Genetics and Pathogenesis of Inherited Ataxias and Spastic Paraplegias

  • Carmen EspinósEmail author
  • Francesc Palau
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 652)


Inherited ataxias and hereditary spastic paraplegias are two heterogeneous groups of neurodegenerative disorders with a wide spectrum of clinical symptoms and also, with a remarkable number of involved loci/genes. Inherited ataxias are clinically characterized by progressive degeneration of cerebellum and spinocerebellar tracts of the spinal cord associated with a variable combination of signs of central and peripheral nervous system. Hereditary spastic paraplegias (HSPs) are characterized by slowly progressive spasticity and weakness of lower limbs, due to pyramidal tract dysfunction. The classification of these diseases is extremely difficult because of overlapping symptoms among different clinical forms. For this reason, the genetic classification for both inherited ataxias and HSP forms, based on the causative loci/genes has reached general acceptance. The aim of this review is to summarize the genetics and the pathogenic mechanisms involved in these two groups of neurodegenerative spinocerebellar disorders.


Inherited ataxia Autosomal recessive cerebellar ataxia (ARCA) Autosomal dominant cerebellar ataxia (ADCA) Spinocerebellar ataxia (SCA) Hereditary spastic paraplegia (HSP) 



This work is supported by the Spanish Ministry of Science and Innovation and the Fondo de Investigación Sanitaria. The CIBER de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III.


  1. 1.
    Palau F, Espinós C. Autosomal recessive cerebellar ataxias. Orphanet J Rare Dis 2006;1:47.PubMedGoogle Scholar
  2. 2.
    Valente EM, Brancati F, Dallapiccola B. Genotypes and phenotypes of Joubert syndrome and related disorders. Eur J Med Genet 2008;51(1):1–23.PubMedGoogle Scholar
  3. 3.
    Saar K, Al-Gazali L, Sztriha L, et al. Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity. Am J Hum Genet 1999;65(6):1666–1671.PubMedGoogle Scholar
  4. 4.
    Keeler LC, Marsh SE, Leeflang EP, et al. Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. Am J Hum Genet 2003;73(3):656–662.PubMedGoogle Scholar
  5. 5.
    Valente EM, Salpietro DC, Brancati F, et al. Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation. Am J Hum Genet 2003;73(3):663–670.PubMedGoogle Scholar
  6. 6.
    Lagier-Tourenne C, Boltshauser E, Breivik N, et al. Homozygosity mapping of a third Joubert syndrome locus to 6q23. J Med Genet 2004;41(4):273–277.PubMedGoogle Scholar
  7. 7.
    Valente EM, Silhavy JL, Brancati F, et al. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 2006;38(6):623–625.PubMedGoogle Scholar
  8. 8.
    Cantagrel V, Silhavy JL, Bielas SL, et al. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am J Hum Genet 2008;83(2):170–179.PubMedGoogle Scholar
  9. 9.
    Ouahchi K, Arita M, Kayden H, et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 1995;9(2):141–145.PubMedGoogle Scholar
  10. 10.
    Cavalier L, Ouahchi K, Kayden HJ, et al. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet 1998;62(2):301–310.PubMedGoogle Scholar
  11. 11.
    Gotoda T, Arita M, Arai H, 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(20):1313–1318.PubMedGoogle Scholar
  12. 12.
    Yokota T, Shiojiri T, Gotoda T, et al. Friedreich-like ataxia with retinitis pigmentosa caused by the His101Gln mutation of the alpha-tocopherol transfer protein gene. Ann Neurol 1997;41(6):826–832.PubMedGoogle Scholar
  13. 13.
    Fernandez-Burriel M, Martinez-Rubio D, Lupo V, et al. A novel delins mutation in the alpha-TTP gene in a family segregating ataxia with isolated vitamin E deficiency. Pediatr Res 2008;64(3):262–264.PubMedGoogle Scholar
  14. 14.
    Koenig M. Ataxia with isolated vitamin E deficiency. In: Klockgether T , ed. Handbook of Ataxia Disorders. New York: Marcel Dekker, Inc. 2000:223–234.Google Scholar
  15. 15.
    Mariotti C, Gellera C, Rimoldi M, et al. Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci 2004;25(3):130–137.PubMedGoogle Scholar
  16. 16.
    Wetterau JR, Aggerbeck LP, Bouma ME, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 1992;258(5084):999–1001.PubMedGoogle Scholar
  17. 17.
    Sharp D, Blinderman L, Combs KA, et al. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature 1993;3656441):65–69.PubMedGoogle Scholar
  18. 18.
    Shoulders CC, Brett DJ, Bayliss JD, et al. Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein. Hum Mol Genet 1993;2(12):2109–2116.PubMedGoogle Scholar
  19. 19.
