Apoptotic nuclear degeneration in Marinesco-Sjögren syndrome.

In 12 patients with the clinical characteristics of Marinesco-Sjögren syndrome including an autosomal recessive inheritance, congenital cataracts, mental retardation, cerebellar ataxia and progressive muscle weakness, the most common pathological finding was rimmed vacuole formation comprising from 0.1% to 10% of fibers in their muscle biopsy samples. The nuclear changes varied from condensed chromatin granules to vacuolation with amorphous inclusions which were predominantly seen in younger patients with prominent rimmed vacuoles, suggesting a close relationship between nuclear change and rimmed vacuole formation. From the severe destructive changes in nuclei, we speculated that the nuclear changes in Marinesco-Sjögren syndrome play a primary role in muscle degeneration resulting in myofibrillar disorganization and rimmed vacuole formation. In 2 patients, the TUNEL method demonstrated scattered myonuclei with fragmented DNA, but "ladder formation" was not found, probably because of the small numbers of nuclei with fragmented DNA. Nuclear degeneration with focal myofibrillar degeneration seen in these muscle samples suggests that the apoptotic process may occur in muscle disorders, especially in diseases with rimmed vacuole formation.

Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses.

To investigate the nature of the inflammatory response in facioscapulohumeral muscular dystrophy (FSHD), we analyzed mononuclear cells in muscle sections obtained from 18 FSHD patients and 8 controls. Monoclonal antibodies reactive for T cells, T cell subsets, B cells, and NK cells were used for cell typing. Macrophages were identified by acid phosphatase reaction. The localization of perforin, granzyme A, MHC-I and -II, dystrophin, and alpha-actinin antigens was also examined. We found that all FSHD patients, both familiar and sporadic cases, had greater amounts of mononuclear cellular infiltrates in muscle than controls, in whose specimens only few extra vascular mononuclear cells were counted. Seventy-two percent (13 of 18) of the patients had more than 50 inflammatory mononuclear cells per 1000 muscle fibers, and 33% (6 of 18) patients had numerous inflammatory cells exceeding 600 per 1000 muscle fibers (1835 +/- 482 SE). Nonnecrotic fibers invaded by mononuclear cells with either T8+, perforin+, or granzyme A+ were not observed in FSHD, while a few degenerating fibers were superficially invaded by T cells and macrophages. Occasional T cells were observed moving through the blood vessel wall. The increased number of necrotic fibers was paralleled by an increased number of inflammatory cells (r = 0.783, P = 0.0001). Genetic analysis, using the probes p13E-11, pFR-1, D4S139, and D4S163, was done in 6 patients (3 familiar, 3 sporadic) who had numerous inflammatory infiltrates. These 6 patients had small (< 28 kb) EcoRI fragments associated with the disease, and the disease was linked to 4q35. These results suggest that, in chromosome 4-linked FSHD: (1) inflammatory changes in muscle are a common histological feature; (2) mononuclear cellular infiltrates may enhance muscle fiber damage; but (3) T-cell-mediated cytotoxicity directed against muscle fibers is unlikely. We speculate that the immune effector mechanism in FSHD is different from that in previously reported inflammatory myopathies and Duchenne muscular dystrophy.

[An autopsied case of Fabry's disease presenting with parkinsonism and cardiomegaly as a cardinal clinical manifestation].

