A new distal myopathy with mutation in anoctamin 5

Abstract

We have been following clinically and with muscle MRI for the past 3-decades a Finnish family with two patients with distal muscular dystrophy. Previously we demonstrated the cellular defect in these patients to be defective membrane repair and more recently have identified the causative gene to be anoctamin 5 (ANO5). The disorder seen in these patients is characterized by onset in the third decade. First symptoms were burning sensation on the calves and later on calf tightness during running. Muscle weakness and wasting were asymmetric and early involving the calf muscles, later spread to the thigh muscles. Biceps brachi was later manifestation. Clinical course was slow. CK levels were high. Muscle biopsy showed dystrophic pattern and multifocal disruption of the sarcolemmal membrane but no subsarcolemmal vesicle accumulation nor active inflammation. We conclude that the disease seen in our cases is a new separate clinical, genetic and histopathologic entity to include within the classification of autosomal recessive distal muscular dystrophies.

Fig. 1

Family pedigree.

Fig. 2

P.1 at age 50 years, he is still able to walk on tiptoes even with slight weakness (A). Note the presence of bilateral calf hypertrophy. Slight right biceps brachi atrophy is present (B). P.2 at age 44 years shows a back-kneeing and hyperextension of the ankle (C). He has quadriceps atrophy, more evident in the left side (D) and atrophy of the biceps brachi more prominent in the right side, as well as, right pectoral muscle atrophy (E).

Fig. 3

Axial T1-weighted magnetic resonance images of the thighs and legs obtained from P.1 at disease duration (DD) of 10 years shows bilateral gastrocnemius medialis severe fibro-fatty degeneration, while thigh muscles are spared (A). In P.2 fatty degeneration is seen to involve only the posterior muscle compartment of the legs at DD of 9 years (B), and progressively affect the left vastus lateralis and intermedius, left hamstring and adductors, and right adductor magnus muscles of thighs at DD of 15 years (C).

Fig. 4

Biopsy obtained from patient P.1 at DD of 21 years from the left vastus lateralis shows a quite severe dystrophic picture with some picnotic nuclei and nuclear clumps (A). Dysferlin shows a positive sarcolemmal staining on immunohistochemistry (B). Electron microscopy shows normal myofibrillar architecture but there is evidence of multifocal loss of sarcolemmal membrane (arrows). Electron microscopy, original magnification ×5000.