Muscle involvement in limb-girdle muscular dystrophy with GMPPB deficiency (LGMD2T)

S.T. Oestergaard , T. Stojkovic (1, 2) , J. Dahlqvist , C. Bouchet-Seraphin (3) , J. Nectoux (4) , F. Leturcq (4) , M. Cossée (5, 6) , G. Solé (7) , C. Thomsen , T.O. Krag , J. Vissing

1 CHU Pitié-Salpêtrière [AP-HP]
2 Institut de Myologie
3 Service de biochimie hormonale, métabolique et génétique
4 Hôpital Cochin [AP-HP]
5 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
6 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
7 CHU Bordeaux

OBJECTIVE : In this study, muscle involvement assessed by MRI and levels of GMPPB and glycosylation of α-dystroglycan expression in muscle were examined in patients with limb-girdle muscular dystrophy (LGMD) type 2T. METHODS : Six new patients with genetically verified mutations in GMPPB were studied. T1-weighted magnetic resonance images were obtained in 4 participants. Muscle strength and potential involvement of extramuscular organs were examined. Glycosylation of α-dystroglycan in muscle was studied, and GMPPB and α-dystroglycan expression was analyzed by Western blotting. Prevalence of LGMD2T was calculated from the total LGMD population in Denmark. GMPPB was sequenced in all unclassified cases. RESULTS : Two patients carried 3 new mutations in GMPPB. The other 4 patients carried previously described pathogenic mutations in GMPPB. MRI showed that the paraspinal muscles were the most affected, followed by involvement of hamstrings. Our results showed a loss of glycosylation of α-dystroglycan as well as secondary loss of merosin expression on Western blotting. The prevalence of LGMD2T in the Danish cohort of patients with LGMD is 1.5%. CONCLUSIONS : The new findings of this study are (1) the consistent finding of a preferential affection of paraspinal and hamstring muscles in LGMD2T, (2) 3 new mutations in GMPPB, (3) variable loss of glycosylation tested with IIH6 and VIA4 antibodies, and (4) a prevalence of LGMD2T of 1.5% in a well-characterized Danish LGMD cohort.

Domaines: Médecine humaine et pathologie

S.T. Oestergaard, T. Stojkovic, J. Dahlqvist, C. Bouchet-Seraphin, J. Nectoux, et al.. Muscle involvement in limb-girdle muscular dystrophy with GMPPB deficiency (LGMD2T). Neurology Genetics, 2016, 2, pp.e112. ⟨10.1212/NXG.0000000000000112⟩. ⟨hal-01818486⟩