Muscle imaging in muscular dystrophies
Muscular dystrophies are characterised by permanent and progressive muscle weakness. Clinical, pathological and genetic classifications are overlapping and heterogeneous. However, the most common separation is made according to the age of onset and the pattern of involved (e.g. facial, proximal, distal) muscles.
In dystrophinopathies, onset of (proximal) weakness is in the first decade of life. Limb-girdle muscular dystrophies (LGMD) are a group of autosomal dominantly or recessively inherited muscular dystrophies that also present with primary proximal (limb-girdle) muscle weakness. However, most LGMDs start in the second decade of life. Myofibrillar myopathies (MFM) are a group of adult-onset myopathies, often beginning in the third or fourth decades of life. In contrast to LGMD, muscle weakness often starts in the distal muscles. Other dystrophies such as myotonic dystrophy or FSHD have often a characteristic pattern of clinical weakness but can start at any age.

Early onset (proximal) LGMD and dystrophinopathies
In western and central Europe, LGMD2I, LGMD2A and LGMD2B are probably the most common LGMD forms. A muscle biopsy including protein expression analysis is usually necessary to distinguish among LGMD subtypes [36, 37]. LGMDs also present with different patterns of muscle involvement on imaging that might help in the genetic diagnosis. An illustration of different muscle imaging findings in LGMD patients is provided in Fig. 4.
Fig. 4 Flowchart showing the approach to LGMD. Most LGMD patients have greater affliction of the posterior rather than the anterior thigh compartment muscles. On the other hand, patients with dystrophinopathy and sarcoglycanopathy often have significant affliction of the quadriceps muscle. Dystrophinopathy often presents with early and marked changes in the gastrocnemii muscles, while patients with sarcoglycanopathy show no affliction of these muscles. Patients with dysferlinopathy most often show posterior thigh and posterior lower leg involvement with sparing of the sartorius, gracilis and biceps femoris. However, muscle affection can be variable, but clinically calf atrophy and absence of scapular winging are commonly present. Calpain-3 and FKRP patients present with predominant posterior thigh and posterior lower leg involvement. Calpain-3 patients usually show marked involvement of the soleus and medial gastrocnemius muscles. Furthermore, calf atrophy and scapular winging are usually observed. Conversely, FKRP patients have a more diffuse involvement of the posterior lower leg muscles, while the tibial anterior muscle is often spared or even hypertrophied

FKRP-related myopathies (LGMD2I)
A few years ago, a novel gene encoding a putative glycosyltransferase, fukutin-related protein (FKRP), was found to be responsible for both a novel form of congenital muscular dystrophy (MDC1C) and for a form of limb girdle muscular dystrophy (LGMD2I) [38, 39]. Recently, we performed a systematic clinical and muscular MRI assessment in several LGMD2I patients and compared these findings with those of other patients with genetically confirmed diagnosis of other forms of autosomal recessive LGMDs or dystrophinopathies [40].
All LGMD2I patients had a characteristic muscular phenotype on MRI of the lower extremities that demonstrated marked signal changes in the adductor muscles, the posterior thigh and posterior calf muscles. Furthermore, data of patients with different clinical disease severity pointed towards a specific temporal pattern. At the pelvic level, the gluteus maximus was involved earlier and more severely than the gluteus medius. At the thigh level the earliest and most severe changes were observed in the adductor (magnus) muscles and the biceps femoris. With further progression degenerative changes were noticed in the remaining hamstring muscles and to a lesser degree in the vastus lateralis and vastus intermedius muscles. Involvement of the vastus medialis and rectus femoris was only observed in the patient with advanced disease, while the sartorius and gracilis muscles were relatively spared. In the lower legs relatively diffuse changes in the medial head of the gastrocnemius and the soleus muscle were observed early in the disease, while involvement of the anterior compartment muscles was only observed in later stages of the disease. The tibialis anterior muscle was usually spared and often hypertrophied.

Calpainopathies (LGMD2A)
Compared with LGMD2I, in patients with LGMD2A, caused by mutation in the calpain-3 gene, we observed a very similar and consistent clinical and muscle imaging phenotype. As in LGMD2I, muscle MRI images have confirmed the clinical observation that in LGMD2A there is early and predominant involvement of posterior compartment muscles such as the gluteus maximus in the pelvis, semimembranosus, biceps femoris and adductor muscles in the thigh, with relative sparing of the vastus lateralis, sartorius and gracilis. These findings were also later confirmed by others [41]. Contrary to LGMD2I, there are, however, some important differences: the vastus lateralis is spared more in LGMD2A compared with LGMD2I; the medial gastrocnemius and soleus muscles are much more selectively involved compared with the diffuse affliction seen in LGMD2I, and hypertrophy of the tibialis anterior muscle is only rarely present in LGMD2A.

