Fragoso-Benítez M, Rasmussen A

Language: Spanish
References: 45
Page: 40-49
PDF size: 382.78 Kb.

ABSTRACT

Autosomal dominant spinocerebellar ataxias (ADCA) have always been difficult to classify because of their inter and intrafamilial heterogeneity. Initially, late onset ataxias were classified by Harding in 1983, dividing them into autosomal dominant ataxias, other progressive dominant diseases, episodic ADCA and late onset autosomal recessive ataxia. This classification takes into consideration major clinical aspects for the autosomal dominant ataxias: ADCA type I includes ophtalmoplegia, optic atrophy and extrapyramidal signs additional to the cardinal feature of ataxia; ADCA type II includes patients with ataxia, plus pigmentary macular degeneration, and extrapyramidal signs; ADCA type III corresponds to a “pure” cerebellar syndrome, usually with onset after the fifth decade of life. Although this classification is still applied in the clinical setting, a more recent classification has been developed since 1991, when the first of the sixteen different types of ADCA described so far, was characterized at the molecular level. This genotype-based classification is the most widely accepted at the present time, and each disorder is identified by the abbreviation of spinocerebellar ataxia (SCA) and an Arabic numeral corresponding to the number of locus discovered for each disorder. At this point, the etiologic diagnosis depends on the results of the molecular testing for SCAs; however the full panel of tests is costly, therefore, the clinical features accompanying ataxia are very important for the differential diagnosis. For example patients with SCA1, 2, 3, 4, 8, 10, 11, 12, 13, 14 and 17 have clinical features of ADCA type I, patients with ADCA type II will in the vast majority of cases have mutations in SCA7. SCA5, 6, 11, 15 and 16 have “pure” cerebellar syndromes (ADCA type III). Some of the SCAs also have signs or symptoms that lead to a high suspicion of the causative gene involved: SCA10 should be considered in any patient with ataxia plus seizures and/or psychiatric disturbances; SCA7 is the cause of ataxia plus blindness in more than 90% of cases.
A less explored, but not less important issue, is the scope of the psychologic and psychiatric disturbances that many ataxia patients suffer. Dementia has been reported in most SCAs, however, it seems to be more frequent in SCA2 and SCA10 patients, and is also prominent in the early onset cases of SCA7; SCA13 is accompanied by mental retardation and a wide array of personality disorders severe depression and anxiety are described in SCA10 and SCA17 patients. The underlying cause for the cognitive and emotional changes is unclear; two hypotheses are being entertained: that the damage to the cerebellum is responsible (in the light of reports of involvement of the cerebellum in cognitive roles); or that it is an adaptative response to a chronic and progressive disease.
The genes for SCA1-3, SCA6-8, SCA10, SCA12 and SCA17 have been cloned and the causative mutation identified. The SCAs are due to expansions of microsatellite repeats either in the coding or non-coding regions of the genes. Repeat expansion disorders are characterized by the clinical phenomenon of anticipation -earlier onset and more severe symptoms in successive generations- and, in most cases, show an autosomal dominant inheritance pattern. Most of the SCAs are due to a triplet repeat expansion in the gene’s coding region, usually a CAG repeat, that is translated into an apparently toxic polyglutamine tract in the protein. Some other SCAs are due to expansions in untranslated regions of the gene, for example, SCA8, which is caused by a nontranslated CGG repeat expansion, and SCA10 which presents a pentanucleotide (ATTCT) expansion in an intron. The different mutational mechanisms suggest a new perspective not only for the ADCAs, but for other repeat expansion disorders and probably other neurodegenerative diseases. This is supported by the findings in Myotonic Distrophy type 2, which is caused by a tetranucleotide repeat expansion. Probably there is more than one pathogenetic mechanism in these disorders, one for the types due to CAG repeat expansions and another for the mutations in non-coding regions of the genes. We describe briefly the mechanisms proposed so far.
In our review, we summarize the clinical features of the SCAs, suggest that the diagnosis of an individual affected by SCA should be based on genotype and phenotype correlations and also, propose a diagnostic algorithm for ataxic patients, including non-hereditary and recessive cases in order to ease differential diagnosis.
Some ethical concerns regarding management as there is not, by now, any effective curative treatment, and the available ones are inefficient and expensive making them inaccessible to most of patients; genetic testing which should be ordered after clinical and epidemiological considerations, in order to reduce the number of molecular tests, genetic counseling, and the possibility of predictive testing, are also outlined.

