Abstract
The clinical classification of autosomal dominant cerebellar ataxias (ADCAs) is intricate due to the variable and unpredictable association of signs and symptoms of central nervous system (CNS) and peripheral nervous system (PNS) deterioration during the life of a patient. However, for many purposes, particularly patient management, clinical systematics is the most useful method for labelling patients; in some instances there is no basis for any more fundamental classification of phenotypes. On the other hand, recent molecular-genetic approaches to dominant ataxias have had a profound impact in nosology, diagnostic procedures and the management of patients, since they are based on the fact that all mendelian neurological diseases can be precisely classified according to the locus involved as well as the particular mutant allele at that locus. Therefore, a clinical and genetic classification of dominant ataxias is herewith proposed as the best nosographical choice. Clinical, neuropathological, genetic, and pathogenetic aspects of ADCAs are reviewed and discussed to help the clinical neurologist guide diagnostic procedures and manage ataxic patients.
Sommario
La classificazione clinica delle atassie cerebellari dominanti autosomiche (ADCA) è intrinsecamente complessa poiché i segni e i sintomi di sofferenza del sistema nervoso centrale e periferico si associano in modo variabile e spesso imprevedibile durante la vita dei pazienti affetti da diverse forme dominanti di atassia. Tuttavia, in assenza di criteri più stringenti per una precisa nosografia, una distinzione semiologica basata sui principali segni clinici è il metodo più utile per un primo inquadramento diagnostico dei malati. Le informazioni di genetica molecolare ottenute recentemente nelle atassie dominanti hanno modificato questa pur utile nosografia, perché portano il contributo di un dato biologico fondamentale consistente nel fatto the ogni malattia ereditaria può essere precisamente classificata sulla base sia del locus genetico coinvolto sia della mutazione eziologicamente responsabile. Sulla base di queste semplici considerazioni si propone una classificazione clinica e genetica delle atassie dominanti. I principali aspetti clinici, neuropatologici, genetici, sono presentati insieme ad una discussione sugli aspetti patogenetici delle ADCA per fornire al neurologo clinico una guida razionale e aggiornata ally diagnosi e alla gestione dei pazienti con atassia.
Similar content being viewed by others
References
Harding AE (1983) Classification of hereditary ataxias and paraplegias. Lancet i:1151–1155
Hammans SR (1996) The inherited ataxias and the new genetics. J Neurol Neurosurg Psychiatry 61:327–332
Hardy J, Gwinn-Hardy K (1998) Genetic classification of primary neurodegenerative disease. Science 282:1075–1079
Zoghbi HY, Jodice C, Sandkuijl LA, Kwiatkowski TJ, McCall AE, Huntoon SA, Lulli P, Spadaro M, Litt M, Cann HM, Frontali M, Terrenato L (1991) The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds. Am J Hum Genet 49:23–30
Jodice C, Frontali M, Persichetti F, Novelletto A, Pandolfo M, Spadaro M, Giunti P, Schinaia G, Lulli P, Malaspina P, Plasmati R, Tola R, Antonelli A, Di Donato S, Morocutti C, Weissenbach J, Camm HM, Terrenato L (1993) The gene for spinal cerebellar ataxia 1 (SCAT) is flanked by two closely linked highly polymorphic microsatellite loci. Hum Mol Genet 2(9):1383–1387
Gispert S, Twells R, Orozco G, Brice A, Weber J, Heredero L, Scheufler K, Riley B, Alotey R, Nothers C, Hillermann R, Lunkes A, Khati C, Stevanin G, Hernandez A, Magarino C, Klockgether T, Durr A, Chneiweiss H, Enczmann J, Farrall M, Beckmann J, Mullan M, Wernet P, Agid Y, Freund H-J, Williamson R, Auburger G, Chamberlain S (1993) Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q2324.1. Nat Genet 4:295–299
Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, Shimazaki H, Soutome M, Endo K, Ohta S, Kagawa Y, Kanazawa I, Mizuno Y, Yoshida M, Yuasa T, Horikawa Y, Oyanagi K, Nagai H, Kondo T, Inuzuka T, Onodera O, Tsuji S (1993) The gene for Machado-Joseph disease maps to human chromosome 14q. Nat Genet 4:300–303
Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert ME, Kaplan C, Ptacek LJ (1996) Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): Clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 59:392–399
Teh BT, Silburn P, Lindblad K, Betz R, Boyle R, Schalling M, Larsson C (1995) Familial periodic cerebellar ataxia without myokymia maps to a 19-cM region on 19p13. Am J Hum Genet 56:1443–1449
Zoghbi HY (1996) The expanding world of ataxins. Nat Genet 14:237–238
Orr HT, Chung M, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beauder AL, McCall AE, Duvick LA, Ranum LPW, Zoghbi HY (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 4:221–226
Banfi S, Servadio A, Chung M, Kwiatkowski TJ Jr, McCall AE, Duvick Shen Y, Roth EJ, Orr HT, Zoghbi HY (1994) Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nat Genet 7:513–520
Ranum LPW, Lundgren JK, Schut LJ et al (1995) Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. Am J Hum Genet 57:603–608
Chung M, Ranum LPW, Duvick LA, Servadio A, Zoghbi HY, Orr HT (1993) Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type 1. Nat Genet 5:254–258
Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, Wakisaka A, Tashiro K, Ishida Y, Ikeuchi T, Koide R, Saito M, Sato A, Tanaka T, Hanyu S, Takiyama Y, Nishizawa M, Shimizu N, Nomura Y, Segawa M, Iwabuchi K, Eguchi I, Tanaka H, Takanashi H, Tsuji S (1996) Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 14:277–284
Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier J-M, Weber C, Mandel J-L, Cancel G, Abbas N, Durr A, Didierjean O, Stevanin G, Agid Y, Brice A (1996) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 14:285–291
Pulst S-M, Nechiporuk A, Nechiporuk T, Gispert S, Chen X-N, Lopez-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, Dejong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa C, Sahba S (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 14:269–276
Schöls L, Gispert S, Vorgerd M et al (1997) Spinocerebellar ataxia type 2. Genotype and phenotype in German kindreds. Arch Neurol 54:1073–1080
Geschwind DH, Perlman S, Figueroa CP, Treiman LJ, Pulst SM (1997) The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia. Am J Hum Genet 60:842–850
Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, Kimura J, Narumiya S, Kakizuka A (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8:221–228
Maruyama H, Nakamura S, Matsuyama Z et al (1995) Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease. Hum Mol Genet 4:807–812
Schols L, Vieira-Saecker AMM, Schols S, Przuntek H, Epplen JT, Riess O (1995) Trinuclectide expansion within the MJDI gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients. Hum Mol Genet 4(6):1001–1005
Giunti P, Sweeney MG, Harding AE (1995) Detection of the Machado-Joseph disease/spinocerebellar ataxia three trinucleotide repeat expansion in families with autosomal dominant motor disorders, including the Drew family of Walworth. Brain 118:1077–1085
Matilla T, McCall A, Subramony SH, Zoghbi HY (1995) Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease. Ann Neurol 38:68–72
Lunkes A, Mandel JL (1997) Polyglutamines, nuclear inclusions and neurodegeneration. Nat Med 3:1201–1202
Brice A (1998) Unstable mutations and neurodegenerative disorders. J Neurol 505–510
Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC (1997) Autosomal dominant cerebellar ataxia (SCA6)associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel. Nat Genet 15:62–69
Gomez CM, Thompson RM, Gammack JT, Perlman SL, Dobyns WB, Truwit CL, Zee DS, Clark HB, Anderson JH (1997) Spinocerebellar ataxia type 6: Gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann Neurol 42:933–950
Schols L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess O (1997) Autosomal dominant cerebellar ataxia: Phenotypic differences in genetically defined subtypes? Ann Neurol 42:924–932
Stevanin G, Durr A, David G, Didierjean O, Cancel G, Rivaud S, Tourbah A, Warter J-M, Agid Y, Brice A (1997) Clinical and molecular features of spinocerebellar ataxia type 6. Neurology 49:1243–1246
Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM (1997) Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations. Neurology 49:1247–1251
