles, which were a single size in the 2 kindreds (22 and 23 units). These studies identified a distinct phenotype associated with SCA6, just as SCA7 (164500) is associated with retinopathy and blindness, and SCA2 (183090) is associated with pronounced slowing or loss of saccadic eye movements. One of the families in which the expanded CAG repeat was identified was the family previously reported by Zee et al. (1976). Schols et al. (1998) studied 9 German families with spinocerebellar ataxia-6 and found that the phenotype comprised predominantly cerebellar signs in accord with isolated cerebellar atrophy on MRI. Noncerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Disease onset ranged from 30 to 71 years of age and was significantly later than in other forms of autosomal dominant cerebellar ataxia. Although age at onset correlated inversely with CAG repeat length, other clinical signs and progression rate did not. By comparison with SCA1, SCA2, and SCA3, no clinical or electrophysiologic findings were specific for SCA6. Moreover, the molecular defect could not be predicted from clinical investigations. Fukutake et al. (2002) described a 55-year-old man, the offspring of first-cousin parents, who presented not only with cerebellar ataxia and vertical antidirectional nystagmus but also with retinitis pigmentosa. The numbers of CAG repeats in the expanded alleles of the SCA6 gene were 21 on each chromosome. The retinal degeneration was thought to be secondary to a genetic disorder of either autosomal or X-linked recessive inheritance rather than SCA6. The association of retinitis pigmentosa with spinocerebellar ataxia is most characteristic of SCA7 (164500). Both parents had staggering gait and slurred speech late in life, but were not available for study. In 7 SCA6 patients, van de Warrenburg et al. (2004) found no significant electrophysiologic evidence of peripheral nerve involvement. - Pathologic Findings Tsuchiya et al. (1998) described a Japanese family with 2 affected sisters and an affected father. The proband developed gait disturbance at age 62 years and died at age 67 years due to subarachnoid hemorrhage. Neuropathologic examination showed severe loss of Purkinje cells in the cerebellum, predominantly in the dorsal vermis, and absence of neuronal loss in the inferior olives. The younger sister developed gait disturbance also at age 62 years. Neuroimaging at the age of 66 years showed cerebellar atrophy, predominantly in the vermis. Tsuchiya et al. (1998) performed a neuropathologic review of Japanese autopsy cases of autosomal dominant cortical cerebellar atrophy and found 2 patterns in the distribution of cerebellar cortical lesions. The distribution of cerebellar cortical lesions in genetically confirmed Japanese patients with SCA6 was more prominent in the vermis than in the hemisphere. Takahashi et al. (1998) described a family with dominantly inherited ataxia of late adult onset with affected individuals in 4 generations. Expansion of a CAG repeat in the CACNA1A gene was identified at autopsy in 1 patient, a 65-year-old woman with a disease duration of 11 years. In this patient, pathologic changes were confined to the cerebellar cortex and inferior olivary complex. The cerebellar cortex showed severe loss of Purkinje cells with proliferation of Bergmann glia, more pronounced in the superior parts of the vermis and hemispheres. In the inferior olivary complex, a reduced neuronal cell population, which could be interpreted as a change secondary to the cerebellar cortical lesion, was evident. They concluded that the pathologic phenotype of SCA6 is cerebelloolivary atrophy, or more strictly cerebellar cortical atrophy.
Schols et al. (1997) compared clinical, electrophysiologic, and MRI findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor suggested SCA2. SCA3 (109150) patients frequently developed diplopia, severe spasticity or pronounced ... Schols et al. (1997) compared clinical, electrophysiologic, and MRI findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor suggested SCA2. SCA3 (109150) patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome, and patients often had onset after 55 years of age. SCA1 (164400) was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. Overlap among the 4 SCA subtypes was broad, however. In an investigation of oculomotor function, Buttner et al. (1998) found that all 3 patients with SCA1, all 7 patients with SCA3, and all 5 patients with SCA6 had gaze-evoked nystagmus. Three of 5 patients with SCA2 did not have gaze-evoked nystagmus, perhaps because they could not generate corrective fast components. Rebound nystagmus occurred in all SCA3 patients, 33% of SCA1 patients, 40% of SCA6 patients, and none of SCA2. Spontaneous downbeat nystagmus only occurred in SCA6. Peak saccade velocity was decreased in 100% of patients with SCA2, 1 patient with SCA1, and no patients with SCA3 or SCA6. Saccade hypermetria was found in all types, but was most common in SCA3. Using an analysis of covariance and multivariate models to examine symptom severity in 526 patients with SCA1, SCA2, SCA3, or SCA6, Schmitz-Hubsch et al. (2008) found that repeat length of the expanded allele, age at onset, and disease duration explained 60.4% of the ataxia score in SCA1, 45.4% in SCA2, 46.8% in SCA3. However, only age at onset and disease duration appeared to explain 33.7% of the score in SCA6. Similar findings were obtained for nonataxic symptoms. The study suggested that SCA1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.
