Biomedical subjects
Publications and source records attributed to R C Griggs.
These mysterious attacks of muscle weakness are difficult to treat because the different forms are hard to define, and potassium plays a different role in each one. New genetic probes should finally resolve these issues. In the meantime, attacks can be prevented in at least some patients. A multicenter study is now under way to determine the best treatment for each subtype.
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.
We studied androgen receptor function in cultured scrotal skin fibroblasts from eight subjects with X-linked spinal and bulbar muscular atrophy (SBMA) (Kennedy's syndrome) from four families. The neuromuscular and endocrine features were similar in all patients. High-affinity dihydrotestosterone binding (Bmax) was decreased in three patients from one family (average, 11.1 fmol/mg) similar to values in subjects with androgen resistance syndromes. Bmax was normal in five SBMA patients from three other families (average, 26.0 fmol/mg). This finding provides direct evidence for abnormal androgen receptor function in some patients with SBMA. There was some correlation between severity of neuromuscular and endocrine dysfunction, providing further evidence that the two types of manifestations are related.
We performed linkage analysis in a pedigree segregating an allele for autosomal dominant, painful myotonia that is potassium sensitive and responsive to acetazolamide. This allele was tightly linked to a skeletal-muscle, sodium channel locus which is now a candidate for the site of the mutational defect in acetazolamide-responsive myotonia congenita. Since this sodium channel locus is completely linked to the disease allele in all hyperkalemic periodic paralysis and paramyotonia congenita pedigrees studied, the molecular alteration causing acetazolamide-responsive myotonia congenita is likely an allelic defect in this human, skeletal-muscle, sodium channel gene.
Three patients with myasthenia gravis demonstrated a distinctive sign of orbicularis fatigue. After momentary opposition on gentle sustained lid closure, the lid margins separated, resulting in widening of the palpebral fissure and scleral exposure. The patient thus appeared to "peek" at the examiner. The "peek" sign was not observed in 200 control patients and in 49 of 50 patients with facial weakness secondary to a spectrum of neuromuscular disorders. Three of 25 patients with myasthenia gravis displayed this sign, and in one patient it was the major diagnostic finding. The presence of the "peek" sign suggests the diagnosis of myasthenia gravis.
The faculty of the Department of Medicine at Cleveland Metropolitan General Hospital has responded to the challenge of fostering general internal medicine in a graduate training program by organizing a "firm" system of medical care which has appealed to academic internists with broad interests in clinical medicine. This firm system consists of four medical teams which care for distinct patient populations, closely integrating their outpatient and inpatient care. The firms are made up of all the house staff in training in internal medicine together with senior and junior faculty members who are directors for the firms. Medical students in general medicine are also assigned to firms. This firm system is relatively simple to understand and establish and is readily applicable to other academic departments with general medical responsibilities.
Hyperkalemic periodic paralysis is frequently considered a disorder in which episodes of weakness and an attendant rise in plasma potassium interrupt a baseline of normal strength and potassium. We studied venous potassium throughout a 36-hour period in two patients with hyperkalemic periodic paralysis and in nine normals under rigidly controlled conditions. At no time did the patients with periodic paralysis have an attack of weakness, but their mean potassium concentrations were above the normal range for 33 to 36 hours. In hyperkalemic periodic paralysis, the postprandial change in potassium relative to insulin release exceeded normal. There appears to be a continuous alteration in potassium regulation in our patients with hyperkalemic periodic paralysis.
Myotonia can occur in the periodic paralyses, particularly the hyperkalemic form. The beneficial response to acetazolamide in hypokalemic and hyperkalemic periodic paralysis has led us to study the effect of acetazolamide in 9 patients with disorders having myotonia as the major problem, 7 with myotonia congenita and 2 with paramyotonia congenita. Patients were studied before acetazolamide administration with glucose and potassium loading tests. All patients had an increase in myotonia with potassium, but no weakness occurred with either test. Acetazolamide treatment decreased myotonia in all patients and in 3 proved the most satisfactory therapy. Side-effects during acetazolamide therapy included paresthesias in 5 patients and renal calculus in 1. Flaccid weakness occurred in a patient with paramyotonia congenita. Acetazolamide treatment was associated in all patients with partially compensated metabolic acidosis and lowering of serum potassium within the normal range. Kaliuresis was also noted during introduction of therapy. Acetazolamide appears to be an acceptable treatment for occasional patients with myotonia who are unresponsive to or intolerant of other therapies.
Centronuclear myopathy, like myotonic dystrophy, is characterized by muscle wasting and type 1 fiber atrophy. To determine whether this disorder might include a derangement in carbohydrate metabolism similar to that in myotonic dystrophy, 3 comparably wasted patients with centronuclear myopathy, myotonic dystrophy, and neurogenic atrophy were investigated. The patient with centronuclear myopathy had mild glucose intolerance and hypoinsulinemia after oral glucose ingestion in bold contrast to the normal glucose tolerance and hyperinsulinemia observed in the myotonic dystrophy patient. No abnormality was seen in oral glucose tolerance in the patient with neurogenic atrophy, and all 3 patients had normal insulin tolerance. Forearm insulin infusion demonstrated normal stimulation of muscle glucose uptake in the patients with centronuclear myopathy and neurogenic atrophy in contrast to the markedly diminished response to insulin seen in the patient with myotonic dystrophy. These data indicate that neither distal wasting or type 1 fiber atrophy are responsible for the abnormalities in carbohydrate metabolism 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.
From early childhood, eight patients in a kindred had paroxysmal bouts of ataxia, dysarthria, and nystagmus. The disorder was inherited as an autosomal dominant. Attacks occurred weekly and lasted 1 to 6 hours; there were slight cerebellar signs between attacks. Although the etiology was not determined, a serendipitous trial of acetazolamide completely abolished attacks, and all patients have remained free of attacks for as long as 5 years.
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This report describes the clinical, laboratory, and muscle biopsy histochemical and electron microscopic studies of one inherited and two sporadic cases of distal myopathy. Histopathologic and histochemical studies showed numerous myopathic alterations and no significant evidence of denervation. Electron microscopic studies showed a broad spectrum of nonspecific alterations similar to those in other forms of muscular dystrophy. Autophagic vacuoles were prominent in all cases. The inherited case was characterized by an unusual focal granular degeneration that, ultrastructurally, was composed of homogeneous fine granules devoid of other organelles or myofilamens.
Acetazolamide has been shown to be effective prophylaxis for both hypokalemic and hyperkalemic paralysis. A patient with paramyotonia congenita, a related disorder with myotonia and episodic weakness, was studied during treatment with acetazolamide. Athough the patient's myotonia was virtually abolished, severe quadriparesis was produced during each trial of acetazolamide. This response distinguished this patient's condition from other forms of familial periodic paralysis and suggests that acetazolamide may be deleterious to some patients with periodic paralysis.
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Electrophoretic mobility measurements were made of red blood cells obtained from patients with Duchenne and myotonic muscular dystrophy, from dystrophic mice and chickens, and from corresponding controls. Alterations in the erythrocyte surface electrokinetic properties were found in dystrophic mice and chickens and in many, but not all, patients with muscular dystrophy. The results are consistent with the concept of muscular dystrophy as a systemic membrane disease not limited to muscle.