1.1 Clinical Features and Prevalence in the Indigenous Population of Western Canada
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is an X-linked recessive neuromuscular disease with slow progression, caused by mutations in the androgen receptor gene [
1,
2]. The disease typically only affects males, but females can be carriers and sometimes experience muscle cramps. It typically has an onset at around 30-40 years of age in patients, with symptoms such as hand tremors, muscle cramps, and back pain arising first [
1,
3]. As the disease progresses, patients begin to experience muscle weakness, usually starting from the lower limbs. Within a few years after the onset of muscle weakness, many patients will require a handrail to climb the stairs [
3]. Fasciculations also appear early in the disease, commonly appearing in the lower areas of the face. As the bulbar muscles start to weaken, SBMA patients notice difficulties with speech and swallowing [
2]. Large natural history studies have identified that these bulbar symptoms begin to appear at an average age of 50 [
3]. Near the end of the disease, patients begin needing assistance from canes or wheelchairs. A common cause of death in SBMA patients is aspiration pneumonia due to bulbar weakness [
3].
Beyond the neuromuscular symptoms, SBMA also has an effect on endocrine function. Changes in the functionality of the androgen receptor result in partial androgen insensitivity in many patients, which often appears prior to any muscular symptoms [
4,
5,
6]. Gynecomastia is the most common manifestation of androgen insensitivity in SBMA, with over 70% of patients experiencing it, according to multiple studies [
4,
5,
6]. Other common symptoms include erectile dysfunction, testicular atrophy, and fertility problems. SBMA also has an effect on metabolism, and many patients display above-average levels of cholesterol and triglycerides, as well as elevated rates of diabetes, insulin resistance, and non-alcoholic fatty liver disease [
6,
7]. No cure currently exists for SBMA [
8]. Typical management strategies include occupational and speech therapies, screening for respiratory problems, and pharmacological therapies to manage symptoms [
9]. However, these approaches fail to address the underlying disease.
SBMA has a prevalence of 1-2 individuals per 100,000 people [
2,
10]. The mutation causing SBMA appears to have occurred independently in various populations worldwide, with different founder haplotypes of the disease found in the Scandinavian countries, Japan, Germany, Italy, Australia, and Canada [
11]. A higher prevalence of the disease in certain areas of the world is associated with founder effects. For example, in the region of Vaasa, Finland, the prevalence of SBMA is estimated to be around 7.65 per 100,000 [
12,
13]. This high prevalence has been attributed to a founder effect resulting from an ancient mutation in Western Finland [
13]. A similar founder effect was also observed in a group of Japanese SBMA patients through genetic analysis [
14].
The highest prevalence of SBMA in a population found thus far is in the Indigenous population of Saskatchewan, Canada, where the estimated prevalence is 14.7 per 100,000 people [
12]. The authors of the study, Leckie et al., also noticed a high representation of patients with Saulteaux background (either from the clinic they were studying or reported relatives), and predicted an even higher prevalence of 184.24 per 100,000 people in the Saulteaux community of Saskatchewan [
12]. Notably, two participants in the study were recruited from the neighboring province of Alberta, indicating that this high prevalence may extend beyond Saskatchewan [
12]. Despite already demonstrating a much higher SBMA prevalence than any other population, the authors of this paper believe that these numbers could still be underestimated, as many individuals living with SBMA in the Indigenous communities do not currently go to the neuromuscular clinic [
12]. [
12]Their findings suggest that the prevalence in Indigenous populations in Saskatchewan may represent the highest carrier rate for SBMA worldwide.
The high prevalence in the Indigenous communities of Saskatchewan has been associated with a founder effect, with the majority of patients in Leckie et al.’s study sharing the same haplotype [
12]. Their findings suggest the founder effect likely originated approximately 250 years ago in this population. A second, distinct haplotype found in the study may also point to further founder effects in Métis and other Indigenous populations [
12]. However, the authors mention that further research incorporating relatedness analyses, comprehensive genetic investigations, and larger ethnically matched control groups is necessary to strengthen these findings and gain more insights into the origin of the mutations.