    Narcisi TM, Shoulders CC, Chester SA, et al. Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia. Am J Hum Genet 1995;57(6):1298–1310.PubMedGoogle Scholar
  20. 20.
    Linton MF, Farese RV, Jr., Young SG. Familial hypobetalipoproteinemia. J Lipid Res 1993;34(4):521–541.PubMedGoogle Scholar
  21. 21.
    Ohashi K, Ishibashi S, Yamamoto M, et al. A truncated species of apolipoprotein B (B-38.7) in a patient with homozygous hypobetalipoproteinemia associated with diabetes mellitus. Arterioscler Thromb Vasc Biol 1998;18(8):1330–1334.PubMedGoogle Scholar
  22. 22.
    Gatti RA, Berkel I, Boder E, et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 1988;336(6199):577–580.PubMedGoogle Scholar
  23. 23.
    Gatti RA, Lange E, Rotman G, et al. Genetic haplotyping of ataxia-telangiectasia families localizes the major gene to an approximately 850 kb region on chromosome 11q23.1. Int J Radiat Biol 1994;66(6 Suppl):S57–S62.PubMedGoogle Scholar
  24. 24.
    Wright J, Teraoka S, Onengut S, et al. A high frequency of distinct ATM gene mutations in ataxia-telangiectasia. Am J Hum Genet 1996;59(4):839–846.PubMedGoogle Scholar
  25. 25.
    Becker-Catania SG, Chen G, Hwang MJ, et al. Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity. Mol Genet Metab 2000;70(2):122–133.PubMedGoogle Scholar
  26. 26.
    Li A, Swift M. Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. Am J Med Genet 2000;92(3):170–177.PubMedGoogle Scholar
  27. 27.
    Lavin MF, Gueven N, Bottle S, et al. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. Br Med Bull 2007;81–82:129–147.PubMedGoogle Scholar
  28. 28.
    Willems PJ, Van Roy BC, Kleijer WJ, et al. Atypical clinical presentation of ataxia telangiectasia. Am J Med Genet 1993;45(6):777–782.PubMedGoogle Scholar
  29. 29.
    Gilad S, Chessa L, Khosravi R, et al. Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 1998;62(3):551–561.PubMedGoogle Scholar
  30. 30.
    Stewart GS, Maser RS, Stankovic T, et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 1999;99(6):577–587.PubMedGoogle Scholar
  31. 31.
    Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995;268(5218):1749–1753.PubMedGoogle Scholar
  32. 32.
    Chen G, Lee E. The product of the ATM gene is a 370-kDa nuclear phosphoprotein. J Biol Chem 1996;271(52):33693–33697.PubMedGoogle Scholar
  33. 33.
    Kastan MB, Zhan Q, el-Deiry WS, et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 1992;71(4):587–597.PubMedGoogle Scholar
  34. 34.
    Khanna KK, Lavin MF. Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells. Oncogene 1993;8(12):3307–3312.PubMedGoogle Scholar
  35. 35.
    Williams RS, Williams JS, Tainer JA. Mre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template. Biochem Cell Biol 2007;85(4):509–520.PubMedGoogle Scholar
  36. 36.
    Klein C, Wenning GK, Quinn NP, et al. Ataxia without telangiectasia masquerading as benign hereditary chorea. Mov Disord 1996;11:217–220.PubMedGoogle Scholar
  37. 37.
    Tranchant C, Fleury M, Moreira MC, et al. Phenotypic variability of aprataxin gene mutations. Neurology 2003;60(5):868–870.PubMedGoogle Scholar
  38. 38.
    Barbot C, Coutinho P, Chorao R, et al. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch Neurol 2001;58(2):201–205.PubMedGoogle Scholar
  39. 39.
    Moreira MC, Barbot C, Tachi N, et al. Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity. Am J Hum Genet 2001;68(2):501–508.PubMedGoogle Scholar
  40. 40.
    Whitehouse CJ, Taylor RM, Thistlethwaite A, et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 2001;104(1):107–117.PubMedGoogle Scholar
  41. 41.
    Le Ber I, Bouslam N, Rivaud-Pechoux S, et al. Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients. Brain 2004;127(Pt 4):759–767.PubMedGoogle Scholar
  42. 42.
    Moreira MC, Klur S, Watanabe M, et al. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet 2004;36(3):225–227.PubMedGoogle Scholar
  43. 43.
    Suraweera A, Becherel OJ, Chen P, et al. Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage. J Cell Biol 2007;177(6):969–979.PubMedGoogle Scholar
  44. 44.
    Chen YZ, Bennett CL, Huynh HM, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 2004;74(6):1128–1135.PubMedGoogle Scholar
  45. 45.
