Selective forces acting on spinocerebellar ataxia type 3/Machado–Joseph disease recurrency: A systematic review and meta‐analysis

Abstract

Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a dominant neurodegenerative disease caused by the expansion of a CAG repeat tract in ATXN3. Anticipation and worsening of clinical picture in subsequent generations were repeatedly reported, but there is no indication that SCA3/MJD frequency is changing. Thus, we performed a systematic review and meta‐analysis on phenomena with potential effect on SCA3/MJD recurrency in populations: instability of CAG repeat transmissions, anticipation, fitness, and segregation of alleles. Transmission of the mutant allele was associated with an increase of 1.23 CAG repeats in the next generation, and the average change in age at onset showed an anticipation of 7.75 years per generation; but biased recruitments cannot be ruled out. Affected SCA3/MJD individuals had 45% more children than related controls. Transmissions from SCA3/MJD carriers showed that the expanded allele was segregated in 64% of their children. In contrast, transmissions from normal subjects showed that the minor allele was segregated in 54%. The present meta‐analysis concluded that there is a segregation distortion favoring the expanded allele, among children of carriers. Therefore, further studies on transmissions and anticipation phenomena as well as more observations about fertility are required to clarify these selective forces over SCA3/MJD.

Spinocerebellar ataxia type 2 from an evolutionary perspective: Systematic review and meta‐analysis

“…Recruitment biases were not clearly avoided in studies on instability and anticipation in SCA2, as observed previously in SCA3/MJD 61 . However, it is important to note that the main recruitment problems would tend to operate in opposite directions.…”

“…We have followed, on purpose, the same approach as the systematic review carried out on another polyQ ataxia, SCA3/MJD 61 . Our intention was to compare the evolutionary destinies of different polyQ diseases by following the same systematic questions.…”

“…Interestingly, this effect was the opposite of that observed in SCA3/MJD, where expanded alleles are favored in segregation. 61 The different directions that the segregation distortion takes place between these two diseases may mean that the polyQs in ataxin-2 and ataxin-3 would not be the real segregation modifiers (Table 1).…”

“…We have followed, on purpose, the same approach as the systematic review carried out on another polyQ ataxia, SCA3/MJD. 61 Our intention was to compare the evolutionary destinies of different polyQ diseases by following the same systematic questions. Similarities would indicate common mechanisms, linked to the polyQ tracts themselves, while differences would point out to the role of the original protein (Table 1).…”

Sleep disorders among Aboriginal Australians with Machado-Joseph Disease: Quantitative results from a multiple methods study to assess the experience of people living with the disease and their caregivers

“…The mutation is typically expanded when passed to the next generation. Known as an 'anticipation effect,' this phenomenon results in more severe symptoms manifesting 8–10 years earlier in each subsequent generation( Sena et al, 2021 ). Multiple generations may be affected concurrently, profoundly impacting caregivers, who may also be affected or at risk of MJD ( Carr et al, 2019b ).…”