Dysferlinopathies (LGMD2B)
Dysferlinopathies, which are genetically characterised by mutations in the dysferlin gene lead to LGMD 2B, distal Miyoshi myopathies and a form of distal anterior compartment myopathy [42, 43]. On MRI, symptomatic patients with dysferlinopathies present with severe dystrophic changes in the anterior and posterior compartments of the thighs with a characteristic sparing of the gracilis and sartorius muscles. In the lower legs, dysferlinopathies predominantly affect the posterior compartment with a relative sparing of the medial head of the gastrocnemius muscle [44–46]. This distinct pattern is different from muscle involvement in LGMD2I and LGMD2A patients in which dystrophic changes in the posterior thigh and posterior calf muscle can frequently be observed [40].

Dystrophinopathies (DMD/ BMD) and sarcoglycanopathies (LGMD2C, D, E and F)
While sarcoglycan deficiencies (LGMD2C, D, E and F) are relatively rare, dystrophinopathies [type Duchenne (DMD) and type Becker (BMD)] are the most common muscular dystrophies worldwide. Therefore, late onset BMD patients or sporadic symptomatic female carriers of DMD often enter the differential diagnosis in sporadic LGMD patients. Furthermore, recently published studies emphasised an overlap between LGMD2I and the group of dystrophinopathies mainly as both often have calf or generalised muscular hypertrophy, and respiratory and cardiac involvement [38, 39]. However, on muscle imaging all our patients with BMD and alpha-sarcoglycanopathy showed pronounced signal changes in the anterior rather than the posterior thigh muscles (as present in LGMD2I patients). In accordance with our results, a predominant affliction of the anterior thigh compartment has been observed in dystrophinopathy and LGMD2D [47–49]. Thus, the relation between knee extensor and flexor involvement might be useful in distinguishing dystrophinopathies and sarcoglycan deficiencies from LGMD2I on muscular MRI. Finally, alpha-sarcoglycanopathy can be differentiated from BMD patients by the greater extent of upper limb involvement [47] and by the different pattern in the lower limbs on muscular MRI [50].

Late onset (distal) myofibrillar myopathies
MFMs are histopathologically characterised by aberrant desmin aggregation and ultrastructurally by myofibrillar degeneration, which led to the introduction of the term `myofibrillar myopathy’ (MFM). Mutations in the human desmin gene (DES) were first shown to be associated with MFM; another form is associated with mutations in the gene encoding αB-crystallin (CRYAB). More recently, mutations in the human Z-disc proteins myotilin (MYOT), ZASP (LDB3) and filamin C (FLNC) have also been shown to cause MFM [51]. Practically, a definitive determination of the MFM subtype can only be established by direct gene sequencing. However, muscle imaging in combination with clinical information is very helpful for separation of distinct MFM subtypes and in scheduling of genetic analysis.
Recently, we performed muscle imaging in 46 MFM patients (19 desminopathy, 12 myotilinopathy, 11 filaminopathy, 1 αB-crystallinopathy and 3 ZASPopathy patients) and observed two major characteristic patterns of muscle involvement [26]. In desminopathy patients, at the thigh the semitendinosus was the most affected muscle, being more affected than the biceps femoris and semimembranosus muscles. Furthermore, the sartorius and gracilis muscles were often involved earlier and more severely than other thigh muscles. At the lower legs, peroneal muscles were more involved than the tibialis anterior muscle or at least equally as involved. Muscle imaging findings in a patient with a R120G αBC mutation were very similar to those in desminopathy patients. The most frequently involved muscles were the gluteus maximus, semitendinosus, sartorius, gracilis and the peroneal muscles.
Highly contrarily, all other MFM patients (caused by mutations of the Z-disc protein-encoding genes myotilin, filamin c and ZASP) showed an opposite posterior thigh affliction with more involvement of the biceps femoris, semimembranosus and the adductor magnus than the semitendinosus muscle. In filaminopathy, the gracilis and sartorius muscles were often relatively equally spared, while in myotilinopathy the sartorius muscle was slightly more involved than the gracilis muscle. In the lower legs, the soleus and the medial gastrocnemius were the most frequently affected muscles, and in the anterior compartment the tibialis anterior muscle was the most frequently affected. Differences among these three MFM subforms were much more subtle, but detectable on statistical analysis. This revealed highly sensitive and specific criteria (Fig. 5) that may be very useful for the detection of individual MFM forms.
Fig. 5 Muscle imaging differences in myofibrillar myopathies. Highly specific and sensitive statistical criteria were identified in a systematic retrospective muscle imaging assessment in a large series of 43 MFM patients [24]. Equal or greater affliction of the semitendinosus than the biceps femoris and equal or greater affliction of the peroneal group than the tibial anterior muscles is highly specific for primary desminopathy and crystallinopathy (18 out of 19 patients). Those of the remaining patients who had equal or greater involvement of the sartorius than the semi-tendinosus and equal or greater involvement of the adductor magnus than the gracilis usually had a myotilin mutation (eight out of nine patients). All eight patients who did not fulfil the criteria for desmin and myotilin mutations and who had more involvement of the medial than the lateral gastrocnemius showed a filamin C mutation. Two of the three remaining patients had a ZASP and the third a myotilin mutation

