The Homogeneous Azorean Machado-Joseph Disease Cohort: Characterization and Contributions to Advances in Research

Abstract

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia worldwide. MJD is characterized by late-onset progressive cerebellar ataxia associated with variable clinical findings, including pyramidal signs and a dystonic-rigid extrapyramidal syndrome. In the Portuguese archipelago of the Azores, the worldwide population cluster for this disorder (prevalence of 39 in 100,000 inhabitants), a cohort of MJD mutation carriers belonging to extensively studied pedigrees has been followed since the late 1990s. Studies of the homogeneous Azorean MJD cohort have been contributing crucial information to the natural history of this disease as well as allowing the identification of novel molecular biomarkers. Moreover, as interventional studies for this globally rare and yet untreatable disease are emerging, this cohort should be even more important for the recruitment of trial participants. In this paper, we profile the Azorean cohort of MJD carriers, constituted at baseline by 20 pre-ataxic carriers and 52 patients, which currently integrates the European spinocerebellar ataxia type 3/Machado-Joseph disease Initiative (ESMI), a large European longitudinal MJD cohort. Moreover, we summarize the main studies based on this cohort and highlight the contributions made to advances in MJD research. Knowledge of the profile of the Azorean MJD cohort is not only important in the context of emergent interventional trials but is also pertinent for the implementation of adequate interventional measures, constituting relevant information for Lay Associations and providing data to guide healthcare decision makers.

Age-dependent somatic expansion of theATXN3CAG repeat in the blood and buccal cell DNA of individuals with spinocerebellar ataxia type 3

“…A group of 142 molecularly confirmed SCA3 affected subjects from the Azorean SCA3 cohort (Lima et al . 2023), were recruited for this study.…”

“…Amplicons were pooled, purified, and sequenced using MiSeq with 400 nt forward reads and 200 nt reverse reads, with an average read depth of ~ 24,000 aligned reads per sample. We used this approach to attempt to sequence the ATXN3 repeat from the blood DNA of 142 individuals inheriting SCA3-associated expansions belonging to the extensively studied Azorean cohort (Lima et al 2023). In addition, we also sequenced the ATXN3 repeat in paired buccal cell swab DNA samples in a subset of eleven individuals.…”

“…SCA3 was first clinically reported in two Portuguese Azorean families that had emigrated to Massachusetts, USA (Nakano et al 1972;Woods and Schaumburg 1972). SCA3 remains more frequent in Portugal, particularly in the Azores islands, with an overall prevalence of ~ 1/2,500 and a remarkable 1/158 on Flores Island (Lima et al 2023). Although the worldwide prevalence of SCA3 is much lower at ~ 1/100,000, SCA3 is nonetheless considered the most common SCA accounting for about 20 to 50% of SCA families (Klockgether et al 2019).…”

“…1972; Woods and Schaumburg 1972). SCA3 remains more frequent in Portugal, particularly in the Azores islands, with an overall prevalence of ∼ 1/2,500 and a remarkable 1/158 on Flores Island (Lima et al . 2023).…”

From stigma to increased social acceptance? Living with Machado-Joseph disease in São Miguel, Azores, Portugal

“…Symptoms generally include progressive motor impairment, incoordination of gait, speech and swallowing and ne movements of the hands, muscle atrophy, as well as involuntary eye movements, which gradually lead to a complete loss of autonomy in daily living (Coutinho & Andrade 1978;Lima and Coutinho 1980). Con rmed carriers in the Azores showed an average age at onset of 36.5 (± 9.55 SD) years (range: 16 to 60 years of age) (Lima et al 2023). MJD is the most frequent spinocerebellar ataxia worldwide, with higher frequencies described in Brazil, Portugal, and China (Sequeiros, Martins, and Silveira 2012).…”