    Gueven N, Chen P, Nakamura J, et al. A subgroup of spinocerebellar ataxias defective in DNA damage responses. Neuroscience 2007;145(4):1418–1425.PubMedGoogle Scholar
  46. 46.
    Takashima H, Boerkoel CF, John J, et al. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet 2002;32(2):267–272.PubMedGoogle Scholar
  47. 47.
    Caldecott KW. DNA single-strand break repair and spinocerebellar ataxia. Cell 2003;112:7–10.PubMedGoogle Scholar
  48. 48.
    Wong LJ, Naviaux RK, Brunetti-Pierri N, et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 2008;29(9):E150–E72.PubMedGoogle Scholar
  49. 49.
    Hakonen AH, Heiskanen S, Juvonen V, et al. Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 2005;77(3):430–441.PubMedGoogle Scholar
  50. 50.
    Tzoulis C, Engelsen BA, Telstad W, et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain 2006;129(Pt 7):1685–1692.PubMedGoogle Scholar
  51. 51.
    Lonnqvist T, Paetau A, Nikali K, et al. Infantile onset spinocerebellar ataxia with sensory neuropathy (IOSCA): neuropathological features. J Neurol Sci 1998;161(1):57–65.PubMedGoogle Scholar
  52. 52.
    Nikali K, Suomalainen A, Saharinen J, et al. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet 2005;14(20):2981–2990.PubMedGoogle Scholar
  53. 53.
    Naviaux RK, Nguyen KV. POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Ann Neurol 2005;58(3):491.PubMedGoogle Scholar
  54. 54.
    Hakonen AH, Goffart S, Marjavaara S, et al. Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. Hum Mol Genet 2008;17(23):3822–3835.PubMedGoogle Scholar
  55. 55.
    Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the ‘the Drew family of Walworth’. Brain 1982;105(Pt 1):1–28.PubMedGoogle Scholar
  56. 56.
    Dubourg O, Durr A, Cancel G, et al. Analysis of the SCA1 CAG repeat in a large number of families with dominant ataxia: clinical and molecular correlations. Ann Neurol 1995;37(2):176–180.PubMedGoogle Scholar
  57. 57.
    Burk K, Abele M, Fetter M, et al. Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain 1996;119 ( Pt 5):1497–1505.PubMedGoogle Scholar
  58. 58.
    Schols L, Amoiridis G, Buttner T, et al. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 1997;42(6):924–932.PubMedGoogle Scholar
  59. 59.
    Jackson JF, Currier RD, Terasaki PI, et al. Spinocerebellar ataxia and HLA linkage: risk prediction by HLA typing. N Engl J Med 1977;296(20):1138–1141.PubMedGoogle Scholar
  60. 60.
    Klockgether T. The clinical diagnosis of autosomal dominant spinocerebellar ataxias. Cerebellum 2008; 7(2):101–105.Google Scholar
  61. 61.
    van de Warrenburg BP, Sinke RJ, Verschuuren-Bemelmans CC, et al. Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurology 2002;58(5):702–708.PubMedGoogle Scholar
  62. 62.
    Schols L. Autosomal dominant spinocerebellar ataxias. Orphanet Encyclopedia, 2003.
  63. 63.
    Leggo J, Dalton A, Morrison PJ, et al. Analysis of spinocerebellar ataxia types 1, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and Friedreich’s ataxia genes in spinocerebellar ataxia patients in the UK. J Med Genet 1997;34(12):982–985.PubMedGoogle Scholar
  64. 64.
    Watanabe H, Tanaka F, Matsumoto M, et al. Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6. Clin Genet 1998;53(1):13–19.PubMedGoogle Scholar
  65. 65.
    Kim JY, Park SS, Joo SI, et al. Molecular analysis of Spinocerebellar ataxias in Koreans: frequencies and reference ranges of SCA1, SCA2, SCA3, SCA6, and SCA7. Mol Cells 2001;12(3):336–341.PubMedGoogle Scholar
  66. 66.
    Silveira I, Miranda C, Guimaraes L, et al. Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus. Arch Neurol 2002;59(4):623–629.PubMedGoogle Scholar
  67. 67.
    Ito H, Kawakami H, Wate R, et al. Clinicopathologic investigation of a family with expanded SCA8 CTA/CTG repeats. Neurology 2006;67(8):1479–1481.PubMedGoogle Scholar
  68. 68.
    Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet 2000;26(2):191–194.PubMedGoogle Scholar
  69. 69.
    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(4):391–392.PubMedGoogle Scholar
  70. 70.
    Ashley CT, Jr., Warren ST. Trinucleotide repeat expansion and human disease. Annu Rev Genet 1995;29:703–728.PubMedGoogle Scholar
  71. 71.