A 68-year-old male had been followed up under a clinical diagnosis of parkinsonism for 5 years. He was admitted to the Kanto Teishin Hospital with a chief complaint of difficulty in swallowing. Physical findings were almost normal. Neurological examination showed parkinsonism including mask-like face, positive Myerson's sign, mild rigidity, marche à petit pas, and retropulsion, and pyramidal signs including mild right hemiparesis, generalized hyperreflexia and positive Babinski's sign on both sides. Routine blood analysis was normal, except for elevated LDH level. He was found to have cardiac enlargement (CTR 58.7%) in chest roentogenogram, left ventricular hypertrophy (LVH), right bundle branch block and myocardial ischemia in electrocardiogram, as well as LVH, asymmetrical septal hypertrophy, mild MR and AR in echocardiogram. A T2 weighted brain MRI disclosed multiple high signal intensities in the basal ganglia and deep white matter regions which suggest parkinsonism resulting from multiple cerebral infarctions. An upper gastrointestinal endoscopic examination revealed esophageal and gastric carcinomas. He died of ventricular fibrillation 14 days after an operation of these carcinomas. Autopsy showed severe cardiomegaly (800 g) and vacuolar change of myocardium with lamellar body on electron microscopic examination. A definite biochemical diagnosis of Fabry's disease was made by demonstration of deposition of a large amount of trihexosylceramide in the myocardium, kidney, and liver. This case presented parkinsonism and cardiomegaly without typical signs of Fabry's disease. Therefore, Fabry's disease should be considered as one of possible underlying diseases, when a patient has cardiomegaly or ischemic cerebrovascular disease without risk factors, even if he has no typical signs of Fabry's disease.

Mononeuropathy multiplex with ulcerative colitis.

We describe acute mononeuropathy multiplex in a patient with chronic ulcerative colitis. The symptoms of neuropathy were well correlated with the disease activity of colitis. Both electrophysiological study and sural nerve biopsy revealed axonal degeneration. Mononeuropathy multiplex may be an extraintestinal manifestation of ulcerative colitis.

[Oculopharyngeal myopathy with autoimmune disease].

A 34-year-old woman had suffered from systemic lupus erythematosus (SLE) and autoimmune hemolytic anemia (AIHA) in the teen age. She developed progressive ptosis of the eyelids, and difficulty in swallowing and speaking for several years. Endocrinological studies showed primary hypothyroidism. A serum IgG level was elevated (1,973 mg/dl), and antinuclear antibody, thyroid test and microsome test were positive. A muscle biopsy showed massive inflammatory cell infiltrates in the perivascular area in addition to some myopathic change; some variation in fiber size. Immunological staining demonstrated most of these inflammatory cell infiltrates were CD3+ cells and CD4+ cells were counted more than CD8+ cells (CD4/CD8 = 2.3). The diagnoses were confirmed as oculopharyngeal myopathy and Hashimoto's disease. In addition, she had suffered from SLE and AIHA. Therefore we conclude that manifestation of this myopathy may be associated with some autoimmune process.

[Two familial cases with exertion-induced heat stroke--relationship to malignant hyperthermia].

Two patients in a family of exertion-induced heat stroke were reported. Case 1: A 23-year-old male, paternal cousin of case 2, was admitted to our hospital because of loss of consciousness during running under a burning sun. On physical and neurological examinations, he was deeply comatose with high fever, tachycardia, and increased deep tendon reflexes. Laboratory findings disclosed rhabdomyolysis, acute renal failure, disseminated intravascular coagulation, liver injury, and brain edema. He recovered after intensive cooling, some antibiotics, glycerol and sodium dantrolene administration. Case 2: A 19-year-old male experienced loss of consciousness and high fever during playing soccer at 15 years of age, and was admitted to a hospital. On admission, he had high fever of 38.7 degrees C, and increased serum CK level. He recovered two weeks after admission. He was readmitted to our hospital to evaluate the predisposition for malignant hyperthermia. His physical and neurological examinations showed no abnormalities. Routine laboratory findings were within normal limits. Muscle biopsy findings of cases 1 and 2 were mildly increased number of fibers with centrally placed nuclei. Caffeine test on skinned muscle fibers from the biopsies showed normal response in both type 1 and 2 fibers. The present patients were diagnosed as having exertion-induced heat stroke, but with no increased muscle fiber sensitivity to caffeine, suggesting that the pathomechanism differs from that of malignant hyperthermia induced by malfunction of sarcoplasmic reticulum.

[A case of chronic progressive external ophthalmoplegia associated with familial hypercholesterolemia].

