Background: Hereditary cerebellar ataxias (HCA) and hereditary spastic paraplegias (HSP) are two groups of neurodegenerative disorders that usually present with progressive gait impairment, often leading to permanent disability. Advances in genetic research in the last decades have improved their diagnosis and brought new possibilities for prevention and future treatments. Still, there is great uncertainty regarding their global epidemiology. Summary: Our objective was to assess the global distribution and prevalence of HCA and HSP by a systematic review and meta-analysis of prevalence studies. The MEDLINE, ISI Web of Science and Scopus databases were searched (1983-2013) for studies performed in well-defined populations and geographical regions. Two independent reviewers assessed the studies and extracted data and predefined methodological parameters. Overall, 22 studies were included, reporting on 14,539 patients from 16 countries. Multisource population-based studies yielded higher prevalence values than studies based primarily on hospitals or genetic centres. The prevalence range of dominant HCA was 0.0-5.6/105, with an average of 2.7/105 (1.5-4.0/105). Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease was the most common dominant ataxia, followed by SCA2 and SCA6. The autosomal recessive (AR) HCA (AR-HCA) prevalence range was 0.0-7.2/105, the average being 3.3/105 (1.8-4.9/105). Friedreich ataxia was the most frequent AR-HCA, followed by ataxia with oculomotor apraxia or ataxia-telangiectasia. The prevalence of autosomal dominant (AD) HSP (AD-HSP) ranged from 0.5 to 5.5/105 and that of AR-HSP from 0.0 to 5.3/105, with pooled averages of 1.8/105 (95% CI: 1.0-2.7/105) and 1.8/105 (95% CI: 1.0-2.6/105), respectively. The most common AD-HSP form in every population was spastic paraplegia, autosomal dominant, type 4 (SPG4), followed by SPG3A, while SPG11 was the most frequent AR-HSP, followed by SPG15. In population-based studies, the number of families without genetic diagnosis after systematic testing ranged from 33 to 92% in the AD-HCA group, and was 40-46% in the AR-HCA, 45-67% in the AD-HSP and 71-82% in the AR-HSP groups. Key Messages: Highly variable prevalence values for HCA and HSP are reported across the world. This variation reflects the different genetic make-up of the populations, but also methodological heterogeneity. Large areas of the world remain without prevalence studies. From the available data, we estimated that around 1:10,000 people are affected by HCA or HSP. In spite of advances in genetic research, most families in population-based series remain without identified genetic mutation after extensive testing.

Keywords:
Hereditary ataxia, Hereditary spastic paraplegia, Spinocerebellar ataxia, Prevalence, Systematic review, Meta-analysis
1.
Alonso V, et al: Epidemiology of hereditary ataxias in Spain: hospital discharge registry and population-based mortality study. Neuroepidemiology 2013;41:13-19.
2.
Leone M, Chandra V, Schoenberg BS: Patterns of mortality from hereditary ataxias in the United States, 1971 and 1973-1978. Neuroepidemiology 1989;8:193-199.
3.
Refsum S, Skre H: Neurological approaches to the inherited ataxias. Adv Neurol 1978;21:1-13.
4.
Polo JM, et al: Hereditary ataxias and paraplegias in Cantabria, Spain: an epidemiological and clinical study. Brain 1991;114(pt 2):855-866.
5.
Harding AE: Classification of the hereditary ataxias and paraplegias. Lancet 1983;1:1151-1155.
6.
Maciel P, et al: Improvement in the molecular diagnosis of Machado-Joseph disease. Arch Neurol 2001;58:1821-1827.
7.
Matilla-Dueñas A: The ever expanding spinocerebellar ataxias (editorial). Cerebellum 2012;11:821-827.
8.
Wraith JE, et al: Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab 2010;99:351-357.
9.
Xia H, et al: RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 2004;10:816-820.
10.
Hoppitt T, et al: A systematic review of the incidence and prevalence of long-term neurological conditions in the UK. Neuroepidemiology 2011;36:19-28.
11.
Sequeiros J, Martins S, Silveira I: Epidemiology and population genetics of degenerative ataxias. Handb Clin Neurol 2012;103:227-251.
12.
Stroup DF, et al: Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-Analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008-2012.
13.
Neyeloff JL, Fuchs SC, Moreira LB: Meta-analyses and Forest plots using a Microsoft Excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes 2012;5:52.
14.
Koht J, Tallaksen CM: Cerebellar ataxia in the eastern and southern parts of Norway. Acta Neurol Scand Suppl 2007;187:76-79.
15.
Silva MC, et al: Hereditary ataxias and spastic paraplegias: methodological aspects of a prevalence study in Portugal. J Clin Epidemiol 1997;50:1377-1384.
16.
Mori M, et al: A genetic epidemiological study of spinocerebellar ataxias in Tottori prefecture, Japan. Neuroepidemiology 2001;20:144-149.
17.
Jardim LB, et al: A survey of spinocerebellar ataxia in South Brazil: 66 new cases with Machado-Joseph disease, SCA7, SCA8, or unidentified disease-causing mutations. J Neurol 2001;248:870-876.
18.
Infante J, et al: Autosomal dominant cerebellar ataxias in Spain: molecular and clinical correlations, prevalence estimation and survival analysis. Acta Neurol Scand 2005;111:391-399.
19.
Magariello A, et al: Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia. J Neurol Sci 2010;288:96-100.
20.
Erichsen AK, et al: Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain 2009;132:1577-1588.
21.
van de Warrenburg BP, et al: Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurology 2002;58:702-708.
22.
