Spinocerebellar ataxia type-6
Name = PAGENAME
DiseasesDB = 12339
ICD10 = ICD10|G|11|2|g|10
ICD9 = ICD9|334.9
OMIM = 183086
eMedicineSubj = neuro
eMedicineTopic = 556
Spinocerebellar ataxia type 6 (SCA6) is a rare, late-onset,
autosomal dominantdisorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, incontinence, peripheral neuropathy, dementia, and ataxiaof gait, stance and the limbs due to cerebellar dysfunction. Unlike other types, SCA 6 is not fatal. This cerebellar function is permanent and progressive, differentiating it from episodic ataxiatype 2 (EA2) where said dysfunction is episodic. In some SCA6 families, some members show these classic signs of SCA6 while others show signs more similar to EA2, suggesting that there is some phenotypic overlap between the two disorders. SCA6 is cased by mutations in CACNA1A, a gene encoding a calcium channelα subunit. These mutations tend to be trinucleotide repeats of CAG leading to stretches of glutaminegreater than 19 and these mutant proteins form intracellular aggregations. Like many other polyglutamine expansion disorders, patients with longer expansions present with disease symptoms at an earlier age.
igns and symptoms
SCA6 is typified by progressive and permanent cerebellar dysfunction. These cerebellar signs include
ataxiaand dysarthria, likely caused by cerebellar atrophy. Prior to diagnosis and the onset of major symptoms, patients often report a feeling of "wooziness" and momentary imbalance when turning corners or making rapid movements. The age at which symptoms first occur varies widely, from age 19 to 71, but is typically between 43 and 52. Other major signs of SCA6 are the loss of vibratory and proprioceptive sensation and nystagmus.cite journal | author = Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton D, Amos C, Dobyns W, Subramony S, Zoghbi H, Lee C | title = Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. | journal = Nat Genet | volume = 15 | issue = 1 | pages = 62–9 | year = 1997 | pmid = 8988170 | doi = 10.1038/ng0197-62]
While most patients present with these severe progressive symptoms, others, sometimes within the same family, display episodic non-progressive symptoms more similar to episodic ataxia. Still others present with symptoms common to both SCA6 and
familial hemiplegic migraine.
Most cases of SCA6 are a result of CAG repeat expansion beyond the normal range, i.e., more than 19 repeats, in the Cav2.1
calcium channelencoding gene CACNA1A. This gene has two splice forms, "Q-type" and "P-type", and the poly glutaminecoding CAG expansion occurs in the P-type splice form. This form is expressed heavily in the cerebellumwhere it is localized in Purkinje cells. In Purkinje cells from SCA6 patients, mutant Cav2.1 proteins form ovular intracellular inclusions, or aggregations, similar in many ways to those seen in other polyglutamine expansion disorders such as Huntington's disease. In cell culture models of the disease, this leads to early apoptotic cell death.cite journal | author = Ishikawa K, Fujigasaki H, Saegusa H, Ohwada K, Fujita T, Iwamoto H, Komatsuzaki Y, Toru S, Toriyama H, Watanabe M, Ohkoshi N, Shoji S, Kanazawa I, Tanabe T, Mizusawa H | title = Abundant expression and cytoplasmic aggregations of [alpha] 1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6. | journal = Hum Mol Genet | volume = 8 | issue = 7 | pages = 1185–93 | year = 1999 | pmid = 10369863 | doi = 10.1093/hmg/8.7.1185]
Interestingly, mutant channels that are able to traffic properly to the membrane have a negatively shifted voltage-dependence of inactivation. The result of this is that the channels are active for a shorter amount of time and, consequently, cell excitability is decreased.cite journal | author = Toru S, Murakoshi T, Ishikawa K, Saegusa H, Fujigasaki H, Uchihara T, Nagayama S, Osanai M, Mizusawa H, Tanabe T | title = Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function. | journal = J Biol Chem | volume = 275 | issue = 15 | pages = 10893–8 | year = 2000 | pmid = 10753886 | doi = 10.1074/jbc.275.15.10893]
There are also a number of point mutations resulting in patients with phenotypes reminiscent of episodic ataxia and SCA6 (C271Y, G293R and R1664Q) or
