Value of muscle magnetic resonance imaging in the differential diagnosis of muscular dystrophies related to the dystrophin-glycoprotein complex

The dystrophin-glycoprotein complex (DGC) or the dystrophin-associated protein complex composed of the cytoplasmic dystrophin, syntrophin, α-dystrobrevin and neuronal nitric oxide synthase (nNOS), the transmembrane β-dystroglycan, α-, β-, γ- and δ-sarcoglycan (SG) and sarcospan, and the extracellular α-dystroglycan (α-DG), is essential for maintaining sarcolemma stability and muscle integrity [1]. Mutations in genes encoding DGC components can trigger sarcolemma instability and eventually lead to the development of muscular dystrophies [1]. DGC-related muscular dystrophies include dystrophinopathies caused by mutations in DMD, sarcoglycanopathies caused by mutations in SGCG, SGCA, SGCB, and SGCD, and dystroglycanopathies caused by mutations in FKRP and other genes associated with the O-mannose glycosylation pathway of α-DG [1‐3].

Clinical phenotypes of DGC-related muscular dystrophies cover a wide and overlapping clinical spectrum [4‐6]. Thus, differential diagnosis among different DGC-related muscular dystrophies cannot be made on clinical characteristics alone. Moreover, under certain conditions, concomitant reduction of dystrophin and sarcoglycans are observed in dystrophinopathies [7] and sarcoglycanopathies [8], and of dystrophin and glycosylated α-DG in dystroglycanopathies [9]; this hampers prediction of the primary genetic defect based on muscle immunoanalysis. Therefore, confirmatory diagnosis of DGC-related muscular dystrophies relies mainly on genetic testing. However, identifying the pathogenic variants responsible for DGC-related muscular dystrophies is complicated by non-coding sequence variants and structural variants, some of which remain undetectable [5]. Hence, it is necessary to establish other tests that can support differential diagnosis among different DGC-related muscular dystrophies.

Muscle magnetic resonance imaging (MRI) is increasingly used for diagnostic workup of neuromuscular disorders, because it contributes to recognition of muscle involvement patterns [10‐12]. The distinctive patterns observed at the thigh level of DGC-related muscular dystrophies, including the trefoil with single fruit sign [13] and concentric fatty infiltration pattern [6], are highly specific for dystrophinopathies and FKRP-associated dystroglycanopathy, respectively. Thus, muscle MRI might potentially be useful for distinguishing these diseases, but this has not yet been tested. Moreover, there has been no comprehensive study on muscle MRI changes in Chinese patients with sarcoglycanopathies. Therefore, this study investigated the value of muscle MRI in differentiating among DGC-related muscular dystrophies and characterized the pattern of involvement on muscle MRI in Chinese patients with sarcoglycanopathies.

In the present study, we determined the value of muscle MRI in the differential diagnosis of DGC-related muscular dystrophies and reported the largest series of Chinese patients with sarcoglycanopathies studied by muscle MRI so far.

As in other studies [4‐6], clinical phenotypes of patients with DGC-related muscular dystrophies in this study were markedly heterogeneous and had overlapping features, which was confirmed by hierarchical clustering that patients with DGC-related muscular dystrophies did not cluster according to the genotypes, making differential diagnosis among these diseases on clinical grounds alone impossible. Variable reduction of dystrophin and sarcoglycans was observed in most of our patients with sarcoglycanopathies or dystrophinopathies, and a slight reduction of sarcoglycans and dystrophin was observed in a few patients with LGMD2I, suggesting that it is sometimes incorrect to predict the primary genetic defect based on muscle immunoanalysis due to secondary reduction of other DGC proteins [7‐9]. The various types of mutations in SGCA, SGCB, SGCG, FKRP, and DMD contributed in part to the marked heterogeneity of clinical phenotypes, because different types of mutations are associated with different expression of DGC-associated proteins [6, 14] and may be associated with different degrees of protein dysfunction.

Our findings in sarcoglycanopathies that the gluteus maximus muscle was the most affected and the gluteus minimus muscle was the least affected at the pelvis level were contrary to the findings of previous studies [5, 20]. However, degree of fatty infiltration of the pectineus, gluteus medius, and obturator externus muscles was similar to the study by Tasca et al. [5]. At the lower leg level, relative sparing of the tibialis posterior and flexor digitorum longus muscles was consistent with the study by Tasca et al. [5], although the extensor halluces/digitorum longus and tibialis anterior muscles were not as severe as in the study by Tasca et al. [5]. As in the studies by Willis et al. [17, 18], the gastrocnemius medialis and gastrocnemius lateralis muscles were also affected with more severe fatty infiltration compared with the other lower leg muscles in LGMD2I, but relative sparing of the soleus muscle in our study was inconsistent with the mild involvement observed in the studies by Willis et al. [17, 18]. Similar to the study by Polavarapu et al. [21], the gastrocnemius lateralis and gastrocnemius medialis muscles were also the most affected in dystrophinopathies, and the little difference between dystrophinopathies and LGMD2I in our study was the mild involvement of the soleus muscle at the lower leg level.