Leckie et al. also explored whether Indigenous individuals with SBMA have different phenotypes compared to those documented previously in other parts of the world [
12]. Like previous findings, their study indicates a slow progression of the disease, with the accumulation of weakness over time, as well as an inverse correlation between age at onset of SBMA and the size of the expanded androgen receptor (AR) repeat [
12]. However, future studies with a larger sample size and more extended observation of the patients over time are needed to confirm potential phenotype differences in Indigenous populations.
The study also highlights the significant health disparities that Indigenous individuals still face in Canada, stemming from Canada’s colonial history and the wide array of social, economic, and political barriers present for Indigenous Canadians [
12,
15]. Indigenous populations often face barriers to accessing specialists for diagnosis and treatment in Canada, and are often not included in genetic research [
16]. Recently, more care has been taken to involve Indigenous populations in genetic research whilst respecting their concerns, allowing better representation and the potential for improved future treatment of genetic conditions in Indigenous communities [
12,
17]. In terms of SBMA, Leckie et al suggest that a Canadian disease registry for SBMA may help further research into this disease and guide clinical efforts towards critical areas [
12].
1.2 Mechanism and genetics
Spinal and bulbar muscular atrophy results from mutations in the
AR gene encoding for the androgen receptor. The androgen receptor protein is one of many steroid hormone receptors belonging to the nuclear receptor superfamily and works to facilitate the effect of androgens on the body [
18,
19]. First discovered in humans in 1988, the
AR gene is located on the long arm of the X chromosome at Xq11-12 and encodes for a 110 kDa protein product [
20,
21,
22,
23,
24]. The
AR gene is comprised of 8 exons that encode the three major domains of AR protein known as the transactivation domain, the DNA-binding domain, and the ligand-binding domain [
18,
25]. Interestingly, these three functional domains demonstrate differing degrees of conservation as the transactivation domain, coded by exon 1, is highly variable and known to have repeated glutamine, proline, and glycine residues [
20]. In contrast, the DNA-binding domain encoded by exons 2 and 3 of the
AR gene is conserved in all members of the steroid receptor superfamily [
20,
26]. The remaining exons 4-8 are less conserved and code for the ligand-binding domain of the AR gene [
20,
27].
SBMA belongs to a class of diseases known as trinucleotide repeat expansion disorders and results from a pathologic polyglutamine expansion in the first exon of the androgen receptor gene, characterized by glutamine residues encoded at a higher-than-normal range near the transcriptional activation domain of the AR protein [
28]. In a healthy individual there are typically between 9-36 CAG repeats in this region, and SBMA begins to manifest with more than 38 repeats present [
29]. Although it is not the most well-known of the group, SBMA holds the title as the first identified repeat expansion disease. In addition to SBMA, 8 other diseases stem from CAG-polyglutamine repeat expansions, all of which are characterized by their progressive neurodegenerative effects on humans [
30]. These include Huntington’s disease, dentatorubral-pallidoluysian atrophy (DRPLA), and Spinocerebellar ataxia types 1, 2, 3, 6,7, and 17 [
30].
The androgen receptor functions as a ligand-dependent transcription factor that regulates, in coordination with other co-regulatory proteins, the transcription of the androgen-responsive genes via binding to their regulatory sites when in its androgen-bound form [
18]. In its inactive form, AR is localized to the cytoplasm where it, like other members of the steroid hormone receptors family, forms a complex with heat shock proteins [
31]. Upon androgen (testosterone or dihydrotestosterone) binding, AR undergoes a conformational change and a subsequent detachment of heat shock proteins, preparing AR for translocation into the nucleus [
28,
31,
32,
33,
34,
35,
36,
37]. Following androgen binding, AR undergoes dimerization and is targeted to the nucleus where it binds to androgen-responsive elements found on androgen-regulated genes, regulating their expression [
30].
