Masaru Inose

Pathological changes in skeletal muscle in HTLV-I-associated myelopathy

The main lesion site of HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the pyramidal tract. In some HAM patients, clinical symptoms and findings indicate neuromuscular involvement, such as muscular atrophy, fasciculation, elevated serum creatine kinase (CK) or significant electrophysiological data. Cases of HAM/TSP complicated with polymyositis or motor neuron disease have been reported. But no investigation has been directed to muscular pathology in many patients of HAM/TSP. We conducted muscle biopsies on 13 HAM patients. Four patients showed neurogenic changes. Six patients showed histological findings indicative of inflammatory myopathy. We investigated surface marker of invading cells in these 6 patients. In all patients, T lymphocytes were more predominant than B lymphocytes and in three of them T helper/inducer cells were more predominant than T suppressor cells. In 2 patients, only slight myopathic change could be seen, such as variation in fiber diameter and increase in the number of internal nuclei. In 1 patient, type 2 fiber atrophy was seen, and was possibly the result of disuse. Disturbance of secondary motor neurons or inflammatory myopathy is thus shown to be possibly associated with HAM/TSP.

Multiple episodes of thrombosis in a patient with Becker muscular dystrophy with marked expression of utrophin on the muscle cell membrane

Abstract We previously reported a patient with Becker muscular dystrophy (BMD) who exhibited a benign clinical phenotype and marked expression of utrophin on the muscle cell membrane. The patient developed multiple episodes of thrombosis (middle cerebral and femoral arteries) in the course of the disease. We re-examined the biopsy muscle specimen from the patient immunohistochemically as to the expression of procoagulant or anticoagulant factors. We found a lower expression of thrombomodulin on the muscle cell membrane in the BMD patient compared with other BMD or Duchenne muscular dystrophy (DMD) patients. Although utrophin up-regulation in muscle is thought to prevent the muscle wasting in dystrophin-deficient DMD or BMD, the data obtained in the present study indicate that up-regulated utrophin may have an unexpected influence on the function of the vascular or coagulation system.

Three cases of juvenile onset HTLV-I-associated myelopathy with pseudohypoparathyroidism

Among 201 patients diagnosed with HAM/TSP at Kagoshima University, 21 juvenile onset patients had manifested clinical signs and symptoms at less than 15 years of age. They appeared to have common characteristics such as short stature and slight mental retardation. These signs prompted us to investigate five of them endocrinologically; and three patients with pseudohypoparathyroidism (PHP) were confirmed. Serum calcium levels were low, and human parathyroid hormone (PTH) infusion (Ellsworth-Howard test) caused low response in urinary cyclic AMP and phosphorus excretion. The first case had IgA nephropathy, which is generally associated with infectious diseases, while the second case had muscular lymphocytic infiltration. The mothers of cases 1 and 2, who were both seropositive for HTLV-I, were suspected to have abnormal calcium metabolism based on Ellsworth-Howard test. A brother of case 1 and two sisters of case 3 had also HAM/TSP and short stature. The early clinical onset of HAM/TSP may be due to PTH receptor anomaly and a low level of 1,25-dihydroxyvitamin D, which is deficient in PHP and is involved in the regulation of the immune response. The association with IgA nephropathy or myositis may result from progressive HTLV-I infection.

An overexpression of fibroblast growth factor (FGF) and FGF receptor 4 in a severe clinical phenotype of facioscapulohumeral muscular dystrophy.

We evaluated the expression of a select panel of growth factors and their receptors, including fibroblast growth factor 1 (FGF‐1), fibroblast growth factor 2 (FGF‐2), platelet‐derived growth factor (PDGF), FGF receptor 1 (FGF‐R1), FGF receptor 3 (FGF‐R3), FGF receptor 4 (FGF‐R4), PDGF receptor α (PDGF‐Rα), PDGF receptor β (PDGF‐Rβ), and heparan sulfate proteoglycan (HSPG), in muscle biopsy specimens from nine facioscapulohumeral muscular dystrophy (FSHD) patients using immunohistochemistry. Two cases of Duchenne‐type muscular dystrophy (DMD), two of Becker‐type muscular dystrophy (BMD), and one of limb‐girdle‐type muscular dystrophy (LGMD) were also investigated. Widespread immunostaining for FGF‐1 and FGF‐2 on the sarcolemma and overexpression of FGF‐R4 in endomysial and perimysial connective tissue were seen in one patient with a severe clinical phenotype of FSHD who had respiratory failure. Standard histochemistry in this patient revealed marked interstitial fibrosis and lobulated fibers. The overexpression of FGF and FGF‐R4 in this severe FSHD case may be associated with the muscle fibrosis and disease severity.

Chronic demyelinating neuropathy and intra-axonal polyglucosan bodies

SummaryIn this study we evaluated the relationship between polyglucosan bodies and peripheral nerve lesions. The biopsied sural nerve from a patient with late-onset chronic sensori-motor neuropathy showed many intra-axonal polyglucosan bodies and segmental demyelination/remyelination. The formation of Schwann cell hyperplasia around the demyelinated axons was found at the sites of polyglucosan bodies. These findings suggest that demyelinating neuropathy is a part of the spectrum of the diseases characterized by the accumulation of polyglucosan bodies within cellular compartments.

