RESUMO
BACKGROUND: Biallelic pathogenic variants in CBS gene cause the most common form of homocystinuria, the classical homocystinuria (HCU). The worldwide prevalence of HCU is estimated to be 0.82:100,000 [95% CI, 0.39-1.73:100,000] according to clinical records and 1.09:100,000 [95% CI, 0.34-3.55:100,000] by neonatal screening. In this study, we aimed to estimate the minimal worldwide incidence of HCU. METHODS: The 25 most common pathogenic alleles of HCU were identified through a literature review. The incidence of HCU was estimated based on the frequency of these common pathogenic alleles in a large genomic database (gnomAD). RESULTS: The minimum worldwide incidence of HCU was estimated to be ~0.38:100,000, and the incidence was higher in Europeans non-Finnish (~0.72:100,000) and Latin Americans (~0.45:100,000) and lower in Africans (~0.20:100,000) and Asians (~0.02:100,000). CONCLUSION: Our data are in accordance with the only published metanalysis on this topic. To our surprise, the observed incidence of HCU in Europeans was much lower than those described in articles exploring small populations from northern Europe but was similar to the incidence described on the basis of neonatal screening programs. In our opinion, this large dataset analyzed and its population coverage gave us greater precision in the estimation of incidence.
Assuntos
Cistationina beta-Sintase/genética , Frequência do Gene , Homocistinúria/genética , Adulto , Bases de Dados Genéticas/estatística & dados numéricos , Europa (Continente) , Homocistinúria/epidemiologia , Homocistinúria/etnologia , Humanos , Incidência , Recém-Nascido , Triagem NeonatalRESUMO
Fumonisins are mycotoxins that contaminate maize, disrupt the folate and sphingolipid metabolism, are associated with neural tube defects, and are considered by the International Agency for Research on Cancer (IARC) as possible human carcinogens. Since maize-based foods are significant components of the Mexican diet and there is a high prevalence of genetic susceptibility for folate deficiency among Mexicans, this essay presents international and national evidence of fumonisin exposure and the relevance that such exposure represents for Mexico.
Assuntos
Ácido Fólico/metabolismo , Contaminação de Alimentos , Fumonisinas/efeitos adversos , Defeitos do Tubo Neural/etiologia , Adolescente , Adulto , Animais , Carcinógenos Ambientais/efeitos adversos , Neoplasias do Sistema Digestório/induzido quimicamente , Neoplasias do Sistema Digestório/epidemiologia , Equidae , Feminino , Receptor 2 de Folato/antagonistas & inibidores , Fumonisinas/química , Fumonisinas/farmacocinética , Fumonisinas/toxicidade , Homocistinúria/epidemiologia , Homocistinúria/genética , Humanos , Necrose Tubular Aguda/induzido quimicamente , Leucoencefalopatias/induzido quimicamente , Leucoencefalopatias/veterinária , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , México , Camundongos , Espasticidade Muscular/epidemiologia , Espasticidade Muscular/genética , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/genética , Gravidez , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/genética , Ratos , Esfingolipídeos/química , Esfingolipídeos/metabolismo , Suínos , Teratogênicos/toxicidade , Adulto Jovem , Zea mays/microbiologiaRESUMO
Las fumonisinas son una familia de micotoxinas que contaminan al maíz, alteran el metabolismo de los esfingolípidos y del folato, se asocian con defectos del tubo neural y están catalogadas por la Agencia Internacional de Investigación en Cáncer (IARC por sus siglas en inglés) como posibles carcinógenos humanos. Debido a que en México los derivados de maíz constituyen una parte importante de la dieta y existe alta prevalencia de población genéticamente susceptible a la deficiencia de folato, en este ensayo se presentan las evidencias mundiales y nacionales de la exposición a fumonisinas y la relevancia que para México representa la evaluación de esta exposición.
Fumonisins are mycotoxins that contaminate maize, disrupt the folate and sphingolipid metabolism, are associated with neural tube defects, and are considered by the International Agency for Research on Cancer (IARC) as possible human carcinogens. Since maize-based foods are significant components of the Mexican diet and there is a high prevalence of genetic susceptibility for folate deficiency among Mexicans, this essay presents international and national evidence of fumonisin exposure and the relevance that such exposure represents for Mexico.
