Clinico-genetic spectrum of limb-girdle muscular weakness in Austria: A multicentre cohort study

Abstract

Background and purpose: Hereditary myopathies with limb-girdle muscular weakness (LGW) are a genetically heterogeneous group of disorders, in which molecular diagnosis remains challenging. Our aim was to present a detailed clinical and genetic characterization of a large cohort of patients with LGW.

Methods: This nationwide cohort study included patients with LGW suspected to be associated with hereditary myopathies. Parameters associated with specific genetic aetiologies were evaluated, and we further assessed how they predicted the detection of causative variants by conducting genetic analyses.

Results: Molecular diagnoses were identified in 62.0% (75/121) of the cohort, with a higher proportion of patients diagnosed by next-generation sequencing (NGS) than by single-gene testing (77.3% vs. 22.7% of solved cases). The median (interquartile range) time from onset to genetic diagnosis was 8.9 (3.7-19.9) and 17.8 (7.9-27.8) years for single-gene testing and NGS, respectively. The most common diagnoses were myopathies associated with variants in CAPN3 (n = 9), FKRP (n = 9), ANO5 (n = 8), DYSF (n = 8) and SGCA (n = 5), which together accounted for 32.2% of the cohort. Younger age at disease onset (p = 0.043), >10× elevated creatine kinase activity levels (p = 0.024) and myopathic electromyography findings (p = 0.007) were significantly associated with the detection of causative variants.

Conclusions: Our findings suggest that an earlier use of NGS in patients with LGW is needed to avoid long diagnostic delays. We further present parameters predictive of a molecular diagnosis that may help to select patients for genetic analyses, especially in centres with limited access to sequencing.

Keywords: Austria; limb-girdle muscular dystrophy; limb-girdle muscular weakness; myopathy; next-generation sequencing.

FIGURE 1

Genetic spectrum and clinical characteristics of patients with limb‐girdle muscular weakness. (a) Causative variants located in 27 different genes could be identified in 75/121 patients. The five most frequent genotypes were CAPN3, FKRP, ANO5, DYSF and SGCA and accounted for over 50% of patients with a molecular diagnosis. (b) Age at onset was most frequent in the second decade with a wide range into late adulthood. (c) In patients with molecular diagnoses, legs were more often and more severely affected by muscle weakness than arms. In patients without molecular diagnoses, by contrast, muscle weakness was similarly distributed to both legs and arms. Frequency of clinical symptoms in the total cohort (d) and as compared between patients with and without molecular diagnoses (e), with none of the symptoms differing significantly between the groups. *CACNA1S was identified together with RYR1 in the same person, and SCN4A together with DMD in another person [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Demographic and clinical characterization of common genetic aetiologies in patients with limb‐girdle muscular weakness. (a) Disease onset was significantly earlier for CAPN3 (F_(5,115) = 4.1, p = 0.002, one‐way analysis of variance with Dunnett's multiple comparison test), and (b) patients were more often unable to walk (χ² _{(10, n = 121)} = 33.5, p < 0.001 with Bonferroni correction for multiple testing) as compared to other genes. (c) Creatine kinase was higher in the FKRP, ANO5 and DYSF subgroups (χ² _{(10, n = 116)} = 29.0, p = 0.001 with Bonferroni correction for multiple testing). Time to molecular diagnosis (d), disease duration (e) and region of onset (f), by contrast, were similar between all groups. CAPN3: n = 9; FKRP: n = 9; ANO5: n = 8; DYSF: n = 8; SGCA: n = 5; Other: n = 82. ULN, upper limit of normal [Colour figure can be viewed at wileyonlinelibrary.com]