RESUMEN
Geographic and sociodemographic aspects may influence the natural history and epidemiology of mucopolysaccharidoses (MPS). The main objective in this work was to evaluate the clinical, molecular, and geographic profile of MPS in a population from Ceará (Northeast Brazil). For this, we have performed a descriptive cross-sectional study based on clinical evaluation, interviews with patients and/or family members, and review of medical records of 76 MPS patients. MPS II was the most common type, with the most affected individuals presenting missense pathogenic variants. Patients with MPS I proved to be the most severe clinical phenotype, presenting the first symptoms (mean: 7.1 months; SD = 4.5) and being diagnosed earlier (2.2 years; SD = 2.1) in comparison with the other types. In addition, we have shown that 13 individuals with MPS VI were born of consanguineous marriages in small, nearby cities, in a place where geographical isolation, consanguinity, and clusters of genetic diseases were previously reported. Ten of these individuals (at least, seven different families) presented a rare pathogenic variant in the ARSB gene, c.1143-8T > G in homozygosity, previously reported only among Iberian and South American patients. The results presented here provide a comprehensive picture of MPS in an important state of the Brazilian Northeast, a region that concentrates many risk factors for rare genetic diseases, such as endogamy, inbreeding, and reproductive isolation. We discuss the possible evolutionary processes and biosocial dynamics that can help to explain this finding in terms of population medical genetics and public health.
RESUMEN
BACKGROUND: The importance of metabolic factors in neural tube defects (NTDs) has been the focus of many investigations. Several authors have suggested that abnormalities in homocysteine metabolism, such as hyperhomocysteinemia, folate deficiency, and low vitamin B12, may be responsible for these malformations and that both nutritional factors and genetic abnormalities are associated with them. METHODS: We conducted a case-control study to investigate the influence of biochemical and genetic factors in NTDs in infants in southern Brazil. Levels of folate, vitamin B12, total homocysteine (t-Hcy) and the 677C>T and 1298A>C polymorphisms of the MTHFR gene were analyzed in 41 NTD child-mother pairs and 44 normal child-mother control pairs. RESULTS: Subjects in the case group had a higher mean blood folate level than those in the control group. The level of vitamin B12 was lower in mothers in the NTD group than in control mothers (p = 0.004). The level of t-Hcy was not different in the two groups, but t-Hcy and vitamin B12 were correlated (p = 0.002). There was no difference in the genotype distribution for 677C>T and 1298A>C polymorphisms of MTHFR in the case and control pairs. The level of t-Hcy was correlated with 677TT. CONCLUSIONS: Despite the small sample in this study, we suggest that low vitamin B12 and, consequently, hyperhomocysteinemia are important risk factors for NTDs in our population.
Asunto(s)
Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Defectos del Tubo Neural/genética , Polimorfismo Genético , Adolescente , Adulto , Brasil , Niño , Preescolar , Femenino , Ácido Fólico/sangre , Homocisteína/sangre , Humanos , Lactante , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Defectos del Tubo Neural/enzimología , Defectos del Tubo Neural/metabolismo , Vitamina B 12/sangreRESUMEN
p53 mutation is a common genetic change in human cancers, but the clinical significance is controversial. We studied 68 patients and estimate the prevalence of intestinal metaplasia of cardia (IMC), Barrett's esophagus (BE), and p53 protein overexpression, and described molecular alterations of p53 gene exons 5 to 8. Immunohistochemical analysis showed positive p53 in 56.1-39.1% (IMC) and 60.9% (BE). Molecular analysis showed 36.6% altered cases in exon 5 and 9.8% in exon 7. In conclusion, p53 protein overexpression is common in IMC and BE. The molecular alterations observed may be due to LOH, genomic instability or other unknown alteration.
Asunto(s)
Esófago de Barrett/genética , Cardias/patología , Esofagitis/genética , Perfilación de la Expresión Génica , Genes p53/genética , Proteína p53 Supresora de Tumor/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Inestabilidad Genómica , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad , Masculino , Metaplasia , Persona de Mediana Edad , Regulación hacia ArribaRESUMEN
In this study we have investigated a group of 29 Brazilian patients, who had been diagnosed with the lysosomal storage disorder, Mucopolysaccharidosis type I (MPS-I). MPS I is caused by a deficiency in the lysosomal hydrolase, alpha-L-iduronidase. Ninety percent of the MPS I patients in this study were genotyped and revealed 10 recurrent and thirteen novel IDUA gene mutations. Eight of these new mutations and three common mutations W402X, P533R, and R383H were individually expressed in CHO-K1 cells and analyzed for alpha-L-iduronidase protein and enzyme activity. A correlation was observed between the MPS I patient clinical phenotype and the associated mutant alpha-L-iduronidase protein/enzyme activity expressed in CHO-K1 cells. This was the first time that Brazilian MPS I patients had been thoroughly analyzed and highlighted the difficulties of mutation screening and clinical phenotype assessment in populations with high numbers of unique mutations.
