Clinical, pathological, imaging, and genetic characterization in a Taiwanese cohort with limb-girdle muscular dystrophy

Abstract

Background: Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous, hereditary disease characterized by limb-girdle weakness and histologically dystrophic changes. The prevalence of each subtype of LGMD varies among different ethnic populations. This study for the first time analyzed the phenotypes and genotypes in Taiwanese patients with LGMD in a referral center for neuromuscular diseases (NMDs). Results: We enrolled 102 patients clinically suspected of having LGMD who underwent muscle biopsy with subsequent genetic analysis in the previous 10 years. On the basis of different pathological categories, we performed sequencing of target genes or panel for NMDs and then identified patients with type 1B, 1E, 2A, 2B, 2D, 2I, 2G, 2 N, and 2Q. The 1B patients with LMNA mutation presented with mild limb-girdle weakness but no conduction defect at the time. All 1E patients with DES mutation exhibited predominantly proximal weakness along with distal weakness. In our cohort, 2B and 2I were the most frequent forms of LGMD; several common or founder mutations were identified, including c.1097_1099delACA (p.Asn366del) in DES, homozygous c.101G > T (p.Arg34Leu) in SGCA, homozygous c.26_33dup (p.Glu12Argfs*20) in TCAP, c.545A > G (p.Tyr182Cys), and c.948delC (p.Cys317Alafs*111) in FKRP. Clinically, the prevalence of dilated cardiomyopathy in our patients with LGMD2I aged > 18 years was 100%, much higher than that in European cohorts. The only patient with LGMD2Q with PLEC mutation did not exhibit skin lesions or gastrointestinal abnormalities but had mild facial weakness. Muscle imaging of LGMD1E and 2G revealed a more uniform involvement than did other LGMD types. Conclusion: Our study revealed that detailed clinical manifestation together with muscle pathology and imaging remain critical in guiding further molecular analyses and are crucial for establishing genotype-phenotype correlations. We also determined the common mutations and prevalence for different subtypes of LGMD in our cohort, which could be useful when providing specific care and personalized therapy to patients with LGMD.

Genetic variations and clinical spectrum of dystroglycanopathy in a large cohort of Chinese patients

“…Several unique frequent mutations were found in our cohort.A founder mutation, c.545A > G in FKRP was detected in 44 compound heterozygous patients and 10 homozygous patients. It was also found as frequent mutations in the LGMD cohort in a Taiwanese study 27 . It was different from the common mutation c.826C > A (p.Leu276Ile) in European countries, 28,29 the USA 23 and Brazil 24 .…”

A Journey with LGMD: From Protein Abnormalities to Patient Impact

“…Bayesian analysis suggests that dysferlinopathy, α-sarcoglycanopathy (R3), and anoctaminopathy may have higher prevalence rates than population studies have shown, especially considering the diagnostic challenges with later onset and more slowly progressing disease [ 30 ]. The other LGMD subtypes generally are uncommon but may manifest more frequently in areas with founder effect, e.g., telethoninopathy (R7) in Taiwan (Table 4 ) [ 24 , 31 ].…”

“…The other LGMD subtypes generally are uncommon but may manifest more frequently in areas with founder effect, e.g., telethoninopathy (R7) in Taiwan (Table 4 ) [ 24 , 31 ].…”

Diagnostic muscle biopsies in the era of genetics: the added value of myopathology in a selection of limb-girdle muscular dystrophy patients

“…Due to the genetic heterogeneity, LGMD diagnosis often remains, nonetheless, a complicated task to this day. A large retrospective study in clinically diagnosed LGMD found that protein expression studies were imperative to judge the causative nature of variants [45].…”