Zhuchenko et al. (1997) performed a genotyping survey using polymorphic CAG repeats and DNA samples from patients with late-onset neurogenic diseases. In the course of these studies they found an expansion of a CAG repeat in the human ... Zhuchenko et al. (1997) performed a genotyping survey using polymorphic CAG repeats and DNA samples from patients with late-onset neurogenic diseases. In the course of these studies they found an expansion of a CAG repeat in the human alpha-1A-voltage-dependent Ca(2+) channel gene (601011.0007), which maps to 19p13. They identified 6 isoforms of the human alpha-1A calcium channel subunit. The CAG repeat was within the open reading frame and was predicted to encode glutamine in 3 of the isoforms. In 8 families, the CAG repeat expansion of the Ca(2+) channel gene was the mutation mechanism for SCA6. One of the families had been reported by Subramony et al. (1996). Analysis of CAG repeat expansion in the CACNL1A4 gene by Ishikawa et al. (1997) revealed expansion in 8 of 15 Japanese families with autosomal dominant cerebellar ataxia; all affected individuals had larger alleles (range of CAG repeats 21 to 25), compared with alleles observed in neurologically normal Japanese (range 5 to 20 repeats). Takiyama et al. (1998) studied a Japanese family that included 13 persons with SCA6 in 5 generations. Molecular testing revealed that the patients carried the smallest known expanded CAG repeat (21 repeat units). The clinical features of these patients included predominantly cerebellar ataxia with onset late in adult life and a very slowly progressive course. In addition, this SCA6 family showed some characteristic clinical and genetic features, including (1) apparent lack of genetic anticipation, with an intergenerationally stable CAG repeat size, and (2) down-beat nystagmus and diabetes mellitus in some of the SCA6 patients. They identified 3 individuals homozygous for an expanded CAG repeat (21/21) in the CACNL1A4 gene; 2 were symptomatic and 1 was asymptomatic at age 50 years. There was no apparent difference in clinical phenotype between the homozygotes and the heterozygotes. Fukutake et al. (2002) stated that 11 patients with genetically verified SCA6 who were homozygous or compound heterozygous for (CAG)n repeats in the CACNA1A gene (601011.0007) had previously been reported. In a family in which multiple members had severe progressive cerebellar ataxia involving the trunk, extremities, and speech, Yue et al. (1997) identified a 1152G-A transition in exon 6 of the CACNA1A gene, resulting in a gly293-to-arg substitution (G293R; 601011.0009). The CAG(n) repeat expansion associated with SCA6 was not present in any family member. In a large Portuguese family in which 17 patients over 4 generations were affected with hemiplegic migraine and/or progressive SCA6, Alonso et al. (2003) found that all patients shared a common haplotype and carried an arg583-to-gln mutation in the CACNA1A gene (R583Q; 601011.0018). - Genetic Anticipation In his studies of families with SCA6, Zhuchenko et al. (1997) noted that there seemed to be a correlation between the repeat number and earlier onset of the disorder. Matsuyama et al. (1997) analyzed 60 SCA6 individuals from 39 independent Japanese SCA6 families and found that the CAG repeat length in the CACNL1A4 gene was inversely correlated with age of onset. SCA6 chromosomes contained 21 to 30 repeat units, whereas normal chromosomes displayed 6 to 17 repeats. There was no overlap between the normal and affected CAG repeat number. Anticipation was observed clinically in all 8 parent-child pairs examined; the mean age of onset was significantly lower (P = 0.0042) in children than in parents. However, a parent-child analysis showed an increase in the expansion of CAG repeats only in 1 pair and no diminution in any affected cases. The results suggested that