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Machado-Joseph, Muscle Cramps, and Mexiletine
Abstract & Commentary
Source: Kanai K, et al. Muscle cramp in Machado-Joseph disease: Altered motor axonal excitability properties and mexiletine treatment. Brain. 2003;126:965-973.
Spinocerebellar ataxia type 3, Machado-Joseph disease (MJD), is an adult onset, autosomal-dominant disorder often presenting as a combination of upper and lower motor neuron signs, including facial and tongue fasciculations, resembling amyotrophic lateral sclerosis (ALS). Associated findings include extrapyramidal signs (dystonia, rigidity), progressive external ophthalmoplegia, and peripheral neuropathy. MJD is the result of a CAG triplicate repeat expansion on chromosome 14q32.1.
In an attempt to shed light on the incidence and pathophysiology of muscle cramps, their clinical and electrical characteristics were studied in 20 genetically confirmed MJD patients. Comparison was made to patients with ALS (n = 22), chronic axonal peripheral neuropathy (PN; n = 37), spinal muscular atrophy (SMA; n = 6), and to 32 age-matched normal controls. Measurements of motor axon excitability included strength-duration time constant (reflective of Na+ channel function), threshold electrotonus (reflective of K+ channel function), refractoriness, and supernormality. Statistical analysis was performed using the Mann-Whitney U test, the paired t-test, and Spearman’s rank correlation.
Sixteen MJD patients (80%) experienced frequent and severe muscle cramps affecting muscles of the limbs and trunk, a frequency greater than that for PN (24%) or SMA (33%) but not unlike that seen in ALS (68%). MJD patients demonstrated a significantly longer strength duration time constant compared to normals (P = .001), as did the PN and SMA groups. ALS and normals did not significantly differ in strength-duration time constant. Other measures of motor axon excitability were not different among MJD and normals, whereas ALS patients had greater threshold changes for depolarizing conditioning currents. Severe muscle cramps were associated with a longer strength duration time constant. Mexiletine provided almost complete relief in 8 of 10 MJD patients treated for severe muscle cramps, concomitantly improving the strength duration time constant, consistent with the premise that increased persistent Na+ conductance is causative of muscle cramps in MJD. Two patients were unable to tolerate the medication due to nausea and diarrhea. Other motor axon excitability measurements remained unchanged. Muscle cramps in MJD may have a different etiopathogenesis from those in ALS, the former involving dysfunction of Na+ channels, the latter of K+ channels. Mexiletine is a safe and beneficial treatment for these disabled MJD patients.
Where along the motor unit do muscle cramps begin? Roeleveld and colleagues1 used a 64-channel surface electromyogram (EMG) of the triceps surface to study the initiation and development of this phenomenon; 8 cramp-prone subjects were examined during both cramp and maximal voluntary contraction (n = 4) or during cramp alone (n = 4).1 Spectral analysis was used to interpret the information regarding the firing process and shape of the motor unit potentials.
Cramp initiation varied widely both within and between subjects, even beginning simultaneously in several locations in the muscle and spreading out slowly. Generation of the action potential appeared to occur at the level of the terminal motor axon or muscle fiber itself, rather than in the spinal cord, given that it appeared as contraction of a slowly moving fraction of muscle fibers. Compared to maximal voluntary contraction, spectral analysis revealed extremely short potentials during cramp, again supporting a nerve terminal or muscle fiber origin of cramps, rather than an origin in the anterior horn cell or more proximally along the axon. — Michael Rubin
Dr. Rubin is Professor of Clinical Neurology, New York Presbyterian Hospital - Cornell Campus.
1. Roeleveld K, et al. J Appl Physiol. 2000;88:1698-1706.