title: Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment.
abstract: Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (tau(SD)), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part reflects Na(+) conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer tau(SD). Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na(+) conductance, possibly associated with axonal regeneration or collateral sprouting.
authors.affiliation: Department of Neurology, Chiba University School of Medicine, Chiba, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kanai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwabara
authors.forename: Kimihito
authors.initials: K
authors.lastname: Arai
authors.forename: Jia-Ying
authors.initials: JY
authors.lastname: Sung
authors.forename: Kazue
authors.initials: K
authors.lastname: Ogawara
authors.forename: Takamichi
authors.initials: T
authors.lastname: Hattori
mesh_terms: D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001369:Axons / Q000502:physiology; D004576:Electromyography; D005260:Female; D006801:Humans; D017827:Machado-Joseph Disease / Q000150:complications* / Q000503:physiopathology; D008297:Male; D008801:Mexiletine / Q000627:therapeutic use*; D008875:Middle Aged; D009046:Motor Neurons / Q000502:physiology*; D009120:Muscle Cramp / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D009431:Neural Conduction
chemical_list: D000889:Anti-Arrhythmia Agents; D008801:Mexiletine