Thymus histology and concomitant autoimmune diseases in Japanese patients with muscle-specific receptor tyrosine kinase-antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: The differences in the characteristics of thymus histology, coexisting autoimmune diseases and related autoantibodies between anti-muscle-specific receptor tyrosine kinase (MuSK)-antibody (Ab)-positive myasthenia gravis (MG) patients, and anti-acetylcholine receptor (AChR)-Ab-positive MG patients are not clearly defined. METHODS: The types of thymus histology, coexisting autoimmune diseases and associated Abs in 83 MuSK-Ab-positive patients nationwide were investigated and were compared with those in AChR-Ab-positive patients followed at our institute (n = 83). As for the autoantibodies associated with thymoma, titin Abs were measured. RESULTS: Thymoma was not present in any of the MuSK-Ab-positive patients but presented in 21 patients (25.3%) amongst the AChR-Ab-positive patients. Titin Abs were absent in MuSK-Ab-positive patients but positive in 25 (30.1%) of the AChR-Ab-positive patients. Concomitant autoimmune diseases were present in eight MuSK-Ab-positive patients (9.6%) amongst whom Hashimoto's thyroiditis and rheumatoid arthritis predominated, whereas 22 AChR-Ab-positive patients (26.5%) had one or more concomitant autoimmune diseases of which Graves' disease predominated. CONCLUSIONS: Differences in frequency of thymoma and thymic hyperplasia, coexisting autoimmune diseases and autoantibody positivity between MuSK-Ab-positive and AChR-Ab-positive MG were indicated, suggesting that, in contrast with AChR-Ab-positive MG, thymus does not seem to be involved in the pathogenic mechanisms of MuSK-Ab-positive MG.

Limbic encephalitis associated with systemic lupus erythematosus.

A 34-year-old woman with systemic lupus erythematosus (SLE) presented with general fatigue, seizures and memory loss. Magnetic resonance imaging of the brain showed a high signal area in the mesial temporal lobe bilaterally. Computed tomography scan of the chest and abdomen and ultrasound of pelvis detected no malignancy and tumour marker, antibodies to antineuronal antibodies (anti-Hu, anti-Ta and anti-Ma) and antibodies to voltage-gated potassium channels were all negative. The present case is limbic encephalitis (LE) associated with SLE and the pathogenesis may include autoimmunity shared. Our experience indicates that the immunologic spectrum of LE will expand to include additional immune mechanisms.

"Dropped head syndrome" caused by Lambert-Eaton myasthenic syndrome.

A 67-year-old man was admitted with a 2-year history of dropped head. Neurological examination revealed ptosis, dysarthria, neck weakness, hyporeflexia of all limbs, and autonomic failure. Electrophysiologic study showed a 400% increment response to high-rate repetitive nerve stimulation. Serum anti-P/Q-voltage-gated calcium channel antibody was positive, confirming the diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). His symptoms and electrophysiological abnormalities improved with oral prednisolone following plasmapheresis. This is the first report of LEMS as a cause of dropped head syndrome.

Prevalence of interrelated autoantibodies in thyroid diseases and autoimmune disorders.

OBJECTIVE: We determined the autoantibody profile in autoimmune thyroid diseases (AITD) and examined the distribution of thyroid-related autoantibodies in other autoimmune disorders. METHODS: We tested sera from 234 patients with Graves' disease (GD), 130 with Hashimoto's thyroiditis (HT), 249 with other autoimmune diseases, and 50 healthy controls by enzyme-linked immunosorbent assay or radioimmunoassay. RESULTS: Autoantibodies except TSH receptor antibody (Ab), anti-thyroglobulin (Tg) Ab and anti-thyroid peroxidase (TPO) Ab were not significantly prevalent in patients with AITD despite a significantly high elevation of thyroid-related Ab. Significant prevalence of autoantibodies related to AITD was observed in type 1 diabetes patients. Elevation of anti-Tg Ab was seen in patients with primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH), and anti-TPO Ab was elevated in patients with PBC. Although the prevalence of anti-acetylcholine receptor Ab and systemic lupus erythematosus (SLE)- related Ab was significant in AIH, primary Sjögren's syndrome (pSS)-related Ab were also found in both liver diseases. In myasthenia gravis (MG) patients, thyroid-related Ab and pSS-related Ab were detected in both MG groups, although SLE-related Ab were limited to the anti-muscle specific kinase Ab-positive MG patients. In patients with connective tissue diseases, anti- Tg Ab and anti-TPO Ab were significantly prevalent. CONCLUSION: Thyroid-related Ab were significantly elevated in all autoimmune diseases. Conversely, the elevations of Ab were not significant in the patients with AITD, suggesting a close relationship between AITD and other immune-mediated diseases.