Characteristic expression of cell adhesion molecules in adhalin deficiency

We have reported the reduction of the B1 subunit of laminin and that of heparan sulfate proteoglycan (HSPG) in two Japanese patients with adhalin deficiency. We here investigated immunohistochemically the expression of cell adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), neural cell adhesion molecule (NCAM), and CD44 (HCAM), in four Japanese patients with adhalin deficiency, compared to other types of muscular dystrophy. We found that NCAM was upregulated in a fair number of muscle fibers, regardless of the type of muscular dystrophy. ICAM-1 was detected on the rare muscle cell membrane in all patients. CD44 was barely detected on the muscle cell membrane in adhalin deficiency, in contrast to the strong expression of CD44 which was observed in other types of muscular dystrophy. These findings suggest that a different degenerative or regenerative process is involved in adhalin deficiency compared to other types of muscular dystrophy.

Abnormal expression of heparan sulfate proteoglycan on basal lamina of muscle fibers in two Japanese patients with adhalin deficiency

We recently reported the selective reduction of the B1 subunit of laminin in two Japanese patients with adhalin deficiency. We here investigated immunohistochemically the expression of other components of the extracellular matrix (ECM), including collagen type IV, heparan sulfate proteoglycan can (HSPG), chondroitin-4-sulfate proteoglycan, decorin, and fibronectin in adhalin deficiency, compared with other types of muscular dystrophy. We found a reduction of HSPG on the basal lamina surrounding each muscle fiber in adhalin deficiency compared with HSPG in other diseases. This finding may be characteristic evidence of the disturbance of the sarcolemma-ECM interaction and the sarcolemmal instability in adhalin deficiency. Recently, a direct role of HSPG in fibroblast growth factor (FGF) signal transduction was demonstrated. Further investigation is required to determine if the dysfunction of FGF is relevant to the pathogenesis of adhalin deficiency.

Steroid-responsive myalgia in a patient with Becker muscular dystrophy

We report a male patient with exercise-induced focal myalgia in the leg muscles. Dystrophin immunostaining of a biopsied muscle specimen from the patient showed the absence of or only faint immunoreactivity in 20% of the muscle fibers. The patient was diagnosed as having Becker muscular dystrophy. The myalgia was intractable and did not respond to non-steroidal anti-inflammatory drugs. The patient was placed on prednisone and found to be sensitive to it. Although he had recurrences of the symptom during tapering of the steroid, slower tapering over one year was tolerated. Steroid treatment may be useful for other Becker muscular dystrophy patients with myalgia.

Characteristic expression of thrombomodulin in the muscle sarcoplasm in patients with the acute phase of rhabdomyolysis

The expression of thrombomodulin and neural cell adhesion molecule (NCAM) was studied immunocytochemically in biopsied muscle specimens from 10 patients with rhabdomyolysis with different etiologic factors, including 5 with malignant hyperthermia. We have already reported that thrombomodulin was expressed on regenerating muscle cell membranes as well as on vessel walls in patients with various neuromuscular diseases, including Duchenne muscular dystrophy, Becker muscular dystrophy and inflammatory myopathy. We found increased expression of thrombomodulin not only on the sarcolemma, but also in the sarcoplasm of a fair number of muscle fibers in the acute phase of rhabdomyolysis. The granular pattern of thrombomodulin expression in the sarcoplasm seems to be a characteristic finding in the acute phase of rhabdomyolysis. Most muscle fibers which expressed NCAM on the sarcolemma also expressed thrombomodulin. However, the muscle fibers which expressed thrombomodulin in the sarcoplasm did not express NCAM, and showed a degenerative appearance on electron microscopic examination. These results suggest that thrombomodulin is expressed in the sarcoplasm during the acute degeneration phase of rhabdomyolysis in addition to the expression on the sarcolemma during the muscle fiber regeneration as shown in our previous study, and the former process, which is characterized by the granular expression of thrombomodulin in the sarcoplasm, may be a characteristic finding in rhabdomyolysis.

Microvascular endothelial abnormality in skeletal muscle from a patient with gastric cancer without dermatomyositis.

Abstract We found a microvascular endothelial abnormality in a biopsy specimen from the gastrocnemius muscle of a patient with gastric cancer, who had severe myalgia and angialgia in the calf region with the symptoms of thrombophlebitis. There were no definite findings of inflammatory myopathy in histochemical and immunohistochemical studies. Electron microscopic examination revealed the accumulation of abnormal mitochondria in the subsarcolemmal area, and a fair number of degenerating capillaries. Immunohistochemical analysis of procoagulant or anticoagulant factors revealed marked reduction of thrombomodulin (TM) expression on small vessels and capillaries. Although a reduction of TM on small vessels has been observed around perifascicular atrophic fibers in patients with dermatomyositis, histochemical findings of the present patient showed no perifascicular atrophy or severely degenerating fibers. These pathological findings in the patient may be related to a malignant neoplasm and may be one of the causes of disseminated intravascular coagulation (DIC), which is the main complication of malignant neoplasms. Further studies are necessary to determine whether the reduction of TM on the small vessels and capillaries in skeletal muscle is a predictor of some severe condition such as DIC or a rare pathological finding in some special condition such as scirrhous carcinoma with thrombophlebitis.