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SMG, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen G-J B, Hofker MH, Ferrari MD, Frants RR (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552
Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, Francia A, Spadaro M, Pierelli F, Salvi F, Ophoff RA, Frants RR, Frontali M (1997) Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Genet 6(11):1973–1978
Gouw LG, Kaplan CD, Haines JH, Digre KB, Rutledge SL, Matilla A, Leppert M, Zoghbi HY, Ptacek LJ (1995) Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet 10:89–93
Benomar A, Krols L, Stevanin G, Cancel G, LeGuern E, David G, Ouhabi H, Martin JJ, Durr A, Zaim A, Ravisé N, Busque C, Penet C, Van Regemorter N, Weissenbech J, Yahyaoui M, Chkili T, Agid Y, Van Broeckhoven C, Brice A (1995) The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3p12-p21.1. Nat Genet 10:84–88
Lindblad K, Savontaus M-L, Stevanin G et al (1996) An expanded CAG sequence in spinocerebellar ataxia type 7. Genome Res 6:965–971
David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C, Imbert G, Saudou F, Antoniou E, Drabkin H, Gemmill R, Giunti P, Benomar A, Wood N, Ruberg M, Agid Y, Mandel JL, Brice A (1997) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 17:65–70
Ranum LPW, Schut LJ, Lundgren JK, Orr HT, Livingston DM (1994) Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 8:280–284
Browne DL, Gancher ST, Nutt JG, Brunt ERP, Smith EA, Kramer P, Litt M (1994) Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet 8:136–140
Lubbers WJ, Brunt ERP, Scheffer H, Litt M, Stulp R, Browne DL, van Weerden TW (1995) Hereditary myokymia and paroxysmal ataxia linked to chromosome 12 is respon sive to acetazolamide. J Neurol Neurosurg Psychiatry 59:400–405
Komure O, Sano A, Nishino N, Yamauchi N, Ueno S, Kondoh K, Sano N, Takahashi M, Murayama N, Kondo I, Nagafuchi S, Yamada M, Kanasawa I (1995) DNA analysis in hereditary dentatorubral-pallidoluysian atrophy. Neurology 45:143–149
Warner TT, Williams LD, Walker RWH, Flinter F, Robb SA, Bundey SE, Honavar M, Harding AE (1995) A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families. Ann Neurol 37(4):452–459
Burke JR, Wingfield MS, Lewis KE, Roses AD, Lee JE, Hulette C, Pericak-Vance MA, Vance JM (1994) The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family. Nat Genet 7:521–524
Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N, Tanaka Y, Kikushima H, Umino K, Kurosawa H, Furukawa T, Nihei K, Inoue T, Sano A, Komure O, Takahashi M, Yoshizawa T, Kanasawa I, Yamada M (1994) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet 6:14–18
Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T, Saito M, Tomoda A, Miike T, Naito H, Ikuta F, Tsuji S (1994) Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet 6:9–13
Nagafuchi S, Yanagisawa H, Ohsaki E, Shirayama T, Tadokoro K, Inoue T, Yamada M (1994) Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA) Nat Genet 8:177–182
Komure O, Sano A, Nishino N, Yamauchi N, Ueno S, Kondoh K, Sano N, Takahashi M, Murayama N, Kondo I, Nagafuchi S, Yamada M, Kanasawa I (1995) DNA analysis in hereditary dentatorubral-pallidoluysian atrophy. Neurology 45:143–149
Yasawa I, Nukina N, Hashida H, Goto J, Yamada M Kanasawa I (1995) Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain. Nat Genet 10:99–103
Villani F, Gellera C, Spreafico R, Castellotti B, Casazza M, Carrara F, Avanzini G (1998) Clinical and molecular findings in the first identified Italian family with dentatorubral-pallidoluysian atrophy. Acta Neurol Scand (in press)
Robitaille Y, Schut L, Kish SJ (1995) Structural and immunocytochemical features of olivopontocerebellar atrophy caused by the spinocerebellar ataxia type 1 (SCA-1) mutation define a unique phenotype. Acta Neuropathol 90:572–581
Durr A, Smadja D, Cancel G, Lezin A, Stevanin G, Mikol J, Bellance R, Buisson G-G, Chneiweiss H, Dellanave J, Agid Y, Brice A, Vernant J-C (1995) Autosomal dominant cere bellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 118:1573–1581
Durr A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean O, Chneiweiss H, Benomar A, Lyon-Caen O, Julien J, Serdaru M, Penet C, Agid Y, Brice A (1996) Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol 39:490–499
