Correlation of clinical and molecular features in spinal bulbar muscular atrophy

Abstract

Objectives: To characterize the clinical and genetic features of spinal bulbar muscular atrophy (SBMA), a rare neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene, in the United Kingdom.

Methods: We created a national register for SBMA in the United Kingdom and recruited 61 patients between 2005 and 2013. In our cross-sectional study, we assessed, by direct questioning, impairment of activities of daily living (ADL) milestones, functional rating, and subjective disease impact, and performed correlations with both CAG repeat size and degree of somatic mosaicism. Ten patients were deceased, 46 patients participated in the study, and 5 declined.

Results: Subjects had an average age at onset of 43.4 years, and weakness onset most frequently occurred in the lower limbs (87%). Impaired mobility was the most frequently reported problem by patients, followed by bulbar dysfunction. Age distribution of the impairment of ADL milestones showed remarkable overlap with a Japanese study. We have identified a significant correlation between the number of CAG repeats and both age at onset and ADL milestones. Somatic mosaicism also showed a correlation with CAG expansion size and age at onset.

Conclusions: Clinical features in SBMA show a substantial overlap when comparing populations with different genetic backgrounds. This finding has major implications, because multicenter trials will be necessary to obtain sufficient power in future clinical trials. Clinical-genetic correlations are strong in SBMA and should inform any clinical research strategy in this condition.

Figure 1. Age distribution of ADL milestones

For each milestone, median age, 10th and 90th percentile (box), and range (whiskers) of age are plotted (A). Median age of ADL from the UK SBMA cohort described in this study (green) and a Japanese SBMA cohort (pink) are plotted (B). ADL = activities of daily living; SBMA = spinal bulbar muscular atrophy; UK = United Kingdom.

Figure 2. Cross-sectional assessment of spinal bulbar muscular atrophy disability and symptoms

Mean score value and score range for all items of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) are plotted (A). Participants were asked to define the 3 major problems caused by disease, and results are plotted (B).

Figure 3. Clinical-genetic correlations

Number of CAG repeats is plotted vs disease onset (A), age when first required handrail (B), age when started using a cane (C), and age when started using a wheelchair (D).

Figure 4. Analysis of CAG repeat somatic mosaicism

Sequence traces allow visualization of somatic mosaicism by analyzing the signal of a single T nucleotide 9 bases downstream of the repeat (A). Sequencing after cloning shows loss of extra peaks, and further reamplification shows appearance only of peaks of smaller sizes than the major peak. Example of peak area calculation performed on fragment analysis results in order to calculate the mosaicism index (MI) (B). MI is plotted with CAG repeat expansion size (C). Age at onset is plotted vs both CAG expansion repeat size and MI (D).