Multimodal Noninvasive Biomarker Characterization of Structural and Functional Alterations in ADSS1 ‐Deficient Myopathy

Adenylosuccinate synthase 1 (ADSS1)-deficient myopathy is an ultra-rare disease characterized by progressive muscle dysfunction. The objective of this investigation was to employ a noninvasive biomarker approach to phenotype (fine-)motor skills, communication and cognition in adults with ADSS1-deficient myopathy. Five individuals with ADSS1-deficient myopathy and five age-sex-matched healthy controls (HCs) underwent a multimodal evaluation. Assessments included, (i) evaluation of motor performance, (ii) speech and voice 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-deficient myopathy participants vs. HCs demonstrated reduced performance on the 9-Hole Peg and grip strength tests as well as lower self-reported mobility. Analysis of speech and voice performance revealed asthenia (vocal weakness) (p = 0.02), lower intelligibility (p = 0.008), and worse voice quality during the sustained vowel task (p = 0.03) in the ADSS1-deficient myopathy cohort. Cognitive functioning remained unaffected in patients with ADSS1-deficient myopathy. On EIM, ADSS1-deficient myopathy 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 (Cliff's δ = 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-deficient myopathy 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-deficient myopathy. This multimodal investigation demonstrates that integrating electrical impedance myography with quantitative motor, speech, musculoskeletal imaging, and proteomic assessments provides a sensitive and noninvasive research framework for capturing neuromuscular dysfunction and functional disease burden in patients with ADSS1-deficient myopathy, thereby supporting the current biomarker strategy for refined phenotyping and longitudinal disease monitoring in this ultra-rare condition.