Pathophysiologic insights into motor axonal function in Kennedy disease.
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.


CONCLUSIONS
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.
Vucic
Steve
S
Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia.
Kiernan
Matthew C
MC
D000200:Action Potentials / Q000235:genetics; D000328:Adult; D000368:Aged; D001369:Axons / Q000473:pathology*; D041321:Chromosomes, Human, X / Q000235:genetics; D004558:Electric Stimulation; D004568:Electrodiagnosis / Q000379:methods; D004576:Electromyography / Q000379:methods; D019054:Evoked Potentials, Motor / Q000235:genetics; D005207:Fasciculation / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D009046:Motor Neurons / Q000473:pathology*; D053580:Muscle Strength / Q000235:genetics; D018908:Muscle Weakness / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D009134:Muscular Atrophy, Spinal / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D009431:Neural Conduction / Q000235:genetics; D010525:Peripheral Nerves / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D011944:Receptors, Androgen / Q000235:genetics; D012680:Sensitivity and Specificity; D013997:Time Factors
D011944:Receptors, Androgen