Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene

Abstract

Desminopathy represents a subgroup of myofibrillar myopathies caused by mutations in the desmin gene. Three novel disease-associated mutations in the desmin gene were identified in unrelated Spanish families affected by cardioskeletal myopathy. A selective pattern of muscle involvement, which differed from that observed in myofibrillar myopathy resulting from mutations in the myotilin gene, was observed in each of the three families with novel mutations and each of three desminopathy patients with known desmin mutations. Prominent joint retractions at the ankles and characteristic nasal speech were observed early in the course of illness. These findings suggest that muscle imaging in combination with routine clinical and pathological examination may be helpful in distinguishing desminopathy from other forms of myofibrillar myopathy and ordering appropriate molecular investigations.

Fig. 1

Clinical findings in the index case of family one (patient 1-1), showing weakness and wasting in the lower extremites (A), and contractures at the Achilles tendons (B) and long finger flexors (C).

Fig. 2

Cryostat consecutive sections stained with modified Trichrome stain (A), H&E (B), NADH (C), and ATPase at pH 4.65 (D). Several fibers contain dark-bluish cytoplasmic inclusions which are devoid of oxidative and ATPase activity.

Fig. 3

Serial consecutive sections showing strong desmin (A), αB-crystallin (B), dystrophin (C) and γ-filamin (D) immunoreactivity, and weak myotilin (E), and ubiquitin (F) immunoreactivity.

Fig. 4

Muscle CT scan images of four desminopathy patients at mid-thigh (A, C, E, G) and mid-lower-leg (B, D, F, H) levels. At the mid-tight level involvement of the semitendinosus (asterisk), sartorius (arrow) and gracilis (arrowhead) are seen in patient 1-1 (A), and in patient 6 (G). At the very early stages of illness initial changes are already seen in the same muscles (C and E, patients 1-2 and 4, respectively). At the mid-calf level (B, D, F and H) areas of decreased attenuation are patchily distributed in the peroneal group, anterior tibialis and later in the posterior group. (A and B: patient 1-1, 20 years after the disease onset; C and D: patient 1-2, 3 years after the disease onset; E and F: patient 4, 2 years after the disease onset; G and H: patient 6, 10 years after the disease onset).