Serial left ventricular wall measurements in Duchenne's muscular dystrophy.

In 19 patients with Duchenne's muscular dystrophy, left ventricular wall thickness in end-systole and end-diastole was determined serially every 12 months by echocardiography and compared with ventricular wall growth in normal subjects. In the normal subjects, left ventricular wall thickness increased linearly with increasing body surface area. A control group of wheelchair-bound patients with a variety of neurologic disorders, although not followed serially, had a distribution of end-diastolic wall thickness values similar to that of the normal subjects. In patients with muscular dystrophy, wall thickness increased linearly with respect to body surface area for some time and then began to thin. The time at which thinning began was not directly related to age, although it was more common in older than in younger patients. Those patients who died demonstrated marked deviation from normal wall growth. Free wall thinning is probably a result of fibrosis and loss of myofibrils.

Abnormal iris vasculature in myotonic dystrophy. An anterior segment angiographic study.

The microvasculature of the iris was studied in 35 patients with neuromuscular disease and 14 control subjects, using anterior segment fluorescein angiography. Myotonic muscular dystrophy, in which a variety of ocular changes have previously been reported, was found to be associated with both focal and generalized vascular abnormalities. Changes were seen in the fluorescein angiograms of all nine of the myotonic dystrophy patients in which the iris vessels could be seen. No evidence of a microcirculatory disorder was seen in patients with Duchenne's dystrophy, for which a vascular pathogenesis has been proposed. The angiograms of patients with limb-girdle dystrophy, facioscapulohumeral dystrophy, and Friedreich's ataxia were also normal.

Hereditary proximal spinal and bulbar motor neuron disease of late onset. A report of six cases.

Six cases of a comparatively rare motor neuron disease are described. Essential features of this syndrome include (1) X-linked inheritance; (2) adult onset in the fourth to fifth decades; (3) slow progression; (4) predominant proximal and bulbar muscle involvement; and (5) absence of sensory or pyramidal tract signs. The previously reported finding of gynecomastia was absent, whereas longitudinal midline furrowing of the tongue was present in only one case. Electromyography in five patients revealed neurogenic changes. Muscle biopsies in two patients showed fiber type grouping with type I fiber predominance. The coexistence of this form of motor neuron disease and diabetes mellitus is prominent in family 2. It is important to recognize that these patients have a chronic, slowly progressive illness. The prognosis for longevity is good, although severe disability is inevitable. Management includes reassurance, supportive therapy, genetic counseling, and periodic testing for diabetes.

Cerebrospinal fluid gamma-aminobutyric acid variations in neurological disorders.

Neuropathologically, Huntington's disease is characterized by a profound reduction in neuronal cells originating in the corpus striatum and globus pallidus. Since one of these cell types utilizes gamma-aminobutyric acid (GABA) as a neurotransmitter, it may be possible to differentially diagnose this disorder on the basis of the CSF content of this amino acid. In order to determine the validity of this hypothesis, cerebrospinal fluid GABA was analyzed, using a recently developed radioreceptor assay procedure and was found to be significantly reduced in patients diagnosed as having Huntington's disease and also lower in patients with Alzheimer's disease, though no difference was noted between Parkinson patients and control subjects. The results suggest that analysis of cerebrospinal fluid GABA may have diagnostic, and perhaps predictive, value in certain neurological disorders.

Myopathy associated with sclerodermal facial hemiatrophy.

A patient who had linear scleroderma associated with ipsilateral hemiatrophy of the tongue and subsequent facial hemiatrophy was studied. Biopsy specimens of the plaque of scleroderma showed the skin changes of scleroderma as well as fascial and muscle changes. The fascia had an impressive plasma cell fasciitis with numerous plasma cells and scattered lymphohistiocytic cells. Histochemical study of the temporalis muscle underlying the plaque of circumscribed scleroderma disclosed severe localized atrophy of type 1 and type 2 fibers similar to the pathologic findings previously described in a patient with localized scleroderma.

Drug trial of superoxide dismutase in Duchenne's muscular dystrophy.