    Cummings CJ, Zoghbi HY. Fourteen and counting: unraveling trinucleotide repeat diseases. Hum Mol Genet 2000;9(6):909–916.PubMedGoogle Scholar
  72. 72.
    Richards RI, Holman K, Friend K, et al. Evidence of founder chromosomes in fragile X syndrome. Nat Genet 1992;1(4):257–260.PubMedGoogle Scholar
  73. 73.
    Goldberg YP, Kremer B, Andrew SE, et al. Molecular analysis of new mutations for Huntington’s disease: intermediate alleles and sex of origin effects. Nat Genet 1993;5(2):174–179.PubMedGoogle Scholar
  74. 74.
    Imbert G, Kretz C, Johnson K, et al. Origin of the expansion mutation in myotonic dystrophy. Nat Genet 1993;4(1):72–76.PubMedGoogle Scholar
  75. 75.
    Myers RH, MacDonald ME, Koroshetz WJ, et al. De novo expansion of a (CAG)n repeat in sporadic Huntington’s disease. Nat Genet 1993;5(2):168–173.PubMedGoogle Scholar
  76. 76.
    Kunst CB, Warren ST. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell 1994;77(6):853–861.PubMedGoogle Scholar
  77. 77.
    Paulson HL, Fischbeck KH. Trinucleotide repeats in neurogenetic disorders. Annu Rev Neurosci 1996;19:79–107.PubMedGoogle Scholar
  78. 78.
    Benton CS, de Silva R, Rutledge SL, et al. Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology 1998;51(4):1081–1086.PubMedGoogle Scholar
  79. 79.
    Ranum LP, Moseley ML, Leppet MF. Massive CTG expansions and deletions may reduce penetrance of spinocerebellar ataxia type 8. Am J Hum Genet 1999;S65:A466(2648).Google Scholar
  80. 80.
    Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 1997;15(1):62–69.PubMedGoogle Scholar
  81. 81.
    Koide R, Kobayashi S, Shimohata T, et al. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet 1999;8(11):2047–2053.PubMedGoogle Scholar
  82. 82.
    Nakamura K, Jeong SY, Uchihara T, et al. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 2001;10(14):1441–1448.PubMedGoogle Scholar
  83. 83.
    Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000;23:217–247.PubMedGoogle Scholar
  84. 84.
    Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med 2004;10 Suppl:10–17.PubMedGoogle Scholar
  85. 85.
    Cummings CJ, Mancini MA, Antalffy B, et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 1998;19(2):148–154.PubMedGoogle Scholar
  86. 86.
    McCampbell A, Taylor JP, Taye AA, et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 2000;9 (14):2197–2202.PubMedGoogle Scholar
  87. 87.
    Schmidt T, Lindenberg KS, Krebs A, et al. Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol 2002;51(3):302–310.PubMedGoogle Scholar
  88. 88.
    Klement IA, Skinner PJ, Kaytor MD, et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 1998;95(1):41–53.PubMedGoogle Scholar
  89. 89.
    Slow EJ, Graham RK, Osmand AP, et al. Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc Natl Acad Sci U S A 2005;102(32):11402–11407.PubMedGoogle Scholar
  90. 90.
    Saudou F, Finkbeiner S, Devys D, et al. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998;95(1):55–66.PubMedGoogle Scholar
  91. 91.
    Arrasate M, Mitra S, Schweitzer ES, et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004;431(7010):805–810.PubMedGoogle Scholar
  92. 92.
    Kayed R, Head E, Thompson JL, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003;300 (5618):486–489.PubMedGoogle Scholar
  93. 93.
    Schaffar G, Breuer P, Boteva R, et al. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell 2004;15(1):95–105.PubMedGoogle Scholar
  94. 94.
    Wacker JL, Zareie MH, Fong H, et al. Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nat Struct Mol Biol 2004;11(12):1215–1222.PubMedGoogle Scholar
  95. 95.
    Behrends C, Langer CA, Boteva R, et al. Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol Cell 2006;23(6):887–897.PubMedGoogle Scholar
  96. 96.
    Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 2007;8(2):101–112.PubMedGoogle Scholar
  97. 97.
    Cummings CJ, Reinstein E, Sun Y, et al. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 1999;24(4):879–892.PubMedGoogle Scholar
  98. 98.
    Matilla A, Gorbea C, Einum DD, et al. Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex. Hum Mol Genet 2001;10(24):2821–2831.PubMedGoogle Scholar
  99. 99.
    Chai Y, Berke SS, Cohen RE, et al. Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways. J Biol Chem 2004;279(5):3605–3611.PubMedGoogle Scholar
  100. 100.
