Masayuki Masuda

Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15q13-15

To date, three loci for autosomal recessive hereditary spastic paraplegia (ARHSP) linked to chromosomes 8p12‐q13, 16qter, and 15q13–15 have been characterized. We have clinically characterized 13 Japanese ARHSP families and performed genetic linkage analyses. All 13 families were classified as having the “complicated” form, which manifests with mental impairment and thin corpus callosum. Linkage to the 8p12‐q13 and 16qter loci was excluded, although 10 of the 13 families showed marker data consistent with linkage to the 15q13–15 locus. The multipoint LOD score of the 10 families linked to chromosome 15 was above 9.00 in the 3‐centimorgan segment flanked by D15S994 and D15S659, with a maximum multipoint LOD score of 9.68 at a position 1.2 centimorgans telomeric from D15S994 to D15S659. We have shown that ARHSP with thin corpus callosum, a subtype of recessive spastic paraplegia, maps to chromosome 15q13–15. Ann Neurol 2000;48:108–112

Clinical implication of peripheral CD4+CD25+ regulatory T cells and Th17 cells in myasthenia gravis patients.

Myasthenia gravis (MG) is an autoimmune disorder generally mediated by antibodies against the acetylcholine receptors (AChR) of the skeletal muscles. CD4 T cells help B cells to produce antibodies through their production of cytokines or chemokines. In this study, we evaluated the frequency of regulatory (Treg) and IL-17 producing CD4 T-cell subsets (Th17) in peripheral blood mononuclear cells (PBMCs) of patients with MG. The transcription factor, forkhead transcription factor (Foxp3), is essential for T-cell regulatory function, and the orphan nuclear receptor, RORgammaT, is important in Th17 cell differentiation. In MG patients, Foxp3 mRNA expression in PBMCs was lower than those in healthy subjects (p=0.007), while there was no significant difference of RORgammaT mRNA expression between MG patients and healthy subjects. Glucocorticoid-induced tumour-necrosis-factor receptor-related protein (GITR) is expressed predominantly on CD4(+)CD25(+) Treg cells. We found that the number of GITR(+)CD4(+)CD25(+) T cells in peripheral lymphocytes in MG patients was lower than that in healthy subjects (P<0.01). In addition, there was a significant positive correlation between the change of the frequency of GITR(+)CD4(+)CD25(+) T cells and the changing rate in quantitative myasthenia gravis scores (%) (p=0.03). Furthermore, there was a significant negative correlation between the change of the percentage of GITR(+)CD4(+)CD25(+) T cells (% lymphocytes) and the changing rate of daily PSL doses (%) (P=0.002). The relative RORgammaT levels in PBMCs negatively correlated with the Th1/Th2 ratio in CD4(+) cells in MG patients (p=0.014). In conclusion, our findings suggest that Th17 cells affect the production of autoantibodies through their influence on the Th1- and Th2-cytokine balance in PBMCs of MG patients. On the other hand, Treg cells are suggested to be involved in the clinical condition or severity of MG disease.

The MG-QOL15 Japanese version: validation and associations with clinical factors.

Our study aim was to produce a Japanese translation of the 15‐item Myasthenia Gravis Quality‐of‐Life Scale (MG‐QOL15), assess its reliability and validity, and examine clinical factors affecting self‐perceived QOL in MG.

Relationship between NMO-antibody and anti-MOG antibody in optic neuritis.

Background: Damage to astrocytes by anti-aquaporin-4 antibody (AQP4-Ab), also known as NMO antibody, has been implicated as the cause of neuromyelitis optica. Myelin oligodendrocyte glycoprotein (MOG) is well known as the causative protein of multiple sclerosis (MS). MOG antigen is currently considered as a cause of optic neuritis (ON) associated with MS because immunization with MOG antigen derived from oligodendrocytes induces murine ON with myelitis. We investigated the relationship between NMO antibody (NMO-Ab) and anti-MOG antibody (MOG-Ab) and potential in patients with ON for recovery of vision. Methods: Thirty-three eyes of 23 patients with ON were studied. At presentation, serum NMO-Ab was measured by immunofluorescence using HEK 293 cells transfected with AQP4–GFP, and anti-MOG1–125 antibody was measured by enzyme-linked immunosorbent assay. MOG-Ab seropositivity was defined by comparing with MOG-Ab level obtained from 8 healthy normal subjects. Results: Eleven (47%) of 23 ON patients were NMO-Ab seropositive, while 8 (34%) of the 23 patients were MOG-Ab seropositive. Six (26%) of 23 patients were seropositive for both NMO-Ab and MOG-Ab. Ten (43%) of 23 patients were seronegative for both antibodies. Three (50%) of 6 eyes of patients seropositive for both antibodies did not respond to corticosteroid pulse therapy and plasmapheresis, and visual acuity remained unchanged. In the NMO-Ab(−)/MOG-Ab(−) group, visual acuity improved significantly (P < 0.0001). In the other 3 groups (NMO-Ab(+)/MOG-Ab(+), NMO-Ab(+)/MOG-Ab(−), and NMO-Ab(−)/MOG-Ab(+)), visual acuity did not change significantly (P = 0.53, 0.42, and 0.45, respectively). Conclusion: NMO-Ab and MOG-Ab could be potential biomarkers to determine visual prognosis in patients with ON.

