Skeletal muscle symptoms and quantitative MRI in females with dystrophinopathy

Abstract

Introduction/aims: The dystrophinopathies primarily affect males; however, female carriers of pathogenic dystrophin variants can develop skeletal muscle symptoms. This study aimed to evaluate muscle involvement and symptoms in females with dystrophinopathy using quantitative magnetic resonance imaging (MRI), functional assessments, and patient-reported outcomes.

Methods: Controls and females with dystrophinopathy with muscle symptoms of pain, weakness, fatigue, or excessive tightness were enrolled in this cross-sectional study. Participants underwent lower extremity MRI to quantify muscle inflammation, replacement by fat, and disease asymmetry. Cardiac MRI, functional ability, muscle symptoms, and serum creatine kinase levels were also evaluated.

Results: Six pediatric females with dystrophinopathy (mean age: 11.7 years), 11 adult females with dystrophinopathy (mean age: 41.3 years), and seven controls enrolled. The mean fat fraction was increased in females with dystrophinopathy compared to controls in the soleus (0.11 vs. 0.03, p = .0272) and vastus lateralis (0.16 vs. 0.03, p = .004). Magnetic resonance spectroscopy water T₂, indicative of muscle inflammation, was elevated in the soleus and/or vastus lateralis in 11 of 17 individuals. North Star Ambulatory Assessment score was lower in the dystrophinopathy group compared to controls (29 vs. 34 points, p = .0428). From cardiac MRI, left ventricle T₁ relaxation times were elevated in females with dystrophinopathy compared to controls (1311 ± 55 vs. 1263 ± 25 ms, p < .05), but ejection fraction and circumferential strain did not differ.

Discussion: Symptomatic females with dystrophinopathy quantitatively demonstrate muscle replacement by fat and inflammation, along with impairments in functional ability and cardiac function. Additional research is needed to evaluate how symptoms and muscle involvement change longitudinally.

Keywords: Duchenne muscular dystrophy; fat fraction; inflammation; magnetic resonance imaging; x‐inactivation.

Figure 1:. Serum creatine kinase and skeletal muscle symptoms.

A) The majority of females with dystrophinopathy had CK levels above the upper limit of normal (ULN), and B) both pediatric and adult females with dystrophinopathy reported muscle pain over the last seven days. C) Self-reported fatigue was increased in both adults and D) pediatric females with dystrophinopathy. In pediatric females with dystrophinopathy, cognitive fatigue was also commonly reported. (CON = control, FD = female with dystrophinopathy, PED = pediatric, GEN = general fatigue subscale of the PedsQL-MFS, SLEEP = sleep/rest fatigue subscale of the PedsQL-MFS, COG = cognitive fatigue subscale of the PedsQL-MFS)

Figure 2:. Skeletal muscle fat fractions.

MRS-derived fat fraction was significantly higher in the A) soleus and B) the vastus lateralis muscles of females with dystrophinopathy compared to controls; however, some females with dystrophinopathy had fat fractions within the range of control participants. C) The heat map of Dixon MRI derived skeletal muscle fat fractions shows a range of values from control levels of muscle fat to nearly complete muscle replacement by fat. (* = p<0.05, CON = control, FD = female with dystrophinopathy, PEDS = pediatric)

Figure 3:. Asymmetry of muscle involvement.

A) A heat map of left/right differences in Dixon MRI-derived muscle fat fraction for the thighs and gluteal muscles. Some females with dystrophinopathy had large differences between the left and right sides. B) Dixon MRI fat maps of the bilateral thighs show that some females with dystrophinopathy show symmetric involvement, some show asymmetric involvement, and one individual had unilateral involvement.

Figure 4:. Skeletal muscle inflammation.

A) Qualitative T₂-weighted Dixon MRI water maps demonstrate the presence of elevated pixel intensity that likely represents muscle inflammation in both children and adult females with dystrophinopathy. B) MRS water T₂ values were not significantly different between the controls and females with dystrophinopathy at the group level in the soleus or vastus lateralis, but some females with dystrophinopathy had highly elevated T₂ values. C) MRI-derived bulk muscle T₂ in pediatric participants and D) adult participants with a range of muscle fat fractions. E) MRI-derived bulk muscle T₂ in only participants with control level muscle fat fractions. Values were elevated in many females with dystrophinopathy, suggesting muscle inflammation is present. (SOL = soleus, MG = medial gastrocnemius, PER = peroneal group, TA = tibialis anterior, TP = tibialis posterior, VL = vastus lateralis, BFLH = biceps femoris long head, ST = semitendinosus, GRA = gracilis)

Figure 5:. Skeletal muscle involvement compared to total NSAA score.

A) Despite perfect or B) nearly perfect scores on the NSAA, some females with dystrophinopathy had clear muscle replacement by fat in several muscles of the thigh as seen in these Dixon MRI fat maps. C) Among all females with dystrophinopathy with NSAA total scores of 33 or 34 points, many had elevated lower leg muscle fat fractions. (NSAA = North Star Ambulatory Assessment, SOL = soleus, MG = medial gastrocnemius, VL = vastus lateralis, BFLH = biceps femoris long head, GMED = gluteus medius, GMAX = gluteus maximus, FD = female with dystrophinopathy, PED = pediatric)

Figure 6:. Cardiac MRI biomarkers.

Neither A) circumferential strain nor B) ejection fraction differed between the control and dystrophinopathy groups; however, native T₁ relaxation constants were elevated in the dystrophinopathy group at the C) mid (p=0.0388) and D) basal left ventricle levels (p=0.013). (LV = left ventricle, CON = control, PEDS = pediatric, FD = female with dystrophinopathy, ns = not significant)