Congenital myopathies
CMs show distinctive morphological abnormalities such as rods, an abnormal number of central nuclei or (central or multiple) cores. Often these findings guide the physician to the correct genetic diagnosis. However, some pathological overlap between genetically distinct disorders has been described, making a genetic diagnosis sometimes difficult. Recently, different muscle imaging patterns in CM have been identified, which can be of help in the differential diagnosis.
Muscle imaging in patients with central core disease (CCD) caused by mutations in the ryanodine receptor 1 gene (RYR1) shows a characteristic pattern with main involvement of the gluteus maximus in the pelvis. At the thigh level, the most severe changes are observed in the medial compartment (adductor magnus) and in the anterior compartment muscles (vastus lateralis, vastus intermedius). Sparing of the adductor longus, gracilis and biceps femoris muscles is common. In the distal lower leg muscles, the soleus and the lateral head of the gastrocnemius muscles are most severely involved [61, 62]. This pattern seems to be highly characteristic, as muscular involvement in other congenital myopathies caused by mutations in the SEPN1, ACTA1, NEB or collagen VI encoding (COL6A1, COL6A2 and COL6A3) genes is different [1]. In addition to RYR1, patients with Ullrich CMD or Bethlem myopathy related to collagen VI encoding genes also present with dominant affliction of the anterior thigh compartment. These patients show an early and selective involvement of the centre of the rectus femoris and vastus lateralis muscles. In addition, in the lower legs there is often a rim of degenerative changes between the soleus and the gastrocnemius muscle, a pattern not observed in other CMs [63, 64].
Contrary to RYR1- and collagen 6A-related disorders, which have marked affliction of the anterior thigh, in most other CM forms the posterior rather than anterior thigh compartment muscles are affected. SEPN1 patients, often presenting as a rigid spine (multi-minicore) myopathy, typically show a selective affliction of the sartorius and posterior compartment muscles and a relative sparing of the quadriceps and the gracilis muscle [25]. In patients with dynamin 2-related autosomal dominant centronuclear myopathy (DNM2-CNM), muscle imaging shows predominantly distal lower leg muscle affliction (medial head of the gastrocnemius, soleus), milder involvement of the posterior thigh compartment (mostly the biceps femoris and semimembranosus muscles) and the gluteus minimus muscle. The sartorius and gracilis are often spared [65]. Congenital (nemaline) myopathies related to ACTA1 gene mutations show predominantly distal anterior lower leg and mild diffuse thigh compartment involvement. On the other hand, nebulin gene-associated nemaline myopathies often spare the thigh muscles and show selective distal involvement of the soleus and tibial anterior muscles [66]. A useful flowchart for the differential diagnosis of CM using muscle imaging is provided in Fig. 7.
Fig. 7 Flowchart showing a useful approach to the differential diagnosis of congenital myopathies. We highly recommend systematically analysing muscle imaging findings beginning with the thigh muscles. The first distinction should be made according to the relation of posterior to anterior thigh muscle involvement. Most CMs show greater affliction of the posterior rather than the anterior thigh muscles. In the second step, the same relation should be assessed in the lower legs. Predominant posterior thigh and posterior lower leg involvement with sparing of the gracilis and sartorius but marked affliction of the soleus and medial gastrocnemius is observed in DNM2-CNM. Predominantly posterior thigh with marked affliction of the sartorius and predominantly diffuse posterior lower leg involvement are typical findings of SEPN1-related CM. Posterior thigh but anterior leg involvement was observed in CM patients with ACTA1 mutations. On the other hand, marked anterior thigh affliction is seen in RYR1- and collagen 6A-related CM. In addition, RYR1 patients show sparing of the rectus femoris, gracilis and biceps femoris and often marked affliction of the soleus muscle, while patients with a collagen 6A defect show a special rim with the beginning of degeneration within the rectus femoris muscle and a degenerative rim between the soleus und gastrocnemius muscles. Typical muscle imaging findings of patients with proven mutations in the DNM2, SEPN1, ACTA1, RYR1 and collagen 6A1 are provided