Wangler, Michael F

ABSTRACT Background Visceral myopathy (VSCM) is an ultra‐rare life‐threatening condition characterized by severe impairment of gastrointestinal (GI), genitourinary, and uterine smooth muscle. This disorder represents a significant clinical challenge due to variable presentation and the lack of standardized diagnostic and therapeutic protocols. Methods To discuss advances in the field, scientists and clinicians with a special interest in VSCM met in Arenzano, Genova, Italy in October 2024 for the second International Forum on Visceral Myopathy 2024 (IFVM2024) ( https://ifvm2024.ge.ibf.cnr.it/ ). Key Results As in the previous edition of the event ( https://poic‐e‐dintorni.org/efvm‐2022/ ), attendees included clinicians and researchers from around the world who study this disease, representatives from support organizations, patients affected by VSCM and their families, and companies that co‐funded the event. The present manuscript aims to summarize knowledge shared during the IFVM2024 conference, thus providing an updated state‐of‐the‐art summary of VSCM biology and disease management. Conclusions Here, we pay particular attention to the epidemiology of the disease, histopathology, genetics, novel treatments, advances in molecular and cell biology, experimental models, and the lived experiences and impact of this disorder on families.

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B , which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.