ADSS1 (adenylosuccinate synthase 1) catalyzes the first committed step in AMP biosynthesis from IMP, serving as a critical component of the purine nucleotide cycle (PNC) 1. This metabolic cycle regulates nucleotide levels across various tissues and contributes to both glycolysis and ammoniagenesis 1. ADSS1 is expressed as a muscle-specific isoform, with high expression in skeletal muscle and cardiac tissue established perinatally through developmental activation of tissue-specific regulatory elements 1. Biallelic pathogenic variants in ADSS1 cause ADSS1 myopathy, an autosomal recessive ultra-rare neuromuscular disease 2. This progressive disorder presents with limb muscle weakness predominantly affecting lower extremities, respiratory muscle weakness, and cardiomyopathy in severe cases 23. Pathological analysis reveals nemaline bodies accumulating in muscle fibers, including novel findings in diaphragm and myocardium, with lower nemaline body frequency compared to other nemaline myopathies 2. Patient studies demonstrate fatigue in nearly all cases (96.8%), significant pain particularly in lower extremities (64.5%), and substantial impact on mobility and quality of life 3. Experimental evidence in C. elegans confirms ADSS1 is essential for neuromuscular function, fertility, and proper development, with deficiency causing excessive synaptic transmission and impaired mechanosensation 4. An ADSS1 myopathy consortium has been established to identify therapeutic targets and develop treatments for this ultra-rare condition 5.