Share

August 2021; 7 (4) ArticleOpen Access

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

Jamie N. Leckie, Matthew M. Joel, Kristina Martens, Alexandra King, Malcolm King, Lawrence W. Korngut, A.P. Jason de Koning, Gerald Pfeffer, Kerri L. Schellenberg
First published July 8, 2021, DOI: https://doi.org/10.1212/NXG.0000000000000607
Full PDF
Citation
Permissions

Make Comment

See Comments

Downloads
1022

Share

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.

Glossary

AR=
androgen receptor;
CI=
confidence interval;
FRS=
Functional Rating Scale;
SMBA=
spinobulbar muscular atrophy

Spinobulbar muscular atrophy (SBMA), also known as Kennedy disease, is an X-linked, progressive neuromuscular disorder in men, caused by a CAG repeat expansion (>38 CAGs) in the first exon of the androgen receptor (AR) gene. SBMA is characterized by the development of spinal and bulbar lower motor neuron disease presenting in adulthood, resulting in debilitating symptoms of muscle weakness, fasciculations, dysarthria, and difficulty swallowing.1 Androgen insensitivity can also be observed, including symptoms of gynecomastia, testicular atrophy, and reduced fertility.2 SBMA causes chronic disability and elevated risk of early mortality due to bulbar dysfunction and aspiration pneumonia.3,4

SBMA is a rare neuromuscular disorder and has an estimated population prevalence ranging from 1 to 2 per 100,000.2 Determining the precise prevalence is challenging because of the extensive clinical variability of this condition,5 and 1 prior study suggested a higher carrier frequency than expected for a disease of this rarity.6 This disease has been observed at a higher prevalence in specific populations, presumably due to founder effects.7,8 Genetic studies have identified unique haplotypes suggesting founder effects for the origins of disease for differing populations.8,–,11

We are aware of multiple anecdotal observations (both from colleagues and from reports in the literature) that suggest that a higher prevalence of SBMA may exist in individuals of Indigenous descent in Canada. One of the families in the original description of SBMA by Dr. Kennedy is alternately described as French Canadian or French Indian who immigrated to Minnesota in the early 19th century.12,13 Another reported family was of Ojibwe descent14 (personal email communication, Dr. Rockman-Greenberg, December 2020). In addition, a worldwide genomic study in 2001 described Indigenous representation from 3 of the 9 participants from the contributing author in Vancouver.11 The possibility of a high SBMA prevalence is also suggested by a prior report of homozygous females with SBMA,15 who are also of Indigenous descent (personal email communication, Dr. Rockman-Greenberg, December 2020).

This led us to perform the following study to attempt to estimate the prevalence of SBMA in the western Canadian province of Saskatchewan, as well as to perform a genetic analysis to identify a potential founder haplotype for comparison to previously published literature.10,11

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

Ethical approval was obtained from the University of Saskatchewan Biomedical Research Ethics Board (Bio-REB 536) and the University of Calgary Conjoint Health Research Ethics Board (REB15-2763). All participants provided written informed consent for clinical data collection, DNA sample collection, and genetic analyses.

Prevalence Estimation

Saskatchewan is a province of approximately 1.1 million persons.16 The only multidisciplinary motor neuron disease clinic is in the city of Saskatoon and is directed by one of the authors (K.L.S.). In general, all patients with motor neuron disease (including SBMA) in Saskatchewan are referred to this clinic for assessment. To attempt to account for all patients with SBMA in Saskatchewan, we reviewed data from the Saskatoon clinic and contacted other neurologists and physiatrists in Saskatchewan who care for patients with neuromuscular disease (listed in acknowledgements). Based on Saskatoon clinic database information, the clinic follows 29 patients with SBMA, 26 of which have self-declared Indigenous ancestry (personal communication, K.L.S.). None of the additional physicians contacted were actively following patients with SBMA, and if physicians had done so in the past, they had either already referred these patients to the clinic in Saskatoon or the patients had been lost to follow-up. To avoid potential duplication of patients, these former patients of colleagues were not included in the total numbers identified. We relied on participants recruited to our study to disclose how many additional family members they had who also had a confirmed diagnosis of SBMA. We used the most recent Statistics Canada population data from the 2016 census16 as the denominators for our prevalence estimates.

