Autonomic dysfunction profiling of Malan syndrome using Pediatric Autonomic Symptom Scales

Abstract Background The autonomic nervous system (ANS) is essential for body homeostasis, and its dysfunction, defined as dysautonomia, is increasingly recognized as a contributor to disease burden in neurodevelopmental/psychiatric disorders (NPDs), although it remains underdiagnosed. Malan syndrome (MALNS), an ultra-rare NPD caused by NFIX haploinsufficiency, has been associated with sporadic autonomic symptoms and autistic-like features, but their extent and clinical relevance have not been systematically investigated. Results We applied the Pediatric Autonomic Symptom Scales (PASS) to a large, molecularly confirmed and clinically homogeneous MALNS cohort, and compared results with previously characterized autism spectrum disorder (ASD), NPD, and healthy control populations. Our findings reveal a clinically relevant burden of autonomic dysfunction in MALNS. Only partial overlap with ASD-specific profiles was evidenced. Symptom-level analysis distinguished features likely attributable to primary ANS dysfunction, such as cardiovascular symptoms, thermoregulatory issues, altered secretomotor activity, hypoalgesia, and sensory processing anomalies, from those secondary to other MALNS-related traits. Notably, PASS results also suggest that the behavioral phenotype appears to be primarily driven by anxiety, language impairment, intellectual disability, and adaptive dysfunction rather than a core autistic profile. Conclusions Our study, which represents the first systematic assessment of ANS dysfunction in a rare genetic NPD, underscores the importance of integrating structured ANS assessment into routine evaluation and management of MALNS. More broadly, this work establishes a model for investigating dysautonomia in rare diseases, with implications for improving patient stratification, proper management, and targeted care.