A multicenter, randomized, double-blind, placebo-controlled drug trial in Duchenne's muscular dystrophy, evaluating a superoxide dismutase in 51 ambulatory patients for 18 months was conducted. Fourteen aspects of muscle strength and five of functional ability, as well as serum creatine phosphokinase (CPK) level were studied. The total change in strength, function, and CPK level did not differ significantly in the two groups. The testing method used was reliable in assessing the natural history of Duchenne's dystrophy and would, therefore, be useful in future multicenter drug trials.

Altered polyamine excretion in Duchenne muscular dystrophy.

Increased urinary levels of the polyamines, putrescine, spermidine, and spermine are present in Duchenne muscular dystrophy (DMD) patients. Alterations in excretion are detectable when based on nanomoles per milligram creatinine, micromoles per 24-hour urine collection, or nanomoles per kilogram body weight per 24-hour urine collection. Evaluation of creatinine levels in spot collections of urine versus 24-hour collections suggests a more consistent urinary creatinine in spot urines from DMD patients and normals, with wider variability in 24-hour specimens. We postulate that polyamines may be useful markers to evaluate disease activity and to screen for drug efficacy, as they have proved useful in cancer patients in assessing alterations in tumor kinetic parameters.

Conduction velocities in single fibers of diseased human muscle.

Focal sarcolemmal lesions, segmental degeneration, and fiber splitting are observed in Duchenne muscular dystrophy and have been proposed to be major contributory causes of dysfunction of this disease. The presence of these abnormalities should affect impulse conduction along the sarcolemma. To test this prediction, we measured conduction velocities of the action potential in normal and diseased human intercostal muscle fibers by means of intracellular microelectrodes. The resting potentials of fibers from patients with Duchenne dystrophy, Becker dystrophy, and motor neuron disease were partially depolarized, and conduction velocities in these fibers were slower than normal. When the membrane potential was artifically hyperpolarized, the conduction velocity in Becker dystrophy fibers was not significantly different from normal. However, conduction velocity values in Duchenne dystrophy or motor neuron disease fibers were significantly lower than normal regardless of the level of membrane hyperpolarization. These data are analyzed in light of the presence of morphologic lesions in the diseased muscle fibers.

Myopathy associated with linear scleroderma. A histochemical and electron microscopic study.

Pathologic findings in biopsied rectus femoris muscle underlying an area of linear scleroderma are described. The affected muscle was weak and atrophic. On electromyography it showed motor unit potentials of decreased amplitude and duration. Light microscopic changes were minimal. There was atrophy of some histochemical type I fibers. More prominent changes were found at the ultrastructural level, where many of the capillary basal laminae were thickened and reduplicated. Most striking was the presence of two types of electron-dense, rounded inclusions within the mitochondria, one ranging from 29 to 47nm in diameter and the other from 54 to 131 nm in diameter.

Factors influencing osmotic fragility of red blood cells in Duchenne muscular dystrophy.

Factors affecting osmotic fragility were studied in red blood cells of patients with Duchenne muscular dystrophy. The mean osmotic fragility (MOF), operationally defined as the NaCl concentration for 50% hemolysis, was found to be higher by 3.63 +/- 0.51 mM in Duchenne cells than in normal cells having an MOF of 60.1 +/- 0.5 mM NaCl buffered with 10 mM sodium phosphate at pH 7.0. However, about 20% of Duchenne patients had red cells indistinguishable from their age- and sex-matched controls. Temperature, pH, preincubation in plasma, and proteolytic digestion all affected Duchenne and normal cells to the same extent. However, after salt loss, induced either by preincubation in isotonic nonelectrolyte solutions or by exposure to ionophore A23187, Duchenne cells showed a greater change in MOF. Osmotic fragility of Duchenne cells was increased even in younger blood cells, suggesting that the membrane was abnormal in the early stages of red cell maturation.

