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.

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

“…Muscle weakness is usually the main clinical feature of the disease and occurs in 97% of the cases. It usually appears at age [35][36][37][38][39][40] and a correlation between CAG-repeats number and age at onset has been noted [9], although poly-Q tracts does not seem to affect disease progression [10], [1].…”

“…Lower limb weakness is indeed the most common presenting symptom (86.7%), followed by upper limb weakness (22.2%) [1]. However, more recently, it has been highlighted that other slighter symptoms are often present long time before the onset of muscular weakness.…”

“…The reduction of vibratory sense, associated with motor impairment, leads to weak or absent deep tendon reflexes and could be related to an alteration of sensory fibers together with possible autonomic dysfunction [23]. The presence of sensory neuropathy may also be associated with neuropathic pain mainly localized distally in lower limbs associated with frequent feet numbness and tingling, which has been reported in up to 58% of the patients [1].…”

“…Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy's Disease (KD), is an X-linked recessive, adult onset, slowly progressive, lower motor neuron disease (MND) characterized by limb and bulbar muscle atrophy, weakness and fasciculations [1]. The disease is caused by a CAG repeat expansion in the first exon of the androgen receptor gene (AR), with a number of CAG repeats bigger than 38 retained to be pathogenic.…”

“…The disease is caused by a CAG repeat expansion in the first exon of the androgen receptor gene (AR), with a number of CAG repeats bigger than 38 retained to be pathogenic. It affects adult males and the CAG repeat size correlates inversely with disease onset but not with disease progression or severity [1].…”