Mapping Sanfilippo Syndrome: A Multisystem Clinicopathological Autopsy

Background/Objectives: Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is an autosomal recessive lysosomal storage disorder caused by deficiencies in enzymes required for heparan sulfate degradation. While primarily recognized for its devastating neurodegenerative course, the systemic extent of glycosaminoglycan (GAG) accumulation remains under-characterized. This study aims to provide a detailed multisystemic pathological mapping of MPS III to challenge the traditional “brain-only” disease paradigm and highlight the clinical relevance of extracerebral involvement. Methods: We present a comprehensive clinicopathological analysis of a 15-year-old female patient with a history of profound neuropsychomotor delay, refractory epilepsy, and spastic tetraplegia. Following her death due to terminal bronchopneumonia during palliative care, a complete forensic and pathological autopsy was conducted. Tissue samples from all major organ systems were processed using routine Hematoxylin–Eosin (HE) staining, immunohistochemical staining for CD68, and specialized histochemical stains to identify intracellular storage products. Results: Macroscopic evaluation revealed significant diffuse cerebral atrophy, meningoencephalic edema, cardiac valvulopathy with compensatory myocardial remodeling, and hepatosplenomegaly. Furthermore, erosive gastrointestinal lesions and degenerative renal changes were identified. Histopathological examination confirmed widespread cytoplasmic vacuolization across diverse cell populations, including neurons, hepatocytes, renal tubular cells, and the reticuloendothelial system. These findings demonstrate that GAG deposition is a generalized process affecting nearly every parenchymal structure. Conclusions: Although neurological decline dominates the clinical phenotype, our findings underscore that MPS III is a true systemic storage disorder. Significant involvement of the cardiovascular and visceral systems contributes to the disease’s complexity and mortality. This case reinforces the critical diagnostic value of a comprehensive autopsy in delineating the full morphological spectrum of Sanfilippo syndrome, providing essential insights for multidisciplinary management.