Serial two-dimensional echocardiography in Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD) are known to have progressive epicardial fibrosis of the free wall of the left ventricle, but standard noninvasive M-mode echocardiographic tests of left ventricular function are relatively insensitive detectors of this cardiomyopathy. We therefore used two-dimensional echocardiography to record three short axis levels of the left ventricle in 13 Duchenne patients. Serial studies were separated by 2 years for most patients. The two-dimensional echocardiographic technique allows qualitative evaluation of segmental contraction of the left ventricle. Four general principles were found during this study: (1) Obvious contraction abnormalities of the left ventricle were present in most patients with DMD. (2) In most patients, the contraction deficit was first noted in the left ventricular posterior free wall behind the mitral valve. (3) Once a contraction deficit was observed, the area of abnormal contraction progressed inferiorly to include additional areas of the left ventricular posterior free wall. (4) Standard M-mode left ventricular function techniques were unreliable for detecting individuals with segmental contraction abnormalities.

Observations on the innervation of human extraocular muscles.

The innervation of human extraocular muscles (EOM) was studied using a comprehensive histological and histochemical approach. In contrast to previous concepts, we have demonstrated that the coarse felderstrucktur muscle fibers are singly innervated by en plaque endings and that the fine and granular fibrillenstruktur fibers are multiply innervated by en grappe endings. Each of the fine and granular fibers is innervated by a single thin axon that travels along the fiber and sends collaterals to the en grappe endings. These findings may provide a new basis for the correlation of morphological and physiological properties of EOM.

Chronic myopathy induced by repeated bupivacaine injections.

The effect of recurrent cycles of muscle fiber degeneration-regeneration was studied by repeated bupivacaine injections into the rat anterior tibial muscle. Injections of 0.6 ml of 0.75% bupivacaine were performed weekly for 6 months. The rats were allowed to recover for another 2 months and then killed. Histological and histochemical stains showed striking changes, including marked variability in fiber size, numerous internal nuclei, extensive fiber splitting and many whorled fibers. Combined staining for end-plate cholinesterase and terminal axons showed a markedly enlarged zone of terminal innervation. These findings suggest that the observed morphological changes usually attributed to a primary myopathic process may instead be the manifestations of impaired and incomplete regeneration occurring after cycles of degeneration-regeneration.

Occurrence of alkaline phosphatase-positive fibers in experimental muscle disorders.

The alkaline phosphatase (AP) reaction was carried out on muscle sections from a large series of rats under various experimental neuromuscular disorders. Only denervated and non-innervated muscle fibers stained positively with the AP reaction. In other conditions including degenerating, regenerating, tenotomized and immature muscles the AP reaction was negative. This suggests that the presence of AP-positive fibers in human neuromuscular disorders reflects a concomitant denervation process.

Hyperthyroid myopathy. Intracellular electrophysiological measurements in biopsied human intercostal muscle.

Morphological and electrophysiological studies were performed on intercostal muscle biopsies from 2 thyrotoxic patients. The diseased fibers had numerous areas of subsarcolemmal glyogen accumulations and abnormal membranous projections. Both Type I and Type II muscle fibers were atrophied. Diseased fibers were substantially depolarized and when artifically hyperpolarized showed earlier inactivation of the sodium conductance as a function of membrane potential, and a critical depolarization potential more depolarized than in normal fibers. When stimulated at 20 pulses/sec, or faster, the diseased fibers could not generate normal action potentials due to membrane depolarization and the appearance of a marked after-hyperpolarization. Muscle weakness associated with hyperthyroidism is attributed to the reduced membrane excitability.

Alterations in lipid incorporation in Duchenne muscular dystrophy. Studies of fresh and cultured muscle.

The incorporation of [3H] glycerol into lipids of fresh and cultured skeletal muscle obtained from patients with Duchenne muscular dystrophy (DMD), patients with myotonic dystrophy (My Dyst), controls, and aborted fetuses (10-12 weeks old) was studied. A significant increase of specific incorporation of [3H] glycerol into phosphatidylcholine (PCh), phosphatidylserine (PS), phosphatidylinositol (PI), and triglycerides (TRI) was found in DMD and fetal muscle in both fresh and cultured muscle. No significant differences, however, were noted between the values of glycerol incorporation in DMD and fetal muscle. The ratio between phospholipids and TRI changed significantly for fresh muscle in DMD (3.5) and fetal muscle (4.9) versus controls (24). The incorporation of glycerol into these lipids in My Dyst fresh and cultured muscle showed the same value as controls when expressed both as incorporation/mg protein and ratio between phospholipids and TRI.

Ultrastructural fiber typing in normal and diseased human muscle.

