The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment.

The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita.

The periodic paralyses are a group of autosomal dominant muscle diseases sharing a common feature of episodic paralysis. In one form, paramyotonia congenita (PC), the paralysis usually occurs with muscle cooling. Electrophysiologic studies of muscle from PC patients have revealed temperature-dependent alterations in sodium channel (NaCh) function. This observation led to demonstration of genetic linkage of a skeletal muscle NaCh gene to a PC disease allele. We now report the use of the single-strand conformation polymorphism technique to define alleles specific to PC patients from three families. Sequencing of these alleles defined base pair changes within the same codon, which resulted in two distinct amino acid substitutions for a highly conserved arginine residue in the S4 helix of domain 4 in the adult skeletal muscle NaCh. These data establish the chromosome 17q NaCh locus as the PC gene and represent two mutations causing the distinctive, temperature-sensitive PC phenotype.

Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor epsilon subunit.

We describe the genetic and kinetic defects in a congenital myasthenic syndrome caused by heteroallelic mutations of the acetylcholine receptor (AChR) epsilon subunit gene. The mutations are an in-frame duplication of six residues in the long cytoplasmic loop (epsilon1254ins18) and a cysteine-loop null mutation (epsilonC128S). The epsilon1254 ins18 mutation causes mode switching in the kinetics of receptor activation in which three modes activate slowly and inactivate rapidly. The epsilon1245ins18-AChR at the endplate shows abnormally brief activation episodes during steady state agonist application and appears electrically silent during the synaptic response to acetylcholine. The phenotypic consequences are endplate AChR deficiency, simplification of the postsynaptic region, and compensatory expression of fetal AChR that restores electrical activity at the endplate and rescues the phenotype.

Primary episodic ataxias: diagnosis, pathogenesis and treatment.

Primary episodic ataxias are autosomal dominant channelopathies that manifest as attacks of imbalance and incoordination. Mutations in two genes, KCNA1 and CACNA1A, cause the best characterized and account for the majority of identified cases of episodic ataxia. We summarize current knowledge of clinical and genetic diagnosis, genotype-phenotype correlations, pathophysiology and treatment of episodic ataxia syndromes. We focus on unresolved issues including phenotypic and genetic heterogeneity, lessons from animal models and technological advancement, rationale and feasibility of various treatment strategies, and shared mechanisms underlying episodic ataxia and other far more prevalent paroxysmal conditions such as epilepsy and migraine.

Decreased insulin sensitivity of forearm muscle in myotonic dystrophy.

Previous studies of patients with myotonic dystrophy have demonstrated hyperinsulinism after glucose loading. This hyperinsulinism has been attributed by some investigators to tissue insulin resistance. We have directly studied insulin sensitivity of forearm muscle in patients having such hyperinsulinism. The effect of an intrabrachial arterial insulin infusion (100 mu U/kg per min) on glucose uptake was determined in six cases of myotonic dystrophy, six normal subjects, and in seven disease control subjects with myotonia or wasting from other disorders. There was no significant difference in insulin tolerance comparing myotonic dystrophy patients to the normal and disease control groups. Glucose tolerance and basal insulin levels were normal in the myotonic dystrophy patients, but hyperinsulinism occurred after glucose ingestion. After 25 min of intra-arterial insulin, the mean peak muscle glucose uptake in myotonic dystrophy was 2.54 +/- 0.54 mu mol/min per 100 ml forearm compared to 5.24 +/- 0.86 mu mol/min per 100 ml for disease controls (P is less than 0.05). Myotonic dystrophy patients showed a peak glucose uptake increment of only 2.6 +/- 0.2-fold over basal contrasted with the disease control value of 6.5 +/- 1.0-fold (P is less than 0.02) and the normal control value of 8.8 +/- 1.1-fold (P is less than 0.01). Thus, there was an absolute as well as a relative decrease in muscle insulin sensitivity in myotonic dystrophy patients compared to both control groups. The peak increments in arterio-superficial venous glucose concentration differences after insulin infusion were not significantly different comparing myotonic dystrophy and control groups. These data suggest that in myotonic dystrophy, there is insulin insensitivity of skeletal muscle.

The primary periodic paralyses: diagnosis, pathogenesis and treatment.

