Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials

Abstract

Background and objective: Dysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests.

Methods: We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed.

Results: In 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment.

Conclusions: The information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials.

Clinical trial registration: NCT01676077.

Keywords: dysferlinopathy; muscle MRI; muscular dystrophy; outcome measures.

Conflict of interest statement

Competing interests: None declared.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

Axial T1-weighted muscle MRI in dysferlinopathy. The cranial muscles (A–B) more commonly replaced by fat are the tongue (T) and the cervical paraspinal muscles (CPs). Levator scapulae (LS) is generally not involved until later stages of the disease (C, no involvement; D, involvement). In the scapular region (E–H) the subscapularis (Sc) is involved at the early stages; other muscles such as deltoid (De), infraspinatus (Is) or supraspinatus (SS) become progressively involved. Rhomboideus (R) tends to be not involved until later stages of the disease (E–G, no involvement; H, involvement in an advanced case). Biceps brachii (Bi), triceps brachii (Tr) and the anterior muscles of the forearm (FA) are commonly involved (I–K), while the posterior muscles of the forearm (FP) are not involved even in later stages of the disease. Latissimus dorsi (LD) tends to be involved before serratus anterior (SA) in most of the patients (I–J). Paraspinal muscles including the multifidus (M), the longissimus (L) and the iliocostalis (Ic) are affected in most of the patients at symptom onset, while abdominal muscles, such as rectus abdominis (RA) are more resistant and become affected only in latter stages (K). Gluteus minor (GMi) is more severely involved than gluteus medius (GMe) and maximus (GMa) (L–M). Pelvic floor muscles are transformed by fat in patients with dysferlinopathy, with the tensor fascia latae (TFL), obturatorius externus (OE) and internus (OI) being the muscles more commonly involved (N–O). The posterior muscles of the thighs (semimembranosus (Sm), biceps femoris long head (BLH), biceps femoris short head (BSH) or adductor major (AM)) are commonly involved in most of the patients (P–S). BSH tend to be less involved than BLH in early and mid-stage patients (Q). Vasti muscles are commonly involved even in early stages of the diseases (vastus intermedius (VI) in R). In contrast Sartorius (Sa) and gracilis (Gr) are not involved until late stages of the disease (Q and S). Analysis of the lower legs (T–W) shows initial involvement of gastrocnemius medialis (GM) and lateralis (GL) and soleus (So). Peroneus muscles (Pe) are also involved in most of the patients (U). Later in the progression of the disease tibialis anterior (TA) and posterior (TP) become transformed by fat (V–W).

Figure 2

Heatmaps showing involvement of scapular muscles. Patients and muscles are ordered according to hierarchical clustering with increasing grading in fat replacement severity from the bottom to the top (patients—rows) and from the left to the right (muscles—columns). The score of a muscle in a patient is indicated by the colour of the square. Grey squares mean that data are not available. The column in the top left contains information related to the phenotype of the patient at onset of the disease (legend in the bottom left). We have also included a column with information about the time from onset of symptoms to the MRI (years symptomatic) in blue and a column to the far right with the results of the Brooke and ACTIVLIM scales (see legends for these scales at the bottom of the figure): the darker the square, the more time from onset (blue) or the worse the result of the Brooke (orange) or ACTIVLIM scales. We found a statistically significant correlation between the median value of the Mercuri score per patient, the years symptomatic and the results of the Brooke and ACTIVLIM scale. LGMD-2B, limb girdle muscular dystrophy type 2B.

Figure 3

Heatmap of the muscle involvement of the thigh muscles. Patients and muscles are ordered according to hierarchical clustering with increasing grading in severity of fat replacement from the bottom to the top (patients—rows) and from the left to the right (muscles—columns). The score of a muscle in a patient is indicated by the colour of the square. Grey squares means that data is not available. A column in the far left contains information related to the phenotype of the patient at onset of the disease (Yellow: LGMD-2B; red: Miyoshi). We have also included a column with information about the time from onset of symptoms to the MRI (years symptomatic) in blue and a column on the far right with the results of the Timed Up & Go and Time to Climb 4 Stairs tests in red: the darker the square the more time from onset (blue) or the worse the result of the Time to Up & Go (red). We found a statistically significant correlation between the median value of the Mercuri score per patient, the years symptomatic and the results of the time to Up & Go test. LGMD-2B, limb girdle muscular dystrophy type 2; MMT, manual muscle testing.

Figure 4

Heatmap of the muscle involvement of the lower leg muscles. Patients and muscles are ordered according to hierarchical clustering with increasing grading in fat replacement severity from the bottom to the top (patients—rows) and from the left to the right (muscles—columns). The score of a muscle in a patient is indicated by the colour of the square. Grey squares means that data is not available. A column in the far left contains information related to the phenotype of the patient at onset of the disease (Yellow: LGMD-2B; red: Miyoshi). We have also included a column with information about the time from onset of symptoms to the MRI (years symptomatic) in blue. We found a statistically significant correlation between the median value of the Mercuri score per patient and the years symptomatic. LGMD-2B, limb girdle muscular dystrophy type 2B.

Figure 5

Heatmap showing the progression of the muscle involvement related to the time from onset of symptoms to the MRI. Patients were divided into six groups for the analysis of the progression of muscle involvement. Muscles (columns) are ordered according to hierarchical clustering with increasing grading of muscle fatty replacement in T1-W imaging from the left to the right. The score of a muscle per every group is indicated by the colour of the square. We obtained a pattern of the progression of the disease related to the time from onset of symptoms to the MRI showing the natural history of the disease.

Figure 6

Heatmap showing the progression of the muscle involvement related to the distance covered in the 6MWT. Patients were divided into eight groups depending on the distance covered in the 6MWT for the analysis of the progression of muscle involvement. Muscles (columns) are ordered according to hierarchical clustering with increasing grading of muscle fatty transformation in T1-W imaging from the left to the right. The score of a muscle per group is indicated by the colour of the square. We obtained a pattern of the progression of the disease in muscles of the pelvis, thighs and lower legs related to the functional test 6MWT.