    Lam YC, Bowman AB, Jafar-Nejad P, et al. ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 2006;127(7):1335–1347.PubMedGoogle Scholar
  101. 101.
    Bowman AB, Lam YC, Jafar-Nejad P, et al. Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nat Genet 2007;39(3):373–379.PubMedGoogle Scholar
  102. 102.
    Warrick JM, Morabito LM, Bilen J, et al. Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol Cell 2005;18(1):37–48.PubMedGoogle Scholar
  103. 103.
    Stenoien DL, Mielke M, Mancini MA. Intranuclear ataxin1 inclusions contain both fast- and slow-exchanging components. Nat Cell Biol 2002;4(10):806–810.PubMedGoogle Scholar
  104. 104.
    Serra HG, Duvick L, Zu T, et al. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 2006;127(4):697–708.PubMedGoogle Scholar
  105. 105.
    Helmlinger D, Hardy S, Sasorith S, et al. Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet 2004;13(12):1257–1265.PubMedGoogle Scholar
  106. 106.
    Palhan VB, Chen S, Peng GH, et al. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci U S A 2005;102(24):8472–8477.PubMedGoogle Scholar
  107. 107.
    La Spada AR, Fu YH, Sopher BL, et al. Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron 2001;31(6):913–927.PubMedGoogle Scholar
  108. 108.
    Koob MD, Moseley ML, Schut LJ, et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet 1999;21(4):379–384.PubMedGoogle Scholar
  109. 109.
    Schols L, Bauer I, Zuhlke C, et al. Do CTG expansions at the SCA8 locus cause ataxia? Ann Neurol 2003;54(1):110–115.PubMedGoogle Scholar
  110. 110.
    Moseley ML, Zu T, Ikeda Y, et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet 2006;38(7):758–769.PubMedGoogle Scholar
  111. 111.
    Ikeda Y, Dalton JC, Moseley ML, et al. Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia. Am J Hum Genet 2004;75(1):3–16.PubMedGoogle Scholar
  112. 112.
    Ikeda Y, Daughters RS, Ranum LP. Bidirectional expression of the SCA8 expansion mutation: One mutation, two genes. Cerebellum 2008;7(2):150–158.Google Scholar
  113. 113.
    Rasmussen A, Matsuura T, Ruano L, et al. Clinical and genetic analysis of four Mexican families with spinocerebellar ataxia type 10. Ann Neurol 2001;50(2):234–239.PubMedGoogle Scholar
  114. 114.
    Teive HA, Roa BB, Raskin S, et al. Clinical phenotype of Brazilian families with spinocerebellar ataxia 10. Neurology 2004;63(8):1509–1512.PubMedGoogle Scholar
  115. 115.
    Zu L, Figueroa KP, Grewal R, et al. Mapping of a new autosomal dominant spinocerebellar ataxia to chromosome 22. Am J Hum Genet 1999;64(2):594–599.PubMedGoogle Scholar
  116. 116.
    Lin X, Ashizawa T. Recent progress in spinocerebellar ataxia type-10 (SCA10). Cerebellum 2005;4(1):37–42.PubMedGoogle Scholar
  117. 117.
    Coates JC. Armadillo repeat proteins: beyond the animal kingdom. Trends Cell Biol 2003;13(9):463–471.PubMedGoogle Scholar
  118. 118.
    Waragai M, Nagamitsu S, Xu W, et al. Ataxin 10 induces neuritogenesis via interaction with G-protein beta2 subunit. J Neurosci Res 2006;83(7):1170–1178.PubMedGoogle Scholar
  119. 119.
    Wakamiya M, Matsuura T, Liu Y, et al. The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10. Neurology 2006;67(4):607–613.PubMedGoogle Scholar
  120. 120.
    Sontag E. Protein phosphatase 2A: the Trojan Horse of cellular signaling. Cell Signal 2001;13(1):7–16.PubMedGoogle Scholar
  121. 121.
    Chen DH, Brkanac Z, Verlinde CL, et al. Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet 2003;72(4):839–849.PubMedGoogle Scholar
  122. 122.
    Chen HK, Fernandez-Funez P, Acevedo SF, et al. Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 2003;113(4):457–468.PubMedGoogle Scholar
  123. 123.
    Lim J, Lu KP. Pinning down phosphorylated tau and tauopathies. Biochim Biophys Acta 2005;1739(2-3):311–322.PubMedGoogle Scholar
  124. 124.
    Ikeda Y, Dick KA, Weatherspoon MR, et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 2006;38(2):184–190.PubMedGoogle Scholar
  125. 125.
    Gold DA, Baek SH, Schork NJ, et al. RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways. Neuron 2003;40(6):1119–1131.PubMedGoogle Scholar
  126. 126.
