A rare complex structural variant of novel intragenic inversion combined with reciprocal translocation t(X;1)(p21.2;p13.3) in Duchenne muscular dystrophy.

Structural variants (SVs) are infrequently observed in Duchenne muscular dystrophy (DMD), a condition mainly marked by deletions and point mutations in the DMD gene. SVs in DMD remain difficult to reliably detect due to the limited SV-detection capacity of conventionally used short-read sequencing technology. Herein, we present a family, a boy and his mother, with clinical signs of muscular dystrophy, elevated creatinine kinase levels, and intellectual disability. A muscle biopsy from the boy showed dystrophin deficiency. Routine molecular techniques failed to detect abnormalities in the DMD gene, however, dystrophin mRNA transcripts analysis revealed an absence of exons 59 to 79. Subsequent long-read whole-genome sequencing identified a rare complex structural variant, a 77 kb novel intragenic inversion, and a balanced translocation t(X;1)(p21.2;p13.3) rearrangement within the DMD gene, expanding the genetic spectrum of dystrophinopathy. Our findings suggested that SVs should be considered in cases where conventional molecular techniques fail to identify pathogenic variants.

Environmental factors affecting the risk of generalization for ocular-onset myasthenia gravis: a nationwide cohort study.

BACKGROUND: The environmental effects on the prognosis of ocular myasthenia gravis (OMG) remain largely unexplored. AIM: To investigate the association between specific environmental factors and the generalization of OMG. DESIGN: The cohort study was conducted in China based on a nationwide multicenter database. METHODS: Adult patients with OMG at onset, who were followed up for at least 2 years until May 2022, were included. We collected data on demographic and clinical factors, as well as environmental factors, including latitude, socioeconomic status (per capita disposable income [PDI] at provincial level and education) and smoking. The study outcome was the time to the development of generalized myasthenia gravis (GMG). Cox models were employed to examine the association between environmental exposures and generalization. Restricted cubic spline was used to model the association of latitude with generalization risk. RESULTS: A total of 1396 participants were included. During a median follow-up of 5.15 (interquartile range [IQR] 3.37-9.03) years, 735 patients developed GMG within a median of 5.69 (IQR 1.10-15.66) years. Latitude of 20-50°N showed a U-shaped relation with generalization risk, with the lowest risk at around 30°N; both higher and lower latitudes were associated with the increased risk (P for non-linearity <0.001). Living in areas with lower PDI had 1.28-2.11 times higher risk of generalization. No significant association was observed with education or smoking. CONCLUSIONS: Latitude and provincial-level PDI were associated with the generalization of OMG in China. Further studies are warranted to validate our findings and investigate their potential applications in clinical practice and health policy.

Mortality of myasthenia gravis: a national population-based study in China.

OBJECTIVE: As a potentially life-threatening condition, myasthenia gravis (MG) has limited epidemiological studies on mortality. We aim to provide demographic distribution, geographical variation, and temporal trend of MG-related mortality in China. METHODS: The national population-based analysis was conducted based on records derived from the National Mortality Surveillance System of China. All deaths related to MG were identified from 2013 to 2020, and MG-related mortality was evaluated by sex, age, location, and year. RESULTS: A total of 4224 deaths were related to MG during 2013-2020, and the median age at death of MG was 59.45 years, significantly lower than that in the general population (75.47 years, P < 0.05). In 2020, the age-standardized mortality rate of MG was 1.86 per million people and markedly higher in males than in females (2.37 vs. 1.31 per million). The mortality rate per million was lower than 1 in young children, peaking at 2.83 only in males (vs. 0.36 in females) aged 10-19 years, and substantially increased with age, reaching the highest rate of 13.31 for males and 10.58 for females aged 80 years and older. Geographical disparity across China was observed with the highest age-standardized mortality rate in Southwest (2.53 per million). From 2013 to 2020, MG-related mortality rate showed an increasing trend with the average annual percentage change of 3.5% (95% CI, 1.4-5.6). The notable increases occurred in age 10-19 years and over 70 years. INTERPRETATION: In China, MG-related mortality was notably high among adolescent males and the elderly. The increasing death burden due to MG highlight challenges to disease management.

A Randomized Open-Labeled Trial of Methotrexate as a Steroid-Sparing Agent for Patients With Generalized Myasthenia Gravis.