Recruitment of Participants

Our inclusion criteria included (1) confirmed diagnosis of SBMA based on clinical genetic testing, (2) age 18 years or older, and (3) ability to provide written informed consent. We identified participants from the clinics of 2 of the authors (K.L.S. and L.W.K.) as they presented for clinical follow-up over a 6-month period and invited them to participate. As part of this study, we also collected data including their age at onset (according to patient recollection and self-report), forced vital capacity, and SBMA Functional Rating Scale (SBMA-FRS) score.17 We also recruited 5 male participants who did not have a diagnosis of SBMA, for purposes of providing control comparison data for our allele sizing assays.

DNA Collection and Quality Control

Saliva samples were collected from all participants into Oragene OG-500 kits (DNA Genotek, Ottawa, Canada) according to the manufacturer's protocol. DNA was extracted according to the manufacturer's suggested protocols and DNA concentration/purity assessed with NanoDrop One Spectrophotometer (Thermo Fisher Scientific, Waltham, MA).

Microsatellite Analysis

Using PCR and fluorescently labeled primers, we performed microsatellite sizing to determine the haplotypes. We used previously published primer sequences for the AR CAG disease expansion, the AR GGC repeat, and the DXS1194, DXS1111, DXS135, and DXS1125 microsatellites.9,18,-,23 Primers for the microsatellite located in the DXS123 locus were created using Primer3web (primer3.ut.ee). All primer sequences and optimized protocols are available on request. Forward primers for each primer pair were labeled with either 5-FAM or CAL Fluor Gold 540 (Biosearch Technologies, Hoddesdon, United Kingdom).

PCR was performed using 20 μL reaction volume and Phusion High-Fidelity DNA Polymerase (Thermo Fisher Scientific), according to the manufacturer's protocols, for 40–42 cycles. The amplification of unique products was confirmed with agarose gel electrophoresis. The amplified products were analyzed in duplex (5-FAM/CAL Flour Gold 540) for cost-efficiency, using capillary electrophoresis (3730xl 96 capillary DNA Analyzer; Applied Biosystems, Waltham, MA). Fragment analysis was performed using Microsatellite Analysis Software (Applied Biosystems).

Identification of Haplotypes

Fragment sizes were recorded, and haplotypes were manually reconstructed in tabular format for comparison between participants and for comparison with previously published data.10,11

Allele Age Estimation

The time to the most recent common ancestor at the disease locus was estimated using a maximum likelihood method based on the length of the shared haplotypes across a group of patients.24 Briefly, the likelihood that the pathogenic variation occurred n generations ago is estimated based on the probability that recombination events occurred on either side of the variant assuming a star genealogy.24 The physical position of each locus on the X chromosome was identified from Ensembl. Genetic distance was estimated to be 1.272 cM/Mbp for the region based on the genetic distances of DXS1213 and DXS1194, from the archived Genethon human genetic linkage map in National Center for Biotechnology Information's retired ProbeDB.25 Recombination fractions were calculated from genetic distance with Kosambi mapping function. Likelihoods were normalized across all tested generations (0–1,000) for graphical representation. When the longest haplotype where individuals share all but the furthest markers could not be identified from the sampled markers, recombination was assumed to occur at a recombination fraction of 0.5.

Participant Engagement

On completion of the study, we offered all participants the opportunity to attend an online presentation. Our objective was to present study results to the research participants and receive direction from them regarding future directions for this work.

Data Availability

Original data will be made available to any qualified investigator on request to the corresponding author. To protect the confidentiality of participants, data will be provided in aggregate and anonymized.

Results

Prevalence Estimation

Based on the review of the Saskatoon neuromuscular clinic database, we identified a total of 29 individuals with SBMA who were being followed by the Motor Neuron Disease Clinic in Saskatoon, 26 of whom reported Indigenous ancestry.

Using publicly available data from the most recent Canadian census in 2016 from Statistics Canada,16 the total number of residents of Saskatchewan reporting single or mixed Aboriginal ancestry is 177,350. Therefore, we estimated the prevalence of SBMA among those of Indigenous descent in Saskatchewan as 14.7 per 100,000 population. The total number of Saulteaux in Saskatchewan (single or mixed ancestry) is 9,770, and in this study, 4 unrelated participants reported Saulteaux ancestry and 14 additional relatives with SBMA (Table). If this is correct, 18 patients with SBMA in a population of only 9,770 persons would equate to a prevalence of 184.24 per 100,000 population.

