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Sandra Martins, PhD; Francesc Calafell, PhD; Claudia Gaspar, PhD; Virginia C. N. Wong, MD, PhD; Isabel Silveira, PhD; Garth A. Nicholson, MD, PhD; Ewout R. Brunt, MD; Lisbeth Tranebjaerg, MD, PhD; Giovanni Stevanin, PhD; Mingli Hsieh, PhD; Bing-wen Soong, MD, PhD; Leal Loureiro, MD; Alexandra Dürr, MD, PhD; Shoji Tsuji, MD, PhD; Mitsunori Watanabe, MD, PhD; Laura B. Jardim, MD, PhD; Paola Giunti, MD, PhD; Olaf Riess, MD; Laura P. W. Ranum, PhD; Alexis Brice, MD; Guy A. Rouleau, MD, PhD; Paula Coutinho, MD, PhD; António Amorim, PhD; Jorge Sequeiros, MD, PhD

Arch Neurol. 2007;64(10):1502-1508.

Background  Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution.

Objectives  To trace back in history the main mutational events in Machado-Joseph disease, we aimed to assess ancestral haplotypes and population backgrounds, to date the mutations, and to trace the routes and time of introduction of the founder haplotypes in different populations.

Design, Setting, and Participants  We studied 264 families with Machado-Joseph disease from 20 different populations. Six intragenic single-nucleotide polymorphisms were used to determine ancestral mutational events; 4 flanking short tandem repeats were used to construct extended haplotypes and measure accumulation of genetic diversity over time within each lineage.

Results  The worldwide-spread lineage, TTACAC, had its highest diversity in the Japanese population, where we identified the ancestral short tandem repeat–based haplotype. Accumulated variability suggested a postneolithic mutation, about 5774 ± 1116 years old, with more recent introductions in North America, Germany, France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA lineage, only 7 families (of 71 families) did not have Portuguese ancestry, although gene diversity was again smaller in Portuguese families (0.44) than in non-Portuguese families (0.93).

Conclusions  The worldwide-spread mutation may have first occurred in Asia and later been diffused throughout Europe, with a founder effect accounting for its high prevalence in Portugal; the other Machado-Joseph disease lineage is more recent, about 1416 ± 434 years old, and its dispersion may be explained mainly by recent Portuguese emigration.

Author Affiliations: Instituto de Patologia e Imunologia Molecular da Universidade do Porto and Faculdade de Ciências (Drs Martins and Amorim), Instituto de Biologia Molecular e Celular (Drs Silveira, Loureiro, and Sequeiros), and Instituto de Ciências Biomédicas Abel Salazar (Dr Sequeiros), University of Porto, Porto, Portugal; Unitat Biologia Evolutiva, Departament de Ciències Experimentals i de la Salut, University of Pompeu Fabra, Barcelona, Spain (Dr Calafell); Centre Hospitalier de l’Université de Montréal, Hôpital Notre Dame, Montreal, Quebec, Canada (Drs Gaspar and Rouleau); Division of Child Neurology, Developmental Paediatrics, and Neurohabilitation, Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong,China (Dr Wong); Department of Medicine, Concord Hospital, University of Sydney, Sydney, Australia (Dr Nicholson); University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands (Dr Brunt); Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark (Dr Tranebjaerg); Department of Medical Genetics, University Hospital of Northern Norway, Tromsø, Norway (Dr Tranebjaerg); Institut National de la Santé et de la Recherche Médicale Unit 679, Federative Institute for Neuroscience Research, Pitié-Salpêtrière Group, Paris, France (Drs Stevanin, Dürr, and Brice); Department of Life Science, Tunghai University, Taichung, Taiwan (Dr Hsieh); Neurological Institute, Veterans General Hospital, Taipei, Taiwan (Dr Soong); Department of Neurology, University of Tokyo, Tokyo, Japan (Dr Tsuji); Department of Neurology, Gunma University School of Medicine, Gunma, Japan (Dr Watanabe); Serviço de Genética Médica, Hospital Clínicas, Porto Alegre, Brazil (Dr Jardim); Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, England (Dr Giunti); Department of Medical Genetics, University of Tübingen, Tübingen, Germany (Dr Riess); Department of Genetics, Cell Biology, and Development and Institute of Human Genetics, University of Minnesota, Minneapolis (Dr Ranum); and Serviço de Neurologia, Hospital São Sebastião, Santa Maria da Feira, Portugal (Dr Coutinho). Dr Watanabe is now with the Department of Neurology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

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