    Waters MF, Minassian NA, Stevanin G, et al. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet 2006;38(4):447–451.PubMedGoogle Scholar
  127. 127.
    Waters MF, Pulst SM. Sca13. Cerebellum 2008;7(2):165–169.Google Scholar
  128. 128.
    Yabe I, Sasaki H, Chen DH, et al. Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma. Arch Neurol 2003;60(12):1749–1751.Google Scholar
  129. 129.
    Schrenk K, Kapfhammer JP, Metzger F. Altered dendritic development of cerebellar Purkinje cells in slice cultures from protein kinase Cgamma-deficient mice. Neuroscience 2002;110(4):675–689.PubMedGoogle Scholar
  130. 130.
    Verbeek DS, Goedhart J, Bruinsma L, et al. PKC gamma mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling. J Cell Sci 2008;121(Pt 14):2339–2349.PubMedGoogle Scholar
  131. 131.
    van Swieten JC, Brusse E, de Graaf BM, et al. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]. Am J Hum Genet 2003;72(1):191–199.PubMedGoogle Scholar
  132. 132.
    Xiao M, Xu L, Laezza F, et al. Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14. Mol Cell Neurosci 2007;34(3):366–377.PubMedGoogle Scholar
  133. 133.
    Wozniak DF, Xiao M, Xu L, et al. Impaired spatial learning and defective theta burst induced LTP in mice lacking fibroblast growth factor 14. Neurobiol Dis 2007;26(1):14–26.PubMedGoogle Scholar
  134. 134.
    Owada K, Ishikawa K, Toru S, et al. A clinical, genetic, and neuropathologic study in a family with 16q-linked ADCA type III. Neurology 2005;65(4):629–632.PubMedGoogle Scholar
  135. 135.
    Ouyang Y, Sakoe K, Shimazaki H, et al. 16q-linked autosomal dominant cerebellar ataxia: a clinical and genetic study. J Neurol Sci 2006;247(2):180–186.PubMedGoogle Scholar
  136. 136.
    Basri R, Yabe I, Soma H, et al. Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families. J Hum Genet 2007;52(10):848–855.PubMedGoogle Scholar
  137. 137.
    Ohata T, Yoshida K, Sakai H, et al. A -16C>T substitution in the 5’ UTR of the puratrophin-1 gene is prevalent in autosomal dominant cerebellar ataxia in Nagano. J Hum Genet 2006;51(5):461–466.PubMedGoogle Scholar
  138. 138.
    Amino T, Ishikawa K, Toru S, et al. Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia. J Hum Genet 2007;52(8):643–649.PubMedGoogle Scholar
  139. 139.
    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(2):392–399.PubMedGoogle Scholar
  140. 140.
    Hellenbroich Y, Bubel S, Pawlack H, et al. Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region. J Neurol 2003;250(6):668–671.PubMedGoogle Scholar
  141. 141.
    Hellenbroich Y, Bernard V, Zuhlke C. Spinocerebellar ataxia type 4 and 16q22.1-linked Japanese ataxia are not allelic. J Neurol 2008;255(4):612–613.PubMedGoogle Scholar
  142. 142.
    Shokeir MHK. X-linked cerebellar ataxia. Clin Genet 1970;1:225–231.Google Scholar
  143. 143.
    Illarioshkin SN, Tanaka H, Markova ED, et al. X-linked nonprogressive congenital cerebellar hypoplasia: clinical description and mapping to chromosome Xq. Ann Neurol 1996;40(1):75–83.PubMedGoogle Scholar
  144. 144.
    Bertini E, des Portes V, Zanni G, et al. X-linked congenital ataxia: a clinical and genetic study. Am J Med Genet 2000;92(1):53–56.PubMedGoogle Scholar
  145. 145.
    Malamud N, Cohen P. Unusual form of cerebellar ataxia with sex-linked inheritance. Neurology 1958;8(4):261–266.PubMedGoogle Scholar
  146. 146.
    Schmidley JW, Levinsohn MW, Manetto V. Infantile X-linked ataxia and deafness: a new clinicopathologic entity? Neurology 1987;37(8):1344–1349.PubMedGoogle Scholar
  147. 147.
    Farlow MR, DeMyer W, Dlouhy SR, et al. X-linked recessive inheritance of ataxia and adult-onset dementia: clinical features and preliminary linkage analysis. Neurology 1987;37(4):602–607.PubMedGoogle Scholar
  148. 148.
    Zanni G, Bertini E, Bellcross C, et al. X-linked congenital ataxia: a new locus maps to Xq25-q27.1. Am J Med Genet A 2008;146A(5):593–600.PubMedGoogle Scholar
  149. 149.
