Methods

Studies were undertaken in six patients with dHMNP from one family (four males; age range 33–65 years; mean age 46 years) with an autosomal dominant pattern of inheritance (fig 1A) and linked to a novel 7q34–q36 locus.11 All patients gave informed consent to the procedures, which were approved by the South East Sydney Area Health Service Human Research Ethics Committee.

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Figure 1

(A) Family pedigree illustrating an autosomal dominant pattern of inheritance in this family with distal hereditary motor neuronopathy with pyramidal tract signs. (B) Deformities of the foot, including pes cavus and hammer toes, evident in all the patients studied (*). (C) Patients exhibiting weakness of toe and ankle dorsiflexion with wasting of the extensor digitorum brevis muscle (arrowhead). (D) Central motor conduction time (ms), measured according to the F-wave method (see Methods), significantly prolonged in distal hereditary motor neuronopathy with pyramidal features (dHMNP) compared with normal controls and amyotrophic lateral sclerosis (ALS) patients. (E) Short interval intracortical inhibition (SICI), defined as the stimulus intensity required to maintain a target output of 0.2 mV (see Methods). Averaged SICI, between interstimulus intervals (ISIs) of 1 to 7 ms was significantly reduced in amyotrophic lateral sclerosis (ALS) patients when compared with patients with distal hereditary motor neuronopathy with pyramidal features (dHMNP) patients and normal controls. **p<0.01; ****p<0.0001.

Cortical excitability was measured by applying TMS to the motor cortex by means of a 90 mm circular coil. A threshold tracking paradigm was applied to record the resting motor threshold (RMT), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) as previously described.7 In addition, single-stimulus TMS was used to record stimulus-response (SR) curves, central motor conduction time (CMCT) and cortical silent period (CSP) duration. In the same sitting, axonal excitability studies were undertaken according to a previously described protocol,12 with the median nerve stimulated at the wrist using 5 mm Ag–AgCl electrodes. The resultant peak-to-peak compound muscle action potential (CMAP) amplitude was recorded over the abductor pollicis brevis (APB), as was the neurophysiological index (NI).13

Statistical analysis

Cortical excitability in dHMNP patients was compared with control data obtained from 55 subjects (28 men; age range 23–73 years; mean 46 years) and 52 clinically probable or definite ALS patients (34 men; age range 26–71 years; mean 59 years) as defined by the revised El Escorial criteria.14 Both the control and ALS groups overlapped with a previous cohort.10 Peripheral nerve excitability parameters were compared with controls12 and ALS patients.15 All ALS patients were clinically staged using the ALS-functional rating scale—revised (ALSFRS-R),16 Medical Research Council score17 and Triggs hand function score.18 The Student t test was used to compare mean differences and analysis of variance (ANOVA) for multiple comparisons. Correlations were analysed using the Spearman rank test. A p value of <0.05 was considered statistically significant. Results are expressed as mean (SEM).

Results

Clinical features

Clinical features for dHMNP and ALS patients are summarised in table 1. An example of a foot deformity in a representative case is depicted in fig 1B,C. Brain and spinal MRI in two index cases were normal.

Neurophysiological features

Conventional neurophysiological testing,4 11 revealed reduced median, ulnar and tibial CMAP amplitudes, and absent common peroneal nerve motor responses. Median, ulnar and sural sensory nerve action potential amplitudes were normal. EMG disclosed chronic neurogenic changes and spontaneous activity in the distal muscle groups of the upper and lower limbs.

Cortical excitability

The motor cortex was excitable in all dHMNP patients. Central motor conduction time was significantly prolonged in dHMNP patients (7.7 (0.7) ms) when compared with ALS and controls (ALS 4.9 (0.3) ms; controls 5.1 (0.2) ms, p<0.01, fig 1D).

The SR curve for TMS studies in dHMNP was significantly smaller when compared with ALS (p<0.05), but comparable when compared with controls (ANOVA, p = 0.4). There was no significant difference in RMT between the groups, which remained stable throughout the testing period.7

Short-interval intracortical inhibition

Short-interval intracortical inhibition was significantly reduced in ALS patients (0.8 (0.7)%, p<0.0001) when compared with dHMNP (6.4 (0.7)%, p<0.0001) and controls (9.0 (0.8)%, fig 1E). Peak SICI was significantly reduced in ALS patients (3.0 (1.6)%) compared with dHMNP patients (11.4 (3.4)%, p<0.05) and controls (13.7 (1.3), p<0.0001). Further, ICF was significantly reduced in dHMNP patients (−0.8 (0.5)%) when compared with ALS patients (−4.2 (0.5)%, p<0.05), but comparable with controls (−0.9 (0.4)%).

