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Pathophysiologic insights into motor axonal function in Kennedy disease

From Prince of Wales Medical Research Institute and Prince of Wales Clinical School (S.V., M.C.K.), University of New South Wales; and Multidisciplinary Motor Neuron Disease Service (S.V., M.C.K.), Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, NSW, Australia.

Address correspondence and reprint requests to A/Professor Matthew C. Kiernan, Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, NSW 2031, Australia

Objective: Kennedy disease (KD), or spinobulbomuscular atrophy, is a slowly progressive inherited neurodegenerative disorder, marked by prominent fasciculations that typically precede the development of other symptoms. Although the genetic basis of KD relates to triplet (CAG) repeat expansion in the androgen receptor (AR) gene on the X chromosome, the mechanisms underlying the clinical presentation in KD have yet to be established. Consequently, the present study applied axonal excitability techniques to investigate the pathophysiologic mechanisms associated with KD.

Methods: Peripheral nerve excitability studies were undertaken in 7 patients with KD with compound muscle action potentials (CMAP) recorded from the right abductor pollicis brevis.

Results: Strength-duration time constant (KD 0.54 ± 0.03 msec; controls, 0.41 ± 0.02 msec, p < 0.01) and the hyperpolarizing current/threshold gradient (KD 0.42 ± 0.01; controls, 0.37 ± 0.01, p < 0.05) were significantly increased in KD. Strength-duration time constant correlated with the CMAP amplitude (R = 0.68) and the fasciculation frequency (R = 0.62). Threshold electrotonus revealed greater changes in response to subthreshold depolarizing (KD TEd [90 to 100 msec], 50.75 ± 1.98%; controls TEd [90 to 100 msec], 45.67 ± 0.67%, p < 0.01) and hyperpolarizing (KD TEh [90 to 100 msec], 128.5 ± 6.9%; controls TEh [90 to 100 msec], 120.5 ± 2.4%) conditioning pulses. Measurements of refractoriness, superexcitability, and late subexcitability changed appropriately for axonal hyperpolarization, perhaps reflecting the effects of increased ectopic activity.

Conclusion: In total, the increase in the strength-duration time constant may be the primary event, occurring early in course of the disease, contributing to the development of axonal hyperexcitability in Kennedy disease, and thereby to the generation of fasciculations, a characteristic hallmark of the disease.

GLOSSARY: AR = androgen receptor; CMAP = compound muscle action potential; EMG = electromyography; I/V = current/threshold; KD = Kennedy disease; MND = motor neuron disease; MRC = Medical Research Council; RRP = relative refractory period; SR = stimulus-response.

M.kiernan{at}unsw.edu.au

S.V. was awarded the Clinical Fellowship of Motor Neurone Disease Research Institute of Australia (MNDRIA), with funding provided by the Motor Neuron Disease Association of NSW. Grant support was also received from the NSW Ministry for Science and Medical Research Spinal Cord Injury & Related Neurological Conditions Research Grant Program and the National Health and Medical Research Council of Australia.

Disclosure: The authors report no conflicts of interest.

Received March 1, 2007. Accepted in final form May 16, 2007.