View this table:
Table

Clinical Data Summary of Recruited Participants

Participant Recruitment and Clinical Data

As described in Methods, we recruited consecutive participants meeting our inclusion criteria over a 6-month period. A total of 23 participants with SBMA were recruited and provided DNA samples. None of the patients with SBMA attending our clinics in the study period declined participation. Of these, DNA from 21 participants met our DNA quality control criteria. Seventeen of these participants were from Saskatchewan, and 4 participants were from Calgary. All participants had a confirmed genetic diagnosis of SBMA and self-declaration of their ethnicity. None of the participants were known to be related to each other, except for participants 4 and 5 who identified as cousins.

Clinical data were available from 19 of the participants recruited to this study (including 2 participants who consented to participate but whose DNA samples failed quality control). Their data are summarized in the table. Their average age at onset was 39.2 years (range 25–65 years), and this was correlated with the size of their CAG repeat expansions (Figure 1A). Their average SBMA-FRS score was 31.5 (range 19–48) after an average disease duration of 16.3 years (range 3–34 years), and the SBMA-FRS score was correlated with disease duration (Fgure 1B). When separating the bulbar and limb subscores of the SBMA-FRS (respectively, components 1–5 and 6–13), limb scores, but not bulbar scores, appeared to be correlated with disease duration (Figure 1, C and D). Participants of Indigenous descent who reside in the province of Saskatchewan totaled 14, and they reported an additional 23 relatives with confirmed diagnoses of SBMA.

Figure 1
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.

Haplotype Analysis

A summary of the results is presented in Figure 2. Thirteen of the participants (numbered 1–13) clearly shared a single haplotype, and all these participants declared themselves to be of Indigenous ancestry. As anticipated, participants 4 and 5 who are cousins shared an identical haplotype. Four additional participants (who did not report Indigenous ancestry) shared a small portion of this same haplotype, but it is possible that this could have occurred by chance. A second haplotype was identified in participants 18 and 19 who were not known to be related to each other and who also reported Indigenous ancestry. Two additional participants with SBMA did not share these haplotypes. The control participants all had unique findings and normal AR repeat lengths, which was expected.

Figure 2
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.

Estimated Age of the Haplotype

The maximum likelihood age of the haplotype in participants 1–13 is 10 generations (95% confidence interval [CI]: 5–24 generations; Figure 3). Assuming a generation time of approximately 25 years, this would age the variant at 250 years (95% CI: 125–600 years). This is likely a liberally young estimate, given recombination of the X chromosome occurs predominantly in females.

Figure 3
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.

Participant Engagement

We invited all participants to an online meeting using a secure platform. This meeting was held in December 2020 and provided background regarding the project and a description of the research findings. Presentations from the researchers were 45 minutes in duration, and we had a further 30 minutes of discussion and questions. Feedback from participants emphasized several themes, namely the need for future research to better understand the high SBMA prevalence in their communities, motivation to increase awareness of SBMA in their communities, and a need for additional resources to support individuals affected by SBMA. There was interest in connecting researchers with Indigenous Knowledge Holders, Elders and local community leadership to discuss the findings. There was also discussion of a patient- and community-led conference to raise awareness about SBMA and connect affected individuals with each other and necessary resources, including Indigenous Elders, Healers and Knowledge Holders. For all participants who could not attend the meeting, we mailed out a letter summarizing the findings and encouraging contact with any questions. Future engagement activities include an educational conference about SBMA, which is planned for spring of 2021.

Discussion

We report a very high prevalence of SBMA in Indigenous persons residing in Canada, which, our genetic analysis indicates, is due to a founder effect, which may have originated or been introduced in this population approximately 250 years ago. Specifically, the majority of participants in our study report their descent as being from the Cree or Saulteaux nations. Because these nations are geographically distributed across several Canadian provinces and territories, this high prevalence and founder effect may exist in other parts of Canada. Indeed, 2 of the participants in this study (8 and 9) were recruited from the neighboring province of Alberta.

In this study, we estimated the prevalence of SBMA in Indigenous persons residing in Saskatchewan as being 14.7 per 100,000 population. This prevalence is several fold higher than the estimated global prevalence for this disease of 1–2 per 100,000 population. One of the expert reviews on SBMA states that it has not been described in Indigenous populations,26 although in retrospect, SBMA has been identified in Indigenous people in scattered reports starting with the original description of this disease.11,–,15 In Veneto, Italy, an elevated prevalence of 2.58 per 100,000 males (i.e., 1.29 per 100,000 population) was reported and attributed to multiple founder effects.8 A founder effect has also been reported in Japan, although population prevalence estimates were not provided.9 The highest previously reported prevalence for SBMA is in the Vasa region of Western Finland, of 13 patients for 85,000 males7 (i.e., 7.65 per 100,000 population). If correct, the prevalence of SBMA in Indigenous people in Saskatchewan is nearly double this and could represent the highest described carrier rate for this disease in the world.