REFERENCES

1. AFIFI AK, BERGMAN RA: Functional Neuroanatomy: Text and Atlas. McGraw-Hill, 303-329, Nueva York, 1998.

2. BOTEZ-MARQUARD T, BOTEZ MI: Cognitive behavior in heredodegenerative ataxias. Eur Neurol, 33:351-357, 1993.

3. CHAFETZ MD, FRIEDMAN AL, KEVORKIAN CG, LEVY JK: The cerebellum and cognitive function: implications for rehabilitation. Arch Phys Med Rehabil, 77:1303-1308, 1996.

4. DAUM I, ACKERMANN H: Cerebellar contributions to cognition. Behav Brain Res, 67:201-210, 1995.

5. DAVID G, DURR A, STEVANIN G, CANCEL G y cols.: Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA 7). Hum Mol Genet, 7:165-170, 1998.

6. DAY JW, SCHUT LJ, MOSELEY ML, DURAND MS, RANUM LPW: Spinocerebellar ataxia type 8: Clinical features in a large family. Neurology, 55:649-657, 2000.

7. GARDNER K, ALDERSON K, GALSTER B, KAPLAN C, LEPPERT M, PTACEK L: Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA 4) in a Utah kindred. Neurology, 44(supl 2):A361, 1994.

8. HARDING AE: Clasification of the hereditary ataxias and paraplegias. Lancet, 1:1151-1153, 1983.

9. HARDING AE: Clinical features and classification of inherited ataxias. Adv Neurol, 61:1-14, 1991.

10. HERMAN-BERT A, STEVANIN G, NETTER JC, RASCOL O y cols.: Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation. Am J Hum Genet, 67:229-235, 2000.

11. HOLMES SE, O’HEARN EE, MCINNIS MG, GORELICKFELDMAN DA y cols.: Expansion of a novel CAG trinucleotide repeat in the 5’ region of PPP2R2B is associated with SCA 12. Nat Genet, 14:391-392, 1999.

12. HOLROYD S, REISS AL, BRYAN RN: Autistic features in Joubert syndrome: a genetic disorder with agenesis of the cerebellar vermis. Biol Psychiatry, 29:287-294, 1991.

13. IMBERT G, SUADOU F, YVERT G, DEVYS D y cols.: Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG /glutamine repeats. Nat Genet, 14:285-291, 1996.

14. JARDIM LB, SILVEIRA I, PEREIRA MI, FERRO A y cols.: A survey of spinocerebellar ataxia in South Brazil- 66 new cases with Machado-Joseph disease, SCA 7, SCA 8, or unidentified disease-causing mutations. J Neurol, 248(10):870- 876, 2001.

15. KAWAGUCHI Y, OKAMOTO T, TANIWAKI M, AIZAWA M y cols.: CAG expansions in a novel gene for Machado- Joseph disease at chromosome 14q32.1. Nat Genet, 8:221- 228, 1994.

16. KISH S J, EL-AWAR M, STUSS D, NOBREGA J y cols.: Neuropsychological test performance in patients with dominantly inherited ataxia: relationship to ataxia severity. Neurology, 44:1738-1746, 1994.

17. KLOCHGETHER T, SKALEJ M, WEDEKIND D, LUFT AR y cols.: Autosomal dominant cerebellar ataxia type 1. MRI-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types 1, 2 and 3. Brain, 121:1687-1693, 1998.

18. KOIDE R, IKEUCHI T, ONODERA O, TANAKA H y cols.: Unstable expansion of CAG repeat in hereditary dentatorubralpallidoluysian atrophy (DRPLA). Nat Genet, 6:9-13, 1994.

19. KOIDE R, KOBAYASHI S, SHIMOHATA T, IKEUCHI T y cols.: A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Human Mol Gen, 8(11):2047-2053, 1999.

20. KOOB MD, MOSELEY ML, SCHUT LJ, BENZOW KA, BIRD TD, DAY JW, RANUM LP: An untranslated CTG expansion causes a novel form of spinocerebellar ataxia. Nat Genet, 21:379-382, 1999.

21. LA SPADA AR: Trinucleotide repeat instability: Genetic features and molecular mechanisms. Brain Pathol, 7:943-963, 1997.

22. LIQUORI CL, MOSELEY ML, JACOBSEN JF, KRESS W, NAYLOR SL, DAY JW, RANUM LP: Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science, 293:864-867, 2001.

23. MATSUURA T, ACHARI M, KHAJAVI M, BACHINSKI LL, ZOGHBI H Y, ASHIZAWA T: Mapping of the gene for a novel spinocerebellar ataxia with pure cerebellar signs and epilepsy. Ann Neurol, 45:407-411, 1999.