factors other than CAG repeats may produce the clinical anticipation. A homozygotic case could not demonstrate unequivocal gene dosage effect on the age of onset. In the 8 families with SCA6 reported by Ishikawa et al. (1997), inverse correlation between the CAG-repeat number and the age of onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proven in these SCA6 families. Riess et al. (1997) observed the trinucleotide expansion in 4 ataxia patients without obvious family history of the disease, indicating the necessity to search for the SCA6 (CAG)n expansion even in sporadic patients. In their series of 32 patients, onset was usually late and the (CAG)n stretch varied between 22 and 28 trinucleotide units, the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. Analyzing 248 apparently healthy octogenarians, Riess et al. (1997) found 1 allele of 18 repeats, the longest normal CAG repeat in the CACNL1A4 gene reported to that time. They could demonstrate no repeat instability of the expanded allele on transmission and no repeat instability was found for the normal allele in 431 meioses in the CEPH families. Mariotti et al. (2001) described an Italian family in which 1 member carried a fully expanded SCA6 allele with 26 CAG repeats, whereas the other affected family member was homozygous for an intermediate allele of 19 CAG repeats. Three family members, heterozygous for the intermediate allele, were clinically unaffected. The findings demonstrated a dose-dependent pathogenic effect of an intermediate CAG expansion in the SCA6 gene. Takahashi et al. (2004) retrospectively analyzed 140 patients with SCA6. They observed an inverse correlation between the age at onset and the length of the expanded allele, and also between the age at onset and the sum of CAG repeats in the normal and the expanded alleles. The ages at onset of 4 homozygous patients correlated better with the sum of CAG repeats in both alleles than with the expanded allele calculated from heterozygous SCA6 patients. Clinically, unsteadiness of gait was the main initial symptom, followed by vertigo and oscillopsia, and cerebellar signs were detected in nearly 100% of the patients. In contrast, extracerebellar signs were relatively mild and infrequent. Neuro-otologic examination performed in 22 patients suggested that the abnormalities of ocular movements were purely cerebellar in nature. There was a close relationship between down-beat positioning nystagmus and positioning vertigo, which became more common in the later stage. Takahashi et al. (2004) concluded that total number of CAG repeat units in both alleles is a good parameter for assessment of age at onset in SCA6, including in homozygous patients. In addition, clinical and neuro-otologic examination suggested that SCA6 is a disease with predominantly cerebellar dysfunction. Van de Warrenburg et al. (2005) applied statistical analysis to examine the relationship between age at onset and number of expanded triplet repeats from a Dutch-French cohort of 802 patients with SCA1 (138 patients), SCA2 (166 patients), SCA3 (342 patients), SCA6 (53 patients), and SCA7 (103 patients). The size of the expanded repeat explained 66 to 75% of the variance in age at onset for SCA1, SCA2, and SCA7, but less than 50% for SCA3 and SCA6. The relation between age at onset and CAG repeat was similar for all groups except for SCA2, suggesting that the polyglutamine repeat in the ataxin-2 protein exerts its pathologic effect in a different way. A contribution of the nonexpanded allele to age at onset was observed for only SCA1 and SCA6. Van de Warrenburg et al. (2005) acknowledged that their results were purely mathematical, but suggested that they reflected biologic variations among the diseases.
Riess et al. (1997) found that the SCA6 mutation accounts for approximately 10% of autosomal dominant SCA in Germany.
