Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease (original) (raw)
Desminopathy manifests with various phenotypes. Phenotypic variability depends on the type of inheritance and the location of mutations within the relatively large and structurally and functionally complex desmin molecule (60). The phenotype can further be influenced by interactions between desmin and other IF proteins and by the activity of chaperones and protein clearance mechanisms that may be capable of compensating for the detrimental effects of mutant desmin.
Clinical features of almost 200 reported desminopathy patients have been characterized as severe childhood-onset cardioskeletal myopathy (4), adult-onset skeletal myopathy with cardiac involvement (13), pure skeletal myopathy (61, 62), cardiomyopathy with distal weakness (15, 63, 64), pure dilated cardiomyopathy (65), and distal myopathy with cardiac, respiratory, bulbar, facial, and smooth muscle involvement (5, 66). Distal, limb-girdle phenotypes and scapuloperoneal weakness with variable cardiac and respiratory involvement have been seen within a set of kindreds segregating with the p.Arg350Pro desmin mutation (67).
Skeletal muscle disease. Progressive skeletal myopathy is one of the clinical variants of desminopathy (68) observed in almost a quarter of patients (69). The illness starts at a later age than in individuals with other disease variants, and the progression is very slow. Skeletal muscle weakness typically starts in distal leg muscles and spreads to proximal muscles, a trend that is about 3 times more common than the opposite (69). In developed disease, all four limbs are affected. Weakness in the trunk, neck, and facial muscles can also be seen in some patients (61). Muscle atrophy is a frequent observation. Electromyographic studies show motor unit potentials and abnormal electric irritability characteristic of myopathy (70).
Muscle imaging studies performed in patients with desminopathy have identified a recognizable pattern of muscle involvement (71). In the lower leg, the peroneal muscles display substantially more myopathic changes than either the tibialis anterior or the muscles of the posterior compartment (the soleus and the medial and lateral gastrocnemius). In the thigh, the earliest and always most severely affected muscle is the semitendinosus (a muscle at the back of the thigh), followed by the sartorius and gracilis. The effects on these muscles always exceeds the involvement of the adductor magnus, biceps femoris, and semimembranosus (71). The anterior compartment (the rectus femoris, vastus lateralis, intermedius, and medialis) is relatively spared. The gluteus maximus is more severely involved than gluteus medius and minimus. Generally, the severity of degeneration in distal muscles always exceeds that of proximal muscles (71).
Skeletal muscle biopsies of patients with desminopathy typically show irregularly shaped abnormal regions containing amorphous deposits that are best identified with modified trichrome stain as dark green or bluish material localized in the subsarcolemma or within the cytoplasm (2, 61, 70) (Figure 4A). It requires a high degree of awareness to recognize these deposits, as some myopathologists consider them nonspecific. In addition, hyaline structures, cytoplasmic bodies, rods, and spheroid-like bodies have been reported (13, 61). Although not specific to desminopathy, rimmed vacuoles have been observed in most cases. Other nonspecific myopathic features, such as variation in fiber size, scattered atrophic fibers, and an increased number of internal nuclei are also frequently observed. Within the abnormal aggregates, proteins of diverse origins, including sarcomeric, cytoskeletal, and enzymatic proteins as well as proteins not known to be normally expressed in skeletal muscle, such as Aβ-amyloid and the amyloid precursor protein, have been identified (72, 73). The proteins most consistently present are desmin, αB-crystallin, dystrophin, myotilin, and ubiquitin (2, 15, 61, 66, 73, 74). The amount of desmin in affected muscle fibers of patients with desminopathy is increased, when compared with the amount in muscle from healthy individuals, as assessed by immunoblotting (75).
Myopathological images of skeletal muscle in patients with desminopathy. (A) Cross-section of a muscle biopsy from a patient with desminopathy, stained with trichrome and examined by light microscopy, shows characteristic amorphous deposits. (B) Serial sections stained with trichrome and immunostained for desmin indicate that these deposits contained desmin. (C) EM analysis of the same sample shows destruction of the Z discs, which eventually leads to disorganization of myofibrils (see text for details). B and C adapted with permission from New England Journal of Medicine (61).
All desminopathy skeletal muscle specimens analyzed by EM have shown accumulation of granulofilamentous material denser than the Z disc and located beneath the sarcolemma and between the myofibrils (76) (Figure 4B). Characteristic Z disc deformities, compact bodies of spheroid or cytoplasmic type, autophagic vacuoles containing myelin-like lamellae and debris (73), and focal groupings of mitochondria have also been observed (15, 26, 30). In some cases, mitochondria are located alongside the granulofilamentous deposits, forming characteristic sandwich-like structures (76).
In the family in which disease segregates with the CRYAB p.Arg120Gly mutation, skeletal muscle biopsy has shown disorganization of filamentous networks and regions characteristic of desminopathy in which the intermyofibrillar network completely disappeared (77). Affected areas contain abnormal aggregates immunopositive for desmin, αB-crystallin, dystrophin, and ubiquitin. A subsarcolemmal and intermyofibrillar accumulation of dense granulofilamentous material with various degenerative changes was also observed by EM (6, 77).
Respiratory dysfunction. Respiratory insufficiency can be a major cause of disability and death in desminopathy patients. It causes nocturnal hypoventilation with oxygen desaturation and, eventually, daytime respiratory failure (78). The diaphragm, unlike other skeletal muscles, functions in an environment in which forces can be transmitted in both longitudinal and transverse directions during each respiratory cycle, and desmin is the only molecule known to have dual orientation and serve as a viscoelastic element that dissipates mechanical energy in both planes (79). Progressive skeletal myopathy with early respiratory muscle involvement requiring respiratory support is observed in about a third of patients with desminopathy (69). A gradient between vital capacity in the upright and supine position of more than 30% suggests a preferential diaphragmatic involvement (78).
Cardiomyopathy. Atrioventricular conduction abnormalities requiring urgent implantation of a permanent pacemaker are a frequent feature of desminopathy attributed to the fact that the heart conduction system is rich in desmin (7). In a quarter of patients, the illness presents with cardiomyopathy (69), and cardiomyopathy alone with no skeletal muscle involvement has also been reported (26, 65, 80, 81). Heart disease is seen in more than 60% of patients in the advanced stages of illness (69). Some patients develop tachyarrhythmia requiring implantation of a cardioverter defibrillator (82). The age of disease onset in cases presenting with cardiomyopathy tends to be earlier and the illness more severe. Desminopathy-associated atrioventricular conduction blocks can be associated with dilated, restrictive, or hypertrophic cardiomyopathy (26, 75, 80).
Variable pathogenic potentials of desmin mutations. One possible explanation for different desmin mutations causing either skeletal or cardiac myopathy is the type and location of the mutation. Mutations located in the N-terminal part of the 2B helical segment of desmin cause primarily late onset skeletal muscle disease, with prolonged duration of illness and cardiomyopathy seen in only 36% of patients, whereas 60%–80% of patients with mutations in either the 1B helical segment or the tail domain develop a more ominous disease with cardiac involvement (83). The earliest onset and the highest frequency of cardiomyopathy are associated with mutations located in the YRKLLEGEESRI motif in the C-terminal end of the 2B helical segment (frequency of cardiomyopathy 88%). The disease is especially severe in carriers of the C-terminal p.Asp399Tyr, p.Glu401Lys, and p.Arg406Trp desmin mutations: age of onset is in the teens or early twenties, and life-threatening dysphagia, cardiomyopathy, and respiratory weakness develop within a few years (23, 24).