Discovery of a Jupiter/Saturn analog with gravitational microlensing.

Searches for extrasolar planets have uncovered an astonishing diversity of planetary systems, yet the frequency of solar system analogs remains unknown. The gravitational microlensing planet search method is potentially sensitive to multiple-planet systems containing analogs of all the solar system planets except Mercury. We report the detection of a multiple-planet system with microlensing. We identify two planets with masses of approximately 0.71 and approximately 0.27 times the mass of Jupiter and orbital separations of approximately 2.3 and approximately 4.6 astronomical units orbiting a primary star of mass approximately 0.50 solar mass at a distance of approximately 1.5 kiloparsecs. This system resembles a scaled version of our solar system in that the mass ratio, separation ratio, and equilibrium temperatures of the planets are similar to those of Jupiter and Saturn. These planets could not have been detected with other techniques; their discovery from only six confirmed microlensing planet detections suggests that solar system analogs may be common.

Autoantibodies against M1 muscarinic acetylcholine receptor in myasthenic disorders.

The Lambert-Eaton myasthenic syndrome (LEMS), often associated with small-cell lung carcinoma (SCLC), is a disorder of acetylcholine (ACh) release from motor nerve terminals. In most patients, it is caused by autoantibodies against the P/Q-type voltage-gated calcium channels (VGCC) that trigger ACh release. However, these antibodies are not detected in approximately 15% of clinically and electrophysiologically typical cases. The M1-type pre-synaptic muscarinic ACh receptor (M1 mAChR) modulates cholinergic neuromuscular transmission by linking to P/Q-type VGCC, and may partially compensate for the reduced calcium entry. Immunoblotting against solubilized human M1 mAChR, we detected autoantibodies in: (a) 14 of 20 (70%) anti-VGCC-positive LEMS patients; (b) all five anti-VGCC-negative LEMS patients, one of whose serum had previously passively transferred LEMS-type electrophysiological defects to mice; (c) all five LEMS patients with autonomic symptoms; (d) seven of 25 (28%) myasthenia gravis (MG) patients in whom increased ACh release partially compensates for post-synaptic defects; (e) none of 10 SCLC patients without LEMS. Although not proving primary pathogenicity of anti-M1 mAChR antibodies, the present results highlight their potential to affect synaptic compensatory mechanisms, more in LEMS than MG.

A novel mutation (T61I) in the gene encoding tumour necrosis factor receptor superfamily 1A (TNFRSF1A) in a Japanese patient with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) associated with systemic lupus erythematosus.

OBJECTIVE: To identify potential mutations in the tumour necrosis factor receptor superfamily 1A gene (TNFRSF1A) in a Japanese female patient with recurrent fever complicated by systemic lupus erythematosus (SLE), and in her family members. METHODS: DNA sequencing of exons 1-10 of the TNFRSF1A gene was performed to determine mutations that might be associated with the tumour necrosis factor receptor-associated periodic syndrome (TRAPS). Moreover, the TNFRSF1A gene was examined in Japanese patients with autoimmune diseases, including SLE, rheumatoid arthritis (RA), mixed connective tissue disease (MCTD) and Behçet's disease, and in healthy Japanese controls. Enzyme-amplified sensitivity immunoassay (EASIA) analysis was used to assess serum levels of TNF, the 55-kDa TNF receptor (TNFRSF1A) and the 75-kDa TNF receptor (TNFRSF1B). Membrane TNFRSF1A expression was analysed on the surface of peripheral blood mononuclear cells by flow cytometry. RESULTS: A novel mutation, a heterozygous C to T transition in exon 3 which substitutes an isoleucine for a threonine at position 61 (T61I) was detected in the TNFRSF1A gene derived from the genomic DNA of a Japanese female TRAPS patient. Two nieces and one nephew, all with a similar clinical phenotype, also possessed the same TNFRSF1A mutation. We further demonstrated the same mutation in five of 60 SLE patients (8.3%) and in five of 120 healthy individuals (4.2%), with no significant differences. Although high titres of serum TNF and soluble TNFRSF1B protein were observed in this patient, low titres of soluble TNFRSF1A protein were detected. However, a defect in TNFRSF1A shedding in vitro was not observed in monocytes derived from this patient. CONCLUSION: This is the first report of a TRAPS patient associated with SLE with a novel TNFRSF1A mutation (T61I).

