Is the Loss of Previously Acquired Skills a Feature of PACS1-, PACS2- and WDR37-Related Syndromes? A Systematized...

PACS1, PACS2 and WDR37 form a clinical-molecular axis with overlapping neurodevelopmental phenotypes. The loss of previously acquired skills, encompassing developmental regression and neurodegenerative deterioration, has been mentioned only sporadically and has not been systematically reviewed. We conducted a systematic narrative synthesis of the literature indexed in PubMed/MEDLINE and Google Scholar, informed by relevant PRISMA principles, to identify patients in whom skill loss had been reported, assess the strength of the supporting evidence, and explore molecular mechanisms that might warrant prospective surveillance. Reports were classified as confirmed, probable, possible, or not reported according to predefined criteria. Most published reports describe patients with psychomotor delay and intellectual disability without loss of skills. Five patients with reported or suspected skill loss were identified among approximately 158 published patients, although this proportion should not be interpreted as prevalence. These cases included two patients with PACS1-related disorder, two with PACS2-related disorder, and one with WDR37-related disorder. The proposed mechanisms, including a shared autoinhibitory switch, HDAC6-dependent synaptic regulation, dynein-mediated transport and endoplasmic reticulum-mitochondria calcium handling, provide a plausible biological substrate but do not establish a causal relationship with skill loss. The available evidence does not support classifying these syndromes as primarily regressive disorders. However, the documented cases justify active surveillance and standardized longitudinal phenotypic characterization.