JOSE FRANCISCO DA SILVA FRANCO

JOSE FRANCISCO DA SILVA FRANCO

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Childhood hypophosphatasia associated with a novel biallelic ALPL variant at the TNSALP dimer interface
2023 - MARTINS, LUCIANE; LESSA, LUIS G.F.; ALI, TACCYANNA M.; LAZAR, MONIZE; KIM, CHONG A.; KANTOVITZ, KAMILA R.; SANTAMARIA, MAURO P.; ARAUJO, CASSIA F.; RAMOS, CAROLINA J.; FOSTER, BRIAN L.; FRANCO, JOSE F.S.; BERTOLA, DEBORA; NOCITI JUNIOR, FRANCISCO H.
The goal of this study was to perform a clinical and molecular investigation in an eight-year-old female child diagnosed with hypophosphatasia (HPP). The proband and her family were evaluated by medical and dental histories, biochemical analyses, radiographic imaging, and genetic analysis of the tissue-nonspecific alkaline phosphatase (ALPL) gene. A bioinformatic analysis was performed to predict the structural and functional impact of the point mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) molecule and to define their potential contribution to the phenotype. We identified a novel combination of heterozygous ALPL missense variants in the proband, p.Ala33Val and p.Asn47His, compatible with an autosomal recessive mode of inheritance and resulting in skeletal and dental phenotypes. Computational modeling showed that the affected Asn47 residue is located in the coil structure close to the N-terminal α-helix, whereas the affected Ala33 residue is localized in the N-terminal α-helix. Both affected residues are located close to the homodimer interface, suggesting they may impair TNSALP dimer formation and stability. Clinical and biochemical follow-up revealed improvements after six years of ERT. Reporting this novel combination of ALPL variants in childhood HPP provides new insights into genotype–phenotype associations for HPP and specific sites within the TNSALP molecule potentially related to a childhood-onset HPP and skeletal and dental manifestations. Beneficial effects of ERT are implicated in skeletal and dental tissues.
Mucopolysaccharidosis VII in Brazil
2021 - GIUGLIANI, ROBERTO; BARTH, ANNELIESE L.; DUMAS, MELISSA R.C.; FRANCO, JOSE F. da S.; GIULIANI, LIANE de R.; GRANGEIRO, CARLOS H.P.; HOROVITZ, DAFNE D.G.; KIM, CHONG A.; LEAO, EMILIA K.E. de A.; MEDEIROS, PAULA F.V. de; MIGUEL, DIEGO S.C.G.; MOREIRA, MARIA E.S.A.; SANTOS, HELENA M.G.P. dos; SILVA, LUIZ C.S. da; SILVA, LUIZ R. da; SOUZA, ISABEL N. de; NALIN, TATIELE; GARCIA, DANIEL
Background: Mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, caused by deficiency of the lysosomal enzyme β-glucuronidase, is an ultra-rare disorder with scarce epidemiological data and few publications about natural history and clinical spectrum. Methods: We conducted a case series report which included retrospective data from all MPS VII patients diagnosed through the “MPS Brazil Network” who were known to be alive in 2020 in Brazil (N = 13). Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population. Results: The majority of the patients were from the Northeast region of Brazil. Among the signs and symptoms that raised the clinical suspicion of MPS, coarse face was the most frequent; 58% of the patients had a history of non-immune hydrops fetalis. All the subjects presented short neck and trunk. The majority presented typical phenotypical signs of MPS disorders. They all presented neurodevelopmental delay and cognitive impairment. About half of this cohort had knees deformities. Dysostosis multiplex was identified in almost all patients and cardiomyopathy was less frequent than observed in other types of MPSs. The mean age at diagnosis was 5 years, ranging from 1 to 14 years. Almost all patients (12/13) were homozygous for the c.526C>T (p.Leu176Phe) mutation. A novel variant of the GUSB gene was found, the c.875T>C (p.Leu292Pro), in a compound heterozygous with the c.526C>T (p.Leu176Phe) variant. Conclusions: This case series is the biggest data collection of MPS VII patients alive in Latin America. The overall clinical picture of the MPS VII patients is very similar to other MPS disorders, including a spectrum of severity and delayed diagnosis.