Studying 77 German families with autosomal dominant cerebellar ataxia of SCA types 1, 2, 3, and 6, ... Riess et al. (1997) found that the SCA6 mutation accounts for approximately 10% of autosomal dominant SCA in Germany. Studying 77 German families with autosomal dominant cerebellar ataxia of SCA types 1, 2, 3, and 6, Schols et al. (1997) found that the SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22%. There was no family history of ataxia in 7 of 27 SCA6 patients. Age at onset correlated inversely with repeat length in all subtypes, yet the average effect of 1 CAG unit on age of onset was different for each SCA subtype. Schols et al. (1998) investigated the SCA6 mutation (expanded repeat in the CACNA1A gene) in 69 German families with autosomal dominant cerebellar ataxia and 61 patients with idiopathic sporadic cerebellar ataxia. The expanded CAG repeat was found in 9 of 69 families, as well as in 4 patients with sporadic disease. Schols et al. (1998) noted that in Germany, SCA6 accounts for about 13% of families with autosomal dominant cerebellar ataxia. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing was therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia. In a study of apparently idiopathic sporadic cerebellar ataxia involving 124 patients, Schols et al. (2000) found the SCA6 mutation in 9 patients with disease onset between 47 and 68 years of age. Using an intragenic marker, D19S1150, and 2 markers (DS19S221 and DS19S226) bracketing 3 cM on either side, Dichgans et al. (1999) found a common haplotype in 7 of 12 German families segregating SCA6. This finding, as well as a clustering of the families from Northrhine-Westfalia, strongly suggests a founder effect. From their study of 15 families with autosomal dominant cerebellar ataxia, Ishikawa et al. (1997) concluded that more than half of Japanese cases of ADPCA map to 19p and are strongly associated with a mild CAG expansion in the SCA6/CACNL1A4 gene. Watanabe et al. (1998) investigated 101 kindreds with spinocerebellar ataxias from the central Honshu island of Japan, using a molecular diagnostic approach with amplification of the CAG trinucleotide repeat of the causative genes. Machado-Joseph disease (109150) was the most prevalent (33.7%) form, followed by dentatorubral-pallidoluysian atrophy (125370; 19.8%), SCA6 (5.9%), and SCA2 (5.9%). All 7 SCA6 patients had expanded alleles of the CACNL1A4 gene and signs of a pure cerebellar syndrome. Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of SCA6 was significantly higher in the Japanese population (11%) compared to Caucasian population (5%). This corresponded to higher frequencies of large normal CACNA1A CAG repeat alleles (greater than 13 repeats) in Japanese controls compared to Caucasian controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA. Yabe et al. (2001) studied 21 Japanese families with SCA6 and found one of 2 haplotypes in each family. They suggested a mechanism by which the second haplotype could have arisen from a single common haplotype, and that therefore there was evidence of a founder effect in SCA6 families in Japan. Storey et al. (2000) examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 in southeastern Australia. Of 63 pedigrees or individuals with positive tests, 30% had SCA1, 15% had SCA2, 22% had SCA3, 30% had SCA6, and 3% had SCA7. Ethnic origin was of importance in determining SCA type: 4 of 9 SCA2 index cases were of Italian origin, and 4 of 14 SCA3 index cases were of Chinese origin. Sinke et al. (2001) determined that SCA6 accounted for approximately 11% of all Dutch families with autosomal dominant cerebellar ataxia. Among 74 Taiwanese families with autosomal dominant cerebellar ataxia and 49 Taiwanese patients with sporadic ataxia, Soong et al. (2001) determined that SCA6 accounted for 10.8% of the familial cases and 4.1% of the sporadic cases. The prevalence of SCA3 was 47.3%, followed by SCA2 (10.8%), SCA1 (5.4%), SCA7 (2.7%), and DRPLA (1.4%). In the families with SCA6, there was significant anticipation in the absence of genetic instability. The same allele of intragenic marker D19S1150 was found in 70% of the SCA6 patients, suggesting a founder effect. Of 253 unrelated Korean patients with progressive cerebellar ataxia, Lee et al. (2003) identified 52 (20.6%) with expanded CAG repeats. The most frequent SCA type was SCA2 (33%), followed by SCA3 (29%), SCA6 (19%), SCA1 (12%), and SCA7 (8%). There were characteristic clinical features, such as hypotonia and optic atrophy for SCA1, hyporeflexia for SCA2, nystagmus, bulging eye, and dystonia for SCA3, and macular degeneration for SCA7. By haplotype analysis of 12 Dutch SCA6 families confirmed by genotype, Verbeek et al. (2004) found that 8 families (approximately 70%) shared a region between markers D19S1165 and D19S840, including the SCA6 gene, which was not observed in 80 control chromosomes. Two additional SCA6 families shared an extended haplotype. Genealogic research showed that most of the families were clustered in North Holland. The authors noted that mutation in the SCA6 gene occurs in 23.4% of the Dutch autosomal dominant cerebellar