Periodic paralyses (PPs) are rare inherited channelopathies that manifest as abnormal, often potassium (K)-sensitive, muscle membrane excitability leading to episodic flaccid paralysis. Hypokalaemic (HypoPP) and hyperkalaemic PP and Andersen-Tawil syndrome are genetically heterogeneous. Over the past decade mutations in genes encoding three ion channels, CACN1AS, SCN4A and KCNJ2, have been identified and account for at least 70% of the identified cases of PP and several allelic disorders. No prospective clinical studies have followed sufficiently large cohorts with characterized molecular lesions to draw precise conclusions. We summarize current knowledge of the clinical diagnosis, molecular genetics, genotype-phenotype correlations, pathophysiology and treatment in the PPs. We focus on unresolved issues including (i) Are there additional ion channel defects in cases without defined mutations? (ii) What is the mechanism for depolarization-induced weakness in Hypo PP? and finally (iii) Will detailed electrophysiological studies be able to correctly identify specific channel mutations? Understanding the pathophysiology of the potassium-sensitive PPs ought to reduce genetic complexity, allow subjects to be stratified during future clinical trials and increase the likelihood of observing true clinical effects. Ideally, therapy for the PPs will prevent attacks, avoid permanent weakness and improve quality of life. Moreover, understanding the skeletal muscle channelopathies will hopefully lead to insights into the more common central nervous system channel diseases such as migraine and epilepsy.

Lack of rapid enhancement of insulin action after oral glucose challenge in myotonic dystrophy.

Oral glucose administration to normal humans stimulates insulin release and simultaneously enhances the action of insulin by producing a rapid increase in tissue insulin sensitivity by a mechanism separate from the amount of hormone released. We determined whether insulin-resistant patients with myotonic dystrophy lose the ability to produce the normal rapid increase in tissue insulin action after oral glucose. Nine ambulatory, nonobese men with myotonic dystrophy were studied with 120-min euglycemic insulin infusions (20 mU X m-2 X min-1) given before and after glucose ingestion (4 and 5 patients received 15- and 25-g loads, respectively). Identical studies were performed in nonobese normal volunteers (16 and 13 patients received 15- and 25-g oral glucose loads, respectively). Glucose infusion rates at 20-120 min (GIR20-120) during euglycemic insulin infusions without prior glucose were 2.87 +/- 0.6 mg X kg-1 X min-1 in patients with myotonic dystrophy compared to 4.70 +/- 0.3 mg X kg-1 X min-1 in normal subjects. Euglycemic insulin infusions after glucose ingestion were begun after arterialized blood glucose values had returned to baseline. After glucose ingestion by normal subjects, GIR20-120 increased by 44.4 +/- 7.1% (P less than .0001) and by 46.8 +/- 8.6% (P less than .0002) with 15- and 25-g glucose loads, respectively. GIR20-120 in the nine patients with myotonic dystrophy showed no significant increase after glucose ingestion. These results confirmed the existence of a decrease in whole-body insulin sensitivity in myotonic dystrophy and indicated that the patients lack the normal mechanism that enhances insulin action after oral glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmic complications in the Guillain-Barré syndrome.

The occurrence of cardiac arrhythmia in Guillain-Barré syndrome (GBS) was examined in a retrospective study of 16 consecutive patients with GBS admitted to an intensive care unit primarily for respiratory insufficiency, Bradyarrhythmias, including sinus arrest or atrioventricular block rhythms, and/or tachyarrhythmias, supraventricular as well as ventricular, were observed in 13 patients. Two patients required pacemaker insertion because of recurrent asystolic episodes. Of the four fatalities, however, none were considered cardiac in origin. While clinically apparent autonomic nervous system dysfunction accompanied many of the observed arrhythmias and may be involved in arrhythmogenesis, these patients also suffered from pulmonary, infectious, and thromboembolic complications that could produce similar arrhythmic complications and must also be considered whenever such arrhythmias are seen.

Effect of testosterone on metabolic rate and body composition in normal men and men with muscular dystrophy.

We have examined the effect of testosterone enanthate injections (3 mg/kg.week, im) on the basal metabolic rate (BMR) estimated by indirect calorimetry and on lean body mass (LBM) estimated by 40K counting in four normal men and nine men with muscular dystrophy. Testosterone treatment increased plasma testosterone levels in all subjects (3-fold mean elevation). BMR increased significantly after 3 months of testosterone treatment (mean, 10%; P less than 0.01; 13% mean increase in the men with muscular dystrophy and 7% mean increase in the normal subjects). BMR remained elevated (mean increase, 9%) after 12 months of testosterone treatment in four men with muscular dystrophy. LBM also was significantly higher after 3 months of treatment (mean, 10%; P less than 0.01) and remained elevated at 12 months. The percent increase in LBM was similar in men with muscular dystrophy (+10%) and normal men (+11%). When BMR was adjusted for the increase in LBM by linear regression, the men with muscular dystrophy had an increase in adjusted BMR after 3 months of testosterone treatment (mean increase, 7%), but not after 12 months. The normal men did not have an increase in adjusted BMR. Testosterone treatment for 12 months slightly reduced body fat, whereas there was an increase in body fat in subjects with muscular dystrophy who were treated with placebo for 12 months. We conclude that there is a significant increase in BMR associated with pharmacological testosterone treatment, which for the most part is explained by the increase in LBM. However, in men with muscular dystrophy, there is a small hypermetabolic effect of testosterone beyond that explained by increased LBM.

