spinocerebellar degenerations

Summary

Summary: A heterogenous group of degenerative syndromes marked by progressive cerebellar dysfunction either in isolation or combined with other neurologic manifestations. Sporadic and inherited subtypes occur. Inheritance patterns include autosomal dominant, autosomal recessive, and X-linked.

Top Publications

  1. van Raamsdonk J. Loss of function mutations in SIL1 cause Marinesco-Sjögren syndrome. Clin Genet. 2006;69:399-400 pubmed
  2. Quinzii C, Kattah A, Naini A, Akman H, Mootha V, DiMauro S, et al. Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Neurology. 2005;64:539-41 pubmed
    ..The authors' observations indicate that CoQ10 deficiency may contribute to the pathogenesis of AOA1...
  3. Weitzmann A, Volkmer J, Zimmermann R. The nucleotide exchange factor activity of Grp170 may explain the non-lethal phenotype of loss of Sil1 function in man and mouse. FEBS Lett. 2006;580:5237-40 pubmed
    ..Here we characterize mammalian Grp170 as alternative nucleotide exchange factor for BiP, thus providing a likely explanation for the non-lethal phenotype of the homozygous human and murine SIL1 mutations...
  4. Koenig M. Rare forms of autosomal recessive neurodegenerative ataxia. Semin Pediatr Neurol. 2003;10:183-92 pubmed
  5. Annesi G, Aguglia U, Tarantino P, Annesi F, De Marco E, Civitelli D, et al. SIL1 and SARA2 mutations in Marinesco-Sjögren and chylomicron retention diseases. Clin Genet. 2007;71:288-9 pubmed
  6. Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, Breitbach Faller N, et al. Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy. Nat Genet. 2005;37:1312-4 pubmed
    ..Identification of SIL1 mutations implicates Marinesco-Sjögren syndrome as a disease of endoplasmic reticulum dysfunction and suggests a role for this organelle in multisystem disorders...
  7. Amouri R, Moreira M, Zouari M, El Euch G, Barhoumi C, Kefi M, et al. Aprataxin gene mutations in Tunisian families. Neurology. 2004;63:928-9 pubmed
    ..Two novel mutations were identified, the complete deletion of the gene, which seems to not correlate with an increased severity of the disease, and a splice mutation on the acceptor splice site of exon 7...
  8. Merlini L, Gooding R, Lochmuller H, Müller Felber W, Walter M, Angelicheva D, et al. Genetic identity of Marinesco-Sjögren/myoglobinuria and CCFDN syndromes. Neurology. 2002;58:231-6 pubmed
  9. Filla A, Mariotti C, Caruso G, Coppola G, Cocozza S, Castaldo I, et al. Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families. Eur Neurol. 2000;44:31-6 pubmed
    ..The number of CAG repeats in SCA1 normal alleles was higher in Northern than in Central-Southern Italy...

