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1.
Biomedicines ; 12(3)2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38540215

RESUMEN

The aim of this study was to associate FGFR4 rs1966265 and rs351855 variants with colorectal cancer (CRC) in a Mexican population and to perform in silico analysis. Genomic DNA from 412 healthy individuals and 475 CRC patients was analyzed. In silico analysis was performed using the PolyPhen-V2, GEPIA, GTEx, and Cytoscape platforms. The GA genotype dominant model (GAAA) of rs1966265 and the AA genotype dominant and recessive models of rs351855 were identified as CRC risk factors (p < 0.05). CRC patients aged ≥ 50 years at diagnosis who consumed alcohol had a higher incidence of the rs351855 GA genotype than the control group (p < 0.05). Associations were observed between the rs1966265 GA genotype and patients with rectal cancer and stage III-IV disease. The rs351855 AA genotype was a risk factor for partial chemotherapy response, and the GA + AA genotype for age ≥ 50 years at diagnosis and rectal cancer was associated with a partial response to chemotherapy (p < 0.05). The AA haplotype was associated with increased susceptibility to CRC. In silico analysis indicated that the rs351855 variant is likely pathogenic (score = 0.998). Genotypic expression analysis in blood samples showed statistically significant differences (p < 0.05). EFNA4, SLC3A2, and HNF1A share signaling pathways with FGFR4. Therefore, rs1966265 and rs351855 may be potential CRC risk factors.

2.
Int J Mol Sci ; 24(21)2023 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-37958671

RESUMEN

In Alzheimer's disease (AD), the age of onset (AoO) exhibits considerable variability, spanning from 40 to 90 years. Specifically, individuals diagnosed with AD and exhibiting symptoms prior to the age of 65 are typically classified as early onset (EOAD) cases. Notably, the apolipoprotein E (APOE) ε4 allele represents the most extensively studied genetic risk factor associated with AD. We clinically characterized and genotyped the APOEε4 allele from 101 individuals with a diagnosis of EOAD, and 69 of them were affected carriers of the autosomal dominant fully penetrant PSEN1 variant c.1292C>A (rs63750083, A431E) (PSEN1+ group), while there were 32 patients in which the genetic cause was unknown (PSEN1- group). We found a correlation between the AoO and the APOEε4 allele; patients carrying at least one APOEε4 allele showed delays, in AoO in patients in the PSEN1+ and PSEN1- groups, of 3.9 (p = 0.001) and 8.6 years (p = 0.012), respectively. The PSEN1+ group presented higher frequencies of gait disorders compared to PSEN1- group, and apraxia was more frequent with PSEN1+/APOE4+ than in the rest of the subgroup. This study shows what appears to be an inverse effect of APOEε4 in EOAD patients, as it delays AoO and modifies clinical manifestations.


Asunto(s)
Enfermedad de Alzheimer , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Edad de Inicio , Alelos , Enfermedad de Alzheimer/diagnóstico , Apolipoproteína E4/genética , Genotipo , Presenilina-1/genética
3.
Brain Sci ; 13(3)2023 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-36979311

RESUMEN

Early-onset Alzheimer's disease (EOAD) is an autosomal dominantly inherited disease, in which a founder effect has been described for A431E mutation in the PSEN1 gene, with most of the affected patients being residents of a small town in the state of Jalisco in Mexico. To date, no studies have been performed in order to know the impact of the disease on this population. Therefore, the objective of this study was to investigate the perceptions in the knowledge, the impact of the disease and the intention to take the predictive genetic testing in the population at genetic risk of Jalisco. For this objective, we performed a mixed study that included a qualitative methodology (semi-structured interviews), and, in addition, we measured suicidal ideation, stress and depression with quantitative instruments in order to compare them with a control group. Of the 28 invited individuals, 9 accepted to participate, from which, 5 (55.56%) participants did not know their genetic risk to develop the disease and 5 (55.56%) would want to take the predictive genetic testing in order to be prepared to face the disease; however, among those who did not want to know, 2 individuals (22.22%) mentioned that they would consider suicide if they were positive for the pathogenic variant. On the impact of the disease, we detected that the adaptation to the familiar's needs was the most frequent answer, including changes in their lifestyle (being responsible since very young, changes in social life and familiar dynamic), this being their main stressor, followed by changes in plans for the future and contemplating the possibility of being affected. Although no differences in stress and depression between groups were observed, we detected that suicidal ideation was significantly higher in the group of cases. These results highlight the importance to involve all the family in genetic counseling in order to clarify any doubts and also to attend to them psychologically to prevent suicidal ideation and attempts.

