Rippling muscle disease and facioscapulohumeral dystrophy-like phenotype in a patient carrying a heterozygous CAV3 T78M mutation and a D4Z4 partial deletion: Further evidence for "double trouble" overlapping syndromes

Abstract

We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the patient's muscle biopsy demonstrated a reduction of caveolin-3 staining, compatible with the diagnosis of caveolinopathy. Interestingly, consistent with the possible diagnosis of FSHD, the patient carried a 35 kb D4Z4 allele on chromosome 4q35. We discuss the hypothesis that the two genetic mutations may exert a synergistic effect in determining the phenotype observed in this patient.

Fig. 1

Proband with bilateral mild winged scapula and hyperlordotic posture.

Fig. 2

Pedigree of the proband family. Arrow indicates the proband. Proband’s father was reported to have difficulties in raising arms in his seventies; he died at the age of 83 years for Parkinson’s disease. Proband’s mother, affected by congestive heart failure, died at the age of 70 years (medical reports are not available). The brother, the sister and the two daughters of the proband resulted completely asymptomatic.

Fig. 3

T1-weighted skeletal muscle MRI of the lower limbs: (a) at thigh level, marked fatty infiltration and atrophy of the left long adductor (arrow); (b) at leg level, fatty infiltration of the medial head of the left gastrocnemius (arrow).

Fig. 4

Quadriceps femoris muscle biopsy: (a) hematoxylin and eosin and (b) modified Gomori’s trichrome staining; magnification 20×. Increase in connective tissue and diameter variability in both fiber types, scattered round shaped atrophic fibers, rare degenerative fibers and a considerable endomysial inflammatory infiltrate.

Fig. 5

Skeletal muscle immunostaining for Cav-3 (monoclonal antibodies diluted 1:100 in 1% BSA-PBS; Transduction Laboratories, Lexington, KY) of a healthy control and of the proband. In the proband the immunolabeling for Cav-3 resulted markedly reduced at the plasmalemma in almost all fibers.