Anti-ryanodine receptor antibodies and FK506 in myasthenia gravis.

Anti-ryanodine receptor (RyR) antibodies were measured in sera from 33 myasthenia gravis (MG) patients using three peptides from the human RyR1 sequence, two C-terminal peptides included in the functional calcium release channel, and an N-terminal peptide implicated in ion-conduction. Antibodies were more frequently positive against the two C-terminal peptides, particularly in thymoma-associated MG. In a preliminary open trial with FK506, immunosuppressant and enhancer of RyR-related sarcoplasmic calcium release, the authors observed the sustained benefits in anti-RyR-positive MG patients.

Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients.

The authors characterized the clinical and immunologic features of 110 patients with Lambert-Eaton myasthenic syndrome (LEMS). Anti-P/Q-type voltage-gated calcium channels (VGCC) antibodies were detected in 85% of the patients (seropositive) but not in the rest (seronegative). Except for the indication that small cell lung carcinoma is less common in seronegative patients, no significant differences were found in the clinical characteristics of patients who had or did not have anti-P/Q-type VGCC antibodies. The results of passive transfer experiments suggest that seronegative LEMS is also an autoantibody-mediated disorder.

[Guillain-barré syndrome associated Campylobacter jejuni serotype Penner 2: a case report].

We described a 15-year-old male who had Guillain-Barré syndrome(GBS). Nine days after watery diarrhea, the patient developed pain and weakness of foot muscles. On admission, the nerve conduction studies revealed peripheral neuropathy with axonal degeneration and demyelination. Campylobacter jejuni(C. jejuni) with serotype of Lior 4, Penner 2 was isolated from his stool culture. IgM anti-GM 1 antibody and other various anti-ganglioside antibodies were detected in his serum. After receiving plasma exchange and intravenous immunoglobulin therapy, he was able to walk without assistance. In general, C. jejuni with the serotype Penner 19 has been isolated from many GBS patients. In this patient, C. jejuni with the serotype of Penner 2 was isolated. The serotype is detected commonly in Miller Fisher syndrome.

Semiquantitative measurement of acetylcholine receptor at the motor end-plate in myasthenia gravis.

OBJECTIVE: The purpose of this study was to investigate whether this semiquantitative measurement of the motor end-plate acetylcholine receptors (AChRs) can be used to confirm the diagnosis of myasthenia gravis (MG), and in particular ocular MG. METHODS: Motor point biopsies were performed from the biceps brachii muscles. Measurement of AChRs was made in peroxidase-labeled alpha-bungarotoxin stained muscle specimens. PATIENTS: Twenty patients with ocular MG, 37 with generalized MG, 5 with Lambert-Eaton myasthenic syndrome, 3 with botulism, 8 with amyotrophic lateral sclerosis, and 8 controls were included in this study. RESULTS: AChRs were decreased in all patients with generalized MG and in 80% of ocular MG including patients without detectable circulating anti-AChR antibodies, as compared with the control subjects. CONCLUSION: This method is useful to confirm the diagnosis of MG, in particular ocular MG without detectable anti-AChR antibodies.

Heart rate elevation and diabetic retinopathy in patients with type 2 diabetes mellitus and normoalbuminuria.