ataxia population. Similar haplotype results were found for SCA3. In a population-based study in Northeastern England, Craig et al. (2004) estimated that the number of people with or at risk for SCA6 was at least 5.21/100,000, or 1 in 19,210. Haplotype analysis suggested a founder effect, and 56% of affected individuals had an identical CAG repeat length (21 repeats). The clinical phenotype of this group was homogeneous. Shimizu et al. (2004) estimated the prevalence of SCA in the Nagano prefecture of Japan to be at least 22 per 100,000. Thirty-one of 86 families (36%) were positive for SCA disease-causing repeat expansions: SCA6 was the most common form (19%), followed by DRPLA (10%), SCA3 (3%), SCA1 (2%), and SCA2 (1%). The authors noted that the prevalence of SCA3 was lower compared to other regions in Japan, and that the number of genetically undetermined SCA families in Nagano was much higher than in other regions. Nagano is the central district of the main island of Japan, located in a mountainous area surrounded by the Japanese Alps. The restricted geography suggested that founder effects may have contributed to the high frequency of genetically undetermined ADCA families. Among 113 Japanese families from the island of Hokkaido with autosomal dominant SCA, Basri et al. (2007) found that SCA6 was the most common form of the disorder, identified in 35 (31%) families. Thirty (27%) families had SCA3, 11 (10%) had SCA1, 5 (4%) had SCA2, 5 (4%) had DRPLA, 10 (9%) had 16q22-linked SCA (117210), and 1 (1%) had SCA14 (605361). The specific disorder could not be identified in 16 (14%) families. Craig et al. (2008) identified a common core haplotype carrying the CACNA1A CAG repeat in 45 SCA6 families from different geographic regions, including Europe, Brazil, and Japan. The haplotype was also present in the unaffected father of a proven de novo Japanese patient, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies immediately downstream of a CpG island, which could act as a cis-acting element predisposing to repeat expansion, as observed for other CAG/CTG repeat diseases.
Spinocerebellar ataxia type 6 (SCA6) is suspected in individuals with adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Because the phenotypic manifestations of SCA6 are not specific, the diagnosis of SCA6 rests on molecular genetic testing. ...
DiagnosisClinical DiagnosisSpinocerebellar ataxia type 6 (SCA6) is suspected in individuals with adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Because the phenotypic manifestations of SCA6 are not specific, the diagnosis of SCA6 rests on molecular genetic testing. Molecular Genetic TestingGene. CACNA1A is the only gene in which mutation is known to cause SCA6. Allele sizes. A polymorphic CAG repeat in exon 47 of CACNA1A is unstable and is expanded in individuals with SCA6. The following are allele sizes for CACNA1A: Normal alleles. 18 or fewer CAG repeats [Shizuka et al 1998] Alleles of questionable significance. 19 CAG repeats. The clinical significance of alleles with 19 CAG repeats is unclear because alleles of this size have been documented in the following: Meiotic expansion of a 19-CAG repeat allele into the known pathologic range [Mariotti et al 2001, Shimazaki et al 2001]. In this instance, the allele is considered an "intermediate allele" or a "mutable normal allele" (i.e., it is not disease causing but predisposes to expansion into the abnormal range). Elderly asymptomatic individuals [Ishikawa et al 1997, Mariotti et al 2001] An individual with atypical features of SCA6 [Katayama et al 2000] An ataxic individual homozygous for the 19 CAG repeat allele [Mariotti et al 2001] Full penetrance alleles. 20 to 33 CAG repeats [Jodice et al 1997, Yabe et al 1998]. Asymptomatic individuals bearing an expansion of (CAG)20 or greater are expected to develop symptoms at some time in their life. The average disease-causing allele has 22 CAG repeats. Clinical testing Targeted mutation analysis. Trinucleotide repeat analysis to determine the size of the CAG trinucleotide repeat in CACNA1A detects an expansion in more than 99% of affected individuals and is nearly 100% specific. Table 1. Summary of Molecular Genetic Testing Used in SCA6View in own windowGene SymbolTest MethodMutation DetectedMutation Detection Frequency by Test Method 1 Test Availability CACNA1ATargeted mutation analysisCAG repeat expansion99%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene Testing StrategyTo confirm the diagnosis in a proband, molecular genetic testing of the CACNA1A must be performed to detect the CACNA1A CAG-repeat expansion. Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis in the family. Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior confirmation of the diagnosis in the family. Genetically Related (Allelic) DisordersSeveral other disorders are caused by mutations in the CACNA1A. Dominantly inherited ataxias may be caused by CACNA1A missense mutation, including p.Gly293Arg or p.Arg1664Gln. These disorders are similar to SCA6, but may have a more severe clinical presentation [Yue et al 1997, Tonelli et al 2006]. Episodic ataxia type 2 (EA2) is caused by CACNA1A mutations that predict protein truncation, abnormal splicing, or missense mutations. It typically starts in childhood or early adolescence and is characterized by attacks of ataxia, vertigo, and nausea that last hours to days. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache. Between attacks, individuals may initially be normal but eventually develop interictal findings that can include nystagmus and ataxia. After years of episodic ataxia, a condition of interictal ataxia indistinguishable from SCA6 may develop [Baloh et al 1997]. Inheritance is autosomal dominant. Familial hemiplegic migraine (FHM) is an autosomal dominant condition with an estimated penetrance of 80%-90% [Montagna 2000]. The two clinical forms are the following: Pure FHM (found in 80% of affected families), in which interictal examination is normal in all family members FHM with permanent cerebellar symptoms (found in 20% of affected families), in which some family members show interictal nystagmus and/or ataxia Approximately 50% of families with FHM, including all those with permanent cerebellar symptoms, have missense mutations in CACNA1A [Battistini et al 1999, Ducros et al 1999, Friend et al 1999]. FHM is characterized by an aura of hemiplegia that is always associated with at least one other aura symptom such as hemianopsia, hemisensory deficit, or aphasia. The aura is followed by a moderate to severe headache. The phenotype includes coma and seizures [Ducros et al 2001], which can be triggered by minor head injury or angiography. Delayed cerebral edema is seen primarily in children and adolescents who sustain minor head trauma, have a lucid period, and subsequently develop uncontrollable cerebral swelling [McCrory & Berkovic 1998]. Trauma-triggered delayed cerebral edema has been associated with the CACNA1A missense mutation p.Ser218Leu [Kors et al 2001]. Despite their well-described phenotypes, SCA6, EA2, and FHM demonstrate clinical overlap:Individuals with SCA6 can present with episodic ataxia. In one study, up to 33% of individualss with 21 or more CAG repeats in CACNA1A had episodic features prominent enough to warrant the diagnosis of EA2 [Geschwind et al 1997]. In one family with a CAG repeat expansion, some members had episodic ataxia and others had progressive ataxia; in all affected members the abnormal allele had 23 CAG repeats [Jodice et al 1997]. In a family with EA2, affected members also had hemiplegia, and one affected member had migraine during episodes of ataxia [Jen 1999]. In one family with a CACNA1A missense mutation, phenotypes of both SCA6 and FHM were observed [Alonso et al 2003]. Some families with a CACNA1A mutation had both SCA6 and EA2 phenotypes [Jodice et al 1997, Cricchi et al 2007].
Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The range in age of onset is from 19 to 71 years. The mean age of onset is between 43 and 52 years. Age of onset and clinical picture vary even within the same family; sibs with the same size full-penetrance allele may differ in age of onset by as much as 12 years, or exhibit, at least initially, an episodic course [Gomez et al 1997, Jodice et al 1997]. ...
Natural HistorySpinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The range in age of onset is from 19 to 71 years. The mean age of onset is between 43 and 52 years. Age of onset and clinical picture vary even within the same family; sibs with the same size full-penetrance allele may differ in age of onset by as much as 12 years, or exhibit, at least initially, an episodic course [Gomez et al 1997, Jodice et al 1997]. Initial symptoms are gait unsteadiness, stumbling, and imbalance in aapproximately 90% of individuals; the remainder present with dysarthria. Symptoms progress slowly, and eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common.Diplopia occurs in approximately 50% of individuals. Others experience visual disturbances related to difficulty fixating on moving objects, as well as horizontal gaze-evoked nystagmus (70%-100%) and vertical nystagmus (65%-83%), which is observed in fewer than 10% of those with other forms of SCA [Yabe et al 2003]. Other eye movement abnormalities, including periodic alternating nystagmus and rebound nystagmus, have also been described [Hashimoto et al 2003]. Hyperreflexia and extensor plantar responses occur in up to 40%-50% of individuals with SCA6. Basal ganglia signs, such as dystonia and blepharospasm, are noted in up to 25% of individuals. Mentation is generally preserved. Formal neuropsychological testing in one series revealed no significant cognitive deficits [Globas et al 2003]. Individuals with SCA6 do not have sensory complaints, restless legs, stiffness, migraine, primary visual disturbances, or muscle atrophy. Life span is not shortened. Pregnancy. The severity of the disease increases during pregnancy. No effect on the viability of the fetus has been reported. Neuropathology. Neuropathologic studies in individuals with SCA6 have demonstrated either selective Purkinje cell degeneration or a combined degeneration of Purkinje cells and granule cells [Gomez et al 1997, Sasaki et al 1998].