More Information

Publications62

  1. Pierson T, Adams D, Bonn F, Martinelli P, Cherukuri P, Teer J, et al. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet. 2011;7:e1002325 pubmed publisher
    ..These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias...
  2. Koht J, Stevanin G, Durr A, Mundwiller E, Brice A, Tallaksen C. SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene. Acta Neurol Scand. 2012;125:116-22 pubmed publisher
    ..We wanted to find the occurence of SCA14 in the dominant ataxia population and describe the phenotype...
  3. Lagier Tourenne C, Tranebaerg L, Chaigne D, Gribaa M, Dollfus H, Silvestri G, et al. Homozygosity mapping of Marinesco-Sjögren syndrome to 5q31. Eur J Hum Genet. 2003;11:770-8 pubmed
  4. Kawai Y, Suenaga M, Watanabe H, Sobue G. Cognitive impairment in spinocerebellar degeneration. Eur Neurol. 2009;61:257-68 pubmed publisher
    It has been reported that patients with spinocerebellar degenerations (SCDs) have cognitive dysfunction as well as limb and truncal ataxia, dysarthria and dysphagia...
  5. Rantamaki M, Krahe R, Paetau A, Cormand B, Mononen I, Udd B. Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family. Neurology. 2001;57:1043-9 pubmed
    ..To describe an unusual kindred with adult-onset ataxia and thalamic lesions detected by brain MRI...
  6. Engert J, Dore C, Mercier J, Ge B, Betard C, Rioux J, et al. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): high-resolution physical and transcript map of the candidate region in chromosome region 13q11. Genomics. 1999;62:156-64 pubmed
    ..Six BAC/PAC clones form a contig between D13S232 and D13S787 for sequencing within the ARSACS critical region...
  7. Engert J, Berube P, Mercier J, Dore C, Lepage P, Ge B, et al. ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet. 2000;24:120-5 pubmed
    ..SACS is expressed in a variety of tissues, including the central nervous system. We identified two SACSmutations in ARSACS families that lead to protein truncation, consistent with haplotype analysis...
  8. Chen D, Raskind W, Bird T. Spinocerebellar ataxia type 14. Handb Clin Neurol. 2012;103:555-9 pubmed publisher
    ..A single autopsy has shown loss of cerebellar Purkinje cells. The disease is caused by mutations in the protein kinase C gamma (PKC?, PRKCG) gene with a hotspot for mutations in exon 4. Genetic testing for SCA14 is clinically available...
  9. Shibata Hamaguchi A, Ishida C, Iwasa K, Yamada M. Prevalence of spinocerebellar degenerations in the Hokuriku district in Japan. Neuroepidemiology. 2009;32:176-83 pubmed publisher
    The prevalence of disease subtypes of spinocerebellar degenerations (SCDs) varies between countries, and even between areas within a country...
  10. Perlman S. Spinocerebellar degenerations. Handb Clin Neurol. 2011;100:113-40 pubmed publisher
    ..Some testing should be done even in individuals with a confirmed genetic cause, as the presence of a secondary factor (nutritional deficiency, thyroid dysfunction) can contribute to the phenotype...
  11. Houlden H, Johnson J, Gardner Thorpe C, Lashley T, Hernandez D, Worth P, et al. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet. 2007;39:1434-6 pubmed
    ..Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration...
  12. Di Bella D, Lazzaro F, Brusco A, Plumari M, Battaglia G, Pastore A, et al. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat Genet. 2010;42:313-21 pubmed publisher
  13. Burk K, Strzelczyk A, Reif P, Figueroa K, Pulst S, Zühlke C, et al. Mesial temporal lobe epilepsy in a patient with spinocerebellar ataxia type 13 (SCA13). Int J Neurosci. 2013;123:278-82 pubmed publisher
    ..This demonstrates that epilepsy of structural-metabolic cause may be contingent upon genetically defined channelopathies...
  14. Minassian N, Lin M, Papazian D. Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13. J Physiol. 2012;590:1599-614 pubmed publisher
    ..Therefore, our data strongly suggest that changes in Kv3.3 gating contribute significantly to an early age of onset in SCA13...
  15. Figueroa K, Waters M, Garibyan V, Bird T, Gomez C, Ranum L, et al. Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13). PLoS ONE. 2011;6:e17811 pubmed publisher
    ..Our objective was to describe the frequency of mutations associated with KCNC3 in a large cohort of index patients with sporadic or familial ataxia presenting to three US ataxia clinics at academic medical centers...
  16. Karim M, Parsian A, Cleves M, Bracey J, Elsayed M, Elsobky E, et al. A novel mutation in BAP/SIL1 gene causes Marinesco-Sjögren syndrome in an extended pedigree. Clin Genet. 2006;70:420-3 pubmed
  17. El Euch Fayache G, Lalani I, Amouri R, Turki I, Ouahchi K, Hung W, et al. Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia. Arch Neurol. 2003;60:982-8 pubmed
    ..Recently, we identified a Tunisian kindred demonstrating linkage to the ARSACS locus...
  18. Erichsen A, Koht J, Stray Pedersen A, Abdelnoor M, Tallaksen C. Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain. 2009;132:1577-88 pubmed publisher
    ..Better inclusion criteria and multiple search strategies may explain the observed differences...
  19. Anttonen A, Siintola E, Tranebjaerg L, Iwata N, Bijlsma E, Meguro H, et al. Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco-Sjögren syndrome. Eur J Hum Genet. 2008;16:961-9 pubmed publisher