4.
Curr Issues Mol Biol ; 44(11): 5221-5233, 2022 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-36354667

RESUMEN

The superoxide dismutase (SOD) is the principal antioxidant defense system in the body that is activated by a reactive oxygen species. Some variants of the SOD2 gene have been associated with cancer. The rs4880 variant was determined by PCR real-time and the rs5746136 variant by PCR-RFLP in healthy subjects and in breast cancer (BC) patients. The rs4880 and rs5746136 variants were associated with BC susceptibility when BC patients and the control group were compared for the CT, TT, CTCC, and the T alleles (p < 0.05). The CT genotype of the rs4880 variant showed significant statistical differences in patients and controls aged ≤ 45 years old, and with hormonal consumption (p < 0.05). The rs4880 variant was associated with BC patients with CTTT genotype and obesity, the presence of DM2-SAH, and a non-chemotherapy response (p < 0.05). Additionally, the rs5746136 variant was associated with susceptibility to BC with Ki-67 (≥20%), luminal A type BC, and a chemotherapy partial response (p < 0.05) in BC patients who carry TT, TC, and CTTT genotypes, respectively. The haplotype T/T (OR 1.98; 95% CI 1.20−3.26, p = 0.005) was observed to be a risk factor for BC. The rs4880 and rs5746136 variants in the SOD2 gene were associated with BC susceptibility.

5.
Biology (Basel) ; 11(9)2022 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-36138766

RESUMEN

Even though a mutation in monogenic diseases leads to a "classic" manifestation, many disorders exhibit great clinical variability that could be due to modifying genes also called minor genes. Fabry disease (FD) is an X-linked inborn error resulting from the deficient or absent activity of alpha-galactosidase A (α-GAL) enzyme, that leads to deposits of globotriaosylceramide. With our proprietary software SNPclinic v.1.0, we analyzed 110 single nucleotide polymorphisms (SNPs) in the proximal promoter of 14 genes that could modify the FD phenotype FD. We found seven regulatory-SNP (rSNPs) in three genes (IL10, TGFB1 and EDN1) in five cell lines relevant to FD (Cardiac myocytes and fibroblasts, Astrocytes-cerebellar, endothelial cells and T helper cells 1-TH1). Each SNP was confirmed as a true rSNP in public eQTL databases, and additional software suggested the prediction of variants. The two proposed rSNPs in IL10, could explain components for the regulation of active B cells that influence the fibrosis process. The three predicted rSNPs in TGFB1, could act in apoptosis-autophagy regulation. The two putative rSNPs in EDN1, putatively regulate chronic inflammation. The seven rSNPs described here could act to modulate Fabry's clinical phenotype so we propose that IL10, TGFB1 and EDN1 be considered minor genes in FD.

