05ORedefining triple a syndrome: a multinational study of the neuromuscular phenotype in the largest genetically confirmed cohort to date

Triple A Syndrome (AAAS) is a rare autosomal recessive multisystem disorder, originally described in 1978 and traditionally defined by the triad of achalasia, alacrima, and ACTH-resistant adrenal insufficiency. While these features form the historical foundation for diagnosis, clinical experience increasingly suggests that this classification does not fully reflect the disease’s breadth. In particular, neurological involvement, and specifically neuromuscular dysfunction, appears to be more than an occasional comorbidity. It is often an early, progressive, and disabling component of the disease. Yet, it remains under-recognized, in part due to the dominance of endocrine features in the existing diagnostic framework. In this study, we examined the neuromuscular phenotype of the largest genetically confirmed AAAS cohort reported to date (n=44), with patients recruited through a multinational network. To minimize referral and selection bias, recruitment extended beyond neurology and included pediatricians, endocrinologists, gastroenterologists, and geneticists. All patients included exhibited neurological symptoms, enabling systematic investigation of the neuromuscular dimension of AAAS. Standardized clinical assessments were performed, including detailed neurological examinations, nerve conduction studies, electromyography, muscle MRI, and muscle biopsy. Electrophysiological evaluation consistently revealed sensorimotor axonal neuropathy across the cohort. Muscle MRI showed variable yet consistent signs of atrophy and selective involvement, while histopathology revealed non-specific myopathic changes. Importantly, eight previously unreported pathogenic variants in the AAAS gene were identified, allowing for refined genotype–phenotype correlations. Variants predicted to affect ALADIN localization at the nuclear pore complex were associated with more pronounced neuromuscular involvement. Proteomic analysis of skeletal muscle tissue offered new insights into disease pathophysiology. The data revealed upregulation of pathways involved in sarcomere organization, cytoskeletal architecture, and muscle contraction. At the same time, key metabolic processes - particularly glycolysis and gluconeogenesis -were downregulated. This pattern suggests a dual mechanism of structural and metabolic dysfunction within affected muscle tissue. The consistency of these alterations across patients further supports a primary role of neuromuscular pathology in the disease. Our findings demonstrate that neuromuscular dysfunction is a central feature of AAAS, not merely an associated symptom. This has direct implications for clinical practice, as neurological signs may precede or occur independently of the classical triad. The current definition fails to capture the full clinical spectrum and may delay diagnosis. We therefore propose a reclassification - and possible renaming- of AAAS as a neuromuscular multisystem disorder with endocrine, autonomic, and gastrointestinal components.