Multimodal Non-Invasive Biomarker Characterization of Structural and Functional Alterations in ADSS1 Myopathy

Adenylosuccinate synthetase 1 (ADSS1) myopathy is an ultra-rare disease characterized by progressive muscle dysfunction. The objective of this investigation was to employ a non-invasive biomarker approach to phenotype (fine-)motor skills, speech production and cognition in adults with ADSS1 myopathy. Five individuals with ADSS1 myopathy and five age-sex-matched healthy controls (HCs) underwent a comprehensive multimodal evaluation. Assessments included, (i) evaluation of motor performance, (ii) speech production and cognitive test batteries, (iii) patient-reported outcomes, (iv) electrical impedance myography (EIM), (v) musculoskeletal magnetic resonance imaging (MRI) and (vi) plasma proteomics. ADSS1 participants vs. HCs demonstrated reduced performance on the 9-Hole Peg and grip strength tests as well as lower self-reported mobility. Speech production analysis revealed asthenia (p=0.02), lower intelligibility (p=0.008), and worse voice quality during the sustained vowel task (p=0.03) in the ADSS1 cohort. Cognitive functioning remained unaffected in patients with ADSS1. On EIM, ADSS1 participants vs. HCs, demonstrated a pattern of higher resistance and lower reactance and phase across upper- and lower-extremity measurements, indicative of poorer muscle health, with large effect sizes (Cliffs 8=0.5-0.9). MRI revealed intramuscular fat infiltration, particularly in posterior compartments of the upper leg (e.g., biceps femoris). Proteomics indicated reduced (p=0.04) Neurotrophin-3 (NTF3; implicated in neuronal development, survival and differentiation) levels in the ADSS1 cohort relative to HCs. Lower NTF3 levels associated with poorer performance on hand-motor tasks as well as higher resistance and lower reactance and phase on EIM. This study highlighted the value of multimodal phenotyping for quantifying disease expression and advancing monitoring strategies in ADSS1 myopathy. Take-home messageThis multimodal investigation demonstrates that integrating electrical impedance myography with quantitative motor, speech, musculoskeletal imaging, and proteomic assessments provides a sensitive and non-invasive research framework for capturing neuromuscular dysfunction and functional disease burden in patients with ADSS1 myopathy, thereby supporting the current biomarker strategy for refined phenotyping and longitudinal disease monitoring in this ultra-rare condition.