Long-term impact of early initiation of enzyme replacement therapy in 34 MPS VI patients
2021 - HOROVITZ, DAFNE D.G.; LEAO, EMILIA K.E.A.; RIBEIRO, ERLANE M.; MARTINS, ANA M.; BARTH, ANNELIESE L.; NERI, JOAO I.C.F.; KERSTENETZKY, MARCELO; SIQUEIRA, ANA C.M.; RIBEIRO, BETHANIA F.R.; KIM, CHONG A.; SANTOS, FRANCISCA C.; FRANCO, JOSE F.S.; LICHTVAN, LENIZA C.L.; GIULIANI, LIANE R.; RODRIGUES, MARIA do C.S.; BONATTI, RENATA C.F.; TEIXEIRA, THAIS B.; GONCALVES, ALEXANDRA; LOURENCO, CHARLES M.; PEREIRA, ANE S.S.; ACOSTA, ANGELINA X.
Patients with mucopolysaccharidosis type VI (MPS VI) present with a wide range of disease severity and clinical manifestations, with significant functional impairment and shortened lifespan. Enzyme replacement therapy (ERT) with galsulfase has been shown to improve clinical and biochemical parameters including patient survival, quality of life and growth. The present study is a resurvey of 34 Brazilian MPS VI patients with rapidly progressive disease (classical phenotype) who initiated ERT with galsulfase under five years of age and had been on ERT until data collection in 2019, with few exceptions (n = 4 patients who died before 2019). Anthropometric measures, urinary glycosaminoglycans, and data regarding cardiac, orthopedic, neurologic, sleep apnea, hearing and ophthalmologic outcomes were filled in by specialists. Pubertal development, clinical complications, hospitalizations, and surgeries were also assessed. In this resurvey study, treatment with galsulfase has shown to be safe and well tolerated in MPS VI patients who initiated ERT under the age of 5 years and who have been undergoing ERT for approximately 10 years. Mortality rate suggests that early initiation of ERT may have a positive impact on patients' survival, improving but not preventing disease progression and death. MPS VI patients on ERT also showed improved growth velocity and the pubertal development was normal in all surviving patients. Follow-up data on pneumonia and hospitalization suggest that early ERT may have a protective effect against major respiratory complications. Cardiac valve disease progressed since their prior evaluation and spinal cord compression was observed in a large number of patients, suggesting that these disease complications were not modified by ERT.
Relato de caso da Síndrome de Scheie
2019 - FRANCO, JOSE F. da S.; MARQUES, ROBERTA M.; PROVEDA, NATHALIE P.
Introdução: A síndrome de Scheie (SS) é uma doença de depósito lisossomal e de padrão autossômico recessivo. Decorre da deficiência da enzima alfa-L-iduronidase e leva ao acúmulo multissistêmico de glicosaminoglicanos (GAGs). O diagnóstico se baseia principalmente na dosagem da atividade enzimática da alfa-L-iduronidase em leucócitos. Terapia de reposição enzimática (TRE) pode ser uma alternativa para pacientes com complicação da doença de base. Relato de Caso: Paciente, sexo feminino, 44 anos, diagnóstico SS aos 17 anos de idade por apresentar deficiência alfa-L-iduronidase (0,5 nm/h/mg prot), mutação homozigótica W402X e fenótipo que incluía baixa estatura, face infiltrada, mãos em garra, disostose multiplex, hepatomegalia, retinose pigmentar, hérnia umbilical. Evoluiu com dilatação de câmaras e insuficiência cardíaca com fração de ejeção (FE)=26. TRE iniciou em 2002 e a paciente decidiu interromper em 2017 devido às graves reações de hipersensibilidade. Níveis de GAGs urinários: 70ug/mg (VR 13-45, antes), 204ug/mg (13-45, na interrupção) e 129ug/mg (13-45, após 1 ano). Atualmente sem queixas aos esforços, estável hemodinâmica, fígado a 4 cm do rebordo costal, em uso de carvedilol, enalapril e diurético de alça, FE 51 e perda de peso 6Kg. Discussão: A falta de aderência ao tratamento enzimático pelas reações à infusão contribuíram para o abandono terapêutico do paciente. O teste de qualidade de vida foi necessário após relatos bem-estar físico e emocional referido pelo doente. Não houve piora clínica após interrupção da TRE, como esperado pela literatura. Até o momento, não houve queixas ou internações. A cardiopatia do paciente responde a medicamentos mas não respondeu a TRE e parece não haver benefício esperado em relação ao coração. Os GAGs urinários aumentados até o presente momento, não tiveram correlação com a estabilidade clínica do quadro. Conclusão: A indicação da TRE na SS deve ser criteriosa e seus benefícios a longo prazo podem não superar seus efeitos adversos.
Ectrodactilia pode fazer parte da Síndrome de Silver Russel (SSR)?
