LIMB GIRDLE MUSCULAR DYSTROPHIES: P.155 Clinical variability in LGMD2B: searching for modifier genes

Abstract

Limb-Girdle Dystrophy 2B (LGMD2B) is an autosomal recessive muscle disease caused by mutations in the DYSF gene. Phenotype variability is often observed among patients. Here we report a large Brazilian family with six LGMD2B affected siblings born from first-degree cousins which was first ascertained in our center 25 years ago. They presented with a remarkable clinical variability, with the onset of symptoms ranging from 12 years of age and severe phenotype in one of them to 40 years old and mild muscle weakness in the older sister. The other four affected siblings showed a milder intermediate phenotype. Muscle biopsy, done in three patients, revealed a total deficiency of dysferlin associated with a secondary lack of calpain 3. A recent clinical and neurological re-evaluation, using the MFM scale, vital capacity, and peak cough flow measurements, showed that respiratory function was well preserved, but muscle weakness progressed in all of them, decreasing their clinical variability. Even so, the older sister, now 77 years old, remains the less affected one, while the most affected sister, currently aged 60, is still the most severely affected. Next generation sequencing identified in the six patients two different pathogenic mutations in the DYSF gene (NM_003494): c.5979dupA, already described in Italian, North American and Australian patients, and c.3485_3486delGG, which is novel. This finding was surprising, once homozygous mutations would be expected due to consanguinity. This compound heterozygous genotype could be explained by the admixture of European and African genetic components in the early ancestry of the family, since part of the father's family was of African background, while part of the mother's family was Caucasian. A comparative exome study is currently underway in the six affected patients, searching for modifier genes and/or markers of ancestral origin, which could explain the clinical variability in this family.