Background: Distal hereditary motor neuronopathy with pyramidal features (dHMNP) is a hereditary neurodegenerative disorder characterised by the presence of upper and lower motor neuron signs. The pathophysiological mechanisms underlying these clinical findings remain elusive. Given that cortical hyperexcitability appears to underlie neurodegeneration in amyotrophic lateral sclerosis (ALS), a disorder that may clinically resemble dHMNP, the present study applied novel cortical excitability studies to further investigate the pathophysiological mechanisms in dHMNP. Methods: Threshold tracking transcranial magnetic stimulation (TMS) studies were undertaken using a 90 mm circular coil. Peripheral nerve excitability was performed by stimulating the median nerve at the wrist, with recording made over the abductor pollicis brevis muscle. Studies were undertaken in six dHMNP and 52 ALS patients, and compared with 55 normal controls. Results: Central motor conduction time (CMCT) was significantly prolonged in dHMNP (dHMNP 7.7 (SEM 0.7) ms; ALS 4.9 (0.3) ms; controls 5.1 (0.2) ms, p<0.01). Short interval intacortical inhibition (SICI) was significantly reduced in ALS patients (0.8 (0.8)%) when compared with dHMNP (6.4 (0.7)%, p<0.0001) and controls (8.6 (1.1)%, p<0.0001). Reduction in SICI was accompanied by significant increases in the magnetic stimulus-response curve gradient and intracortical facilitation, and reduction in cortical silent period duration in ALS, while all these parameters of cortical excitability were normal in dHMNP. Conclusions: The present study has established a prolonged CMCT and normal cortical excitability in dHMNP, thereby providing further support for the hypothesis that cortical hyperexcitability underlies neurodegeneration in ALS.