Neurogenic muscle weakness in chronic progressive external ophthalmoplegia (CPEO)
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Adult↗
Biomedical subjects
H Mitsumoto
Publications and source records attributed to H Mitsumoto.
Histometric characteristics and regenerative capacity in wobbler mouse motor neuron disease.
In wobbler mice, histometric features and the response to injury in the less affected hindlimb nerves were compared with the severely affected forelimb nerves which were studied previously. The frequency of vacuolated anterior horn cells was not different at the individual ages studied (3 and 6 weeks, 3 months), but with the three ages combined, the frequency in the two systems differed significantly, being 1.7 +/- 0.9% in the cervical and 0.6 +/- 0.7% in the lumbar anterior horns (P = 0.005). The number of large myelinated nerve fibres (greater than or equal to 6 microns in diameter) became progressively reduced in ventral roots as the disease advanced, particularly for the forelimb. The total number of myelinated axons was well preserved in the hindlimb ventral roots because of an increase in the number of small myelinated nerve fibres. The regenerative capacity of motor neurons after axotomy (tested by radiolabelling growth cones) was well preserved. In the hindlimb, the increased numbers of small myelinated fibres in ventral roots and the normal regenerative capacity in the sciatic nerve and its branches contrast with the severely affected forelimb system. Our studies suggest that cervical and lumbar anterior horn cells have different susceptibilities to the wobbler gene, producing vulnerability in one system and disease resistance in the other.
Animals↗
Fiber-type specific caffeine sensitivities in normal human skinned muscle fibers.
Caffeine sensitivity was studied in chemically skinned muscle fibers from vastus lateralis muscle obtained by biopsy during reconstructive knee surgery from 15 otherwise healthy young individuals. Muscle fiber type was determined by contracture occurring in strontium (slow-oxidative, type I fiber) or calcium (both type I and type II, fast glycolytic fiber) solutions and in several fibers after contracture testing by ATPase enzyme histochemistry. Caffeine sensitivity (mean +/- SD), defined as the threshold concentration inducing more than 10% of the maximal tension obtained with a calcium 3 x 10(-5) mM solution was 2.7 +/- 1.3 mM in 37 type I fibers, whereas it was 6.9 +/- 2.4 mM in 61 type II fibers. A paired t test showed a significantly increased sensitivity to caffeine in type I fibers (P less than 0.001) in 13 individuals in whom the two fiber types were identified. The mean (+/- SD) difference between type I and type II fibers was 4.1 +/- 1.9 mM. Type I fibers contracted with greater tension in response to the increasing concentration of caffeine than did type II fibers (P less than 0.05). These skinned fiber studies showed significantly different caffeine sensitivities between human type I and type II muscle fibers, as previously shown in animal muscles. The findings that human type I muscle fibers have higher caffeine sensitivity than type II muscle fibers should be helpful for the interpretation of the in vitro contracture test done in muscle strips containing type I and type II fibers in varying proportions.
Adenosine Triphosphatases↗
Ashkenazi-Jewish and non-Jewish adult GM2 gangliosidosis patients share a common genetic defect.
The adult form of Tay-Sachs disease, adult GM2 gangliosidosis, is an autosomal recessive neurological disorder caused by a partial deficiency of beta-hexosaminidase A. We had previously identified, in Ashkenazi-Jewish adult GM2 gangliosidosis patients, a Gly269----Ser mutation in the beta-hexosaminidase alpha-subunit. All of the Ashkenazi patients were found to be compound heterozygotes with an allele containing the Gly269----Ser mutation together with one of the Ashkenazi infantile Tay-Sachs alleles. We have now found the same Gly269----Ser mutation in six adult GM2 gangliosidosis patients from four different non-Jewish families. Genomic DNA from three of the patients, two of whom were brothers, exhibited a hybridization pattern consistent with homozygosity for the Gly269----Ser mutation. The remaining non-Jewish patients were compound heterozygotes of the Gly269----Ser mutation together with an unidentified alpha-subunit mutation. The results demonstrate that individuals homozygous for the Gly269----Ser change can be clinically affected. The same Gly269----Ser mutation in both the Ashkenazi and non-Jewish patients may be the result of a common ancestor, given that the ancestry of these non-Jewish patients, like the Ashkenazim, can be traced to eastern Europe.