SBMA is a disease characterized by both gain- and loss-of-function mechanisms [
38] (
Figure 1). The neurotoxic effects seen across the majority of polyglutamine expansion diseases indicate a toxic gain-of-function as the cause of neurodegeneration, consistent with the dominant pattern of inheritance in almost all these diseases [
39,
40]. This suggests that the encoded polyQ-AR protein is structurally modified in a way that enables it to introduce a new function that is pathogenic to neurons [
39]. Interestingly, a secondary loss-of-function component is also believed to contribute to the pathogenesis of polyglutamine diseases, which manifests as partial androgen insensitivity [
38].
Figure 1.
The effects of androgens binding on Wild-Type (WT) and polyglutamine (PolyQ) androgen receptors (AR) and their function in cells. Androgen binding to AR in the cytoplasm induces a conformational change in the AR before its subsequent translocation into the nucleus, where it functions as a transcription factor. However, in the case of polyQ AR, a distinct formation of aggregates upon Androgen binding is evident. These PolyQ AR aggregates are characterized by their gain and loss of function mechanisms. Some of the gain of function mechanisms resulting from polyQ AR aggregates include neuronal degeneration, altered protein-protein interactions, sequestration of cellular components, and inhibition of cellular transport. On the other hand, a Loss of function mechanism that results from polyQ AR aggregates is the loss of AR trophic support via the downregulation of the transcription of growth factors like VEGF.
Figure 1.
The effects of androgens binding on Wild-Type (WT) and polyglutamine (PolyQ) androgen receptors (AR) and their function in cells. Androgen binding to AR in the cytoplasm induces a conformational change in the AR before its subsequent translocation into the nucleus, where it functions as a transcription factor. However, in the case of polyQ AR, a distinct formation of aggregates upon Androgen binding is evident. These PolyQ AR aggregates are characterized by their gain and loss of function mechanisms. Some of the gain of function mechanisms resulting from polyQ AR aggregates include neuronal degeneration, altered protein-protein interactions, sequestration of cellular components, and inhibition of cellular transport. On the other hand, a Loss of function mechanism that results from polyQ AR aggregates is the loss of AR trophic support via the downregulation of the transcription of growth factors like VEGF.
The mechanism underlying the neurodegenerative gain-of-function symptoms present in SBMA is not yet fully understood [
41]. A leading hypothesis is that the well-documented accumulation and aggregation of polyQ-AR in the nucleus could be contributing to disease and motor neuron degeneration. The formation of nuclear aggregates of mutant AR is evident in both motor neurons of the spinal cord and the brain stem as well as some non-neural tissue [
42]. The expansion of the polyglutamine tract in AR affects the folding of the final AR product and is associated with an increase in α-helical structures [
43,
44,
45]. Further, it increases the stability of α-helices via the unconventional hydrogen binding of the glutamine side chain and main chain carbonyl group [
43,
45]. It has also been reported that this abnormal hydrogen bonding plays a role in the formation of antiparallel β-strands of polyglutamine repeats into sheets or barrels [
46]. These structural changes may result in abnormal protein-protein interaction and/or the subsequent degradation of mutant proteins [
39]. Others have argued that aggregation arises as the expanded polyglutamine tract could serve as a substrate for the catalysis of cross-linked protein products via transglutaminase activity, leading to the formation of aggregates and their possible breakdown [
39,
40,
47]. While it remains unclear exactly how these protein aggregates cause disease, they are thought to be closely related to the impaired axonal transport and ultimate neuronal degeneration observed in SBMA [
48,
49,
50].
The loss-of-function mechanism has been better characterized and is a combination of androgen insensitivity and reduced trophic support. Androgen insensitivity arises due to a reduction in the appropriate function of polyQ-AR protein, corresponding with a decrease in expression of genes typically activated by testosterone and dihydrotestosterone [
27]. Additionally, polyQ-AR has been shown to display altered binding to CREB binding protein (CBP), leading to reduced transcriptional activity for genes modulated by this complex, most notably vascular endothelial growth factor (VEGF) [
51]. VEGF has previously been reported to be downregulated in SBMA mice, and it is thought that this loss of trophic support could also contribute to the motor neuron pathogenesis of SBMA [
38,
51].