RESUMO
BACKGROUND: Disease-related variants in PHEX cause XLH by an increase of fibroblast growth factor 23 (FGF23) circulating levels, resulting in hypophosphatemia and 1,25(OH)2 vitamin D deficiency. XLH manifests in early life with rickets and persists in adulthood with osseous and extraosseous manifestations. Conventional therapy (oral phosphate and calcitriol) improves some symptoms, but evidence show that it is not completely effective, and it can lead to nephrocalcinosis (NC) and hyperparathyroidism (HPT). Burosumab (anti-FGF23 antibody) has shown to be effective and safety in the clinical trials. METHODS: The current real-world collaborative study evaluated genetic, clinical and laboratory data of XLH Brazilian adult patients treated with burosumab. RESULTS: Nineteen unrelated patients were studied. Patients reported pain, limb deformities and claudication, before burosumab initiation. 78% of them were previously treated with conventional therapy. The severity of the disease was moderate to severe (15 patients with score >5). At the baseline, 3 patients presented NC (16.7%) and 12 HPT (63%). After 16 ± 8.4 months under burosumab, we observed a significant: increase in stature (p = 0.02), in serum phosphate from 1.90 ± 0.43 to 2.67 ± 0.52 mg/dL (p = 0.02); in TmP/GFR from 1.30 ± 0.46 to 2.27 ± 0.64 mg/dL (p = 0.0001), in 1,25 (OH)2 D from 50.5 ± 23.3 to 71.1 ± 19.1 pg/mL (p = 0.03), and a decrease in iPTH from 86.8 ± 37.4 pg/mL to 66.5 ± 31.1 (p = 0.002). Nineteen variants were found (10 novel). HPT tended to develop in patients with truncated PHEX variants (p = 0.06). CONCLUSIONS: This study confirms the efficacy and safety of burosumab on XLH adult patients observed in clinical trials. Additionally, we observed a decrease in iPTH levels in patients with moderate to severe HPT at the baseline.
Assuntos
Anticorpos Monoclonais Humanizados , Raquitismo Hipofosfatêmico Familiar , Adulto , Humanos , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Anticorpos Monoclonais/uso terapêutico , Brasil , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fosfatos/uso terapêuticoRESUMO
Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe, rare autosomal recessive disorder caused by variants in the heparan-α-glucosaminide N-acetyltransferase (HGSNAT) gene which result in lysosomal accumulation of heparan sulfate. We analyzed clinical presentation, molecular defects and their haplotype context in 78 (27 novel) MPSIIIC cases from 22 countries, the largest group studied so far. We describe for the first time disease-causing variants in the patients from Brazil, Algeria, Azerbaijan, and Iran, and extend their spectrum within Canada, Colombia, Turkey, and the USA. Six variants are novel: two missense, c.773A>T/p.N258I and c.1267G>T/p.G423W, a nonsense c.164T>A/p.L55*, a splice-site mutation c.494-1G>A/p.[P165_L187delinsQSCYVTQAGVRWHHLGSLQALPPGFTPFSYLSLLSSWNC,P165fs], a deletion c.1348delG/p.(D450fs) and an insertion c.1479dupA/p.(Leu494fs). The missense HGSNAT variants lacked lysosomal targeting, enzymatic activity, and likely the correct folding. The haplotype analysis identified founder mutations, p.N258I, c.525dupT, and p.L55* in the Brazilian state of Paraiba, c.493+1G>A in Eastern Canada/Quebec, p.A489E in the USA, p.R384* in Poland, p.R344C and p.S518F in the Netherlands and suggested that variants c.525dupT, c.372-2G>A, and c.234+1G>A present in cis with c.564-98T>C and c.710C>A rare single-nucleotide polymorphisms, have been introduced by Portuguese settlers in Brazil. Altogether, our results provide insights into the origin, migration roots and founder effects of HGSNAT disease-causing variants, and reveal the evolutionary history of MPSIIIC.
Assuntos
Acetiltransferases/genética , Mucopolissacaridose III/genética , Mutação , Acetiltransferases/química , Argélia , Animais , Azerbaijão , Brasil , Células COS , Canadá , Chlorocebus aethiops , Colômbia , Evolução Molecular , Feminino , Efeito Fundador , Haplótipos , Humanos , Irã (Geográfico) , Masculino , Países Baixos , Linhagem , Filogeografia , Polônia , Dobramento de ProteínaRESUMO
PURPOSE: The aim of this study was to describe the relation between occlusal features and enzyme replacement therapy in patients with mucopolysaccharidoses. MATERIALS AND METHODS: A cross-sectional study was conducted. The sample consisted of 20 patients with mucopolysaccharidoses, 10 of whom were undergoing treatment at a hospital in northeast Brazil. Occlusal features were evaluated by clinical examination and panoramic radiography. A structured questionnaire was administered to evaluate the dental care of each patient. Pearson χ2, Fisher exact, and Mann-Whitney tests were used for data analysis, with a level of significance of 5%. RESULTS: Marked overjet (75%) and anterior open bite (70%) were the most frequent occlusal alterations, and 15% had Class III disorders. Radiography visualized the presence of impacted teeth (75%) and prolonged retention of deciduous teeth (65%). Patients with enzyme replacement therapy had a lower average maximum protrusion (P = .033). A total of 75% of mothers said they had not been advised to take their children to the dentist and 10% of children had never been to the dentist. CONCLUSION: Patients with mucopolysaccharidoses exhibited notable occlusal alterations, especially marked overjet and anterior open bite. Enzyme replacement therapy seems to influence the maximum protrusion of patients.