Background and Purpose: Two clinical trials assessing the steroid-sparing effect of methotrexate (MTX) yielded conflicting results. Our objective was to investigate whether MTX would show a steroid-sparing effect in the treatment of generalized myasthenia gravis (MG) patients who fitted Myasthenia Gravis Foundation of America (MGFA) Class II and Class III. Methods: We performed an 18-month prospective, randomized, open-labeled trial of prednisone combined with MTX 10 mg orally every week versus prednisone alone in 40 recently diagnosed MG patients of MGFA Class II and Class III between July 2014 and July 2018. The primary endpoint was the prednisone area under the dose-time curve (AUDTC) from months 3 to 18. Secondary endpoints included changes of the Quantitative Myasthenia Gravis Score (QMG), the Myasthenia Gravis Activity of Daily Living Score (MG-ADL), initial time of prednisone reduction, the median prednisone daily dose in each month, adverse events, and treatment failures in each group. Results: Forty participants were included; among those, 5 individuals withdrew. A total of 35 participants completed 18 months of follow-up (18 in prednisone+MTX, 17 in prednisone group). Combined use of MTX reduced the month 3-18 prednisone AUDTC (prednisone+MTX 5,663.44 ± 1,678.08 mg, prednisone 6,683.94 ± 678.08 mg, p = 0.03, 95% confidence interval -1916.01 to -124.98). The initial times of prednisone reduction were 4.34 ± 1.44 months in the prednisone+MTX group and 5.56 ± 2.05 months in the prednisone group (p = 0.04, 95% CI -2.41 to -0.03). The median daily prednisone dose was significantly lower in the prednisone+MTX group at month 6 and months 9-18. No significant differences were found in QMG and MG-ADL scores between the two groups. No serious drug-related adverse events were observed in both groups. Conclusions: This study provides evidence that MTX has the steroid-sparing ability in generalized MG patients of MGFA Class II and Class III. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=10563 identifier ChiCTR-IPR-15006081.

Beyond the Motor Cortex: Thalamic Iron Deposition Accounts for Disease Severity in Amyotrophic Lateral Sclerosis.

Objective: Previous studies have reliably identified iron deposition in the motor cortex as potential pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we intended to investigate iron deposition, gray matter (GM) atrophy, and their associations with disease severity in the motor cortex and the thalamus in patients with ALS. Methods: A total of 34 patients with ALS (age 51.31 ± 8.24 years, 23 males) and 34 nonneurological controls (age 50.96 ± 9.35 years, 19 males) were enrolled between 2018 and 2020. The Revised ALS Functional Rating Scale (ALSFRS-R) and the Penn upper motor neuron (UMN) score were measured. MRI data included quantitative susceptibility mapping (QSM) for iron deposition and three-dimensional (3D) T1 for gray matter volume. After a between-group comparison, Pearson's correlation coefficient was used for identifying correlations of iron deposition, GM volume, and clinical measurements. Results: The two-sample t-tests revealed increased iron deposition in the left precentral gyrus (peak voxel T = 4.78, P SVC = 0.03) and the thalamus (peak voxel: right: T = 6.38, P SVC < 0.001; left: T = 4.64, P SVC = 0.02) in patients with ALS. GM volume of the precentral gyrus (T = -2.42, P = 0.02) and the bilateral thalamus (T = -4.10, P < 0.001) were reduced. Negative correlations were found between the increased QSM values and the decreased GM volume (P < 0.04, one-tailed) in patients with ALS. Iron deposition in the left precentral gyrus was positively correlated with the UMN score (R = 0.40, P = 0.02) and the GM volume was negatively correlated with the UMN score (R = -0.48, P = 0.004). Negative correlation between thalamic iron deposition and the ALSFRS-R (R = -0.36, P = 0.04) score was observed. Discussion: Iron deposition in the thalamus, in addition to the motor cortex, is accompanied by GM atrophy and is associated with disease severity in patients with ALS, indicating that the thalamus is also a pathological region in patients with ALS.

CYP3A5*3 polymorphism and age affect tacrolimus blood trough concentration in myasthenia gravis patients.

The study aims to identify clinical factors affecting tacrolimus blood trough concentration (C0) in myasthenia gravis (MG) patients and to optimize the initial dose of tacrolimus in MG treatment. A total of 103 MG patients participated in this study, and their clinical factors, medication regimens, C0 values and CYP3A5*3 polymorphisms were collected in detail. We used a linear mixed model to analyze the effect of multiple factors on the dosage-weighted C0 (C0:D) and performed subgroup analyses to investigate the consistency of correlations between influencing factors and the C0:D ratios. Among all factors, CYP3A5*3 polymorphism and age showed a strong positive correlation with C0:D ratios. The C0:D ratios (ng/ml·mg-1) were higher for CYP3A5*3/*3 than for CYP3A5*1 (mean difference: 1.038, 95% confidence interval [CI]: 0.820-1.256, P-value <0.001), and for age in the range of 45-64 and ≥ 65 years than for age < 45 years (mean difference [95% CI] and P-value: 0.531[0.257-0.805] and P-value <0.001, 0.703 [0.377-1.029] and P-value <0.001, respectively). The C0:D ratios were not related to corticosteroid dosage, body weight, sex, hematocrit or the concomitant use of calcium channel blockers. The consistencies of the correlations between C0:D ratios and CYP3A5*3 polymorphism or age were confirmed by subgroup analyses. Thus, CYP3A5*3 polymorphism and age should be considered in optimizing the initial dose of tacrolimus for MG treatment.