Rubinsztein DC, Amos W, Leggo J, Goodburn S, Ramesar RS, Old J, Bontrop R, McMahon R, Barton DE, Ferguson-Smith MA (1994) Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence. Nat Genet 7:525–530
Kameya T, Abe K, Aoki M et al (1995) Analysis of spinocerebellar ataxia type 1 (SCA1)-related CAG trinucleotide expansion in Japan. Neurology 45:1587–1594
Giunti P, Sabbadini G, Sweeney MG et al (1998) The role of SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates. Brain 121:459–467
Silveira I, Lopes-Cendes I, Kish S et al (1996) Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients. Neurology 46:214–218
Pareyson D, Gellera C, Castellotti B, Antonelli A, Riggio MC, Mazzucchelli F, Girotti F, Pietrini V, Mariotti C, Di Donato S (1998) Clinical and molecular studies in 73 Italian ADCA I families; SCA I1and SCA 2 are the most common genotypes. J Neurol (in press)
Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM (1997) Spinocerebella ataxia type 6. Frequency of the mutation and genotype-phenotype correlations. Neurology 49:1247–1251
Pulst S-M, Nechiporuk A, Starkman S (1993) Anticipation in spinocerebellar ataxia type 2. Nat Genet 5:8–10
Chong SS, McCall AE, Cota J, Subramony SH, Orr HT, Hughes MR, Zoghbi HY (1995) Gametic and somatic tissue-specific heterogeneity of the expanded SCA 1 CAG repeat in spinocerebellar ataxia type 1. Nat Genet 10:344–350
Lopes-Cendes I, Maciel P, Kish S, Gaspar C, Robitaille Y, Clark HB, Koeppen AH, Namce M, Schut L, Silveira I, Coutinho P, Sequeiros J, Rouleau GA (1996) Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease. Ann Neurol 40:199–206
Servadio A, Beena K, Armstrong D, Antalffy B, Orr HT, Zoghbi HY (1995) Expression analysis of the ataxin-1 protein in tissue from normal and spinocerebellar ataxia type 1 individuals. Nat Genet 10:94–98
Paulson HL, Das SS, Crino PB, Perez MK, Patel SC, Gotsdiner D, Fischbeck, Pittman RN (1997) Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann Neurol 41:453–462
Hurtley SM (1998) Neurodegeneration. Science 282:1071
Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A (1996) Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 13:196–202
Burringht EN, Clark HB, Servadio A, Matilla T, Feddersen RM, Yunis WS, Duvick LA, Zoghbi HY, Orr HT (1995) SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82:937–948
Matsumura R, Futamura N, Fujimoto Y, Yanagimoto S, Horikawa H, Suzumura A, Takayanagi T (1997) Spinocerebellar ataxia type 6. Molecular and clinical fea tures of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology 49:1238–1243
Perutz MF (1996) Glutamine repeats and inherited neurodegenerative diseases: molecular aspects. Curr Opin Struct Biol 6:848–858
Skinner PJ, Koshy BT, Cummings CJ, Klement IA, Helin K, Servadio A, Zoghbi HY, Orr HT (1997) Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389:971–974
Matilla A, Koshy BT, Cummings CJ, Isobe T, Orr HT, Zoghbi HY (1997) The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389:974–978
Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel J-L, Fischbeck KH, Pittman RN (1997) Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19:333–344
Igarashi S, Koide R, Shimohata T, Yamada M, Hayashi Y, Takano H, Date H, Oyake M, Sato T, Egawa S, Ikeuchi T, Tanaka H, Nakano R, Tanaka K, Hozumi I, Inuzuka T, Takanashi H, Tsuji S (1998) Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet 18:111–117
Price DL, Sisodia SS, Borchelt DR (1998) Genetic neurodegenerative diseases: the human illness and transgenic models. Science 282:1079–1083
Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of Intranuclear inclusions. Cell 95:55–66
Koshy B, Matilla T, Burright EN, Merry DE, Fischbeck KH, Orr HT, Zoghbi HY (1996) Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase. Hum Mol Genet 5(9):1311–1318
Klement IA, Skinner PJ, Kayton MD, Yi H, Hersh SM, Clark HB, Zoghbi HY, Orr HT (1998) Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA-1 transgenic mice. Cell 95:41–53
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Di Donato, S. The complex clinical and genetic classification of inherited ataxias. I. Dominant ataxias. Ital J Neuro Sci 19, 335–343 (1998). https://doi.org/10.1007/BF02341779
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02341779