SBMA is a rare, debilitating, neurodegenerative disorder with no effective treatment. Although the cause of SBMA is known, there are unanswered questions about its natural history and the factors that determine its clinical course. Information regarding those prognostic factors and the clinical manifestations of SBMA may be essential for the design and conduct of future therapeutic trials.
In the development of a treatment for SBMA, early intervention may also be important to affect disease progression. The subjects in our study did not seek medical attention until an average of 2 years after symptom onset, and there was an additional 3 years from first medical evaluation until a clinical diagnosis of SBMA was made. Increased knowledge about SBMA and its clinical manifestations, together with increased availability of confirmatory genetic testing, should speed the diagnosis of SBMA.
The principal clinical features of SBMA in this study confirm the findings of other retrospective analyses (Kennedy et al.
; Lieberman et al.
). Muscle cramps were often reported as a first symptom, but leg weakness, tremor and bulbar involvement were also common. Sixteen of 50 subjects had no known family history, which is likely to be due to inheritance through non-manifesting female carriers.
The weakness affected upper and lower extremities and proximal and distal muscles similarly. A majority of the patients had some asymmetry in muscle strength, and interestingly 69% of these had greater weakness on the dominant side. Such dominant-side predominant weakness has been described in other neuromuscular disorders, particularly facioscapulohumeral dystrophy, and it may reflect asymmetric muscle use.
We found an inverse association between CAG repeat length and age at evaluation as reported previously (Atsuta et al.
). Androgen levels and strength both correlated inversely with the age of the subjects in this study. However, after adjusting for age (or disease duration) and repeat length, serum testosterone still correlated positively with muscle strength, as indicated by QMA and timed 2 min walk ().
In contrast to previous reports, our SBMA subjects had mean cholesterol and glucose levels similar to a national sample of men in the same age range, although 53% had elevated cholesterol and 12% increased fasting glucose levels relative to the laboratory reference standards ().
As shown in , the SBMA population scored consistently lower in functional, physiological, and self-reported quality of life measures than age-matched healthy controls. SBMA scores resembled those reported in other impaired populations, e.g. the timed 2 min walk in 12 subjects (7 men and 5 women) with Parkinson's disease (Light et al.
), and the IIEF scores in patients with symptomatic erectile dysfuction (Dinsmore et al.
The decrease in physical function in SBMA is associated with lower scores in ADL and quality of life. The activity scores in the ADL questionnaire were decreased 5%-47% from maximal (normal). The mean ambulation velocities, both with and without gait aids, were less than what is normally required to cross a street in a pedestrian crosswalk (1.2 m/s) (http://mutcd.fhwa.dot.gov/pdfs/2003r1r2/mutcd2003r1r2complet.pdf
). The divergence of the PCS and MCS scores on the SF-36v2 points to the physical burden of SBMA and indicates the patients' relatively normal psychological well being.
Reliable outcome measures will be needed to assess therapeutic efficacy in future clinical trials of SBMA. In this analysis, we examined several different measures used to quantify disease related deficits. Our cross-sectional analysis indicates that the QMA and timed 2 min walk appear promising as feasible, quantitative, and potentially meaningful measures of clinical status in SBMA. Each correlated with self-assessed quality of life as indicated by ADL, SF-36v2 and IIEF scores (Supplementary Table 2
). The statistical MUNE may also be useful as a relatively objective, easily blinded, physiological biomarker of motor neuron degeneration. Additional research will be necessary to establish the reliability and sensitivity of these measures in SBMA, and to define the clinical course of the disease prospectively.
Trials of anti-androgen treatment in SBMA have been based on evidence of efficacy from animal models (Katsuno et al.
; Chevalier-Larsen et al.
; Banno et al.
). The animal studies indicate that the toxicity of the mutant androgen receptor protein in SBMA is ligand-dependent, and that reducing testosterone levels may be beneficial. However, our finding that higher, not lower, testosterone levels are associated with better muscle strength and function indicates that it may be necessary to balance the anabolic strengthening effects of androgens against any potentially deleterious effects of androgen-activated mutant androgen receptor toxicity, such as can be inferred from the animal studies. A limitation of this interpretation is that it is based on a cross-sectional analysis. The therapeutic implications are best addressed in prospective, randomized clinical trials.