familial hemiplegic migraineand SCA6 (R583Q and I1710T). C287Y and G293R are both located in the pore region of domain 1 and are present in a single family each. Expression of these mutant channels results in cells with drastically decreased current density compared to wild-type expressing cells. In cell-based assays, it was found that these mutant channels aggregate in the endoplasmic reticulum, not dissimilar from that seen in the CAG expansion mutants above.cite journal | author = Wan J, Khanna R, Sandusky M, Papazian D, Jen J, Baloh R | title = CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics. | journal = Neurology | volume = 64 | issue = 12 | pages = 2090–7 | year = 2005 | pmid = 15985579 | doi = 10.1212/01.WNL.0000167409.59089.C0] R1664Q is in the 4th transmembrane spanning segment of domain 4 and, presumably, affects the channel's voltage dependence of activation.cite journal | author = Tonelli A, D'Angelo M, Salati R, Villa L, Germinasi C, Frattini T, Meola G, Turconi A, Bresolin N, Bassi M | title = Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene. | journal = J Neurol Sci | volume = 241 | issue = 1-2 | pages = 13–7 | year = 2006 | pmid = 16325861 | doi = 10.1016/j.jns.2005.10.007] Little is known about the point mutations resulting in overlapping phenotypes of familial hemiplegic migraineand episodic ataxia. R583Q is present in the 4th transmembrane spanning region of domain 2 while the I1710T mutation is segment 5 of domain 4.cite journal | author = Alonso I, Barros J, Tuna A, Coelho J, Sequeiros J, Silveira I, Coutinho P | title = Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family. | journal = Arch Neurol | volume = 60 | issue = 4 | pages = 610–4 | year = 2003 | pmid = 12707077 | doi = 10.1001/archneur.60.4.610] cite journal | author = Kors E, Vanmolkot K, Haan J, Kheradmand Kia S, Stroink H, Laan L, Gill D, Pascual J, van den Maagdenberg A, Frants R, Ferrari M | title = Alternating hemiplegia of childhood: no mutations in the second familial hemiplegic migraine gene ATP1A2. | journal = Neuropediatrics | volume = 35 | issue = 5 | pages = 293–6 | year = 2004 | pmid = 15534763 | doi = 10.1055/s-2004-821082]
There is currently no cure for SCA 6; however, there are supportive treatments that may be useful in managing symptoms.
There is no known prevention of spinocerebellar ataxia. Those who are believed to be at risk can have genetic sequencing of known SCA loci performed to confirm inheritance of the disorder.
The prevalence of SCA6 varies by culture. In
Germany, SCA6 accounts for 10-25% of all autosomal dominant cases of SCA (SCA itself having a prevalence of 1 in 100,000).cite journal | author = Riess O, Schöls L, Bottger H, Nolte D, Vieira-Saecker A, Schimming C, Kreuz F, Macek M, Krebsová A, Klockgether T, Zühlke C, Laccone F | title = SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene. | journal = Hum Mol Genet | volume = 6 | issue = 8 | pages = 1289–93 | year = 1997 | pmid = 9259275 | doi = 10.1093/hmg/6.8.1289] cite journal | author = Schöls L, Amoiridis G, Büttner T, Przuntek H, Epplen J, Riess O | title = Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? | journal = Ann Neurol | volume = 42 | issue = 6 | pages = 924–32 | year = 1997 | pmid = 9403486 | doi = 10.1002/ana.410420615] This prevalence in lower in Japan, however, where SCA6 accounts for only ~6% of spinocerebellar ataxias.cite journal | author = Watanabe H, Tanaka F, Matsumoto M, Doyu M, Ando T, Mitsuma T, Sobue G | title = Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6. | journal = Clin Genet | volume = 53 | issue = 1 | pages = 13–9 | year = 1998 | pmid = 9550356 | doi = 10.1034/j.1399-0004.1998.531530104.x] In Australia, SCA6 accounts for 30% of spinocerebellar ataxia cases while 11% in the Dutch.cite journal | author = Storey E, du Sart D, Shaw J, Lorentzos P, Kelly L, McKinley Gardner R, Forrest S, Biros I, Nicholson G | title = Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia. | journal = Am J Med Genet | volume = 95 | issue = 4 | pages = 351–7 | year = 2000 | pmid = 11186889 | doi = 10.1002/1096-8628(20001211)95:4<351::AID-AJMG10>3.0.CO;2-R | doilabel = 10.1002/1096-8628(20001211)95:4351::AID-AJMG103.0.CO;2-R] cite journal | author = Sinke R, Ippel E, Diepstraten C, Beemer F, Wokke J, van Hilten B, Knoers N, van Amstel H, Kremer H | title = Clinical and molecular correlations in spinocerebellar ataxia type 6: a study of 24 Dutch families. | journal = Arch Neurol | volume = 58 | issue = 11 | pages = 1839–44 | year = 2001 | pmid = 11708993 | doi = 10.1001/archneur.58.11.1839]
Familial hemiplegic migraine
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