    ..These data imply that aggregation of mutant proteins may contribute to MSS pathogenesis. The genetic background of a subgroup of patients with MSS remains uncovered...
  20. Yoon G, Westmacott R, MacMillan L, Quercia N, Koutsou P, Georghiou A, et al. Complete deletion of the aprataxin gene: ataxia with oculomotor apraxia type 1 with severe phenotype and cognitive deficit. J Neurol Neurosurg Psychiatry. 2008;79:234-6 pubmed publisher
  21. Shimazaki H, Takiyama Y, Sakoe K, Ikeguchi K, Niijima K, Kaneko J, et al. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations. Neurology. 2002;59:590-5 pubmed
    ..A new clinical entity named early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) has been proposed to explain these two diseases...
  22. Cagnoli C, Stevanin G, Brussino A, Barberis M, Mancini C, Margolis R, et al. Missense mutations in the AFG3L2 proteolytic domain account for ?1.5% of European autosomal dominant cerebellar ataxias. Hum Mutat. 2010;31:1117-24 pubmed publisher
    ..Screening for SCA28, is warranted in patients who test negative for more common SCAs and present with a slowly progressive cerebellar ataxia accompanied by oculomotor signs...
  23. Brusse E, Maat Kievit J, van Swieten J. Diagnosis and management of early- and late-onset cerebellar ataxia. Clin Genet. 2007;71:12-24 pubmed
    ..An appropriate diagnosis is of utmost importance to such considerations as prognosis, genetic counselling and possible therapeutic implications...
  24. Dudding T, Friend K, Schofield P, Lee S, Wilkinson I, Richards R. Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus. Neurology. 2004;63:2288-92 pubmed
    ..Most patients with pure nonprogressive congenital cerebellar ataxia have a sporadic form of unknown heredity and etiology. Several small families have been reported with a dominantly inherited nonprogressive congenital ataxia (NPCA)...
  25. Choudhry S, Mukerji M, Srivastava A, Jain S, Brahmachari S. CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. Hum Mol Genet. 2001;10:2437-46 pubmed
    ..Our study also provides new haplotypes associated with SCA2 that should prove useful in further understanding the mutational history and mechanism of repeat instability at the SCA2 locus...
  26. Anttonen A, Mahjneh I, Hämäläinen R, Lagier Tourenne C, Kopra O, Waris L, et al. The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone. Nat Genet. 2005;37:1309-11 pubmed
    ..These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjögren syndrome...
  27. Gascon G, Abdo N, Sigut D, Hemidan A, Hannan M. Ataxia-oculomotor apraxia syndrome. J Child Neurol. 1995;10:118-22 pubmed
  28. Burk K, Globas C, Bosch S, Graber S, Abele M, Brice A, et al. Cognitive deficits in spinocerebellar ataxia 2. Brain. 1999;122 ( Pt 4):769-77 pubmed
    ..Intellectual impairment should therefore not be interpreted as a secondary effect of progressive motor disability, but represents an important and independent part of the SCA2 phenotype...
  29. Harding A. Clinical features and classification of inherited ataxias. Adv Neurol. 1993;61:1-14 pubmed
  30. Quan F, Janas J, Popovich B. A novel CAG repeat configuration in the SCA1 gene: implications for the molecular diagnostics of spinocerebellar ataxia type 1. Hum Mol Genet. 1995;4:2411-3 pubmed
  31. Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert M, 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;59:392-9 pubmed
    ..93 at theta = .00). In addition, we present clinical and electrophysiological data regarding the distinct and previously unreported phenotype consisting of ataxia with the invariant presence of a prominent axonal sensory neuropathy...
  32. Pulst S, Nechiporuk A, Nechiporuk T, Gispert S, Chen X, Lopes Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996;14:269-76 pubmed
    ..The most common disease allele contained (CAG)37, one of the shortest expansions seen in a CAG expansion syndrome. The repeat occurs in the 5'-coding region of SCA2 which is a member of a novel gene family...
  33. Gotoda T, Arita M, Arai H, Inoue K, Yokota T, Fukuo Y, et al. Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein. N Engl J Med. 1995;333:1313-8 pubmed
    ..Accumulated evidence suggests that the alpha-tocopherol-transfer protein, which is presumed to function in the intracellular transport of alpha-tocopherol, is abnormal in these patients...
  34. Orr H, Chung M, Banfi S, Kwiatkowski T, Servadio A, Beaudet A, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993;4:221-6 pubmed
    ..We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat...
  35. Gispert S, Twells R, Orozco G, Brice A, Weber J, Heredero L, et al. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1. Nat Genet. 1993;4:295-9 pubmed
    ..Investigation of linkage to the interval containing SCA2 for seven French ADCA families, previously excluded from linkage to SCA1, provides preliminary data suggesting the existence of a third ADCA locus (SCA3)...
  36. Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, et al. The gene for Machado-Joseph disease maps to human chromosome 14q. Nat Genet. 1993;4:300-4 pubmed