6.
PeerJ ; 10: e13379, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35573183

RESUMEN

Background: Variants of the estrogen receptor b (ESR2) gene have been associated with different types of cancer. However, these associations have been inconsistent. We genotyped the ESR2 variants (rs1256049, rs4986938, and rs1256030) in breast cancer (BC) patients and in healthy women. Results: The variants rs1256049 and rs4986938 in the ESR2 gene were not associated with risk susceptibility in BC patients. However, the rs1256030 variant had an association as a risk factor for BC patients when compared with controls and BC patients for the TT genotype (odds ratio (OR) 1.86, 95% confidence intervals (CI) [1.05-3.28], p = 0.042). In addition, differences were observed in patients and controls carrying the TT genotype under 50 years of age (OR 1.85, 95% CI [1.05-3.27], p = 0.043). Thus, evident differences showed the rs1256030 variant in patients with TT, TC, and TC+TT genotypes with: (1) Stage IV (OR 1.60, 95% CI [1.06-2.54], p = 0.033), and (2) Luminal A (OR 1.60, 95% CI [0.47-0.21], p = 0.041), as well as in BC carriers of the TT genotype with indices of cellular proliferative (Ki-67) elevated (>20%) and overweight (OR 1.67, 95% CI [0.85-3.28], p = 0.041), respectively. In BC HER2 with lymph node metastasis, the TT genotype was a protective factor (OR 0.38, 95% CI [0.18-0.78], p = 0.005). The identification of haplotypes included two common GAT as risk factors (OR 3.1, 95% CI [1.31-7.72], p = 0.011) and GGC as a protective factor (OR 0.7, 95% CI [0.60-0.97], p = 0.034). The haplogenotype GGGATC was a risk factor (OR 2.5, 95% CI [1.28-5.0], p = 0.008). Conclusion: The variant rs1256030 (TT) of the ESR2 gene and haplotype GAT were associated with susceptibility to BC as risk factors in this sample from the Mexican population.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Polimorfismo de Nucleótido Simple/genética , Estudios de Casos y Controles , Receptor beta de Estrógeno/genética , Factores de Riesgo
7.
J Med Genet ; 59(9): 865-877, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34815299

RESUMEN

BACKGROUND: Musculocontractural Ehlers-Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated. METHODS: We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations. RESULTS: Sixty-six patients in 48 families (33 males/females; 0-59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype-phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE. CONCLUSION: This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.


Asunto(s)
Anomalías Múltiples , Síndrome de Ehlers-Danlos , Anomalías Múltiples/genética , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Fenotipo , Sulfotransferasas/genética
8.
Am J Med Genet C Semin Med Genet ; 184(4): 1014-1022, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33283427

RESUMEN

Hypertrichosis is a rare condition characterized by excessive hair in areas of the body that are not predominantly androgen dependent. We can identify three main syndromes with congenital generalized hypertrichosis terminalis described in Mexico. The first is X-linked generalized hypertrichosis, an ultra-rare disease, with few cases reported to date. The second is Cantú syndrome, also known as hypertrichotic osteochondrodysplasia, which has a wide spectrum of clinical manifestations and is caused by pathogenic variants in ABCC9 and KCNJ8. The third is congenital hypertrichosis terminalis with or without gingival hyperplasia, which displays other features and involves several associated genes. The first two syndromes were described by the Mexican geneticist José María Cantú, and the concept of atavistic genes was invoked to explain the emergence of this outstanding trait. By understanding the genetic and pathophysiological basis of hypertrichosis, we can offer effective treatment to patients and help solve esthetic problems related to hair growth.


Asunto(s)
Hipertricosis , Osteocondrodisplasias , Humanos , Hipertricosis/genética , México , Nigeria , Síndrome
9.
Am J Med Genet C Semin Med Genet ; 184(4): 1023-1029, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33274538

RESUMEN

Mutations in three genes (APP, PSEN1, and PSEN2) are the main cause of the autosomal dominant early-onset Alzheimer's disease (AD-EOAD). In PSEN1, the A431E (c.1292C>A, rs63750083) mutation is suspected to have exerted a founder effect in the State of Jalisco, Mexico. In Guadalajara, Jalisco, Mexico, this mutation was found in 46 index cases evaluated for AD-EOAD. In our genealogical analysis, 301 affected relatives of the mutation carriers were identified, 195 of whom were already deceased at the time of interview. Moreover, 560 descendants had a 50% risk of carrying the mutation, and 348 were potentially at risk. A systematic phenotyping was performed in 39 patients. The mean onset age was 42.5 ± 3.9 years, and no significant difference in onset age was observed between the male and female patients. Furthermore, a substantial clinical heterogeneity and high frequencies of spastic paraparesis, language disorders, and neuropsychiatric symptoms were observed. To our knowledge, the investigated families represent the second biggest population carrying a PSEN1 mutation in Latin America, offering a unique opportunity to study the genetic basis of Alzheimer's disease. Addressing AD-EOAD warrants an integral approach involving a deep understanding of its clinical behavior, as well as counseling protocols and prevention studies.


Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Adulto , Edad de Inicio , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Presenilina-1/genética
10.
Clin Dysmorphol ; 26(4): 209-216, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28737552

RESUMEN

In this study, we describe two patients with a recombinant chromosome secondary to a maternal intrachromosomal insertion. Patient 1 was a girl with dup(6)(p22.3p25.3). Patient 2 was a boy with dup(2)(q24.2q32.1). Both familial rearrangements were characterized by means of GTG-bands, fluorescence in-situ hybridization, and comparative genomic hybridization microarray analyses. Patient 1 had an ∼23 Mb gain that involved the bands 6p22.3-6p25.3. Patient 2 had an ∼23 Mb gain (cytobands 2q24.2-2q32.1) and a further ∼1.9 Mb gain of 2p16.2-p16.3. The phenotype of each patient was in agreement with the typical 6p duplication or 2q24.2q32.1 duplication syndrome. The compound macular lesion in patient 1 suggests that retinal anomalies may be a part of the 6p trisomy phenotype. Among the 70 intrachromosomal insertions compiled here (including 68 from the literature), four were submicroscopic unbalanced insertions inherited from a balanced carrier and 66 were detectable on banded chromosomes (with or without array comparative genomic hybridization or other high-resolution assessment) and therefore spanned at least 5 Mb. Pericentric insertions are found in most chromosomes, whereas the paracentric ones are mainly observed in large and medium chromosome arms. That the former outnumber the latter in almost a 2 : 1 ratio appears to be related to the technique of diagnosis, size of the insertion, and size of the involved chromosome. Regardless of the apparent excess of carrier mothers, carriers of an intrachromosomal insertion beget almost twice as many children with a duplication than with a deletion.


Asunto(s)
Duplicación Cromosómica/genética , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 6/genética , Recombinación Genética/genética , Bandeo Cromosómico , Hibridación Genómica Comparativa , Familia , Resultado Fatal , Femenino , Humanos , Lactante , Cariotipificación , Masculino
11.
J Genet ; 96(1): 161-164, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28360401

RESUMEN

Fabry disease (FD) is a lysosomal storage disorder, which develops due to a deficiency in the hydrolytic enzyme, α-galactosidase A (α-Gal A). Alpha-Gal A hydrolyzes glycosphingolipid globotriaosylceramide (Gb3), and an α-Gal A deficiency leads to Gb3 accumulation in tissues and cells in the body. This pathology is likely to involve multiple systems, but it is generally considered to affect primarily vascular endothelium. In this study, we investigated mutations in the GLA gene, which encodes α-Gal A, in Mexican families with FD. We included seven probands with FD that carried known mutations. We analysed pedigrees of the probands, and performed molecular screening in 65 relatives with the potential of carrying a GLA mutation. Five mutations (P40S, IVS4+4, G328V, R363H, R404del) were detected in seven unrelated Mexican families with the classic FD phenotype. Of the 65 relatives examined, 42 (64.6%) had a GLA gene mutation. In summary, among seven Mexican probands with FD, 65 relatives were at risk of carrying a known GLA mutation, and molecular screening identified 42 individuals with the mutation. Thus, our findings showed that it is important to perform molecular analysis in families with FD to detect mutations and to provide accurate diagnoses for individuals that could be affected.