Asunto(s)
Iduronidasa/genética , Mucopolisacaridosis I/genética , Animales , Western Blotting , Células CHO , Cricetinae , ADN/química , ADN/genética , Análisis Mutacional de ADN , Regulación Enzimológica de la Expresión Génica , Humanos , Iduronidasa/metabolismo , Mucopolisacaridosis I/enzimología , Mutación , Polimorfismo Conformacional Retorcido-Simple , TransfecciónRESUMEN
Mucopolysaccharidosis type VI, or Maroteaux-Lamy syndrome, is an autosomal recessive disease caused by the deficiency of arylsulfatase B (ARSB; N-acetyl-galactosamine-4-sulfatase, E.C.3.1.6.12), which is involved in the stepwise degradation of dermatan sulfate and chondroitin sulfate. The deficiency of this enzyme causes storage in the lysozomes and excretion in the urine of partially degraded dermatan sulfate. Twenty patients with MPSVI were analyzed, including 2 siblings. Genomic DNA from patients was extracted and amplified by PCR followed by analysis by single-strand conformation polymorphism (SSCP), which detects altered patterns in the single-stranded DNA. Amongst the patients analyzed for exon 8 of the ARSB gene, 5 patients presented an altered band pattern when compared to controls. After sequencing, we have detected a 23-bp deletion, extending from nucleotides 1,533 to 1,555, causing a frameshift and changing 2 amino acids before creating a premature stop codon at amino acid 514.
Asunto(s)
Mutación del Sistema de Lectura , Mucopolisacaridosis VI/genética , N-Acetilgalactosamina-4-Sulfatasa/genética , Brasil , Estudios de Casos y Controles , Humanos , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADNRESUMEN
The mucopolysaccharidoses (MPS) are a heterogeneous group of inborn errors of lysosomal glycosaminoglycan (GAG) metabolism. The importance of this group of disorders among the inborn errors of metabolism led us to report 19 cases. METHOD: We performed clinical, radiological, and biochemical evaluations of the suspected patients, which allowed us to establish a definite diagnosis in 19 cases. RESULTS: Not all patients showed increased GAG levels in urine; enzyme assays should be performed in all cases with strong clinical suspicion. The diagnosis was made on average at the age of 48 months, and the 19 MPS cases, after a full clinical, radiological, and biochemical study, were classified as follows: Hurler -- MPS I (1 case); Hunter -- MPS II (2 cases); Sanfilippo -- MPS III (2 cases); Morquio -- MPS IV (4 cases); Maroteaux-Lamy -- MPS VI (9 cases); and Sly -- MPS VII (1 case). DISCUSSION: The high relative frequency of Maroteaux-Lamy disease contrasts with most reports in the literature and could express a population variability
Asunto(s)
Humanos , Masculino , Femenino , Preescolar , Niño , Adolescente , Adulto , Mucopolisacaridosis/diagnóstico , Glicosaminoglicanos/metabolismo , Glicosaminoglicanos/orina , Mucopolisacaridosis/fisiopatología , Mucopolisacaridosis VI/diagnóstico , Mucopolisacaridosis VI/fisiopatologíaRESUMEN
Friedreich ataxia (FRDA), the most commom autosomal recessive ataxia, is caused in 94 per cent of cases by homozygous expansions of an unstable GAA repeat localised in intron 1 of the X25 gene. We have investigated this mutation in five Brazilian patients: four with typical FRDA findings and one patient with atypical manifestations, who was considered to have some other form of cerebellar ataxia with retained reflexes. The GAA expansion was detected in all these patients. The confirmation of FRDA diagnosis in the atypical case may be pointing out, as in other reports, that clinical spectrum of Friedreich's ataxia is broader than previously recognised and includes cases with intact tendon reflexes.
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Humanos , Masculino , Femenino , Niño , Adulto , Ataxia de Friedreich/diagnóstico , Brasil , Ataxia de Friedreich/genética , Ataxia de Friedreich/fisiopatología , Reacción en Cadena de la Polimerasa , Expansión de Repetición de TrinucleótidoRESUMEN
As mucopolissacaridoses (MPS) constituem, devido às suas características bioquímicas, genéticas e clínicas, um grupo grande e heterogêneo dentro das doenças lisôssomicas de depósito (LSD), e säo causadas pela deficiência de enzimas específicas que säo responsáveis pela quebra de gicosaminoglicanos (GAGs) em passos diferentes da sua rota de degradaçäo. Sendo as MPS responsáveis por aproximadamente 32 por cento dos erros inatos do metabolismo (EIM) e 54 por cento das LSD identificadas em nosso laboratório (Laboratório Regional dos Erros Inatos do Metabolismo (RLIEM), Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre), que é um centro de referência para o diagnóstico de LSD no Brasil, nós decidimos implantar uma rotina para detecçäo e o diagnóstico diferencial de MPS em pacientes com características clínicas sugestivas deste grupo de doenças.