Mutations in MME cause an autosomal-recessive Charcot–Marie–Tooth disease type 2

The objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT.

Health-related quality-of-life and treatment targets in myasthenia gravis.

Introduction: The aim of this study was to determine factors affecting health‐related quality of life (HRQOL) and to propose appropriate treatment targets for patients with myasthenia gravis (MG). Methods: We evaluated 640 consecutive patients with MG seen at 11 neurological centers. Two‐year follow‐up data were obtained for 282 patients. Correlations between detailed clinical factors and the Japanese version of the 15‐item MG‐specific QOL scale score were analyzed. Results: In a cross‐sectional analysis of 640 MG patients, multivariate regression revealed that disease severity, as evaluated by the MG Composite (P < 0.0001), total dose of oral prednisolone during the last year (P = 0.002), and Cushingoid appearance index (P = 0.0004), showed significant negative effects on HRQOL, but the quantitative MG score and current prednisolone dose did not. Conclusions: Achieving minimal manifestations (MM) status or better with prednisolone ≤5 mg/day was found to exert a major positive impact on HRQOL in both the cross‐sectional and 2‐year follow‐up patient samples and can be recommended as a treatment target. Muscle Nerve 50: 493–500, 2014

Factors associated with depressive state in patients with myasthenia gravis: a multicentre cross-sectional study

Objectives The objective of this study was to examine clinical factors associated with depressive state in patients with myasthenia gravis (MG). Design Cross-sectional study. Setting and participants We evaluated 287 consecutive cases of MG seen at six neurological centres located in Eastern Japan. Outcome measures All MG patients completed the Japanese version of the Beck Depression Inventory–Second Edition (BDI-II). Disease severity was determined according to the MG Foundation of America (MGFA) quantitative MG score, MG activities of daily living scale and MG composite scale (MG composite). Clinical state following treatment was categorised according to MGFA postintervention status. Associations between detailed clinical parameters of MG and BDI-II score were then examined statistically. Results Mean BDI-II score for patients with MG (11.0±8.1) did not differ substantially from and overlapped with that reported as the Japanese standard (8.7±6.4). The mean +2 SDs for the Japanese standard is 21.5, approximately equal to the cut-off level indicative of moderate or worse depression (>20 points) in the original English version. We thus defined BDI-II >21.5 as depressive state, with a frequency of 13.6% in patients with MG. Multivariate logistic regression analysis revealed current dose of oral prednisolone (OR 1.09, 95% CI 1.02 to 1.17; p=0.01), unchanged MGFA postintervention status (OR 3.55, 95% CI 1.18 to 10.71; p=0.02), time since onset (OR 0.93, 95% CI 0.87 to 0.99; p=0.03) and MG composite (OR 1.16, 95% CI 1.00 to 1.34; p=0.046) as factors independently associated with depressive state in MG. Conclusions Dose of oral corticosteroids appears to represent the major factor associated with depressive state in MG. Unchanged status despite treatment and early disease stage are also significant background factors for depressive state, along with disease severity.

Clinical features and treatment status of adult myasthenia gravis in Japan

Myasthenia gravis (MG) is classified as early‐onset MG (EOMG; age at onset ≤49 years), late‐onset MG (LOMG; age at onset ≥50 years) or thymoma‐associated MG (TAMG) (E‐L‐T classification). To clarify the characteristics of each group in the E‐L‐T classification in Japan, we carried out multicenter analyses of MG.

Oral corticosteroid therapy and present disease status in myasthenia gravis

Introduction: The aim of this study was to elucidate the effectiveness of oral prednisolone (PSL) according to dosing regimen in 472 patients with myasthenia gravis (MG). Methods: We compared the clinical characteristics and PSL treatment between 226 patients who achieved minimal manifestations (MM) or better and 246 patients who remained improved (I) or worsened, according to the MG Foundation of America postintervention status. Results: Achievement of MM or better at peak PSL dose (odds ratio 12.25, P < 0.0001) and combined use of plasma exchange/plasmapheresis (PE/PP) and/or intravenous immunoglobulin (IVIg) (odds ratio 1.92, P = 0.04) were associated positively, and total PSL dose during the past year (odds ratio 0.17, P = 0.03) was associated negatively with present MM or better status. Conclusions: Higher PSL dose and longer PSL treatment do not ensure better outcome. In the absence of a good response, the PSL dose should be decreased by combining with modalities such as PE/PP or IVIg. Muscle Nerve 51:692–696, 2015

International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r.

Introduction: The MG‐QOL15 is a validated, health‐related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties. Methods: We first performed Rasch analysis on >1,300 15‐item Myasthenia Gravis Quality of Life scale (MG‐QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG‐QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on >1,300 MG‐QOL15r scales. Results: The MGQOL15r performed slightly better than the MG‐QOL15. The 3‐response option MG‐QOL15r demonstrated better clinimetric properties than the 4‐ or 5‐option scales. Relative distributions of item and person location estimates showed good coverage of disease severity. Conclusions: The MG‐QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG‐QOL15. Muscle Nerve 54: 1015–1022, 2016