It should be emphasized that based on the approach we applied to ascertain SBMA cases in persons of Indigenous descent in Saskatchewan, our prevalence estimate is likely to be a substantial underestimate. This is also based on anecdotal observations that many affected family members of clinic attendees do not access the clinic and reports from colleagues that patients are frequently lost to follow-up. This question deserves further study to correctly identify the prevalence of this condition in these populations, ideally with the development of a Canadian disease registry for SBMA. This would identify populations and regions that would benefit from additional resources to support patients living with this chronic and disabling condition.

An important question to answer is whether the phenotype of Indigenous people who have SBMA differs from that which has been described in studies of other populations (recently reviewed27). The age at onset in our cohort was inversely correlated with the size of the expanded AR repeat, consistent with prior studies.28 Based on the clinical data in our study (presented in the Table and Figure 1), our patient cohort appears to share similar clinical characteristics with previous studies, including the inverse correlation of CAG repeat size with onset age and the gradual accumulation of disability with longer disease duration. However, the small sample size, lack of longitudinal measurements, and determination of disease onset based on participant recollection are limitations of the clinical aspects of this project. Future study will be required to confirm whether the phenotype of SBMA differs in these Indigenous populations.

This study defines the founder haplotype for SBMA in the majority of participants of Indigenous descent who were recruited. This haplotype was identified in participants recruited from both Saskatchewan and Alberta and as mentioned above may be more geographically widespread. A separate distinct haplotype is shared by 2 other participants reporting Métis descent, and future study may determine whether this haplotype is also responsible for a large proportion of SBMA cases in Métis and other Indigenous populations.

Previous studies have identified possible founder effects in different countries by studying the same 5 microsatellites.10,11 However, the results yielded by these studies differ substantially from the typically reported microsatellite repeats reported for these markers. It is possible that methodologic differences contributed to these discrepancies. As a result, it was unfortunately not possible to compare results from our study to the previously described studies.

Some limitations of our study include the small sample size and the small number of participants with SBMA from other populations. The finding of a major shared haplotype in most of the participants could have occurred if the participants are all in fact directly related to each other, but we believe this to be unlikely, especially given that 2 of the participants with the same haplotype resided in Alberta and were not aware of any relatives in Saskatchewan. For future studies, relatedness analyses and more thorough genetic investigations would be of value to give even greater confidence to the findings. Further investigation would also benefit from the inclusion of a larger number of ethnically matched controls. This may demonstrate whether the founder event occurred de novo on a common haplotype in Indigenous populations, or whether the haplotype is unique, which could provide information regarding the origins of the mutation.

The estimation of the age of the haplotype in this population preliminarily suggests that this is a fairly recent mutation in this population, occurring in the last 250 years. Despite the plausibility of this finding, it should be interpreted in light of the simplicity of the underlying method, which did not consider the potential effects of mutation, selection, population demography, or differential relatedness. Among 4 participants who share a small portion of the main common haplotype, 3 declared European descent. Further study would be required to confirm whether there is any possible relationship between this founder haplotype and European populations. Ideally, such future study would include large numbers of participants from diverse Canadian and international populations and apply more comprehensive genetic analyses. As we develop engagement with affected communities, we aim to incorporate Indigenous concepts of health in educational initiatives and future research.

There are significant health inequalities between Indigenous and non-Indigenous people in Canada, influenced by a variety of historical and sociopolitical factors.29 Many Indigenous populations have reduced access to specialist assessment and testing30 and have historically been underrepresented or even exploited in genetic research.31 Recent efforts have attempted to engage and include Indigenous populations.32 This may yet reveal other important genetic discoveries that could have an impact on the diagnosis and care for genetic conditions in Indigenous communities or other underserved populations.

Study Funding

J.N. Leckie is the recipient of a University of Calgary Program for Undergraduate Research Experience (PURE) award in 2019. Infrastructure used in this study was supported by a Canada Foundation for Innovation grant to G. Pfeffer. This study was funded by internal funds from the Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary.

Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NG for full disclosures.

Acknowledgment

The authors thank the patients for their participation in this study. They are grateful to Susan Clark for her assistance with collecting clinical data. They specially thank Dr. Cheryl Rockman-Greenberg for providing additional information regarding patients in 2 prior publications. They acknowledge the responses from Haley Block, Brad Selk, Jennifer Shi, Gary Linassi, Brendan Kushneriuk, Shane Wunder, Jackie Kraushaar, Amanda Kleisinger, Barry Bernacki, Andrew Kirk, Wendi Fitzpatrick, Ilia Poliakov, Brett Graham, and Claire Vayalumkal regarding SBMA prevalence in clinic. They also thank Rachel Vanneste, Kellie Davis, and Janet Lucas for providing information on genetic testing in Saskatchewan and Dr. Chris White who aided in identifying one of the participants for this study. They acknowledge Brooke Belanger for her assistance with Figure 2. They thank Dr. Christopher Labos for helpful discussion regarding disease prevalence estimation. They are grateful for the assistance and support of the Indigenous Research Support Team at University of Calgary's Research Services Office. Calgary is found on the traditional territories of the people of the Treaty 7 region in Southern Alberta and is also home to Métis Nation of Alberta, Region 3. Saskatoon is on Treaty 6 Territory and the Homeland of the Métis.

Appendix Authors

Table

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

  • ↵* These authors contributed equally to this work.

  • The Article Processing Charge was funded by the authors.

