The Role of Muscle Imaging in the Diagnosis and Assessment of Children with Genetic Muscle Disease

Abstract

Muscle magnetic resonance imaging (MRI) and ultrasound (US) are emerging tools to assist in the diagnosis of children with genetic muscle disease. Increasing number of studies demonstrate that these imaging techniques can identify selective patterns of muscle atrophy, fatty degeneration, and muscle edema that help to distinguish between different early-onset genetic myopathies and muscular dystrophies. Recognizing patterns of pathology by muscle imaging can help to guide genetic testing and avoid the more invasive procedure of a muscle biopsy. Conversely, since massive parallel sequencing is now more commonly used as the initial step in diagnostic testing, imaging techniques can help to confirm or exclude if a variant of uncertain significance is indeed disease causing and compatible with a pattern of pathology as detected by muscle imaging. Whereas for diagnostic purposes and pattern recognition, muscle pathology does not need to be quantified, measuring disease progression is increasingly supported by quantitative muscle imaging, which is critical given the recent increment in rare disease therapeutic trials. Here, we discuss the value of muscle imaging techniques in pediatric muscle disease and summarize data identifying specific patterns of involvement in muscle MRI and US in some of the more common genetic myopathies and muscular dystrophies.

Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores

“…46,47 Various genetically defined core myopathies with clinical overlap, including RYR1and MYH7-related myopathies, can present with a characteristic and recognizable pattern of muscle involvement and sparing when assessed by muscle imaging. [48][49][50] However, a selective and potentially diagnostic pattern of muscle involvement was thus far not evident on muscle imaging in our UNC45B cohort. Instead, imaging revealed a fairly uniform involvement of all muscles and a possible hint of relative sparing of the semimembranosus muscle of the hamstring group.…”

“…In contrast to a dystrophic process, which is characterized by uniform fatty infiltration, or to a neurogenic process in which we typically see a coarse ''moth-eaten'' appearance on MR imaging, the muscle of UNC45B-affected individuals had a characteristic ''marbled-like'' appearance on fat-sensitive T1 MR imaging sequences, which could potentially be a characteristic and thus diagnostically helpful finding. 49 Given the potential developmental role of UNC-45B, 14,15 it is of note that the myofibrillar apparatus in the individuals reported here appears to be normal at baseline with normal in vitro contractile performance and myosin cross-bridge cycling. Therefore, we hypothesize that with ongoing use and stress on the muscle fibers over time, the sarcomere is inadequately maintained because of reduction in myosin chaperone availability and/or functioning.…”

Early skeletal muscle pathology and disease progress in the dy3K/dy3K mouse model of congenital muscular dystrophy with laminin α2 chain-deficiency

“…The development of diagnostic techniques (e.g. magnetic resonance imaging, electromyogram, electrical impedance myography, tomography, ultrasound imaging) facilitates relatively non-invasive, detailed characterisation of defects in different tissues of LAMA2-CMD patients 51–53 . For example, these techniques helped to recognise that different muscles from LAMA2-CMD individuals, as in the case of dy 3K /dy 3K mice, are affected to various degrees: vastus lateralis, vastus medialis, hamstring group, gluteus, soleus and gastrocnemius show robust atrophy and fatty infiltration, while other muscles (e.g.…”

“…For example, these techniques helped to recognise that different muscles from LAMA2-CMD individuals, as in the case of dy 3K /dy 3K mice, are affected to various degrees: vastus lateralis, vastus medialis, hamstring group, gluteus, soleus and gastrocnemius show robust atrophy and fatty infiltration, while other muscles (e.g. gracilis, sartorius) show minor involvement in most LAMA2-CMD cases 53–55 . It cannot be excluded that a complicated task of treating entire muscle mass could be narrowed down to fewer muscles, and it needs to be assessed which non-limb muscles that are crucial for feeding and respiration are affected the most.…”

GNE Myopathy With Novel Mutations and Pronounced Paraspinal Muscle Atrophy

“…Muscle MRI is a modality that has demonstrated utility in a number of genetic myopathies and can provide added value in correlation with clinical phenotype, genetic testing and muscle pathology ( 21 ), and additionally has value in longitudinal studies and clinical trials ( 22 ). In GNE myopathy, MRI of the lower extremity muscles typically demonstrates severe and early involvement of the biceps femoris short head ( 12 ).…”