Lower Extremity Muscle Involvement in the Intermediate and Bethlem Myopathy Forms of COL6-Related Dystrophy and Duchenne Muscular Dystrophy: A Cross-Sectional Study

Abstract

Collagen VI-related dystrophies (COL6-RDs) and Duchenne muscular dystrophy (DMD) cause progressive muscle weakness and disability. COL6-RDs are caused by mutations in the COL6 genes (COL6A1, COL6A2 and COL6A3) encoding the extracellular matrix protein collagen VI, and DMD is caused by mutations in the DMD gene encoding the cytoplasmic protein dystrophin. Both COL6-RDs and DMD are characterized by infiltration of the muscles by fatty and fibrotic tissue. This study examined the effect of disease pathology on skeletal muscles in lower extremity muscles of COL6-RDs using timed functional tests, strength measures and qualitative/ quantitative magnetic resonance imaging/spectroscopy measures (MRI/MRS) in comparison to unaffected (control) individuals. Patients with COL6-RD were also compared to age and gender matched patients with DMD.Patients with COL6-RD presented with a typical pattern of fatty infiltration of the muscle giving rise to an apparent halo effect around the muscle, while patients with DMD had evidence of fatty infiltration throughout the muscle areas imaged. Quantitatively, fat fraction, and transverse relaxation time (T2) were elevated in both COL6-RD and DMD patients compared to unaffected (control) individuals. Patients with COL6-RD had widespread muscle atrophy, likely contributing to weakness. In contrast, patients with DMD revealed force deficits even in muscle groups with increased contractile areas.

Keywords: Collagen VI-related dystrophies; duchenne muscular dystrophy; force production; magnetic resonance imaging.

Conflict of interest statement

CONFLICT OF INTERESTS

The authors declare that they have no conflict of interests.

Figures

Fig. 1.

T1-weighted images (thigh muscles) of patients with COL6-RD in comparison to unaffected (control) individuals (first axial slice), indicating the pattern of fibro-fatty material with increased disease severity (B–E). There is a characteristic inward progression of fibro-fatty material from fascia to deep inside the vastus lateralis muscle. Also, there is a characteristic central shadow (target)-like appearance in the rectus femoris (RF) muscle (white arrow).

Fig. 2.

T1-weighted trans-axial images of the lower leg of age-matched patients with COL6-RD, DMD and unaffected (control) individuals showing the different patterns of disease progression with fibro-fatty infiltration in two different forms of muscular dystrophies. The characteristic inwards progression (fascia to deep inside muscle compartment) of fibro-fatty material (shown by white arrow) in the lateral gastrocnemius (LG) of subject with COL6-related dystrophy is seen. Note: Representative scans of COL6-RD progressed in figure are from left lower leg.

Fig. 3.

Comparison of cross-sectional area max (CSAmax) between COL6-RD, DMD and control groups. +significantly different from control; * significantly different from COL6 p < 0.05; COL6-RD-Collagen VI related dystrophy, DMD- Duchenne Dystrophy, VIVastus Intermedius, VL- Vastus Lateralis, VM- Vastus Medialis, RF- Rectus Femoris, Sol- Soleus, MG- Medial Gastrocnemius, LG- Lateral Gastrocnemius.

Fig. 4.

Comparison of thigh and lower leg Non-Fat area between COL6-RD, DMD and control groups. +significantly different from control. *significantly different from COL6; p < 0.05; COL6-RD-Collagen VI related dystrophy, DMD- Duchenne Muscular Dystrophy, VI- Vastus Intermedius, VL- Vastus Lateralis, VM- Vastus Medialis, RF- Rectus Femoris, Sol- Soleus, MG- Medial Gastrocnemius, LG- Lateral Gastrocnemius.

Fig. 5.

(A) Comparison of MR T2 in both thigh and lower leg muscles between COL6-RD, DMD, and control groups (Whole data). (B) Comparison of MRI T2 between Control, COL6-RD and DMD groups (Age and Sex Matched subset). *Significantly different from controls at p < 0.05. COL6-RD- Collagen VI related dystrophy, VL- Vastus Lateralis, Sol- Soleus, MG- Medial Gastrocnemius, BFLH – Bicep Femoris Long Head, GRA - Gracilis, PER - Peroneus, TA – Tibialis Anterior.

Fig. 6.

1H MRS FF comparison between age matched COL6-RD, DMD and control groups for Sol and VL muscles. *Signifcantly different from controls at p < 0.05. COL6-RD- Collagen VI related dystrophy, VL- Vastus Lateralis, Sol- Soleus, 1H MRS - 1H Magnetic Resonance Spectroscopy.

Fig. 7.

(A) Comparison of peak torque production in COL6-RD, DMD and control groups. (B) Comparison of peak torque normalized to Non-Fat area between COL6-RD, DMD and control groups. *significantly different between DMD and COL6-RD at p < 0.05. +Significantly different from control at p < 0.05. COL6-RD- Collagen VI related dystrophy, DMD- Duchenne Muscular Dystrophy, KE – Knee extensors, PF – Plantar Flexors.