Assuntos
Adolescente , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Gravidez , Ratos , Adulto Jovem , Ácido Fólico/metabolismo , Contaminação de Alimentos , Fumonisinas/efeitos adversos , Defeitos do Tubo Neural/etiologia , Carcinógenos Ambientais/efeitos adversos , Neoplasias do Sistema Digestório/induzido quimicamente , Neoplasias do Sistema Digestório/epidemiologia , Equidae , /antagonistas & inibidores , Fumonisinas/química , Fumonisinas/farmacocinética , Fumonisinas/toxicidade , Homocistinúria/epidemiologia , Homocistinúria/genética , Necrose Tubular Aguda/induzido quimicamente , Leucoencefalopatias/induzido quimicamente , Leucoencefalopatias/veterinária , Proteínas de Membrana Transportadoras/metabolismo , /deficiência , /genética , México , Espasticidade Muscular/epidemiologia , Espasticidade Muscular/genética , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/genética , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/genética , Esfingolipídeos/química , Esfingolipídeos/metabolismo , Suínos , Teratogênicos/toxicidade , Adulto Jovem , Zea mays/microbiologiaRESUMO
OBJECTIVE: To allow early recognition of cystathionine beta-synthase by newborn screening. STUDY DESIGN: Total homocysteine was determined in dried blood spots with a novel, robust high-performance liquid chromatography method with tandem mass spectrometry. Quantification of homocysteine was linear over a working range up to 50 micromol/L. For mutation analysis, DNA was tested for 2 mutations common in Qatar. RESULTS: Both methods proved to be suitable for high throughput processing. In 2 years, 7 infants with classic homocystinuria were identified of 12,603 native Qatari infants, yielding an incidence of 1:1800. Molecular screening would have missed 1 patient homozygous for a mutation not previously identified in the Qatari population. Over a period of 3 years, a total of 14 cases of classic homocystinuria were detected by screening of homocysteine from all newborn infants born in Qatar (n = 46 406). Homocysteine was always elevated, whereas methionine was elevated in only 7 cases. CONCLUSIONS: The study offers a reliable method for newborn screening for cystathionine beta-synthase deficiency, reaching a sensitivity of up to 100%, even if samples are taken within the first 3 days of life.
Assuntos
Homocisteína/sangue , Homocistinúria/diagnóstico , Triagem Neonatal , Cromatografia Líquida de Alta Pressão , Cistationina beta-Sintase/genética , Análise Mutacional de DNA , Heterozigoto , Homocistinúria/epidemiologia , Homocistinúria/genética , Homozigoto , Humanos , Recém-Nascido , Metionina/sangue , Catar/epidemiologia , Sensibilidade e Especificidade , Espectrometria de Massas em TandemRESUMO
OBJECTIVES: To estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme. STUDY DESIGN: Mutation c.1105C>T was analyzed in 600 anonymous Czech newborn blood spots. Catalytic activity and quaternary structure of the p.R369C mutant was evaluated after expression in 2 cellular systems. RESULTS: Population frequency of the c.1105C>T mutation was 0.005, predicting the birth prevalence of homocystinuria of 1:40000, which increased to 1:15500 in a model including 10 additional mutations. In Escherichia coli the p.R369C mutant misfolded, and its activity was severely reduced, and expression in Chinese hamster ovary cells enabled proper folding with activity decreased to 63% of the wild-type enzyme. This decreased activity was not due to impaired K(m) for both substrates but resulted from V(max) lowered to 55% of the normal cystathionine beta-synthase enzyme. CONCLUSIONS: The c.1105C>T (p.R369C) allele is common also in the Czech population. Although the p.R369C mutation impairs folding and decreases velocity of the enzymatic reaction, our data are congruent with rather mild clinical phenotype in homozygotes or compound heterozygotes carrying this mutation.
Assuntos
Cistationina beta-Sintase/genética , Frequência do Gene , Homocistinúria/epidemiologia , Homocistinúria/genética , Mutação/genética , Animais , Células CHO/enzimologia , Cricetinae , Cricetulus , República Tcheca/epidemiologia , Escherichia coli/enzimologia , Expressão Gênica , Genótipo , Homocistinúria/enzimologia , Humanos , Recém-Nascido , Prevalência , Dobramento de ProteínaRESUMO
Classical homocystinuria is due to cystathionine beta-synthase (CBS) deficiency. More than 130 mutations, which differ in prevalence and severity, have been described at the CBS gene. Mutation p.I278T is very prevalent, has been found in all European countries where it has been looked for with the exception of the Iberian peninsula, and is known to respond to vitamin B6. On the other hand, mutation p.T191M is prevalent in Spain and Portugal and does not respond to B6. We analysed 30 pedigrees from Spain, Portugal, Colombia and Argentina, segregating for homocystinuria. The p.T191M mutation was detected in patients from all four countries and was particularly prevalent in Colombia. The number of p.T191M alleles described in this study, together with those previously published, is 71. The prevalence of p.T191M among CBS mutant alleles in the different countries was: 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina and 0.14 in Brazil. Haplotype analyses suggested a double origin for this mutation. No genotype-phenotype correlation other than the B6-nonresponsiveness could be established for the p.T191M mutation. Additionally, three new mutations, p.M173V, p.I429del and c.69_70+8del10, were found. The p.M173V was associated with a mild, B6-responsive, phenotype.
Assuntos
Cistationina beta-Sintase/genética , Homocistinúria/epidemiologia , Homocistinúria/genética , Mutação , Prevalência , Alelos , Distribuição de Qui-Quadrado , Colômbia/epidemiologia , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação , Linhagem , Portugal/epidemiologia , Espanha/epidemiologiaRESUMO
Serious complications of homocystinuria caused by cystathionine beta-synthase deficiency can be prevented by early intervention. We determined the prevalence of 6 specific mutations in 1133 newborn blood samples. Our results suggest that homocystinuria is more common than previously reported. Newborn screening for homocystinuria through mutation detection should be further considered.