Machado Joseph disease: clinical and genetic aspects, and current treatment

Abstract

Introduction: Spinocerebellar ataxia (SCA) type 3/Machado–Joseph disease (SCA3/MJD) is the most common SCA worldwide. SCA3/MJD is an adult onset cerebellar ataxia associated with pyramidal, lower motor neuron and extrapyramidal findings, resulting in heterogeneous phenotypic presentations. SCA3/MJD is caused by a CAG repeat expansion at the ATXN3 gene that codes for ataxin-3. Mutant ataxin-3 trigger multiple, interconnected pathogenic cascades, but many of key disease mechanisms remain unclear.

Areas covered: This review focused on the present knowledge about the genetic characteristics, ancestral origins, selective forces, clinical course and determinants of phenotypic heterogeneity of SCA3/MJD. Disease-modifying and symptomatic therapies were also detailed.

Expert opinion: Although no evidence exists for disease-modifying therapies for SCA3/MJD, symptomatic treatments for some disease signs are available. Genetic counseling is fundamental and should include discussion on options such as prenatal or pre-implantation diagnoses, and adoption, as ways to prevent the disease. Basic and translational science trying to speed the exchange of novel therapies (e.g., gene silencing) to the clinics will be central to the development of effective therapies, together with consortiums to define surrogate disease biomarkers and essential data for planning future clinical trials on SCA3/MJD.

Keywords:

• ataxin-3
• disease-modifying treatment
• Machado–Joseph disease
• polyglutamine disorders
• pre-implantation diagnosis
• spinocerebellar ataxia type 3
• symptomatic treatment

Acknowledgements

We are most grateful to all patients and families with SCA3/MJD. We thanks to Maria Luiza Saraiva-Pereira who is a long-time research partner in the field of SCAs and who is responsible for all the molecular diagnosis of the SCAs families we have been following in Brazil. We thank Eduardo Preusser Mattos for his help on building Figure 1. We are also grateful to all collaborators and to the institutions that supported our work.

Declaration of interest

LB Jardim has received institutional funding from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil; Fundação para o Amparo á Pesquisa do Rio Grande do Sul (FAPERGS), Brazil; Fundo de Apoio à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HCPA), Brazil. JAM Saute has received institutional funding from CNPq and FIPE-HCPA, Brazil. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

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