Cortical silent period

In a contracting muscle, MEP is followed by a period of electrical silence that interferes with ongoing EMG activity, known as the CSP. As the stimulus intensity increased from 60 to 150% RMT, the mean CSP duration increased from 0 to 176.7 (8.5) ms in ALS patients and was significantly shorter when compared with dHMNP patients (0–202.3 (10.2) ms, p<0.05) and controls (0–208.8 (4.8) ms, p<0.001).

Peripheral nerve excitability

The CMAP amplitude (dHMNP 7.2 (1.0) mV; ALS, 6.1 (3.6) mV; controls 10.4 (0.7) mV, p<0.05) and NI (1.4 (0.4), p<0.05; ALS, 0.8 (0.1), p<0.00001; controls, 2.5 (0.2)) were significantly reduced in dHMNP and ALS patients when compared with controls, while there was no significant difference between dHMNP and ALS patients. Further, the mean MRC from the target muscle (APB) was similar between groups (dHMNP 4.5 (0.2); ALS 4.2 (0.1)). Together, these findings indicate a comparable degree of peripheral disease burden between dHMNP and ALS patients.

The strength–duration time constant (τ_SD) reflects nodal persistent Na⁺ conductance, while rheobase is defined as the threshold current for a stimulus of infinitely long duration.19 There were no significant differences in the mean τ_SD and rheobase in dHMNP patients when compared with controls and ALS patients. In addition, there were no significant differences in threshold electrotonus, the recovery cycle or current–threshold relationship in dHMNP patients when compared with ALS and controls.

Correlation between cortical abnormalities, clinical and neurophysiological parameters in dHMNP

Combining measures of cortical and peripheral axonal excitability, clinical assessment and disease severity, it was evident that CMCT correlated with disease duration (R = 0.50) and the CMAP amplitude (R = −0.70). Together, these correlations suggest that prolongation of CMCT was a late feature in dHMNP.

Discussion

The present study, using a combination of novel threshold tracking techniques to explore central and peripheral processes, has established normal cortical excitability in dHMNP patients, markedly different to findings from ALS patients. Although dHMNP patients exhibited upper motor neuron dysfunction, as reflected by marked prolongation of central motor conduction time, this appeared to be a late feature of the disease, thereby suggesting that upper motor neuron dysfunction may be a secondary event. In addition, the present study has reaffirmed the presence of cortical hyperexcitability in sporadic ALS patients and supports the hypothesis that, at least with regard to progressive motor neurodegenerative disorders, cortical hyperexcitability appears specific to ALS.

Central motor conduction time

Central motor conduction time is determined by rapidly conducting large-diameter fibres.20 Although technical and physiological factors may influence CMCT,20 pathological factors such as impaired excitation of cortiomotoneurons, degeneration of large-diameter axons, excessive synaptic delay and demyelination of corticospinal axons will all result in prolongation of the CMCT.

In the present series, there was a significant prolongation of CMCT, in keeping with findings from the dHMNP phenotype due to senataxin gene mutation [ALS4].3 4 5 Although pathological studies in the ALS4 phenotype revealed demyelination of corticospinal tracts,5 the degree of CMCT prolongation in the present cohort of dHMNP patients is not diagnostic of demyelination. Specifically, in multiple sclerosis, the mean CMCT to the APB muscle has previously been reported to be 14.8 ms.21 Therefore, it may be argued that the CMCT prolongation in the present study most probably reflects degeneration of large-diameter axons. Further, the fact that CMCT correlated with CMAP amplitude and disease duration suggests that CMCT prolongation is a late feature of the disease, possibly developing as a secondary effect of the disease process.

Are the pathophysiological mechanisms underlying neurodegeneration in dHMNP similar to ALS?

Previous studies have suggested that cortical hyperexcitability underlies neurodegeneration in ALS.22 These studies have received recent support based on findings that SICI was more prominent in the early stages of disease and that cortical hyperexcitability correlated with measures of axonal loss.9 In contrast to ALS, there was no evidence of cortical hyperexcitability in dHMNP as measured by SICI, MEP amplitude, magnetic SR curve gradient and intracortical facilitation. Further, in the clinically pure lower motor neuron forms of ALS, recent studies have documented the presence of cortical hyperexcitability,23 compared with normal excitability in monomelic amyotrophy and Kennedy disease, thereby distinguishing between the different motor neuronopathies.24 25 Together, these findings suggest that despite the phenotypic similarities, cortical hyperexcitability does not underlie neurodegeneration in dHMNP but rather appears to be specific for ALS.