A 52-year-old woman with chronic progressive external ophthalmoplegia (CPEO) with familial hypercholesterolemia (FH) was reported. Her mother died from heart disease, and her elder sister has hypercholesterolemia with swelling of Achilles tendons. She had slowly progressive external ophthalmoplegia, bilateral ptosis, swelling of Achilles tendons since twenties. At 40 years of age, she was pointed out hypercholesterolemia. Physical examination was within normal limits except for bilateral swelling of Achilles tendons. Neurological findings showed bilateral ptosis, disturbance of eye movements, mild proximal muscle weakness and dysesthesia in bilateral hands. Routine laboratory findings were within normal limits except for high serum cholesterol level (512 mg/dl). In the biopsied muscle, there was mild variation in fiber size with several ragged-red fibers and focal cytochrome c oxidase defective fibers. Biochemical analysis of the biopsied muscle revealed normal values in the mitochondrial fraction. Southern blot analysis of the mitochondrial DNA (mtDNA) of the muscle disclosed mixed population of mtDNA, consisting of the normal one and partially deleted (4.9-kilobase). Southern blot analysis of the leukocytes from the patient against the cDNA of LDL receptor was normal at least using the restriction enzyme of BglII, XbaI, EcoRI, PvuII and BamHI. This case has CPEO with deleted mtDNA associated with familial hypercholesterolemia, which is caused to nuclear DNA abnormalities, and is thought to be an important case for us to study the relationship between deleted mtDNA and abnormal nuclear DNA in CPEO.

Analysis of inflammatory cells and complement C3 in bupivacaine-induced myonecrosis.

Immunohistochemical analysis of the inflammatory cells and complement C3 in the rat skeletal muscle was performed chronologically in bupivacaine-induced myonecrosis. At 30 minutes after injection, polymorphonuclear leukocytes appeared and increased in number, with a peak value at 12 hours, while macrophages reached the highest level at 2 days. In contrast, T cells comprised only a small population. Two weeks after the injection, all types of the inflammatory cells returned to the normal level. Deposition of complement C3 was recognized at 60 minutes at the surface membrane of degenerating muscle fiber. Our observation suggests the importance of both polymorphonuclear leukocytes and complement C3 in the early stage, and macrophages in the later stage of bupivacaine-induced myonecrosis. In addition, our findings cast doubt on the pathological significance of T cells in this model.

[A case of sarcoidosis presenting ataxic hemiparesis as an initial clinical manifestation].

A case of sarcoidosis presenting ataxic hemiparesis was reported. A 25-year-old man was admitted to Kanto Teishin Hospital because of slight weakness and dysesthesia in the right side of his body. His physical findings were normal. Neurological findings disclosed mild right hemiparesis (MMT 4+), cerebellar signs and mild dysesthesia in the same side. Laboratory findings were within normal limits except for elevated serum ACE and lysozyme. Chest roentgenogram showed bilateral hilar lymphadenopathy and TBLB disclosed sarcoid granuloma. Though brain CT, brain MRI and cerebral angiography were within normal limits, the neurological features were thought to be due to sarcoidosis. They disappeared along with the decrease of ACE and lysozyme. This is the first report of ataxic hemiparesis due to sarcoidosis, and it is interesting in that ataxic hemiparesis, which is one of signs of diseases in central nervous system, is the first manifest clinical feature of sarcoidosis.

A case of "myopathy with tubular aggregates" with increased muscle fibre sensitivity to caffeine.

A 23-year-old man with "myopathy with tubular aggregates" had suffered from exercise-induced muscle cramps for 1 year. His general and neurological findings were normal. Laboratory investigations were within normal limits except for a slightly elevated serum creatine kinase level. Muscle biopsy showed some small angular fibres and scattered type 2B fibres with prominent tubular aggregates originating from the sarcoplasmic reticulum. Since the muscle fibres contracted at a lower concentration of caffeine, increased muscle fibre sensitivity to caffeine is probably related to muscle cramps in this disorder. Tubular aggregates are then secondarily formed in the muscle fibres.