The amount of fat in leg and thigh muscles measured on magnetic resonance imaging (MRI) scans correlates with disease severity and disability in people with Charcot-Marie-Tooth (CMT) type 1A, a small study suggests.
The researchers said the amounts of fat could be a useful biomarker for determining the effects of new treatments in clinical trials.
The study, “Fat fraction distribution in lower limb muscles of patients with CMT1A: a quantitative MRI study,” was published in the journal Neurology.
Charcot-Marie-Tooth (CMT) disease is a group of disorders that affects the peripheral nerves — the network of nerves that supply movement and sensation to the body. The disease is classified into several types, termed CMT1, CMT2, CMT3, CMT4, CMTX, and DI-CMT, or dominant intermediate Charcot-Marie-Tooth.
CMT1 is the most common, characterized by muscle weakness and atrophy, and reduced sensation — touch, heat, and cold — particularly in the feet, lower legs, hands, and forearms. It is caused by genetic defects that damage myelin, a fat-rich substance covering the nerves that promotes the efficient transmission of nerve impulses.
Demyelination, or the loss of myelin, slows the conduction of nerve signals, leading to nerve fiber loss, disability, motor deficits, and sensory symptoms.
CMT1 is further subdivided — into CMT1A, CMT1B, CMT1C, CMT1D, and CMT1X — based on the specific genes that are mutated. CMT1A is caused by a duplication of the PMP22 gene and is the dominant type of CMT1.
Given that CMT1A progresses slowly, researchers must find biomarkers that are sensitive enough to measure disease progression, yet could be used as endpoints in future clinical trials to evaluate the disease-retarding or halting effects of new treatments.
Magnetic resonance imaging has been used for many years to characterize CMT, but quantitative MRI measurements were employed only recently. One of the metrics evaluated was fat fraction, the amount of fat in tissues. Up to now, fat fraction was only assessed in a single region of the leg muscle in CMT patients. It matched well with disease severity and had a high sensitivity to detect alterations.
Now, the researchers wanted to extend those initial studies and gather additional evidence to determine whether fat fraction could be a marker of CMT severity. For that, they combined MRI scans with a specific segmentation method — a technique to section MRI images for quantitative assessments.
Combining both, they measured fat infiltration in 14 different muscle compartments of the leg and thigh. They compared the results of 16 patients with CMT1A with those of 11 healthy people (controls). The mean age of the patients was 36.8 years; the healthy controls had similar age and sex distribution.
To investigate correlations with disease severity, the fat fraction values were compared with the degree of disability and disease severity of patients, measured by muscle strength tests and clinical scores incorporating symptoms, signs, and nerve conduction studies.
The results demonstrated that the individuals with CMT1A had a significantly larger accumulation of fat in both their leg and thigh muscles.
The largest fat infiltration was detected in the front and lateral compartments of the leg, compared with controls. At the thigh, fat infiltration was milder and ranged from 26.9% (adductor muscles) to 92.7% (rectus femoris muscle).
The MRI data revealed that fat accumulated along a proximal-to-distal gradient, meaning there was greater fat infiltration in muscles that are farther away from the trunk (distal muscles). The infiltration was comparatively less in muscles closest to the center of the body (proximal muscles). Such a gradient tended to increase with CMT1A disease severity and was not observed in the control group.
The gradient also confirms the length-dependent degeneration of motor nerve fibers characteristic of CMT. That means the longest nerves, those that connect the spinal cord to the extremities of the body — distal limbs, feet, and hands — are the most affected.
More fat in the legs was significantly associated with older age, longer disease duration, and greater disease severity — especially in the front muscles of the leg — as rated by clinical scores based on examination of symptoms, and signs, and nerve conduction results.
Walking ability, specifically time and distance, was not correlated with the fat in the legs, but did correlate to the amount of fat in some muscles of the thigh.
Muscle strength while doing plantar flexion — a movement in which the top of the foot is pointed downward, away from the leg — significantly correlated with the amount of fat in the leg and thigh.
Such correlation with clinical variables and muscle strength confirms the value of using quantitative muscle MRI for future CMT clinical trials, the researchers said.
The study “described the quantitative MRI pattern of muscle fatty degeneration in individual muscles of patients with CMT1A,” they said. The team concluded that quantification of fat in the front muscle of the leg “appears to be of interest in future clinical trials.”