New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy

Abstract

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3–6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.

Clinical Determinants of Disease Progression in Patients with Beta-sarcoglycan Gene Mutations.

“…Concerning the impact of the genetic background, all group A's patients have at least one truncating mutation which has already been demonstrated to relate to a more severe phenotype [15]. Consistently with these data, all patients in group A lost ambulation in early teens or even before and, investigating differences between mutation groups, we observed homogeneity in patient of group A which showed a steeper decline in the variables CPK, EF, VC, FVC and FEV1.…”

“…As it has been recently demonstrated that patients with truncating mutations, and therefore lower proteins' concentrations, may show a more severe clinical progression [15] and in view of our preliminary observations, in order to highlight any possible genotype-phenotype correlation, patients were analysed both as total and as grouped in two genetic subgroups: group A, for patients carrying in homozygosis or in compound heterozygosis a speci c truncating mutation in exon 3 (c.377_384duplCAGTAGGA), which is known to cause severe disease [4;18], and group B for patients with every other kind of alteration. In our cluster of patient variants were found in exon 3, exon 4, exon 6 and exon 1, which is known for causing a mild subtype of LGMDR4 [18].…”

“…Nonetheless, the evaluation of lung function and respiratory muscle activity should not be underestimated in monitoring disease progression and to identify early signs of ventilatory insu ciency, to plan optimal interventions for improving the quality of life and to quantify the effects of new genemodifying and pharmacological therapeutic strategies [13,14]. A recent study by J. Manera Diaz et al [15] established independent risk factors associated with loss of ambulation before 18 years of age for sarcoglycanopathies based on the onset of symptoms during the rst decade of life and protein expression in muscle biopsy lower than 30%. Therefore, there is still little knowledge to predict the development of cardiac and respiratory involvement in LGMDR4 patients.…”

Les sarcoglycanopathies

“…Les mutations du SGCA sont les plus répandues en Europe [7], tandis que les mutations du SGCG sont les plus courantes dans la population nord-africaine et tzigane [8]. Les mutations du SGCB sont ubiquitaires [7,[9][10][11]…”

“…Les sarcoglycanopathies puis les gènes impliqués ont été identifiés dans les années 1990 [14] et depuis, plusieurs études ont essayé de préciser les caractéristiques phénotypiques et génotypiques de chacune d'entre elles [11,[15][16][17]. La présentation clinique des sarcoglycanopathies est celle d'une LGMD caractérisée par une atteinte symétrique des muscles des ceintures pelvienne et scapulaire ainsi que du tronc, avec divers degrés d'atteinte cardiorespiratoire [11,16,18,19]. Un décollement des omoplates, une pseudohypertrophie des mollets et de la langue, ainsi que des CPK très élevées (> 1 000 U/l) complètent typiquement le tableau clinique (Figure 2).…”