Asunto(s)
Enfermedad de Fabry/genética , Mutación , alfa-Galactosidasa/genética , Análisis Mutacional de ADN , Enfermedad de Fabry/diagnóstico , Femenino , Genotipo , Humanos , Masculino , México , Repeticiones de Microsatélite , Linaje , Fenotipo
12.
Arch Med Sci ; 11(3): 551-60, 2015 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-26170848

RESUMEN

INTRODUCTION: The progesterone receptor (PR) gene plays an important role in reproduction-related events. Data on polymorphisms in the PR gene have revealed associations with cancer, particularly for the Alu insertion polymorphism, which has been suggested to affect progesterone receptor function and contribute to tumor promotion in the mammary gland. MATERIAL AND METHODS: We examined the role of the Alu insertion polymorphism in the PR gene by comparing the genotypes of 209 healthy Mexican women with those of 481 Mexican women with breast cancer (BC). RESULTS: The genotype frequencies observed in the controls and BC patients were 0% and 4% for T2/T2 (Alu insertion), 16% and 21% for T1/T2, and 84% and 75% for T1/T1 (Alu deletion), respectively. The obtained odds ratio (OR) was 1.7, with a 95% confidence interval (95% CI) of 1.1-2.6, p = 0.009, for the T1/T2-T2/T2 genotypes. The association was also evident when the distributions of the T1/T2-T2/T2 genotypes in patients in the following categories were compared: obesity grade II (OR = 1.81, 95% CI: 1.03-3.18, p = 0.039) and the chemotherapy response (OR = 1.91, 95% CI: 1.27-3.067, p = 0.002). CONCLUSIONS: The T1/T2-T2/T2 genotypes of the Alu insertion polymorphism in the PR gene are associated with BC susceptibility in the analyzed Mexican population.

14.
Rev Med Inst Mex Seguro Soc ; 50(2): 157-61, 2012.
Artículo en Español | MEDLINE | ID: mdl-22882983

RESUMEN

Kallmann syndrome is characterized by hypogonadotropic hypogonadism and anosmia/hyposmia. The hypogonadotropic hypogonadism is due to deficiency of gonadotropin-releasing hormone, caused by a defect in the migration of neurons synthesizing gonadotropin-releasing hormone, and anosmia/hyposmia is related to the absence or hypoplasia of the olfactory bulb and tracts. Some patients may have other associated abnormalities such as renal agenesis, cleft palate, dental agenesis, synkinesis, shortening of metacarpal, sensory neural hearing loss and seizures. The aim of this paper is to present an updated review of the clinical and molecular basis, highlighting the relevance of knowledge of phenotypic variants in Kallmann syndrome.


Asunto(s)
Síndrome de Kallmann/genética , Humanos , Síndrome de Kallmann/diagnóstico , Fenotipo
16.
Asia Pac J Clin Nutr ; 21(2): 312-8, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22507620

RESUMEN

Some studies, that consider polymorphisms of the apolipoprotein B (APOB) gene as risk factors for coronary artery disease (CAD), have reported discordant results. The aim of the present study was to search for associations between plasma lipid profiles with the DNA Xba I polymorphism of the APOB gene in CAD patients diagnosed by angiography (CAD+). In the present study we compared 114 Mexican patients (80 men and 34 women) with CAD+ and 132 control patients (59 men and 73 women) without evidence of ischemia or arterial damage (CAD-). The frequency of X+/X+ genotype of Xba I polymorphism, in CAD+ group, was 23% (26/114) compared with 8% (11/132) in the CAD- (OR 3.25, p = 0.002). The patients with X+/X+ for the Xba I genotype APOB gene had higher concentration of triglycerides (TG) and VLDL in plasma than CAD- (p< 0.05). The genotype X+/X+ in the CAD had an effect increasing the TG and VLDL plasma levels when compared with individuals with X-/X- and X-/X+ genotypes. The present study indicated that the X+X+ genotype of Xba I polymorphism is associated with CAD+ patients and high plasma levels of TG and VLDL, in the Mexican population.