    ..been described in non-Azorean families from various countries, being one of the most common hereditary spinocerebellar degenerations. With the use of highly polymorphic microsatellite DNA polymorphisms, we have assigned the gene for ..
  37. Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier J, et al. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet. 1996;14:285-91 pubmed
    ..The sequence of three of them revealed pure CAG stretches. The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglutamine expansion diseases...
  38. Skinner P, Koshy B, Cummings C, Klement I, Helin K, Servadio A, et al. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature. 1997;389:971-4 pubmed
    ..We therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear matrix-associated domain...
  39. Pearson C, Eichler E, Lorenzetti D, Kramer S, Zoghbi H, Nelson D, et al. Interruptions in the triplet repeats of SCA1 and FRAXA reduce the propensity and complexity of slipped strand DNA (S-DNA) formation. Biochemistry. 1998;37:2701-8 pubmed
  40. Richter A, Rioux J, Bouchard J, Mercier J, Mathieu J, Ge B, et al. Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11. Am J Hum Genet. 1999;64:768-75 pubmed
    ..The haplotype groups do not appear to be closely related. Therefore, although chromosomes within each haplotype group may harbor a single ARSACS mutation identical by descent, the two mutations could have independent origins...
  41. Frontali M, Novelletto A, Annesi G, Jodice C. CAG repeat instability, cryptic sequence variation and pathogeneticity: evidence from different loci. Philos Trans R Soc Lond B Biol Sci. 1999;354:1089-94 pubmed
    ..Because point mutations at the same gene with similar phenotypic consequences are highly unlikely to have this effect, an alternative common pathogenetic mechanism for all these mutations, including small expansions, can be hypothesized...
  42. Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996;14:277-84 pubmed
    ..DIRECT is a robust strategy for identification of pathologically expanded trinucleotide repeats and will dramatically accelerate the search for causative genes of neuropsychiatric diseases caused by trinucleotide repeat expansions...
  43. Koob M, Moseley M, Schut L, Benzow K, Bird T, Day J, et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet. 1999;21:379-84 pubmed
    ..SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract...
  44. Slavotinek A, Goldman J, Weisiger K, Kostiner D, Golabi M, Packman S, et al. Marinesco-Sjögren syndrome in a male with mild dysmorphism. Am J Med Genet A. 2005;133A:197-201 pubmed
  45. Klunder A, Chiang M, Dutton R, Lee S, Toga A, Lopez O, et al. Mapping cerebellar degeneration in HIV/AIDS. Neuroreport. 2008;19:1655-9 pubmed publisher
    ..Profound cerebellar deficits in HIV/AIDS (P=0.007, corrected) were associated with depression, suggesting a surrogate disease marker for antiretroviral trials...
  46. Kim J, An J, Lee K, Chung Y, Choi J, Lee K. PET evidence of cerebellar hypometabolism in a patient with familial episodic ataxia-myokymia syndrome. Mov Disord. 2008;23:1483-5 pubmed publisher
  47. Sakai N, Saito N, Seki T. Molecular pathophysiology of neurodegenerative disease caused by ?PKC mutations. World J Biol Psychiatry. 2011;12 Suppl 1:95-8 pubmed publisher
    ..To elucidate the pathophysiology of SCA14, we have analyzed the character of mutant ?PKC causing SCA14, expressed in cultured cells...
  48. King S, Schneider R, Serra A, Leigh R. Critical role of cerebellar fastigial nucleus in programming sequences of saccades. Ann N Y Acad Sci. 2011;1233:155-61 pubmed publisher
    ..Our results support the crucial role of the cerebellum, especially FOR, in programming sequences of saccades...
  49. Shuvaev A, Horiuchi H, Seki T, Goenawan H, Irie T, Iizuka A, et al. Mutant PKC? in spinocerebellar ataxia type 14 disrupts synapse elimination and long-term depression in Purkinje cells in vivo. J Neurosci. 2011;31:14324-34 pubmed publisher
  50. Perlman S. Spinocerebellar degenerations: an update. Curr Neurol Neurosci Rep. 2002;2:331-41 pubmed
    Over the past decade, the spinocerebellar degenerations have gone from a diverse group of loosely defined phenotypes to a family of diseases with many identifiable genotypes and the promise of gene-specific treatments...
  51. Krysa W, Rajkiewicz M, Sułek A. Rapid detection of large expansions in progressive myoclonus epilepsy type 1, myotonic dystrophy type 2 and spinocerebellar ataxia type 8. Neurol Neurochir Pol. 2012;46:113-20 pubmed
  52. Bettencourt C, Quintans B, Ros R, Ampuero I, Yáñez Z, Pascual S, et al. Revisiting genotype-phenotype overlap in neurogenetics: triplet-repeat expansions mimicking spastic paraplegias. Hum Mutat. 2012;33:1315-23 pubmed publisher
    ..This complex scenario makes the necessity of high-quality, curated mutation databases even more urgent, in order to develop adequate diagnostic guidelines, correct interpretation of genetic testing, and appropriate genetic counseling...
  53. Liszewski C, O HEARN E, Leroi I, Gourley L, Ross C, Margolis R. Cognitive impairment and psychiatric symptoms in 133 patients with diseases associated with cerebellar degeneration. J Neuropsychiatry Clin Neurosci. 2004;16:109-12 pubmed
    ..Psychopathology, including depression, personality change, cognitive impairment, anxiety, and psychosis was noted in 51% of 133 patients...