Comprehensive Characterization of a Cluster of Mucopolysaccharidosis IIIB in Ecuador

Background/Objectives: Sanfilippo Syndrome type B or Mucopolysaccharidosis type IIIB (MPS IIIB, OMIM 252920) is a lysosomal storage disease caused by deficiency of alpha-N-acetylglucosaminidase (NAGLU, E.C. 3.2.1.50) due to pathogenic variants in the NAGLU gene (17q21.2). The disease is characterized by progressive neurological manifestations, marked by cognitive decline, with relatively mild somatic involvement. We aim to present relevant information on a cluster of MPS IIIB identified in Ecuador, particularly regarding their clinical, biochemical, genetic, demographic, and ancestry characteristics. Methods: We present a characterization of a clinical, biochemical, genetic and demographic cluster of MPS IIIB patients in Ecuador, located in four main regions: Manabí, Guayas, Los Ríos, and Santo Domingo de los Tsáchilas. The patients included were diagnosed due to increased levels of urinary glycosaminoglycans (uGAG), plus deficient activity of NAGLU, and/or identification of biallelic pathogenic mutations in the NAGLU gene. Patients' charts were reviewed for biochemical findings, medical history, clinical manifestations and assessments. Results: We present the results of clinical, biochemical, genetic and demographic characterization of a cluster in Ecuador with 24 patients identified with Sanfilippo syndrome type IIIB, resulting in an estimated incidence of 1.5/100,000. The mean age at diagnosis was 8.8 years, with symptom onset at 4.5 years on average. All patients exhibited elevated levels of uGAG and undetectable NAGLU activity, and all of them presented the c.1487T>C (p.Leu496Pro) variant in the NAGLU gene in homozygosis, indicating a possible founder effect, with the exception of one heterozygous one (p.Leu496Pro/p.Arg482Gln). A positive correlation between age of diagnosis and the concentration of one isoform of heparan sulfate (HS-OS) was found (p < 0.05). Clinical findings included neuropsychomotor developmental delay (75%), neurological regression (65%), hepatomegaly (55%), growth deficiency (50%), coarse facies (45%) and hernia (40%). Male patients presented earlier onset of symptoms. Maternal ancestry was successfully determined for 21 of the 24 patients. The majority were of Native American ancestry (71.4%), followed by European (19%), African (4.8%), and Asian (4.8%) lineages. Haplogroup A was the most prevalent (42.9%), followed by haplogroups D (19%), C, U, and H (each 9.5%), and R and L2 (each 4.8%). Conclusions: Ancestry can indicate a possible mechanism to explain the heterogeneous symptomatic presentation. These findings highlight the need for further research on genetic and environmental influences on disease severity in this population.