Unveiling Mucopolysaccharidosis IIIC in Brazil: Diagnostic Journey and Clinical Features of Brazilian Patients Identified Through the MPS Brazil Network

TL;DR

This study reports on the largest cohort of Brazilian patients with Mucopolysaccharidosis IIIC, highlighting clinical features, genetic variants, and regional differences in diagnosis.

Contribution

The study presents the largest MPS IIIC patient cohort in Brazil, identifying novel genetic variants and regional diagnostic patterns.

Findings

101 Brazilian MPS IIIC patients were confirmed, representing one of the largest global cohorts.

Novel and recurrent HGSNAT gene mutations were identified, expanding the mutational spectrum.

Diagnostic delays averaged six years, with regional differences in diagnosis timing and consanguinity rates.

Abstract

Background: Mucopolysaccharidosis type IIIC (MPS IIIC) is a rare lysosomal storage disorder caused by pathogenic variants in the HGSNAT gene. Data from large patient cohorts remain scarce, particularly in Latin America. Methods: We retrospectively analyzed clinical, biochemical, and genetic data from patients diagnosed with MPS IIIC through the MPS Brazil Network. Diagnosis was based on reduced activity of acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), elevated urinary glycosaminoglycans (uGAGs), and/or molecular genetics tests. Results: A total of 101 patients were confirmed with MPS IIIC, representing one of the largest cohorts worldwide. Females accounted for 60% of cases. The mean age at symptom onset was 5.4 ± 3.9 years, while the mean age at diagnosis was 11.7 ± 6.9 years, reflecting a 6-year diagnostic delay. Most patients initially presented with developmental delay (82%) and facial dysmorphism (80%), whereas behavioral manifestations were less frequently identified (25%), suggesting a milder phenotype than previously reported. Genetic information was available for 28% of patients, showing recurrent alleles (c.372-2A>G, c.252dupT) and several novel mutations, which expand the mutational spectrum of the disease. Genotype–phenotype similarities with Portuguese, Italian, and Chinese cases suggest shared ancestry contributions. Regional differences included earlier diagnoses in the North of Brazil and high consanguinity rates in the Northeast region. Conclusions: This study describes the largest Brazilian cohort of MPS IIIC, documenting novel variants and regional heterogeneity. Findings highlight diagnostic delays, ancestry influences, and the urgent need for disease-modifying therapies.

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