Heterozygous individuals. Although the age of onset of symptoms of SCA6 correlates inversely with the length of the expanded CAG repeat, the same broad range of onset has been noted for individuals with 22 CAG repeats, the most common disease-associated allele [Gomez et al 1997, Schols et al 1998]. In the few individuals with (CAG)30 or (CAG)33, onset has been later than in individuals with (CAG)22 and (CAG)23 [Matsuyama et al 1997, Yabe et al 1998]. A recent retrospective study showed even closer correlation of age of onset with the sum of the two allele sizes [Takahashi et al 2004]. ...
Genotype-Phenotype CorrelationsHeterozygous individuals. Although the age of onset of symptoms of SCA6 correlates inversely with the length of the expanded CAG repeat, the same broad range of onset has been noted for individuals with 22 CAG repeats, the most common disease-associated allele [Gomez et al 1997, Schols et al 1998]. In the few individuals with (CAG)30 or (CAG)33, onset has been later than in individuals with (CAG)22 and (CAG)23 [Matsuyama et al 1997, Yabe et al 1998]. A recent retrospective study showed even closer correlation of age of onset with the sum of the two allele sizes [Takahashi et al 2004]. Homozygous individuals. Several individuals who are homozygous for an abnormal expansion in CACNA1A have been reported [Geschwind et al 1997, Ikeuchi et al 1997, Matsuyama et al 1997]. In three, the onset was earlier and symptoms appeared more severe than in individuals who were heterozygous [Geschwind et al 1997, Ikeuchi et al 1997]; in one study age of onset correlated with the sum of two disease alleles [Takahashi et al 2004]. Note: The increase in severity of symptoms with homozygosity of the CACNA1A expansion is not as great as that observed in individuals with SCA3 (Machado-Joseph disease), another autosomal dominant cerebellar ataxia caused by a CAG repeat expansion [Lang et al 1994, Lerer et al 1996, Sobue et al 1996].
Individuals with spinocerebellar ataxia type 6 (SCA6) may present with unexplained ataxia that is part of the larger differential diagnosis of hereditary and acquired ataxias (see Ataxia Overview)....
Differential DiagnosisIndividuals with spinocerebellar ataxia type 6 (SCA6) may present with unexplained ataxia that is part of the larger differential diagnosis of hereditary and acquired ataxias (see Ataxia Overview).