Cyanotic congenital heart disease with suspected stroke. Should all patients receive antibiotics?

Two patients with cyanotic congenital heart disease (CHD) and erythremia were seen for abrupt onset of focal neurologic deficits and/or seizure without signs of infection or increased intracranial pressure. Clinical features and initial computed tomography (CT) in both cases suggested stroke. Subsequent CT scans demonstrated cerebral abscess, proved at operation. Review of records of patients with CHD at the University of Rochester (NY) Medical Center from 1965 to 1981 disclosed 12 cases with brain abscess but only two cases with aseptic cerebral infarction. All but one patient with abscess were cyanotic. One third of patients with abscess had a clinical picture suggesting stroke. Clinical or radiologic features of half the cases indicated that cerebral infarction may have led to abscess formation. Diagnosis of brain abscess and immediate antibiotic therapy should be strongly considered in patients with cyanotic CHD who suffer a suspected cerebral infarction.

Intravenous treatment of hypokalemic periodic paralysis.

Acute attacks of weakness in patients with hypokalemic periodic paralysis can usually be treated with oral potassium preparations. Occasional patients, however, require intravenous (IV) potassium administration. We studied a patient with hypokalemic periodic paralysis to determine the effect of using 5% glucose as a diluent for potassium administration during acute attacks of weakness. Administration of IV potassium chloride in 5% glucose (50 mEq/L) was associated with a worsening of strength and no rise in potassium level. Intravenous potassium in 5% mannitol was associated with a rise in potassium and improvement in strength. This study confirms the hazard of using glucose-containing solutions for correction of hypokalemia.

Severe neonatal centronuclear myopathy with autosomal dominant inheritance.

We studied a boy with severe infantile centronuclear myopathy (CNM) and his mother with clinical, electrophysiological, and pathological signs of skeletal muscle, peripheral nerve, and brain-stem disorder, and we believe that her condition represents a variation of her son's disease. His brother had similar symptoms and died at 4 days of age. The occurrence of this syndrome in a symptomatic mother and two severely affected sons suggests an autosomal dominant inheritance with variable expressivity. To our knowledge, this inheritance pattern has not been previously reported in severe (fatal) infantile CNM. The different courses in the mother and her offspring may be manifestations of a single or separate abnormal gene causing alteration of muscle and nerve maturation.

Dissociation of glucose and potassium arterial-venous differences across the forearm by acetazolamide. A possible relationship to acetazolamide's beneficial effect in hypokalemic periodic paralysis.

We studied the effect of acetazolamide on arterial-venous (A-V) glucose and potassium differences across the forearm following oral glucose loading in eight normal subjects. Administration of acetazolamide for 72 hours prior to glucose loading resulted in increased A-V glucose differences and decreased A-V potassium differences. Acetazolamide may, therefore, increase glucose uptake across muscle while decreasing potassium uptake following glucose ingestion. This glucose-potassium dissociation observed in normal subjects may relate to acetazolamide's beneficial effect in hypokalemic periodic paralysis.

Effect of acetazolamide on insulin sensitivity in myotonic disorders.

Acetazolamide is effective treatment for myotonia in certain patients with myotonia congenita. Since potassium metabolism may be abnormal in myotonia congenita, we studied the effect of acetazolamide administration on potassium regulation and glucose disposal, using the euglycemic insulin clamp technique in patients with myotonic disorders and in normal subjects. Glucose disposal was normal in patients with myotonia congenita; administration of acetazolamide increased glucose disposal in normal subjects and in patients with myotonia congenita. By contrast, patients with myotonic dystrophy showed insulin resistance and decreased glucose disposal that was not improved by acetazolamide administration. Patients with myotonia congenita had elevated potassium levels in the basal state and a greater fall in potassium level during the insulin clamp procedure than controls. Patients with myotonic dystrophy had normal or low basal potassium levels and a subnormal decrease in potassium level during the insulin clamp procedure. Administration of acetazolamide did not alter these abnormalities in potassium metabolism in patients with either myotonia congenita or myotonic dystrophy.

