Dysferlinopathy in a Cohort of Chinese Patients: Clinical Features, Mutation Spectrum, and Imaging Findings
Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by mutations in the dysferlin (DYSF) gene. This condition encompasses several clinical phenotypes, including Miyoshi myopathy (MM), limb-girdle muscular dystrophy type 2B (LGMD2B), and atypical presentations such as the proximo-distal (PD) phenotype and distal anterior compartment myopathy. Despite advancements in genetic research, the genotype-phenotype correlation in dysferlinopathy remains poorly understood, particularly due to the increasing identification of atypical cases and significant intra-familial variability. This study aimed to provide a comprehensive analysis of the clinical features, mutation spectrum, and imaging findings in a cohort of Chinese patients with dysferlinopathy, offering new insights into the disease’s genetic and phenotypic diversity.
The study retrospectively analyzed 28 consecutive patients and 27 relatives from 23 families between July 2014 and February 2019. Comprehensive clinical evaluations were conducted, including serum creatine kinase activity, electromyography, muscle biopsy, and muscle magnetic resonance imaging (MRI). Fatty infiltration in the thigh and lower leg muscles was quantified based on increased signal intensity in MRI scans. Genetic testing was performed using targeted next-generation sequencing (NGS) with an inherited neuromuscular disease (NMD) panel covering 420 known NMD-associated genes. Identified mutations were confirmed by Sanger sequencing, and novel variants were interpreted according to the American College of Medical Genetics and Genomics guidelines. The study adhered to ethical standards, and informed consent was obtained from all participants.
Among the 23 families, 26 different mutations were identified across the entire coding sequence of the DYSF gene. Thirteen of these mutations were novel, including ten pathogenic and three likely pathogenic variants. Notably, the c.1667T>C mutation was found in five unrelated families, accounting for 19.6% of the alleles in the cohort. Haplotype analysis suggested that this mutation might be a founder mutation in the Chinese population. Additionally, the c.797-798delTT and c.836A>T mutations were each present in four alleles. The c.1667T>C and c.836A>T mutations have only been reported in Chinese patients, highlighting the ethnic specificity of DYSF mutations.
The cohort exhibited a range of clinical phenotypes: 11 patients presented with MM, 13 with LGMD2B, and four with the PD phenotype. Lower limb involvement was observed in 15 out of 28 patients, with upper limbs remaining clinically unaffected. This pattern was more common in MM patients (8/11) than in LGMD2B patients (3/13). The mean age of symptom onset was 22.0 ± 7.2 years, with MM patients presenting earlier (17.9 ± 7.2 years) compared to LGMD2B patients (25.0 ± 8.1 years). Patients carrying the c.1667T>C mutation had a significantly later onset (27.5 ± 9.5 years) than those without the mutation (19.6 ± 4.6 years).
Remarkable intra-familial phenotypic variability was observed in two families. In Family 3, one sibling presented with MM, characterized by distal lower limb weakness progressing to proximal weakness over three years, while another sibling exhibited LGMD2B, with initial symptoms of difficulty running and mild proximal lower limb weakness. In Family 23, one patient displayed the PD phenotype with compound heterozygous mutations (c.1644delA and c.5828_5843delCCTTGGACCAGCTGGA), while another family member with the homozygous c.1644delA mutation presented with MM. These findings underscore the complexity of phenotype-genotype correlations in dysferlinopathy.
Muscle MRI findings revealed distinct patterns of fatty infiltration in the lower limbs. At the thigh level, the posterior thigh muscle groups (semimembranosus, semitendinosus, and biceps femoris), vastus lateralis, and adductor magnus were commonly affected, while rectus femoris, sartorius, and gracilis were involved only in advanced stages. The mean fat infiltration scores for the anterior, medial, and posterior thigh muscle groups were 1.0, 1.0, and 2.0, respectively. In the lower leg, the posterior compartment (soleus, gastrocnemius medialis, and gastrocnemius lateralis) was most severely affected, with a mean fat infiltration score of 3.0, significantly higher than the anterior and central compartments.
The study identified a high proportion of novel mutations (50%), with 11 located in the C2 domains or DysF domains of the DYSF gene. C2 domains are highly conserved regions involved in calcium and phospholipid binding, which are critical for membrane repair. Mutations in these domains, particularly the C2G domain, likely disrupt protein function, leading to dysferlin degradation. Additionally, mutations in the inner DysF domains may destabilize the protein structure, further contributing to disease pathology.
The c.1667T>C and c.836A>T mutations appear to be unique to the Chinese population, suggesting that DYSF mutations are influenced by ethnic background. The c.1667T>C mutation, in particular, was the most frequent in this cohort and was associated with a later onset of symptoms, expanding the understanding of genotype-phenotype correlations. The absence of common mutations found in Japanese populations further supports the ethnic specificity of DYSF mutations.
Intra-familial variability in clinical phenotypes was a notable finding in this study. Despite carrying the same mutations, affected family members exhibited different disease presentations, indicating that factors beyond the DYSF gene, such as environmental influences and modifier genes, play a role in disease manifestation. This complexity highlights the need for further research to elucidate the mechanisms underlying phenotypic variability in dysferlinopathy.
In conclusion, this study provides a detailed characterization of dysferlinopathy in a Chinese cohort, identifying a high proportion of novel mutations and demonstrating the ethnic specificity of DYSF mutations. The c.1667T>C and c.836A>T mutations are unique to Chinese patients and are associated with distinct clinical features. The significant intra-familial variability observed underscores the multifactorial nature of dysferlinopathy, involving genetic, epigenetic, and environmental factors. These findings contribute to a deeper understanding of the disease and pave the way for more personalized approaches to diagnosis and management.
doi.org/10.1097/CM9.0000000000001343
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