The differential staining of the 3 fiber types for oxidative enzyme activity at the histochemical level provides the basis of their identification at the ultrastructural level. Type I fibers have the largest and most numerous mitochondria, the Type IIA smaller and less numerous mitochondria, and Type IIB have the smallest and least numerous mitochondria as studied in 4 patients without neuromuscular disease. Type I fibers could be distinguished from Type II fibers on the basis of mean Z-line width and IIA fibers could be distinguished from IIB fibers on the basis of mean M-line width. Type I fibers had wide Z-lines (95 nm) and wide M-lines (89 nm), Type IIA had narrow Z-lines (74 nm) and wide M-lines (79 nm) and Type IIB fibers had narrow Z-lines (69 nm) and narrow M-lines (60 nm). This system of fiber typing based on relative Z-line and M-line widths was applied to several abnormal muscle biopsies each of which showed a deficiency in at least 1 of the major histochemical fiber types. In each case, the same deficiency was revealed at the ultrastructural level by measuring the relative Z-line and M-line widths of the remaining fiber types.

Accumulation of CK-MM is impaired in innervated and contracting cultured muscle fibers of Duchenne muscular dystrophy patients.

No specific abnormalities have been reproducibly manifested in aneurally cultured muscle of Duchenne muscular dystrophy (DMD) patients. We now report that the accumulation of the muscle-"specific" isozyme of creatine kinase (CK-MM) was significantly and preferentially impaired in long-term innervated contracting muscle fibers cultured from 4 DMD patients (DMD-InnCMFs) compared to: i) their noninnervated sister-cultured muscle fibers, and ii) innervated contracting control cultured human muscle fibers (Control-InnCHMFs). Accumulation of other muscle-"specific" isozymes (MSIs), viz. glycogen phosphorylase, phosphoglycerate mutase, and lactic dehydrogenase, was not significantly impaired. We have not observed preferentially-impaired CK-MM accumulation in any Control-InnCHMFs from 22 patients (children and adults) with a variety of neuromuscular diseases. There was no apparent difference between DMD-InnCMFs and Control InnCHMFs regarding: acceptance of innervation; neuronally-driven, virtually continuous muscle-fiber contractions; characteristic myofiber organization by phase-contrast microscopy, and increased longevity of the innervated fibers.

Alterations in creatine kinase, ornithine decarboxylase, and transglutaminase during muscle regeneration.

Creatine kinase (CK), transglutaminase (TGase) and ornithine decarboxylase (ODC), enzymes implicated in the regulation of growth processes, were studied during muscle regeneration subsequent to the injection of bupivacaine into rat tibialis anterior. Within 2 days, the percent BB isozyme of CK detected in the muscle was elevated 70-fold coincident with a marked decrease in total CK activity. The MB isozyme also increased and was 15-fold of control at 4-5 days postinjection. TGase activity was increased significantly to greater than 2-fold of control within 2 days of injection and significantly decreased at days 3 through 7 compared to controls. ODC activity was elevated significantly to 2- to 3-fold of control from 2-7 days after injection. These results suggest an early alteration in the expression of a coordinated battery of genes in this model of muscle degeneration-regeneration. The increased expression of MB and BB isozymes of CK in various human neuromuscular diseases may be a manifestation of an ongoing process of degeneration-regeneration.

Myositis specific antibodies: frequency in different populations.

Myositis specific autoantibodies (MSA) are the most specific markers of idiopathic inflammatory myopathies (IIM). There is no evidence of presence MSA in patients with other neuromuscular or connective tissue diseases. We compared the frequency of MSA in two groups of IIM patients, one from Poland and one from North America and found no significant statistical differences (21% and 25% respectively). There was a significant difference between the occurrence of immunological marker PM-Sci in scleromyositis patients (22.85% in group I and 7.1% in group II). This figure was also greater than those previously reported in North Americans (2-10%) and Japanese (extremely seldom). These findings confirm the association between MSA and several homogenous clinical syndromes: antisynthetases with the antisynthetase syndrome, anti-SRP with severe, resistant to treatment myositis, anti-Mi-2 with classic, benign dermatomyositis. They underscore the importance of including MSA in the routine diagnostic workup of IIM.