2018 - FRANCO, JOSE F.S.; AMENDOLA, RAFAEL de M.
Introdução: A SSR é uma síndrome genética caracterizada por assimetria do corpo, face triangular restrição no crescimento intrauterino (RCIU), baixo peso e comprimento pós natal dentre outras características. Há heterogeneidade da condição e o imprinting genômico, relacionado à diferença de expressão gênica de alelos maternos e paternos foi apontado também como um dos mecanismos etiológicos da SSR que envolvem genes localizados na região 7p11.2-p13 e 7q31-qter 15-17. A Ectrodactilia também conhecida por SHFM apresenta ausência congênita dos raios centrais, formados pelo segundo, terceiro e quarto raios, gerando uma grande fenda mediana na mão ou pés, associada à aplasia/hipoplasia de metacarpos ou metatarsos e/ou falanges. Algumas vezes pode ser causa de mutações em SHFM1 em 7q21-q22, SHFM2 (Xq26), SHFM3 (FBXW4/DACTYLIN em 10q24), TP63, entre outros . Nesse relato, apresentamos um paciente que possui SSR com ectrodactilia, ainda não descrita na literatura. Descrição do caso: RTC, filho de pais não consanguíneos, sem história familiar para ectrodactilia, RCIU, sexo masculino, 6 meses de vida, internado na UTI pediátrica por um quadro de sepse. Ao exame apresentou microssomia e assimetria corporal (DE), face triangular, hipertelorismo ocular, desproporção crânio-corpo, ectrodactilia mãos bilateral e hipospádia. Cariótipo Banda G, pesquisa de microARRAY, dissomia uniparental do cromossomo 7 e exoma não mostraram evidência para diagnóstico para a SSR ou SHFM. Análise por MLPA mostrou hipometilação para ICI (H19) em 11p15, confirmando o diagnóstico. Discussão: Não há relatos na literatura da ectrodactilia associada a alterações fenotípicas clássicas da SSR. Investigação familiar e molecular para SHFM foram negativas. Acompanhamento de crianças com SSR inclui medidas como a administração do hormônio do crescimento, investigação imunológica, planos individualizados de terapia e ensino, abordagens clínicas e cirúrgicas, acompanhamento de múltiplas especialidades além do aconselhamento genético. Conclusão: Devido a condição da SSR e SHFM serem heterogêneas, mais estudos para essa possível associação são necessários.
Long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis type VII
2020 - WANG, RAYMOND Y.; FRANCO, JOSE F. da S.; LOPEZ-VALDEZ, JAIME; MARTINS, ESMERALDA; SUTTON, VERNON R.; WHITLEY, CHESTER B.; ZHANG, LIN; CIMMS, TRICIA; MARSDEN, DEBORAH; JURECKA, AGNIESZKA; HARMATZ, PAUL
Vestronidase alfa (recombinant human beta-glucuronidase) is an enzyme replacement therapy for mucopolysaccharidosis type VII (MPS VII), a highly heterogeneous, ultra-rare disease. Twelve subjects, ages 8–25 years, completed a Phase 3, randomized, placebo-controlled, blind-start, single crossover study (UX003- CL301; NCT02230566), receiving 24–48 weeks of vestronidase alfa 4 mg/kg IV. All 12 subjects completed the blind-start study, which showed significantly reduced urinary glycosaminoglycans (uGAG) and clinical improvement in a multi-domain responder index, and enrolled in a long-term, open-label, extension study (UX003-CL202; NCT02432144). Here, we report the final results of the extension study, up to an additional 144 weeks after completion of the blindstart study. Three subjects (25%) completed all 144 weeks of study, eight subjects (67%) ended study participation before Week 144 to switch to commercially available vestronidase alfa, and one subject discontinued due to non-compliance after receiving one infusion of vestronidase alfa in the extension study. The safety profile of vestronidase alfa in the extension study was consistent with observations in the preceding blind-start study, with most adverse events mild to moderate in severity. There were no treatment or study discontinuations due to AEs and no noteworthy changes in a standard safety chemistry panel. There was no association between antibody formation and infusion associated reactions. Subjects receiving continuous vestronidase alfa treatment showed a sustained uGAG reduction and clinical response evaluated using a multidomain responder index that includes assessments in pulmonary function, motor function, range of motion, mobility, and visual acuity. Reductions in fatigue were also maintained in the overall population. Results from this study show the long-term safety and durability of clinical efficacy in subjects with MPS VII with long-term vestronidase alfa treatment.