    Polo JM, Calleja J, Combarros O, et al. Hereditary ataxias and paraplegias in Cantabria, Spain. An epidemiological and clinical study. Brain 1991;114(Pt 2):855–866.PubMedGoogle Scholar
  150. 150.
    Filla A, De Michele G, Marconi R, et al. Prevalence of hereditary ataxias and spastic paraplegias in Molise, a region of Italy. J Neurol 1992;239(6):351–353.PubMedGoogle Scholar
  151. 151.
    Leone M, Bottacchi E, D’Alessandro G, et al. Hereditary ataxias and paraplegias in Valle d’Aosta, Italy: a study of prevalence and disability. Acta Neurol Scand 1995;91(3):183–187.PubMedGoogle Scholar
  152. 152.
    Silva MC, Coutinho P, Pinheiro CD, et al. Hereditary ataxias and spastic paraplegias: methodological aspects of a prevalence study in Portugal. J Clin Epidemiol 1997;50(12):1377–1384.PubMedGoogle Scholar
  153. 153.
    Harding AE. Hereditary “pure” spastic paraplegia: a clinical and genetic study of 22 families. J Neurol Neurosurg Psychiatry 1981;44(10):871–883.PubMedGoogle Scholar
  154. 154.
    Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet 1983;1(8334):1151–1155.PubMedGoogle Scholar
  155. 155.
    McMonagle P, Webb S, Hutchinson M. The prevalence of “pure” autosomal dominant hereditary spastic paraparesis in the island of Ireland. J Neurol Neurosurg Psychiatry 2002;72(1):43–46.PubMedGoogle Scholar
  156. 156.
    Coutinho P, Barros J, Zemmouri R, et al. Clinical heterogeneity of autosomal recessive spastic paraplegias: analysis of 106 patients in 46 families. Arch Neurol 1999;56(8):943–949.PubMedGoogle Scholar
  157. 157.
    Boukhris A, Stevanin G, Feki I, et al. Hereditary spastic paraplegia with mental impairment and thin corpus callosum in Tunisia: SPG11, SPG15, and further genetic heterogeneity. Arch Neurol 2008;65(3):393–402.PubMedGoogle Scholar
  158. 158.
    Depienne C, Fedirko E, Forlani S, et al. Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. J Med Genet 2007;44(4):281–284.PubMedGoogle Scholar
  159. 159.
    Zuchner S, Wang G, Tran-Viet KN, et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet 2006;79(2):365–369.PubMedGoogle Scholar
  160. 160.
    Rainier S, Chai JH, Tokarz D, et al. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet 2003;73(4):967–971.PubMedGoogle Scholar
  161. 161.
    Reed JA, Wilkinson PA, Patel H, et al. A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia. Neurogenetics 2005;6(2):79–84.PubMedGoogle Scholar
  162. 162.
    Valdmanis PN, Meijer IA, Reynolds A, et al. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am J Hum Genet 2007;80(1):152–161.PubMedGoogle Scholar
  163. 163.
    Reid E, Kloos M, Ashley-Koch A, et al. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 2002;71(5):1189–1194.PubMedGoogle Scholar
  164. 164.
    Fichera M, Lo Giudice M, Falco M, et al. Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology 2004;63(6):1108–1110.PubMedGoogle Scholar
  165. 165.
    Blair MA, Ma S, Hedera P. Mutation in KIF5A can also cause adult-onset hereditary spastic paraplegia. Neurogenetics 2006;7(1):47–50.PubMedGoogle Scholar
  166. 166.
    Lo Giudice MN, Falco M, Sturnio M, Calzolari E, Di Benedetto D, Fichera M. A missense mutation in the coiled-coil domain of the KIF5A gene and late-onset hereditary spastic paraplegia. Arch Neurol 2006;63:284–287.PubMedGoogle Scholar
  167. 167.
    Hansen JJ, Durr A, Cournu-Rebeix I, et al. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am J Hum Genet 2002;70(5):1328–1332.PubMedGoogle Scholar
  168. 168.
    Klebe S, Durr A, Bouslam N, et al. Spastic paraplegia 5: Locus refinement, candidate gene analysis and clinical description. Am J Med Genet B Neuropsychiatr Genet 2007;144B(7):854–861.PubMedGoogle Scholar
  169. 169.
    Tsaousidou MK, Ouahchi K, Warner TT, et al. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet 2008;82(2):510–515.PubMedGoogle Scholar
  170. 170.
    Goizet C, Boukhris A, Mundwiller E, et al. Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Hum Mutat 2009;30(2):376–385.Google Scholar
  171. 171.