Asunto(s)
Apolipoproteínas B/genética , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/genética , Lipoproteínas VLDL/sangre , Polimorfismo de Longitud del Fragmento de Restricción , Triglicéridos/sangre , Anciano , Alelos , Enfermedad de la Arteria Coronaria/etnología , Enfermedad de la Arteria Coronaria/fisiopatología , Femenino , Estudios de Asociación Genética , Homocigoto , Humanos , Hipercolesterolemia/etnología , Hipercolesterolemia/genética , Hipertrigliceridemia/etnología , Hipertrigliceridemia/genética , Masculino , México , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad
17.
Am J Hum Genet ; 88(6): 819-826, 2011 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-21636067

RESUMEN

X-linked congenital generalized hypertrichosis (CGH), an extremely rare condition characterized by universal overgrowth of terminal hair, was first mapped to chromosome Xq24-q27.1 in a Mexican family. However, the underlying genetic defect remains unknown. We ascertained a large Chinese family with an X-linked congenital hypertrichosis syndrome combining CGH, scoliosis, and spina bifida and mapped the disease locus to a 5.6 Mb critical region within the interval defined by the previously reported Mexican family. Through the combination of a high-resolution copy-number variation (CNV) scan and targeted genomic sequencing, we identified an interchromosomal insertion at Xq27.1 of a 125,577 bp intragenic fragment of COL23A1 on 5q35.3, with one X breakpoint within and the other very close to a human-specific short palindromic sequence located 82 kb downstream of SOX3. In the Mexican family, we found an interchromosomal insertion at the same Xq27.1 site of a 300,036 bp genomic fragment on 4q31.2, encompassing PRMT10 and TMEM184C and involving parts of ARHGAP10 and EDNRA. Notably, both of the two X breakpoints were within the short palindrome. The two palindrome-mediated insertions fully segregate with the CGH phenotype in each of the families, and the CNV gains of the respective autosomal genomic segments are not present in the public database and were not found in 1274 control individuals. Analysis of control individuals revealed deletions ranging from 173 bp to 9104 bp at the site of the insertions with no phenotypic consequence. Taken together, our results strongly support the pathogenicity of the identified insertions and establish X-linked congenital hypertrichosis syndrome as a genomic disorder.


Asunto(s)
Secuencias Invertidas Repetidas , Factores de Transcripción SOXB1/genética , Pueblo Asiatico/genética , Secuencia de Bases , Cromosomas Humanos X/genética , Proteínas Activadoras de GTPasa/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Hipertricosis/congénito , Hipertricosis/genética , Hipertricosis/patología , Datos de Secuencia Molecular , Mutagénesis Insercional , Linaje , Proteína de Unión al GTP rhoA
18.
Genet Med ; 12(11): 668-79, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20962662

RESUMEN

Enzyme replacement therapy with α-galactosidase A has been used to treat Fabry disease since 2001. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations. We focused on heart, kidney, and nervous system manifestations, which impact both quality of life and overall prognosis. A literature search was undertaken to identify prospective open or randomized controlled trials of enzyme replacement therapy in patients with Fabry disease published since 2001. To date, no definitive conclusion can be drawn from studies that have directly compared therapeutic responses between the two commercially available enzyme preparations. Significant clinical benefits of enzyme replacement therapy have been demonstrated, mainly in patients at an early phase of the disease, with beneficial effects on heart, kidneys, pain, and quality of life in treated patients. Incidence of antibodies against agalsidase alfa and agalsidase beta observed during major clinical studies suggests a greater antigenic response to agalsidase beta. Further studies are required to confirm the long-term clinical benefits of enzyme replacement therapy. More studies with female patients are needed as are investigations of early initiation of enzyme replacement therapy to determine the optimal time to start treatment to prevent irreversible organ damage. The value of adjunctive and supportive therapies should also be rigorously analyzed.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Isoenzimas/uso terapéutico , Enfermedades del Sistema Nervioso/etiología , alfa-Galactosidasa/uso terapéutico , Adulto , Niño , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/fisiopatología , Femenino , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/fisiopatología , Humanos , Inmunoglobulina G/inmunología , Isoenzimas/inmunología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/fisiopatología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes , Resultado del Tratamiento , alfa-Galactosidasa/inmunología
19.
Genet Med ; 12(11): 713-20, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20975569

