The Use of Muscle Ultrasound in the Diagnosis and Differential Diagnosis of Congenital Disorders of Muscle in the Age of Next Generation Genetics.


Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA. Electronic address: [Email]


Congenital disorders of muscle most importantly encompass the congenital muscular dystrophies as well as the congenital myopathies. With the broader availability of next generation genetic testing there has been an expansion of phenotypes and genotypes, while the very large genes such as titin, nebulin, and RYR1 have also become accessible to complete sequencing. This development has had considerable diagnostic power while at the same time also creating challenges in the interpretation of the many variants of uncertain significance that will need a solid clinical plausibility test, based on "deep" phenotyping, taking into account clinical, extended clinical, histological, and physiological data. One tool in this context is imaging of skeletal muscle, including by ultrasound. Muscle ultrasound is a useful, noninvasive, child-friendly technique for visualizing normal and pathological skeletal muscle. By virtue of its different mode of image acquisition compared to muscle MRI, it allows for the assessment of different and often earlier changes, also circumventing the need for sedation. Herein we highlight the important role of muscle ultrasound as a diagnostic tool and an extension of the physical exam in the work-up of congenital onset muscle disease, presenting various relevant clinical scenarios. We show how muscle ultrasound can confirm or refute skeletal muscle involvement and yield information about the nature of the involvement (myopathic vs neurogenic). Muscle ultrasound can also guide the appropriate next diagnostic steps and recognize diagnostically important qualitative patterns to help confirm or refute genetic considerations raised by next generation sequencing. We illustrate specific muscle ultrasound involvement patterns, which constitute accessible diagnostic hints and show that muscle ultrasound, in conjunction with the clinical phenotype, the histological appearance of the muscle biopsy (when available), and the ascertained genotype, can be a very powerful tool in integrating all available information into a final accurate and precise diagnosis in the age of next generation sequencing.