24. MIYOSHI Y, YAMADA T, TANIMURA M, TANIWAKI T y cols.: A novel autosomal dominant spinocerebellar ataxia (SCA 16) linked to chromosome 8q22.1-24.1. Neurology, 57(1):96- 100, 2001.

25. O’HEARN, HOLMES SE, CALVERT PC, ROSS CA, MARGOLIS RL: SCA 12: tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion. Neurology, 56:299-303, 2001.

26. ORR HT, CHUNG M, BANFI S, KWIATKOWSKI TJ y cols.: Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet, 4:221-226, 1993.

27. ORR HT, ZOGHBI HY: SCA 1 molecular genetics: a history of a 13 year collaboration against glutamines. Hum Mol Genet 10(20):2307-2311, 2001.

28. PAULSON H, AMMACHE Z: Ataxia and hereditary disorders. Neurol Clin, 19:759-782, 2001.

29. PULST SM, NECHIPORUK A, NECHIPORUK T, GISPERT S y cols.: Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet, 14:269-276, 1996.

30. RANUM LPW, SCHUT LJ, LUNDGREN JK, ORR HT, LIVINGSTON DM: Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet, 8:280-284, 1994.

31. RASMUSSEN A, MATSUURA T, RUANO L, YESCAS P, OCHOA A, ASHIZAWA T, ALONSO E : Clinical and genetic analysis of four Mexican families with SCA type 10. Ann Neurol, 50:234-239, 2001.

32. RIVA D, GIORGI C: The cerebellum contributes to higher functions during development: evidence from a series of children surgically treated for posterior fossa tumours. Brain, 123:1051-1061, 2000.

33. SANPEI K, TAKANO H, IGARASHI S, SATO T y cols.: Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet, 14:277-284, 1996.

34. SCHÖLS L, GISPERT S, VORGERD M, MENEZES AM y cols.: Spinocerebellar ataxia type 2: genotype and phenotype in german kindreds. Arch Neurol, 54:1073-1080, 1997.

35. SCHMAHMANN JD: Neuropsychological abnormalities in cerebellar syndromes: fact or fiction? Int Rev Neurobiol, 41:455-471, 1997.

36. SCHMAHMANN JD, SHERMAN JC: Cerebellar cognitive affective syndrome. Int Rev Neurobiol, 41:433-440, 1997.

37. STOREY E, GARDNER RJ, KNIGHT MA, KENNERSON ML, TUCK RR, FORREST SM, NICHOLSON GA: A new autosomal dominant pure cerebellar ataxia. Neurolog y, 57(10):1913-1915, 2001.

38. SUBRAMONY SH, FILLA A: Autosomal dominant spinocerebellar ataxias ad infinitum? Neurology, 56:287-289, 2001.

39. TROJANO L, CHIACCHIO L, GROSSI D, PISACRETA AI y cols.: Determinants of cognitive disorders in Autosomal Dominant Cerebellar Ataxia type 1. J Neurol Sci, 157:162- 167, 1998.

40. VELAZQUEZ L, ALMAGUER L, SANTOS-FALCON N, HECHAVARRIA R y cols.: Spinocerebellar ataxia type 2 in Cuba. A study of the electrophysiological phenotype and its correlation with clinical and molecular variables. Rev Neurol, 33:1129-1136, 2001.

41. VICTOR M, ROPPER A H: Adams and Victor’s Principles of Neurology. Chapter 5. Incordination and new disorders of cerebellar function. Mcgraw-Hill, 86-98, Nueva York, 2001.

42. WORTH PF, GIUNTI P, GARDNER-THORPE C, DIXON PH, DAVIS MB, WOOD NW: Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3. Am J Hum Genet, 65:420-426, 1999.

43. YAMASHITA I, SASAKI H, YABE I, FUKAZAWA T y cols.: A novel locus for dominant cerebellar ataxia (SCA 14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4. Ann Neurol, 48(2):156-163, 2000.

44. ZHUCHENKO O, BAILEY J, BONNEN P, ASHIZAWA T y cols.: Autosomal dominant cerebellar ataxia (SCA 6) associated with small polyglutamine expansions in the α1Avoltage dependent calcium channel. Nat Genet, 15:62-69, 1997.

45. ZOGHBI HY, ORR HT: Spinocerebellar ataxias. En: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B (eds). The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, 5741-5758, Nueva York, 2001.