RESUMEN

PURPOSE: Fabry disease is a progressive multiorgan, multisystem disorder that is caused by a deficiency in the lysosomal enzyme α-galactosidase A. Serious renal, cardiac, and cerebrovascular involvement are responsible for much of the morbidity and premature mortality associated with Fabry disease, and neuropathic pain, gastrointestinal problems, and hypohidrosis negatively affect quality of life of patients with Fabry disease. Fabry disease is X-linked, but women are often symptomatic and may be as severely affected as men. METHODS: We propose a series of therapeutic and symptomatic goals for use in setting the expectations of enzyme replacement therapy and for assessing the response to enzyme replacement therapy in the treatment of Fabry disease. RESULTS: Enzyme replacement therapy has been available since 2001 and has been associated with benefit in clinical trials, including stabilization of kidney function, improvement of cardiac structure and function, reduction in severity of neuropathic pain, and improvement in gastrointestinal involvement. CONCLUSIONS: The presentation of these therapeutic goals will aid in the evaluation of response to enzyme replacement therapy and be useful in establishing an overall management plan for individual patients.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/etiología , Ensayos Clínicos como Asunto , Enfermedad de Fabry/fisiopatología , Femenino , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/etiología , Pérdida Auditiva/tratamiento farmacológico , Pérdida Auditiva/etiología , Humanos , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/etiología , Masculino , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Calidad de Vida
20.
Clin Cancer Res ; 16(16): 4148-54, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20592014

RESUMEN

PURPOSE: Paragangliomas of the head and neck are neuroendocrine tumors and are associated with germ line mutations of the tricarboxylic acid cycle-related genes SDHB, SDHC, SDHD, and SDHAF2. Hypoxia is important in most solid tumors, and was directly implicated in tumorigenesis over 40 years ago when it was shown that dwelling at high altitudes increases the incidence of carotid body hyperplasia and paragangliomas. Although recent research has now elucidated several pathways of hypoxia in paragangliomas, nothing is currently known of the genetics or of gene-environment interactions in high-altitude paraganglioma. We postulated that SDH mutations might play a role in these tumors. EXPERIMENTAL DESIGN: Patients from a Mexican family, originating and resident in Guadalajara, were tested for mutations of SDHD, and subsequently, for mutations of SDHB followed by immunohistochemical confirmation of SDHB loss. RESULTS: Two patients, born and resident at altitudes of between 1,560 and 2,240 m, were found to have head and neck paragangliomas, including a remarkably aggressive recurrent tumor. Mutation analysis identified a pathogenic missense mutation in exon 7 of SDHB, c.689G>A, p.Arg230His, and loss of the SDHB protein was confirmed by immunohistochemistry. CONCLUSIONS: This is the first report of a SDH gene mutation in paraganglioma at high altitude. A rapidly recurrent head and neck paraganglioma is a very rare finding in an SDH mutation carrier, suggesting a gene-environment interaction. Neither patient showed evidence of sympathetic paraganglioma.


Asunto(s)
Altitud , Tumor del Cuerpo Carotídeo/genética , Hipoxia de la Célula/genética , Succinato Deshidrogenasa/genética , Anciano , Tumor del Cuerpo Carotídeo/etiología , Tumor del Cuerpo Carotídeo/patología , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/etiología , Neoplasias de Cabeza y Cuello/genética , Humanos , Inmunohistoquímica , Masculino , Mutación , Neoplasias Primarias Múltiples/patología , Neoplasias Ováricas/patología , Linaje , Reacción en Cadena de la Polimerasa
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