Highly Elevated Prevalence of Spinobulbar Muscular Atrophy in Indigenous Communities in Canada Due to a Founder Effect

Abstract

Objective: Spinobulbar muscular atrophy (SBMA) is an X-linked adult-onset neuromuscular disorder that causes progressive weakness and androgen insensitivity in hemizygous males. This condition is reported to be extremely rare, but has higher prevalence in certain populations due to multiple founder effects. Anecdotal observations of a higher prevalence of SBMA in patients of Indigenous descent in Saskatchewan led us to perform this study, to estimate the disease prevalence, and to attempt to identify a founder effect.

Methods: For our prevalence estimation, we identified patients with confirmed SBMA diagnosis from the Saskatoon neuromuscular clinic database for comparison with population data available from Statistics Canada. For our haplotype analysis, participants with SBMA were recruited from 2 neuromuscular clinics, as well as 5 control participants. Clinical data were collected, as well as a DNA sample using saliva kits. We performed targeted quantification of DXS1194, DXS1111, DXS135, and DXS1125 microsatellite repeats and the AR GGC repeat to attempt to identify a disease haplotype and compare it with prior studies.

Results: We estimate the prevalence of SBMA among persons of Indigenous descent in Saskatchewan as 14.7 per 100,000 population. Although we believe that this is an underestimate, this still appears to be the highest population prevalence for SBMA in the world. A total of 21 participants were recruited for the haplotype study, and we identified a unique haplotype that was shared among 13 participants with Indigenous ancestry. A second shared haplotype was identified in 2 participants, which may represent a second founder haplotype, but this would need to be confirmed with future studies.

Conclusions: We describe a very high prevalence of SBMA in western Canadians of Indigenous descent, which appears to predominantly be due to a founder effect. This necessitates further studies of SBMA in these populations to comprehensively ascertain the disease prevalence and allow appropriate allocation of resources to support individuals living with this chronic disease.

Figure 1. Clinical Data in This SBMA Cohort

(A) This figure demonstrates an inverse correlation between the age at onset and the CAG expansion size in our cohort, suggesting a more severe phenotype for participants with larger expansions, as has been reported previously. (B) Longer disease duration is correlated with a lower SBMA-FRS score. (C) Compared with disease duration, the bulbar subscores of the SBMA-FRS score (components 1–5) do not appear to be associated with disease duration, whereas in (D), the limb subscores (components 6–13) appear to be correlated. SBMA-FRS = Spinobulbar Muscular Atrophy Functional Rating Scale.

Figure 2. Manually Reconstructed Haplotypes From the Participants in This Study

This figure demonstrates the location of the haplotype on the X chromosome and the loci of the different markers drawn to scale. The table represents allele sizes at different microsatellite loci, and AR repeat locations, for participants in this study. The mutant expansion in AR associated with SBMA is in the column designated “AR (CAG).” The shared haplotypes are shaded for ease of reference. In the “ID” column, participants numbered 1–21 have a diagnosis of SBMA, and their declared ethnicity is provided. Participants C1–C5 are control participants with other neuromuscular disorders (for comparison). Assuming the minimum number of recombinations, there may be up to 17 participants in this study who share a single haplotype, although for participants labeled 14–17, the small amount of similarity may have arisen by chance. Participants 18–19 appear to share a distinct haplotype. Two other participants (20 and 21) did not share either haplotype. For 2 of the participants, quantification of the AR GGC repeat failed and is represented as “NA” (not available). SBMA = spinobulbar muscular atrophy.

Figure 3. Calculated Probability That the Pathogenic Allele Occurred at Each Generation

Most likely value for the date of the most recent common ancestor of the allele in participants 1–13 is 10 generations, with 95% of the probability mass falling between 5 and 24 generations.