ESTUDO DETALHADO DE UM CLUSTER DE MUCOPOLISSACARIDOSE TIPO IIIB NA PROVÍNCIA DE MANABÍ, EQUADOR

Abstract

ABSTRACT This study describes in detail a cluster of mucopolysaccharidosis IIIB (MPS IIIB) identified in the province of Manabí, Ecuador, between 2018 and 2020. MPS IIIB is an ultrarare lysosomal storage disorder, with autosomal recessive inheritance, caused by the deficiency of the α-N-acetylglucosaminidase enzyme and characterized by progressive neurodegeneration. The MPS Brazil Network diagnosed over 50 MPS patients in Ecuador, of whom 24 confirmed MPS IIIB cases originated from Manabí province, a notable concentration for an ultrarare disease for which few studies exist on its natural history and cluster formation. The main objective of this study was to characterize the phenotype, biochemical and molecular profile, and characteristics of affected groups within this cluster, aiming to expand knowledge about the disease, facilitate diagnosis, and propose community genetics and public health actions. In a descriptive retrospective study of 24 confirmed MPS IIIB patients, the results revealed a remarkably high incidence of 1.51:100,000 live births in Manabí, approximately 7.5 times higher than the global average. The average diagnostic delay was 4.3 years. Molecular analysis identified the pathogenic variant c.1487T>C (p.Leu496Pro) in homozygosity in almost all patients (23/24), indicating a strong founder effect. Clinically, progressive neurodegeneration was observed, with delayed neuropsychomotor development (75%) and neurological regression (65%). A notable finding was the greater symptom severity and earlier onset of neurological manifestations in male patients. Maternal ancestry analysis revealed a predominance of Amerindian lineages (71,4%) and, for the first time, demonstrated a statistically significant correlation between ancestral background and heterogeneity of symptomatic presentation. In conclusion, this study confirms that the high prevalence of MPS IIIB in Manabí is primarily attributed to the founder effect of the c.1487T>C variant, exacerbated by historical consanguinity and geographical isolation of the population. The unprecedented correlation between ancestry and clinical expressivity offers a new perspective on the factors modulating disease variability. These findings reinforce the urgency of targeted public health strategies in the region, including newborn screening for early identification, strengthening community genetics centers for genetic counseling, and educational campaigns. This work serves as a valuable model for understanding and intervening in clusters of rare genetic diseases, contributing to the advancement of MPS IIIB knowledge and management globally. Descriptors: mucopolysaccharidoses; mucopolysaccharidosis III; population genetics; cluster; rare diseases.