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 6 (SCA6), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 6 (SCA6), the following evaluations are recommended:Medical history Neurologic examination, including use of a rating scale to be used annually to assess progression Brain MRI to gauge the extent of atrophy of cerebellum or other structures Treatment of ManifestationsManagement is supportive.Vitamin supplements are recommended, particularly if caloric intake is reduced. Acetazolamide may eliminate episodes of ataxia, but does not delay or slow the overall progression. Vestibular suppressants can reduce vertigo. Although neither exercise nor physical therapy stems the progression of incoordination or muscle weakness, affected individuals should maintain activity. Canes and walkers help prevent falling. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary. Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria. Weighted eating utensils and dressing hooks help maintain a sense of independence. Weight control is important because obesity can exacerbate difficulties with ambulation and mobility. When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration. Speech disturbances occasionally occur and may be managed as in other settings. Clonopin may be used for REM sleep disorders unless sedative effects increase imbalance in the morning. Continuous positive airway pressure may be used for sleep apnea. SurveillanceAffected individuals should be followed annually or semiannually by a neurologist, with consultations as needed by physiatrist and physical and/or occupational therapist.Agents/Circumstances to AvoidAgents with sedative/hypnotic properties such as ethanol or certain medications may produce marked increases in incoordination.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationGazulla & Tintore [2007] suggested gabapentin and pregabalin as potential therapeutic agents.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherTremor-controlling drugs are not usually effective in reducing cerebellar tremors. Patients and their families should be informed about natural history, treatment, mode of inheritance, genetic risks to other family members, and consumer-oriented resources.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Spinocerebellar Ataxia Type 6: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCACNA1A19p13.2Voltage-dependent P/Q-type calcium channel subunit alpha-1ACalcium channel, voltage-dependent, P/Q type, alpha 1A subunit (CACNA1A) @ LOVDCACNA1AData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Spinocerebellar Ataxia Type 6 (View All in OMIM) View in own window 183086SPINOCEREBELLAR ATAXIA 6; SCA6 601011CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1ANormal allelic variants. CACNA1A consists of 47 exons. A polymorphic CAG repeat in the 3' end of the gene occurs within a portion of the gene previously thought to be only non-coding. The identification of expansions of this CAG repeat associated with autosomal dominant ataxia was accompanied by the recognition of a novel long splice form of the alpha 1A mRNA in which the reading frame includes the CAG repeat translated into glutamine residues. The CAG repeats range from (CAG)4 to (CAG)18. Pathologic allelic variants. Disease-associated CAG-repeat alleles ranging from (CAG)21 to (CAG)33 have been reported. The most common allele is (CAG)22. One individual with a (CAG)20 allele has episodic ataxia [Jodice et al 1997]. Normal gene product. CACNA1A encodes an alpha-1A subunit that serves as the pore-forming subunit of a voltage-dependent P/Q-type calcium channel (reviewed in Greenberg 1997). Voltage-dependent calcium channels are made up of beta and gamma-s accessory subunits. Alpha-1A subunits are membrane glycoproteins of approximately 2400 amino acids in length in which primary structure predicts the presence of four homologous domains, each consisting of six transmembrane domains and a pore-forming P loop. P/Q-type calcium channels are high-voltage-activated calcium channels found primarily on neurons and expressed at high levels in granule cells and Purkinje cells of the cerebellar cortex. Their principal role is believed to be in synaptic transmission. The alpha1 (2.1), formerlyα1A, subunit is the major pre-forming subunit of the CaV2.1 (PLQ type) voltage-gated calcium channel. CACNA1A gives rise to several alternatively spliced mRNAs of approximately 7-8 kb [Ophoff et al 1996]. The predicted polypeptides range from 195 to 270 kd and vary in sequence internally and in the carboxy terminus. The discovery of the polymorphic CAG repeat in the 3' end of the gene was associated with the identification of a novel long splice form of the alpha-1A mRNA [Zhuchenko et al 1997]. In the long splice form, inclusion of additional nucleotides at the end of exon 46 eliminates a stop codon and places an additional 237 nucleotides of 3' sequence, including the polymorphic CAG repeat, in translational frame. The CAG repeat encodes a tract of glutamine residues, in which wild type alleles range from four to 18 glutamates in length. The function of the different splice forms of the CACNA1A gene products remains to be demonstrated, although differences have been measured in phosphorylation acceptor sites. Abnormal gene product. The expanded CAG repeat in CACNA1A in SCA6 codes for an expanded polyglutamine tract in the carboxy terminus of a long splice form of the alpha-1A subunit of a P/Q-type calcium channel [Zhuchenko et al 1997]. Whether the action of the mutant gene product is to perturb calcium channel function or to bind to nuclear-binding proteins remains to be demonstrated. The allelic disorder, autosomal dominant cerebellar ataxia associated with CACNA1A mutations (including p.Gly293Arg in the P loop of the first domain, p.Ala454Thr in the I-II loop, and p.Arg1664Gln), has a very similar phenotype to that of SCA6 associated with CAG-repeat expansions [Yue et al 1997, Tonelli et al 2006, Cricchi et al 2007]. As these mutations are not likely to act via the hypothetical nuclear binding mechanisms or transamination, an effect on calcium channel function is the most likely scenario for either pathogenic allele [Chen & Piedras-Renteria 2007, Kordasiewicz & Gomez 2007]. As these mutations do not act through nuclear translocation of an expanded polyglutamine tract in the C terminus, the disease presumably occurs through perturbed calcium channel function caused by the abnormal allele.