  • Received January 29, 2021.
  • Accepted in final form June 1, 2021.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Rhodes LE,
    2. Freeman BK,
    3. Auh S, et al
    . Clinical features of spinal and bulbar muscular atrophy. Brain. 2009;132(pt 12):3242-3251.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Breza M,
    2. Koutsis G
    . Kennedy's disease (spinal and bulbar muscular atrophy): a clinically oriented review of a rare disease. J Neurol. 2019;266(3):565-573.
    OpenUrlPubMed
  3. 3.↵
    1. Atsuta N,
    2. Watanabe H,
    3. Ito M, et al
    . Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain. 2006;129(pt 6):1446-1455.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Grunseich C,
    2. Fischbeck KH
    . Spinal and bulbar muscular atrophy. Neurol Clin. 2015;33(4):847-854.
    OpenUrl
  5. 5.↵
    1. Mariotti C,
    2. Castellotti B,
    3. Pareyson D, et al
    . Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord. 2000;10(6):391-397.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Gardiner SL,
    2. Boogaard MW,
    3. Trompet S, et al
    . Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts. JAMA Neurol. 2019;76(6):650-656.
    OpenUrl
  7. 7.↵
    1. Udd B,
    2. Juvonen V,
    3. Hakamies L, et al
    . High prevalence of Kennedy's disease in Western Finland: is the syndrome underdiagnosed? Acta Neurol Scand. 1998;98(2):128-133.
    OpenUrlPubMed
  8. 8.↵
    1. Bertolin C,
    2. Querin G,
    3. Martinelli I,
    4. Pennuto M,
    5. Pegoraro E,
    6. Soraru G
    . Insights into the genetic epidemiology of spinal and bulbar muscular atrophy: prevalence estimation and multiple founder haplotypes in the Veneto Italian region. Eur J Neurol. 2019;26(3):519-524.
    OpenUrlPubMed
  9. 9.↵
    1. Tanaka F,
    2. Doyu M,
    3. Ito Y, et al
    . Founder effect in spinal and bulbar muscular atrophy (SBMA). Hum Mol Genet. 1996;5(9):1253-1257.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Lund A,
    2. Udd B,
    3. Juvonen V, et al
    . Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia. Eur J Hum Genet. 2000;8(8):631-636.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Lund A,
    2. Udd B,
    3. Juvonen V, et al
    . Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world. Eur J Hum Genet. 2001;9(6):431-436.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Kennedy WR,
    2. Alter M,
    3. Sung JH
    . Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology. 1968;18(7):671-680.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Kennedy WR,
    2. Alter M,
    3. Sung JH
    . Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology. 1998;50(3):583 and 10 pages following.
    OpenUrl
  14. 14.↵
    1. Belsham DD,
    2. Yee WC,
    3. Greenberg CR,
    4. Wrogemann K
    . Analysis of the CAG repeat region of the androgen receptor gene in a kindred with X-linked spinal and bulbar muscular atrophy. J Neurol Sci. 1992;112(1–2):133-138.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Schmidt BJ,
    2. Greenberg CR,
    3. Allingham-Hawkins DJ,
    4. Spriggs EL
    . Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. Neurology. 2002;59(5):770-772.
    OpenUrlCrossRef
  16. 16.↵
    Statistics Canada. Canadian Census Data. Statistics Canada; 2016. www12.statcan.gc.ca/census-recensement/2016/dp-pd/index-eng.cfm (accessed 13 September 2020).
  17. 17.↵
    1. Hashizume A,
    2. Katsuno M,
    3. Suzuki K, et al
    . A functional scale for spinal and bulbar muscular atrophy: cross-sectional and longitudinal study. Neuromuscul Disord. 2015;25(7):554-562.
    OpenUrlPubMed
  18. 18.↵
    1. Cox TC,
    2. Kozman HM,
    3. Raskind WH,
    4. May BK,
    5. Mulley JC
    . Identification of a highly polymorphic marker within intron 7 of the ALAS2 gene and suggestion of at least two loci for X-linked sideroblastic anemia. Hum Mol Genet. 1992;1(8):639-641.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Donnelly A,
    2. Kozman H,
    3. Gedeon AK, et al
    . A linkage map of microsatellite markers on the human X chromosome. Genomics. 1994;20(3):363-370.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. La Spada AR,
    2. Wilson EM,
    3. Lubahn DB,
    4. Harding AE,
    5. Fischbeck KH
    . Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352(6330):77-79.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Markiewicz S,
    2. DiSanto JP,
    3. Chelly J, et al
    . Fine mapping of the human SCIDX1 locus at Xq12-13.1. Hum Mol Genet. 1993;2(6):651-654.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Twigg SR,
    2. Matsumoto K,
    3. Kidd AM, et al
    . The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males. Am J Hum Genet. 2006;78(6):999-1010.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Nagashima H,
    2. Shiraishi K,
    3. Ohkawa S, et al
    . Induction of somatic mutations by low-dose X-rays: the challenge in recognizing radiation-induced events. J Radiat Res. 2018;59(suppl_2):ii11-ii7.
    OpenUrl
  24. 24.↵
    1. Genin E,
    2. Tullio-Pelet A,
    3. Begeot F,
    4. Lyonnet S,
    5. Abel L
    . Estimating the age of rare disease mutations: the example of Triple-A syndrome. J Med Genet. 2004;41(6):445-449.
    OpenUrlFREE Full Text
  25. 25.↵
    Genethon Human Linkage Map 1995. ftp.ncbi.nih.gov/pub/ProbeDB/legacy_unists/UniSTS_MapReports/Homo_sapiens/9606.Genethon.txt (accessed 13 September 2020).
  26. 26.↵
    1. Adam MP,
    2. Ardinger HH,
    3. Pagon RA, et al.
    1. La Spada A
    . Spinal and bulbar muscular atrophy. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. University of Washington, Seattle; 1993.
  27. 27.↵
    1. Pradat PF,
    2. Bernard E,
    3. Corcia P, et al
    . The French national protocol for Kennedy's disease (SBMA): consensus diagnostic and management recommendations. Orphanet J Rare Dis. 2020;15(1):90.
    OpenUrl
  28. 28.↵
    1. Fratta P,
    2. Nirmalananthan N,
    3. Masset L, et al
    . Correlation of clinical and molecular features in spinal bulbar muscular atrophy. Neurology. 2014;82(23):2077-2084.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. King M,
    2. Smith A,
    3. Gracey M
    . Indigenous health part 2: the underlying causes of the health gap. Lancet. 2009;374(9683):76-85.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Martin D,
    2. Miller AP,
    3. Quesnel-Vallee A,
    4. Caron NR,
    5. Vissandjee B,
    6. Marchildon GP
    . Canada's universal health-care system: achieving its potential. Lancet. 2018;391(10131):1718-1735.
    OpenUrl
  31. 31.↵
    1. Guglielmi G
    . Facing up to injustice in genome science. Nature. 2019;568(7752):290-293.
    OpenUrl
  32. 32.↵
    1. Caron NR,
    2. Chongo M,
    3. Hudson M, et al
    . Indigenous genomic databases: pragmatic considerations and cultural contexts. Front Public Health. 2020;8:111.
    OpenUrl

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
Advertisement

Related Articles

  • No related articles found.

Topics Discussed

Alert Me

Recommended articles