Base Sequence↗
Amyotrophic lateral sclerosis. Recent advances in pathogenesis and therapeutic trials.
We reviewed the current status of pathogenesis and therapeutic trials in amyotrophic lateral sclerosis (ALS). Clinical studies have identified several rare but definable causes for apparent ALS. Certain clinical features previously considered unlikely to occur in ALS are found on careful examination. Epidemiologic surveillance and recent studies of neurotoxic plant seeds used in Guam have shed light on the pathogenesis of endemic ALS. Extensive analyses of biochemical, metabolic, immunologic, viral, and toxic factors have provided provocative results requiring further studies. Reflecting on some of these hypotheses, therapeutic trials have been performed more vigorously than ever. Amyotrophic lateral sclerosis is now investigated at the molecular genetic level. Human autopsy and experimental animal studies have expanded our understanding of basic mechanisms involving motoneuronal degeneration. In the future, we must continue a relentless search for the pathogenesis of ALS, prospective clinical studies to define the limits of ALS, and well-designed, controlled therapeutic trials.
Amyotrophic Lateral Sclerosis↗
Inclusion body myositis presenting as treatment-resistant polymyositis.
Inclusion body myositis (IBM) has been viewed as a distinct and rare form of inflammatory myopathy. Previously reported findings from series of IBM patients have suggested that clinical and pathologic features are present which readily distinguish it from idiopathic polymyositis. We report 4 cases of IBM presenting clinically and pathologically as polymyositis, each of which was refractory to therapy. Our data suggest that IBM may be a more common and heterogeneous form of inflammatory myopathy than has been previously suggested. Furthermore, IBM may be clinically and electrophysiologically indistinguishable from polymyositis. Reasons for failing to recognize IBM by pathologic studies appear to include: the skip lesion nature of the pathologic findings, failure to examine tissues by electron microscopy, and a low level of suspicion or lack of recognition. Because of its insidious clinical course and its failure to respond to immunosuppressive therapy, IBM may be an important variant of treatment-resistant polymyositis.
Adult↗
Chloroquine neuromyotoxicity. Clinical and pathologic perspective.
Six cases of toxic myopathy and/or neuropathy with chloroquine and/or hydroxychloroquine therapy are described. Two patients had unique clinical and pathologic evidence of cardiomyopathy secondary to chloroquine or hydroxychloroquine therapy. One patient had polyneuropathy secondary to chloroquine toxicity. This may be the first documentation of several features of chloroquine/hydroxychloroquine toxicity: morphologic changes in human peripheral nerve in chloroquine toxicity; chloroquine/hydroxychloroquine cardiomyopathy diagnosed by endomyocardial biopsy; and hydroxychloroquine myotoxicity. Chloroquine is a neuromyotoxin that affects nerves and cardiac and skeletal muscles. Discontinuation of chloroquine and hydroxychloroquine resulted in marked improvement in most cases. The reversibility of the symptoms emphasizes the importance of recognizing potential signs of nerve, muscle, and cardiac toxicity in patients being treated with chloroquine or hydroxychloroquine.
Aged↗
Thyrotropin-releasing hormone (TRH) in murine motor neuron disease (the wobbler mouse).
Clinical benefits of thyrotropin-releasing hormone (TRH) were tested in wobbler mice, an animal model of motor neuron disease. After the disease was clinically recognized at 3-4 weeks, the animals were divided into two groups, each group consisting of 5 pairs of wobbler mice and normal littermates. TRH (50 mg/kg) and normal saline (NS) were injected intraperitoneally daily, 6 times per week for 9 weeks, in a double-blind study. Weekly assessments consisted of front paw grip strength, push walking, body weight, and semiquantitative grading. At the end of the trial, the brain and spinal cord were sampled to measure TRH and cyclo (His-Pro) concentrations. Progression of motor neuron disease was evident in wobbler mice, regardless of treatment. Descriptive semiquantitative gradings showed the tendency of improvement in TRH-treated wobbler mice. In saline-injected controls, TRH levels in the cervical spinal cord were significantly increased (P less than 0.01) in wobbler mice compared to littermates. However, with TRH treatment, there was no significant difference in TRH and cyclo (His-Pro) levels in any neural tissue between wobbler and controls. The lack of clinical benefits with TRH in wobbler mice may be due to increased TRH levels found in diseased spinal cord in murine motor neuron disease.