Scapuloperoneal syndromes. Absence of linkage to the 4q35 FSHD locus.

OBJECTIVE: To investigate whether two forms of the scapuloperoneal syndrome result from genetic defects allelic to facioscapulohumeral dystrophy (FSHD). DESIGN: Two kindreds with scapuloperoneal syndromes underwent clinical, histologic, and electrophysiologic evaluation followed by genetic evaluation with probes closely linked to FSHD. RESULTS: Although the proband in each kindred had facial, scapular stabilizer, and humeral weakness, raising the possibility of FSHD, evaluation of multiple other affected family members showed patterns of involvement that were clinically distinct from typical FSHD. In addition, DNA studies showed no linkage to the 4q35 FSHD locus in either kindred. CONCLUSION: We conclude that these two forms of the scapuloperoneal syndrome are genetically distinct from FSHD.

Lack of relationship of hypogonadism to muscle wasting in myotonic dystrophy.

Myotonic dystrophy is frequently associated with testicular atrophy. Since androgens may play a role in the maintenance of muscle mass, we have studied the levels of plasma testosterone and gonadotropins and of urinary 17-ketosteroids in 22 men with myotonic dystrophy, 36 normal men, and 16 men (control group) with muscle wasting. Results were correlated with muscle mass as estimated by creatinine excretion and total body potassium. Patients with myotonic dystrophy had significantly lower testosterone and higher gonadotropin levels than normal, and these changes were progressive in longitudinal studies. Testosterone levels were also lower than normal in disease control subjects. There was no correlation between low testosterone levels and diminished muscle mass in either myotonic dystrophy or disease control patients. The low plasma concentration of testosterone in men with myotonic dystrophy and other neuromuscular diseases does not appear to be directly related to their muscle wasting. This study does not exclude the possibility that an alteration in testosterone receptor or tissue effects may contribute to a loss of muscle tissue.

Dementia of adult polyglucosan body disease. Evidence of cortical and subcortical dysfunction.

OBJECTIVES: To characterize the dementia associated with adult polyglucosan body disease (APBD) and to correlate the cognitive deficits with abnormalities found on magnetic resonance imaging (MRI). METHODS: Quantitative neuropsychological testing and MRI in one man with APBD and a review of the literature. RESULTS: The dementia of APBD affects cortical and subcortical functions. The cognitive deficits correlate with MRI findings of cortical atrophy and white-matter abnormalities. CONCLUSION: Neuropsychological testing and MRI are helpful in the evaluation of patients with APBD.

Sjögren's syndrome and polymyositis or dermatomyositis.

Of four patients with Sjögren's syndrome, three had polymyositis and one had dermatomyositis. In all, deposition of IgG, IgA, IgM, and C3 was observed in muscle by immunofluorescent techniques. Serologic studies revealed elevated levels of serum IgG and IgM, rheumatoid factor, and antinuclear antibody with specificity for SS-A and SS-B antigens. In muscle there was a mononuclear cell infiltrate with plasma cell predominance around small vessels and capillaries. Ultrastructural changes in the vessels included reduplication of the basement membrane, endothelial thickening, and numerous tubuloreticular and dense inclusions. In two patients, electrondense deposits were noted in the microvasculature. This combination of immunoglobulin deposition in muscle, prominent microvascular changes, and characteristic serology suggests that the myositis in Sjögren's syndrome may result from small-vessel injury by autoantibodies or circulating immune complexes.

Recovery from the 'locked-in' syndrome.

Four patients made substantial recovery following the locked-in syndrome of vascular origin. Clinical and radiologic features supported the presence of ventral pontine infarction secondary to basilar artery occlusion. Quadriplegia and mutism persisted for one to 12 weeks before recovery of motor function began. Improvement continued over several years. All patients regained functional though dysarthric speech. Three of the four patients are ambulatory, one without assistance. As a few patients make a notable recovery from the locked-in syndrome resulting from ventral pontine infarction, aggressive supportive therapy should be considered in the early months of the syndrome.

Evaluation of pulmonary function in neuromuscular disease.

Pulmonary function tests were performed on 40 patients with neuromuscular disease. The maximum expiratory pressure was the most sensitive indicator of weakness and was decreased in 87% of adult patients. A comparison of Stead-Wells, electronic (Vanguard), and bellows spirometry (Vitalor) indicated an excellent correlation between the Stead-Wells and electronic devices. The bellows spirometer consistently underestimated volumes, particularly in severely weak patients.