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.

Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain.

Limb-girdle muscular dystrophies (LGMD) are a group of clinically and genetically heterogeneous diseases characterized by weakness and wasting of the pelvic and shoulder girdle muscles. Twenty-four recessive LGMD (types R1-R24) and five dominant LGMD (types D1-D5) have been identified with characterization of mutations in various genes. To date, LGMD D3 (previously known as LGMD1G) has been characterized in only two families with Brazilian or Uruguayan origin. Each was caused by a distinct mutation at codon 378 in the prion-like domain of HNRNPDL encoding heterogeneous nuclear ribonucleoprotein D like (HNRNPDL), an RNA processing protein. Our study characterized eight patients suffering from LGMD D3 in a Chinese family spanning three generations. Muscle biopsy specimens from two patients showed a myopathy with rimmed vacuoles. Sequencing analysis revealed a heterozygous c.1132G > A (p.D378N) mutation in HNRNPDL that co-segregated with disease phenotype in the family. The same mutation has been identified previously in the Brazilian family with LGMD D3. However, most patients in the current family showed distal as well as proximal limb weakness rather than weakness of toe and finger flexor muscles that were typical features in the other two LGMD D3 families reported previously. The present study indicates that the same mutation in HNRNPDL results in various phenotypes of LGMD D3. That all mutations in three unrelated families with different ethnic background occur at the same position in codon 378 of HNRNPDL gene suggests a mutation hotspot. Acceleration of intrinsic self-aggregation of HNRNPDL caused by mutation of the prior-like domain may contribute to the pathogenesis of the disease.

A mouse muscle-adapted enterovirus 71 strain with increased virulence in mice.

Enterovirus 71 (EV71) infections can usually cause epidemic hand, foot, and mouth disease (HFMD), and occasionally lead to aseptic meningitis, encephalitis, and polio-like illness. Skeletal muscles have been thought to be crucial for the pathogenesis of EV71-related diseases. However, little is known about the virulence of mouse muscle-adapted EV71. The EV71 0805 were subjected to four passages in the mouse muscle to generate a mouse-adapted EV71 strain of 0805a. In comparison with the parental EV71 0805, the mouse muscle-adapted EV71 0805a displayed stronger cytotoxicity against Rhabdomyosarcoma (RD) cells and more efficient replication in RD cells. Furthermore, infection with the EV71 0805a significantly inhibited the gain of body weight, accompanied by increased muscle virus load and multiple tissue distribution in the infected mouse. Histological examinations indicated that infection with the EV71 0805 did not cause obvious pathogenic lesions in mice, while infection with the muscle-adapted 0805a resulted in severe necrotizing myositis in the skeletal and cardio muscles, and intestinitis in mice on day 5 post infection. Further analysis revealed many mutations in different regions of the genome of mouse muscle-adapted virus. Collectively, these data demonstrated the mouse muscle-adapted EV71 0805a with increased virulence in mice.