Amyotrophic Lateral Sclerosis↗
Vacuolated anterior horn cells in wobbler mouse motor neuron disease: peripheral axons and regenerative capacity.
We investigated whether vacuolated cervical anterior horn cells of the wobbler mouse maintain axons to the periphery, and if these morphologically abnormal neurons are capable of supporting axonal regeneration. Using retrograde axonal transport, we applied horseradish peroxidase (HRP) to peripheral nerves or muscles and with electron microscopy sought evidence for perikaryal labeling in vacuolated neurons in 23 wobbler mice. When HRP was injected into forelimb muscles, 12 of 36 vacuolated neurons became positively labeled indicating that these neurons have axons in continuity with the periphery. In regeneration studies, after nerve crush at the brachial plexus, 23 out of 85 vacuolated neurons were labeled after HRP application at the elbow level. However, after a sufficient regeneration period, none of the 36 vacuolated neurons were labeled if HRP was applied in muscles below the elbow. In all experiments, morphologically normal neurons were always labeled. Our studies indicate that some vacuolated neurons of wobbler mice not only maintain axons into the periphery, but are also capable of supporting regeneration. However, the overall function of these vacuolated neurons appears marginal compared with the majority of morphologically normal neurons in this motor neuron disease.
Animals↗
Respiratory insufficiency in adult-onset acid maltase deficiency.
Although the adult form of acid maltase deficiency is characterized by weakness of the limb girdle muscles, weakness of the respiratory muscles out of proportion to that of the limb muscles may make the diagnosis less obvious. We present four patients aged 35 to 57 with respiratory muscle weakness associated with signs of cor pulmonale and symptoms of alveolar hypoventilation. Each had symptoms of fatigue, hypersomnolence, morning headache, and orthopnea, the cause of which was misdiagnosed. The key to diagnosis was paradoxic abdominal motion on inspiration. This finding, consistent with diaphragmatic paralysis, led to neurologic evaluation, electromyographic examination, and muscle biopsy to confirm the diagnosis. The symptoms of alveolar hypoventilation were reversed with chronic nocturnal ventilation, which assisted in rehabilitating some patients.
Adult↗
Impaired slow axonal transport in wobbler mouse motor neuron disease.
We studied slow axonal transport and morphometry of forelimb axons in wobbler mice and controls. In wobbler mice, the total radioactivity migrating with the slow transport was decreased by 50%. The velocity of transport also appeared to be reduced; 15 days following administration of a radioisotope, polypeptides migrating with slow component a of transport did not form a peak and remained mostly 2 mm from the spinal cord, while in controls slow component a was distributed as a peak which was located 4 mm from the cord. The ratios of the 68-kDa neurofilament subunit to tubulin and actin were significantly decreased (p less than 0.01 and p less than 0.005, respectively). This finding is consistent with a preferential reduction of the radioactivity migrating with neurofilament proteins in wobbler mice. Moreover, both the size and number of myelinated axons were markedly diminished, but their length was not significantly different, indicating that dying-back does not take place in axons of wobbler mice up to 12 mm from the spinal cord. The reduction in axonal transport may be due to the reduction in number and caliber of the axons and/or to reduced protein synthesis in cervical lower motor neurons; however, the abnormal distribution of the radioactive substance definitely results from impairment of the slow transport in the axons of the forelimb roots of wobbler mice. The transport impairment is not related to the presence of morphological changes in the perikaryon of wobbler mouse lower motor neurons, as it is much more widespread than would be expected if only altered neurons were involved.(ABSTRACT TRUNCATED AT 250 WORDS)
Actins↗
Motor neuropathy associated with a facilitating myasthenic syndrome.
We report a patient with progressive muscle weakness, areflexia, and no sensory loss. Electromyography revealed normal sensory nerve conductions, mild slowing of motor nerve conduction velocities, low amplitude compound muscle action potentials, a neuromuscular transmission defect characterized by prominent facilitation, and diffuse fibrillation potentials. Muscle biopsies showed acute denervation atrophy, and at autopsy, there was anterior horn cell loss and gliosis in the spinal cord. The findings suggest the coexistence of a motor neuropathy and a facilitating myasthenic syndrome.