    Stevanin G, Santorelli FM, Azzedine H, et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 2007;39(3):366–372.PubMedGoogle Scholar
  172. 172.
    Denora PS, Schlesinger D, Casali C, et al. Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion. Hum Mutat 2009; 30(3):500–519.Google Scholar
  173. 173.
    Hanein S, Martin E, Boukhris A, et al. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am J Hum Genet 2008;82(4):992–1002.PubMedGoogle Scholar
  174. 174.
    Elleuch N, Depienne C, Benomar A, et al. Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. Neurology 2006;66(5):654–659.PubMedGoogle Scholar
  175. 175.
    Arnoldi A, Tonelli A, Crippa F, et al. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat 2008;29(4):522–531.PubMedGoogle Scholar
  176. 176.
    Depienne C, Stevanin G, Brice A, et al. Hereditary spastic paraplegias: an update. Curr Opin Neurol 2007;20(6):674–680.PubMedGoogle Scholar
  177. 177.
    Tamagaki A, Shima M, Tomita R, et al. Segregation of a pure form of spastic paraplegia and NOR insertion into Xq11.2. Am J Med Genet 2000;94(1):5–8.PubMedGoogle Scholar
  178. 178.
    Crosby AH, Proukakis C. Is the transportation highway the right road for hereditary spastic paraplegia? Am J Hum Genet 2002;71(5):1009–1016.PubMedGoogle Scholar
  179. 179.
    White SR, Evans KJ, Lary J, et al. Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing. J Cell Biol 2007;176(7):995–1005.PubMedGoogle Scholar
  180. 180.
    Tarrade A, Fassier C, Courageot S, et al. A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition. Hum Mol Genet 2006;15(24):3544–3558.PubMedGoogle Scholar
  181. 181.
    Evans K, Keller C, Pavur K, et al. Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. Proc Natl Acad Sci U S A 2006;103(28):10666–10671.PubMedGoogle Scholar
  182. 182.
    Mannan AU, Krawen P, Sauter SM, et al. ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. Am J Hum Genet 2006;79(2):351–357.PubMedGoogle Scholar
  183. 183.
    Namekawa M, Muriel MP, Janer A, et al. Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis. Mol Cell Neurosci 2007;35(1):1–13.PubMedGoogle Scholar
  184. 184.
    Bakowska JC, Jupille H, Fatheddin P, et al. Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking. Mol Biol Cell 2007;18(5):1683–1692.PubMedGoogle Scholar
  185. 185.
    Simpson MA, Cross H, Proukakis C, et al. Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet 2003;73(5):1147–1156.PubMedGoogle Scholar
  186. 186.
    Goytain A, Hines RM, El-Husseini A, et al. NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter. J Biol Chem 2007;282(11):8060–8068.PubMedGoogle Scholar
  187. 187.
    Ebbing B, Mann K, Starosta A, et al. Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. Hum Mol Genet 2008;17(9):1245–1252.PubMedGoogle Scholar
  188. 188.
    Gupta S, Knowlton AA. HSP60, Bax, apoptosis and the heart. J Cell Mol Med 2005;9(1):51–58.PubMedGoogle Scholar
  189. 189.
    Casari G, De Fusco M, Ciarmatori S, et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 1998;93(6):973–983.PubMedGoogle Scholar
  190. 190.
    Atorino L, Silvestri L, Koppen M, et al. Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia. J Cell Biol 2003;163(4):777–787.PubMedGoogle Scholar
  191. 191.
    Ferreirinha F, Quattrini A, Pirozzi M, et al. Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. J Clin Invest 2004;113(2):231–242.PubMedGoogle Scholar
  192. 192.
    Lu J, Rashid F, Byrne PC. The hereditary spastic paraplegia protein spartin localises to mitochondria. J Neurochem 2006;98(6):1908–1919.PubMedGoogle Scholar
  193. 193.
    Ito D, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain 2009;132:8–15.Google Scholar
  194. 194.
    Rosenthal A, Jouet M, Kenwrick S. Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus. Nat Genet 1992;2(2):107–112.PubMedGoogle Scholar
  195. 195.
    Dahme M, Bartsch U, Martini R, et al. Disruption of the mouse L1 gene leads to malformations of the nervous system. Nat Genet 1997;17 (3):346–349.PubMedGoogle Scholar
  196. 196.
    Boison D, Stoffel W. Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice. Proc Natl Acad Sci U S A 1994;91(24):11709–11713.PubMedGoogle Scholar
  197. 197.
    Klugmann M, Schwab MH, Puhlhofer A, et al. Assembly of CNS myelin in the absence of proteolipid protein. Neuron 1997;18(1):59–70.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina de Valencia, CSIC, and CIBER de Enfermedades Raras (CIBERER)ValenciaSpain

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