To investigate the role of heart rate (HR) and blood pressure (BP) for diabetic retinopathy, 24-h ambulatory HR and BP were monitored for 162 in patients with type 2 diabetes and normoalbuminuria. The fundus was assessed as no retinopathy, simple diabetic retinopathy (SDR) and proliferative retinopathy (PDR). Comparing the highest with the lowest quartile of diabetic duration, the relative risk for retinopathy was 9.3 and for nocturnal HR, it was 3.6. Comparison among three retinopathy groups (no retinopathy, group 1, n=122; SDR, group 2, n=24; Pre-PDR or PDR, group 3, n=16) showed that 24-h and nocturnal HR were significantly higher in group 3 (80+/-9 and 71+/-9 beats per min) than in group 2 (73+/-8 and 64+/-8) and group 1 (72+/-7 and 60+/-7). In multiple logistic analysis, the odds ratio of diabetic duration and nocturnal HR to the existence of retinopathy was 1.17 (95% CI, 1.10-1.25, P=0.00001) and 1.11 (95% CI, 1.05-1.17, P=0.0002). We concluded that diabetic retinopathy is related to diabetic duration and high heart rate in type 2 diabetes mellitus with normoalbuminuria. Heart rate elevation may be a predictor of advanced retinopathy.

Isolation of cortical MTs from tobacco BY-2 cells.

We isolated the cortical microtubules (CMTs) from tobacco BY-2 cells to identify their components. By centrifugation of protoplasts homogenized in the presence of taxol, a MT-stabilizing reagent, in a density gradient of Percoll, we obtained membranous vesicles to which MTs forming a sheet-like bundle were attached. Rhodamine-conjugated Ricinus communis agglutinin I (RCA-I), a lectin that bound to the surface of protoplasts, stained these vesicles, indicating that they were plasma membrane (PM) vesicles that retained CMTs. CMTs were released by solubilization of PM vesicles with Triton X-100. A sheet-like array of CMTs was retained even after solubilization of PM vesicles. Immunoblot analysis of the isolated CMTs demonstrated the presence of tubulin, actin, the 65 kDa microtubule-associated protein (MAP) and a 130 kDa RCA-I binding protein. Purification of the isolated CMTs by the temperature dependent disassembly-reassembly cycling method revealed four polypeptides, 190, 120, 85 and 65 kDa, co-assembling with CMTs.

Neurogenic bladder in Lambert-Eaton myasthenic syndrome and its response to 3,4-diaminopyridine.

Autonomic dysfunction, as well as neuromuscular involvement, is a common manifestation of Lambert-Eaton myasthenic syndrome (LEMS). Dry mouth and impotence have been described as typical features of autonomic dysfunction, but neurogenic bladder is infrequent or subclinical in LEMS. We report a patient with neurogenic bladder secondary to LEMS whose condition responded to 3,4-diaminopyridine (3,4-DAP). In this patient's serum, results of repeated measurement with P/Q-type VGCC antibodies proved positive, but not with N-type VGCC and synaptotagmin antibodies. A review of the literature turned up a few patients with voiding dysfunction related to LEMS, but no urodynamic studies were done on these patients. Ours is the first case in which 3,4-DAP was efficacious in treating LEMS and neurogenic bladder. Responses of 3,4-DAP in urodynamic studies suggest that in this LEMS patient neurogenic bladder was caused by defective neurotransmission both in the autonomic detrusor and skeletal abdominal muscles.

[Lambert-Eaton myasthenic syndrome: diagnosis and treatment].

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular and autonomic transmission in which IgG autoantibodies lead to presynaptic voltage-gated calcium channel (VGCC) loss, or as a paraneoplastic disorder in association with small cell lung carcinoma (SCLC). Recent results strongly suggest that the antibodies to P/Q-type VGCC are the principal pathogenic factors in LEMS. Here, we present diagnosis and treatment of LEMS patients. Proximal weakness, depressed tendon reflexes, autonomic symptoms, and electrical posttetanic potentiation together are essential to accurately diagnose LEMS. The diagnosis is established immunologically by the presence of anti-P/Q-type VGCC antibodies, detected using the (125)I-omega-conotoxin MVIIC radioimmunoassay, which will be present in 85% of LEMS patients. The drug 3,4-diaminopyridine with anti-cholinesterase inhibitor is most effective in LEMS patients with or without SCLC. In LEMS with SCLC, specific tumor therapy will often improve the neurological disorder. In some cases plasmapheresis or intravenous immunoglobulin may be indicated.