Almost consistent with the previous studies [5, 17, 18, 20, 22], relative sparing of the lower leg muscles and more severe fatty infiltration of the pelvis and thigh muscles were observed in all subtypes of DGC-related muscular dystrophies. Hierarchical clustering of patients according to the pelvis or lower leg individual muscles revealed that patients did not cluster according to the genotypes, indicating that muscle MRI at the pelvis or lower leg level may not have any differential value in distinguishing different DGC-related muscular dystrophies, mainly because of no consistent pattern of muscle involvement at the pelvis or lower leg level.

At the thigh level, the muscle most severely affected by fatty infiltration in sarcoglycanopathies was the adductor magnus muscle, followed by the vastus intermedius and vastus medialis muscles. These findings were almost consistent with the previously reported selective muscle involvement wherein the adductor magnus and vastus intermedius muscles, with or without the vastus medialis muscle, were severely affected in LGMD2C [23], LGMD2D [20, 22, 24], LGMD2E [5], and LGMD2F [5]. Similar to previous studies [5, 20, 23, 24], the vastus lateralis, sartorius, and gracilis muscles were relatively spared in sarcoglycanopathies in our study. A pattern of selective muscle involvement, i.e., the concentric fatty infiltration pattern, appears to be distinctive for sarcoglycanopathies, because it was observed in most patients with various sarcoglycanopathies, including the most severely affected patients, consistent with the previously reported pattern observed in LGMD2C–2F proposed by Tasca et al. [5] and was also noted in other reports of LGMD2C [23] and LGMD2D [20, 24]. Our findings varied slightly from the pattern proposed by Tasca et al. [5], relative sparing of the medial part of the adductor longus muscle in sarcoglycanopathies was less frequent in our study than in the study of Tasca et al. [5], although it was a rather peculiar pattern.

As no statistically significant differences in the individual muscles could be found between sarcoglycanopathies and LGMD2I at the thigh level, the concentric fatty infiltration pattern was also apparent in most patients with LGMD2I. Additionally, relative sparing of the medial part of the adductor longus muscle was observed in nearly half of patients with sarcoglycanopathies or LGMD2I. These two distinctive patterns, particularly the concentric fatty infiltration pattern, seems to be homogeneous among LGMD2I [6] and different sarcoglycanopathies, which supports the idea that as sarcoglycans and glycosylated α-DG are relatively close to each other on the sarcolemma (Fig. 2b), any defects in these proteins likely cause damage to similar target muscles [5]. As we previously described [6], the concentric fatty infiltration pattern was rarely observed in other muscular dystrophies including dystrophinopathies [13], laminopathies [25], congenital muscular dystrophy with rigid spine syndrome [26], collagen VI-related myopathy [11], RYR1-related myopathies [27], Emery-Dreifuss muscular dystrophy [28], and dysferlinopathy [12]. Therefore, this pattern could be useful in the differential diagnosis between sarcoglycanopathies or LGMD2I and other muscular dystrophies.

The major difference we found between sarcoglycanopathies or LGMD2I and dystrophinopathies at the thigh level was that fatty infiltration of the adductor longus muscle in sarcoglycanopathies or LGMD2I was more severe than that in dystrophinopathies, which was a major contribution to the trefoil with single fruit sign [13] observed in most patients with dystrophinopathies. Although only a few patients with sarcoglycanopathies or LGMD2I showed the trefoil with single fruit sign, these overlapping patterns may indicate a common pathophysiology for different DGC-related muscular dystrophies: different defects in DGC proteins eventually lead to instability of the sarcolemma [1], which might result in similarities among the affected muscles.

In conclusion, a distinctive pattern of muscle involvement, the concentric fatty infiltration pattern around the distal femoral diaphysis, is shared by the different sarcoglycanopathies and FKRP-associated dystroglycanopathy. While differential diagnosis of DGC-related muscular dystrophies based on clinical phenotypes or muscle immunoanalysis is problematic, most patients with sarcoglycanopathies or FKRP-associated dystroglycanopathy can be distinguished from dystrophinopathies by muscle MRI at the thigh level based on the concentric fatty infiltration pattern and trefoil with single fruit sign.