Tsuji S, et al: Sporadic ataxias in Japan: a population-based epidemiological study. Cerebellum 2008;7:189-197.
23.
Coutinho P, et al: Hereditary ataxia and spastic paraplegia in Portugal: a population-based prevalence study. JAMA Neurol 2013;70:746-755.
24.
Shibata-Hamaguchi A, et al: Prevalence of spinocerebellar degenerations in the Hokuriku district in Japan. Neuroepidemiology 2009;32:176-183.
25.
Sasaki H, Yabe I, Tashiro K: The hereditary spinocerebellar ataxias in Japan. Cytogenet Genome Res 2003;100:198-205.
26.
Sridharan R, et al: Prevalence and pattern of spinocerebellar degenerations in northeastern Libya. Brain 1985;108:831-843.
27.
Hirayama K, et al: Spinocerebellar degenerations in Japan: a nationwide epidemiological and clinical study. Acta Neurol Scand Suppl 1994;153:1-22.
28.
Farghaly WM, et al: Epidemiology of cerebellar ataxia in Al-Kharga district-New Valley (Egypt). Egypt J Neurol Psychiatry Neurosurg 2010;47:527-532.
29.
Joo BE, Lee CN, Park KW: Prevalence rate and functional status of cerebellar ataxia in Korea. Cerebellum 2012;11:733-738.
30.
Muzaimi MB, et al: Population based study of late onset cerebellar ataxia in south east Wales. J Neurol Neurosurg Psychiatry 2004;75:1129-1134.
31.
Zortea M, et al: Prevalence of inherited ataxias in the province of Padua, Italy. Neuroepidemiology 2004;23:275-280.
32.
Harada H, Takahashi K: Epidemiology of spinocerebellar degeneration in Tottori prefecture (in Japanese). Rinsho Shinkeigaku 1989;29:164-166.
33.
Sugawara M, et al: Hereditary ataxias in Akita prefecture (in Japanese). Rinsho Shinkeigaku 1999;39:763-766.
34.
Kita K: Spinocerebellar degeneration in Japan: the feature from an epidemiological study (in Japanese). Rinsho Shinkeigaku 1993;33:1279-1284.
35.
Woods CG, et al: Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am J Hum Genet 2006;78:889-896.
36.
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;72:43-46.
37.
Zhao Y, et al: Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore. Clin Genet 2002;62:478-481.
38.
Brignolio F, et al: Prevalence of hereditary ataxias and paraplegias in the province of Torino, Italy. Ital J Neurol Sci 1986;7:431-435.
39.
Leone M, et al: Hereditary ataxias and paraplegias in Valle d'Aosta, Italy: a study of prevalence and disability. Acta Neurol Scand 1995;91:183-187.
40.
Matilla T, et al: Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias. Hum Mol Genet 1993;2:2123-2128.
41.
Filla A, et al: Prevalence of hereditary ataxias and spastic paraplegias in Molise, a region of Italy. J Neurol 1992;239:351-353.
42.
Braschinsky M, et al: The prevalence of hereditary spastic paraplegia and the occurrence of SPG4 mutations in Estonia. Neuroepidemiology 2009;32:89-93.
43.
Wardle M, et al: The genetic aetiology of late-onset chronic progressive cerebellar ataxia: a population-based study. J Neurol 2009;256:343-348.
44.
Moseley ML, et al: Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 1998;51:1666-1671.
45.
Jiang H, et al: Frequency analysis of autosomal dominant spinocerebellar ataxias in mainland Chinese patients and clinical and molecular characterization of spinocerebellar ataxia type 6. Chin Med J 2005;118:837-843.
46.
Stevanin G, et al: Clinical and molecular features of spinocerebellar ataxia type 6. Neurology 1997;49:1243-1246.
47.
Schols L, et al: Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 1997;42:924-932.
48.
Tsai HF, et al: Analysis of trinucleotide repeats in different SCA loci in spinocerebellar ataxia patients and in normal population of Taiwan. Acta Neurol Scand 2004;109:355-360.
49.
Velãzquez-Pérez L, et al: Epidemiology of Cuban hereditary ataxia (in Spanish). Rev Neurol 2001;32:606-611.
50.
Saleem Q, et al: Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation. Hum Genet 2000;106:179-187.
51.
Giunti P, et al: The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families: frequency, clinical and genetic correlates. Brain 1998;121:459-467.
52.
Anheim M, et al: Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics 2010;11:1-12.
53.
Palau F, Espinós C: Autosomal recessive cerebellar ataxias. Orphanet J Rare Dis 2006;1:47.
54.
le Ber I, Brice A, Dürr A: New autosomal recessive cerebellar ataxias with oculomotor apraxia. Curr Neurol Neurosci Rep 2005;5: 411-417.
55.
Schüle R, et al: Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 2009;80:1402-1404.
56.
Goizet C, et al: SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum. Neurology 2009;73:1111-1119.
57.
Boukhris A, et al: Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity. Clin Genet 2009;75:527-536.
58.
Brussino A, et al: FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia. Neurology 2005;64:145-147.
59.
Pelayo-Negro AL, et al: Screening for POLG W748S and A467T mutations in ataxia patients from Spain. Mov Disord 2012;27:1326.
60.
Craig K, et al: The A467T and W748S POLG substitutions are a rare cause of adult-onset ataxia in Europe. Brain 2007;130(pt 4):E69, author reply E70.
61.
Cagnoli C, et al: Mutations in the POLG1 gene are not a relevant cause of cerebellar ataxia in Italy. J Neurol 2008;255:1079-1080.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.