Other muscular dystrophies
Diagnosis of common muscular dystrophies such as myotonic dystrophy type 1, facio-scapulo-humeral muscular dystrophy and oculopharyngeal muscular dystrophy is usually based on classical clinical findings. Therefore, in these muscular dystrophies the role of muscle imaging has yet to be defined. Recent studies performed on these myopathies suggested that some characteristic findings are present, even if there is less diagnostic value compared with CM, LGMD and MFM (Fig. 6).
Fig. 6 Muscle MRI of lower extremities in other muscular dystrophies. Myotonic dystrophy type I (a) is typically characterised by distal more than proximal muscle involvement showing predominant affliction of the soleus, medial gastrocnemius and proximally the anterior thigh compartment with relative sparing of the rectus femoris. Patients with myotonic dystrophy type II (or proximal myotonic myopathy = PROMM) (b) are often less affected and show no fatty degeneration. Affected patients show more involvement of the proximal muscles with affliction of the quadriceps and sparing of the rectus femoris and gracilis muscles. FSHD (c) patients are often characterised by marked asymmetry with the adductor magnus, hamstrings, rectus femoris and tibial anterior being the most frequently affected muscles. OPMD (d) patients show predominantly posterior thigh (adductor magnus, semimembranosus and biceps femoris muscles) and posterior lower leg (soleus) muscle involvement

Myotonic dystrophy
Myotonic dystrophy types 1 and 2 (DM1, DM2) are autosomal dominantly inherited multisystem disorders and genetically characterised by pathogenic repeat mutations. DM1 is—with an estimated prevalence of 1 in 8,000—the second most common muscular dystrophy worldwide [52]. The clinical phenotype and pattern of muscle affliction differ between DM1 and DM2 (or proximal myotonic myopathy = PROMM) but also show some overlap. Almost all DM1 patients show signs of fatty degeneration and/or oedematous changes in the striated muscles on muscular MRI. Most of the patients show severe fatty degeneration of the proximal and distal lower limb muscles. There is a predominant affliction of the anterior compartment of the thighs compared with the posterior compartment with a relative sparing of the rectus femoris muscles [27, 53, 54]. Particularly, the vastus muscles frequently show a semi-lunar peri-femoral area of fatty degeneration [53, 55]. In the lower legs of DM1 patients, the gastrocnemius muscles show early and frequent involvement, whereas the posterior tibial muscles are relatively unaffected. In addition, whole-body MRI protocols can frequently detect the involvement of other organs in DM1 patients. Dypshagia is a common clinical finding in DM1 patients, which is reflected by a substantial dilatation of the oesophagus that can be easily detected and rated on MRI (Fig. 2).
Contrary to DM1, patients with DM2 are less affected based on MRI findings. A recently published whole-body MRI study including DM1 and DM2 patients showed that most of the DM2 patients showed no fatty degeneration, and none of the patients showed any inflammatory changes. The affected patients were exclusively men and showed damage predominantly of the trunk muscles (such as the erector spinae and gluteus) and in some cases involvement of the proximal and lower leg muscles with sparing of the rectus femoris and gracilis muscles in all DM2 patients [27].

Facio-scapulo-humeral muscular dystrophy
Facio-scapulo-humeral muscular dystrophy (FSHD) is the third most common muscular dystrophy (worldwide prevalence 1:20,000) [52]. FSHD is characterised by asymmetric loss of strength and atrophy of muscular tissue starting in the face and shoulder region [56]. These typical clinical findings are also mirrored on muscle imaging, which shows marked asymmetry and involvement of the medial gastrocnemius, the tibial anterior and the soleus muscles in the lower legs. At the thigh, the most frequently involved muscles are the semimembranosus, followed by the biceps femoris, the semitendinosus muscle and the adductor group muscles [57, 58].

Oculopharyngeal muscular dystrophy
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant dystrophy, and is clinically characterised by slowly progressive ptosis, dysphagia and dysphonia. Proximal limb weakness often develops subsequently [59]. There are few reports on muscle imaging in OPMD. Abnormal fatty infiltration of the tongue, masseter, neck, shoulder girdle, lumbar paraspinous and the gluteus muscles have been described [60].