Molecular characterization of phenylketonuria patients from the North Region of Brazil: State of Pará.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disease resulting from a deficiency of the enzyme phenylalanine hydroxylase (PAH). Hyperphenylalaninemias (HPA) due to PAH deficiency are accompanied by a wide variety of clinical, biochemical, and molecular features. To identify and characterize pathogenic variants in the PAH gene and establish a correlation between genotype and biochemical phenotype in patients with PKU from state of Pará in the North Region of Brazil. METHODS: All 13 exons of the PAH gene from 32 patients (21 PKU and 11 non-PKU HPA) were amplified by PCR and submitted to DNA sequencing (Sanger). Biochemical data were obtained from the patients' medical records. RESULTS: Molecular analysis identified 17 pathogenic variants and 3 nonpathogenic variants. The most frequent pathogenic variants were IVS10-11G>A (7.9%), p. Arg261Gln (7.9%), p. Val388Met (6.3%) and p. Ile65Thr (4.7%). Was observed correlations and inconsistencies between genotype and biochemical phenotype. CONCLUSION: In PKU patients from state of Pará, North Region of Brazil, a heterogeneous mutation spectrum was revealed, in which the most frequent mutations are variants commonly observed in other Brazilian studies and in the region of the Iberian Peninsula.

Mucopolysaccharidoses in northern Brazil: Targeted mutation screening and urinary glycosaminoglycan excretion in patients undergoing enzyme replacement therapy

Mucopolysaccharidoses (MPS) are rare lysosomal disorders caused by the deficiency of specific lysosomal enzymes responsible for glycosaminoglycan (GAG) degradation. Enzyme Replacement Therapy (ERT) has been shown to reduce accumulation and urinary excretion of GAG, and to improve some of the patients' clinical signs. We studied biochemical and molecular characteristics of nine MPS patients (two MPS I, four MPS II and three MPS VI) undergoing ERT in northern Brazil. The responsiveness of ERT was evaluated through urinary GAG excretion measurements. Patients were screened for eight common MPS mutations, using PCR, restriction enzyme tests and direct sequencing. Two MPS I patients had the previously reported mutation p.P533R. In the MPS II patients, mutation analysis identified the mutation p.R468W, and in the MPS VI patients, polymorphisms p.V358M and p.V376M were also found. After 48 weeks of ERT, biochemical analysis showed a significantly decreased total urinary GAG excretion in patients with MPS I (p < 0.01) and MPS VI (p < 0.01). Our findings demonstrate the effect of ERT on urinary GAG excretion and suggest the adoption of a screening strategy for genotyping MPS patients living far from the main reference centers.