Action Potentials↗
Amyotrophic lateral sclerosis: effects of acute intravenous and chronic subcutaneous administration of thyrotropin-releasing hormone in controlled trials.
We performed double-blind crossover trials to assess the effects of thyrotropin-releasing hormone (TRH) on amyotrophic lateral sclerosis patients. For acute intravenous trials, 500 mg TRH or placebo with norepinephrine was given at 1-week intervals (16 patients). CSF TRH concentration increased, and clinical side effects appeared with TRH. For chronic studies, 25 mg TRH and a saline placebo were given subcutaneously every day for 3 months (25 patients). CSF TRH level increased 29-fold after a single TRH injection, and mild transient side effects occurred. Vital signs, respiratory function, semiquantitative and quantitative neurologic function, muscle strength by manual and dynamometer testing, and EMG were studied. With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials.
Adult↗
Motor neuron disease and adult hexosaminidase A deficiency in two families: evidence for multisystem degeneration.
We studied three patients from two unrelated families with adult hexosaminidase A deficiency. A 30-year-old, non-Jewish proband in the first family had juvenile amyotrophic lateral sclerosis that evolved to mild dementia, ataxia, and axonal (neuronal) motor-sensory peripheral neuropathy. A 36-year-old Jewish proband in the second family had "pure" spinal muscular atrophy. One supposedly healthy brother of the first proband was found to have borderline IQ, mild spasticity, and ataxia but no evidence of motor neuron disease. Marked cerebellar atrophy was detected by head scans in all three patients. In both probands electromyograms were characterized by prominent, complex repetitive discharges in many muscles. Hexosaminidase A activities against the artificial substrate were similar to those reported in infantile Tay-Sachs disease; however, the hexosaminidase A level against GM2 substrates was higher than that found in infantile Tay-Sachs disease. The hexosaminidase A levels of the parents were in the heterozygous range. Motor neuron disease in our patients and in those previously described appears to be part of a multisystem degeneration of the nervous system.
Adult↗
Axonal regeneration in wobbler motor neuron disease: quantitative histologic and axonal transport studies.
The regenerative capacity of the cervical anterior horn cells was studied at 4 and 7 days following forelimb nerve crush in 19 wobbler mice and 18 normal littermates. Quantitative histologic and radiolabeled axonal transport techniques showed that the axotomized neurons of the wobbler mouse supported active axonal elongation. However, the average axon outgrowth rate determined by histologic technique was diminished by 25% and the fastest axon outgrowth rate determined by axonal transport technique was also decreased by 30% in wobbler mice as compared to controls. The distal labeled peak was absent in the wobbler mouse at 7 days, indicating that the regeneration rate of individual axons was widely dispersed. Histologic studies also showed that the wobbler axons grew slowly. This study suggests that axonal regeneration does occur in motor neurons undergoing a primary neuronopathy. However, the regenerative capacity was reduced and this appears to reflect an impairment of functional integrity in the anterior horn cells of the wobbler mouse.
Animals↗
Chronic progressive external ophthalmoplegia (CPEO): clinical, morphologic, and biochemical studies.
We studied skeletal muscles from eight chronic progressive external ophthalmoplegia patients with ragged-red fibers (group A), five CPEO patients without ragged-red fibers (group B), and five controls. The EM morphometric fraction of structurally abnormal mitochondria was increased in group A, and there was a similarly increased fraction of normal-appearing mitochondria in group B. State 3 respiration and uncoupled respiration were severely decreased in both groups. The morphometric mitochondrial fraction and respiratory functions were inversely related in all three groups. The cytochrome content in group A was normal; cytochromes b and cc1 were decreased in group B. These studies point to a central role of mitochondrial dysfunction in all types of CPEO, but the basic abnormalities remain to be elucidated.
Adult↗
Generalized myokymia and gold therapy.
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Adult↗
A case of congenital Werdnig-Hoffmann disease with glial bundles in spinal roots.
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Female↗