The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII
2020 - WANG, RAYMOND Y.; FRANCO, JOSE F. da S.; LOPEZ-VALDEZ, JAIME; MARTINS, ESMERALDA; SUTTON, VERNON R.; WHITLEY, CHESTER B.; ZHANG, LIN; CIMMS, TRICIA; MARSDEN, DEBORAH; JURECKA, AGNIESZKA; HARMATZ, PAUL
Vestronidase alfa (recombinant human beta-glucuronidase) is an enzyme replacement therapy (ERT) for Mucopolysaccharidosis (MPS) VII, a highly heterogeneous, ultra-rare disease. Twelve subjects, ages 8–25 years, completed a Phase 3, randomized, placebo-controlled, blind-start, single crossover study (UX003-CL301; NCT02377921), receiving 24–48 weeks of vestronidase alfa 4 mg/kg IV. All 12 subjects completed the blind-start study, which showed significantly reduced urinary glycosaminoglycans (GAG) and clinical improvement in a multi-domain responder index, and enrolled in a long-term, open-label, extension study (UX003-CL202; NCT02432144). Here, we report the final results of the extension study, up to an additional 144 weeks after completion of the blind-start study. Three subjects (25%) completed all 144 weeks of study, eight subjects (67%) ended study participation before Week 144 to switch to commercially available vestronidase alfa, and one subject discontinued due to noncompliance after receiving one infusion of vestronidase alfa in the extension study. The safety profile of vestronidase alfa in the extension study was consistent with observations in the preceding blind-start study, with most adverse events mild to moderate in severity. There were no treatment or study discontinuations due to AEs and no noteworthy changes in a standard safety chemistry panel. Out of the eleven subjects who tested positive for anti-drug antibodies at any time during the blind-start or extension study, including the baseline assessment in the blind-start study, seven subjects tested positive for neutralizing antibodies and all seven continued to demonstrate a reduction in urinary GAG levels. There was no association between antibody formation and infusion associated reactions. Subjects receiving continuous vestronidase alfa treatment showed a sustained urinary GAG reduction and clinical response evaluated using a multi-domain responder index that includes assessments in pulmonary function, motor function, range of motion, mobility, and visual acuity. Reduction in fatigue was also maintained in the overall population. As ERT is not expected to cross the blood brain barrier, limiting the impact on neurological signs of disease, and not all subjects presented with neurological symptoms, outcomes related to central nervous system pathology are not focused on in this report. Results from this study show the long-term safety and durability of clinical efficacy in subjects with MPS VII with long-term vestronidase alfa treatment.
Mucopolysaccharidosis type I, II and VI and response to enzyme replacement therapy
2017 - FRANCO, JOSE F. da S.; EL DIB, REGINA; AGARWAL, ARNAV; SOARES, DIOGO; MILHAN, NOALA V.M.; ALBANO, LILIAN M.J.; KIM, CHONG A.
Mucopolysaccharidoses (MPS) types I, II and VI are associated with deficiencies in alpha- L-iduronidase, iduronate-2-sulfatase and N-acetylgalactosamine-4-sulfatase, respectively, and generally involve progressive and multi-systemic clinical manifestations. Enzyme replacement therapy (ERT) appears to be reasonably well tolerated. The aim of this study was to examine clinical and diagnostic findings of a series of pediatric and adult MPS patients, and assess the safety and efficacy of ERT in children and adults with MPS type I, II and VI. Pediatric and adult patients were treated weekly with 1 mg/kg recombinant human N-acetylgalactosamine-4-sulphatase (rhASB), 0.45 mg/kg alpha-L-iduronidase, or 0.5 mg/kg iduronate-2-sulfatase. Clinical and biochemical parameters with ERT were evaluated for a mean duration of 5 years. Mantel-Haenszel risk ratios and associated 95% confidence intervals (CIs) were calculated for rates of death among different types of enzyme replacement therapies (ERTs). Twenty-seven patients (mean ages – pediatric: 6.8 years; adult: 29 years) were included. ERT was found to be consistently well tolerated and effective in attenuating symptoms, but did not prevent the progression of the disease or reduce mortality rates. Our findings demonstrated that early diagnosis and initiation of ERT are critical for improvements in patient-important outcomes and quality of life, although disease progression and mortality rates remain high.
Fluorescent study of human blood plasma albumin in diabetic patients
2012 - GOMES, CINTHIA Z.; COURROL, LILIA C.; FRANCO, JOSE F. da S.; SILVA, FLAVIA R. de O. da; MESQUITA, CARLOS H.; SCHOR, NESTOR; BELLINI, MARIA H.