RESUMEN
A prospective study was conducted to determine the outcome of pregnancies with 1st trimester nuchal translucency measurement of ≥ 6.5 mm. The risk of fetal abnormalities increases with enlarging nuchal translucency, being around 45% with a measurement of ≥ 6.5 mm. A total of 27,144 women with singleton pregnancies participated in the combined Down syndrome screening within the public healthcare system in Northern Finland. The study period was 1 May 2002 to 31 May 2009. The nuchal translucency measurement was ≥ 6.5 mm in 16 cases (0.06%). Pregnancy outcome was normal in one case (6.3%). The risk of abnormality was higher in our study than reported in the literature. According to our study, immediate diagnostic tests should be offered after an nuchal translucency measurement of ≥ 6.5 mm. We should also consider analysis of fetal micro-deletions associated with certain syndromes.
Asunto(s)
Anomalías Congénitas/diagnóstico por imagen , Medida de Translucencia Nucal , Resultado del Embarazo , Adulto , Femenino , Humanos , Embarazo , Estudios ProspectivosRESUMEN
Gene expression studies have demonstrated the altered expression level of placental angiogenesis related genes in severe pre-eclampsia (PE). In cord compression, the transportation of oxygen from the placenta to the fetus is blocked, and it is speculated that during blockade the originally hypoxic placenta may become hyperoxic. We compared the placental gene expression profiles of one pre-eclamptic patient with cord compression (the index patient) to the profiles of patients with PE and those of normal pregnancy controls (including one woman with cord compression). The gene expression of the cord compression PE patient resembled that observed in the normal pregnancies. We hypothesize that umbilical blockade may in a short period of time lead to placental hyperoxia, which in turn has an effect on angiogenic gene expression profile.
Asunto(s)
Neovascularización Fisiológica/genética , Placenta/metabolismo , Preeclampsia/genética , Complicaciones Hematológicas del Embarazo/patología , Cordón Umbilical/patología , Adulto , Estudios de Casos y Controles , Femenino , Regulación de la Expresión Génica , Humanos , Cordón Nucal/genética , Circulación Placentaria/genética , Circulación Placentaria/fisiología , Embarazo , Complicaciones Hematológicas del Embarazo/genéticaRESUMEN
Epidermolysis bullosa (EB) in a group of genodermatoses characterized by the fragility of skin. Previous studies on the dystrophic (scarring) forms of EB have suggested abnormalities in anchoring fibrils, morphologically recognizable attachment structures that provide stability to the association of the cutaneous basement membrane to the underlying dermis. Since type VII collagen is the major component of the anchoring fibrils, we examined the genetic linkage of dominant dystrophic EB (EBDD) and the type VII collagen gene (COL7A1) locus, which we have recently mapped to chromosome 3p, in three large kindreds with abnormal anchoring fibrils. Strong genetic linkage of EBDD and COL7A1 loci was demonstrated with the maximum logarithm of odds (LOD) score of 8.77 at theta = 0. This linkage was further confirmed with two additional markers in this region of the short arm of chromosome 3, and these analyses allowed further refinement of the map locus of COL7A1. Since there were no recombinants between the COL7A1 and EBDD loci, our findings suggest that type VII collagen is the candidate gene that may harbor the mutations responsible for the EB phenotype in these three families.
Asunto(s)
Colágeno/genética , Epidermólisis Ampollosa Distrófica/genética , Ligamiento Genético , Mapeo Cromosómico , Genes Dominantes , Marcadores Genéticos , Humanos , Mutación , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
We compared cognitive performance and hippocampal volumes using magnetic resonance imaging (MRI) in adult fragile-X [fra(X)] males and females with either premutation (pM) or full mutation (fM) (n = 10 in all groups). Cognitive performance of fM males in the Wechsler Adult Intelligence Scale-Revised was worse than that of pM males, and the deficits in fM females were qualitatively similar, but less severe. In a visual memory test, both fM groups were impaired. In a list learning test, fM males were impaired in the learning phase and in delayed recognition. In a logical memory test, fM males and females were not significantly different from pM subjects. Hippocampal volumes normalized for intracranial or brain area did not significantly differ between fM and pM groups. However, positive correlations between left normalized hippocampal volumes and performance in many delayed memory tests observed in pM subjects were absent in fM subjects. Furthermore, in > 50% of the fM subjects, nonspecific changes, such as enlargement of ventricles and perivascular spaces, focal hyperintensities in temporal pole white matter, and/or subjectively assessed atypical appearance of hippocampal morphology, were observed in MRI. The data suggest minor abnormalities in temporal lobe structures in adult fra(X) subjects with fM.
Asunto(s)
Cognición , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/psicología , Hipocampo/patología , Proteínas de Unión al ARN , Repeticiones de Trinucleótidos/genética , Adulto , ADN/análisis , ADN/sangre , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Pruebas Neuropsicológicas , Escalas de WechslerRESUMEN
The expression of hyaluronan (HA) in fetal human skin was studied by using a biotinylated HA-binding probe. The uniform expression of HA in primitive skin was changed after the 9th week, when differentiation of the basement membrane zone increased HA in the subepidermal mesenchyme. Maturation of the papillary dermis at the 12-20th weeks led to the thickening of this HA-enriched zone; the underlying reticular layer was less intensely stained. In epidermis the number of cell layers rapidly increased after the 9th week. At first all epidermal layers were HA-positive. A complete loss of HA from the upper intermediate cells on the 18th week preceded the formation of mature granular and cornified layers. Peridermal cells remained HA-positive even when the underlying stratum corneum turned negative. The tightly apposed basal epithelial cells, the first stage of hair follicle and eccrine sweat gland formation, became almost completely depleted of HA. With advancing bulb development HA returned in the epithelial compartment, until maturation of the hair follicles restricted its expression to the outer root sheath and hair matrix. Maturation of the sebaceous glands led to the expression of HA pericellularly in the germinative cells and intracellularly in the mature sebocytes. Marked changes thus occur in the distribution of HA during fetal skin development; the primitive tissues exhibited a uniform widespread expression of HA, and maturing tissues showed distinct locally regulated patterns. The loss of epithelial HA in the hair follicle anlagen and upper intermediate cells turned out to be early differentiation markers.
Asunto(s)
Ácido Hialurónico/biosíntesis , Piel/embriología , Diferenciación Celular , División Celular , Tejido Conectivo/química , Tejido Conectivo/metabolismo , Células Epiteliales , Epitelio/química , Epitelio/metabolismo , Feto/citología , Folículo Piloso/efectos de los fármacos , Folículo Piloso/crecimiento & desarrollo , Humanos , Ácido Hialurónico/fisiología , Queratinas/biosíntesis , Glándulas Sebáceas/citología , Piel/metabolismo , Glándulas Sudoríparas/químicaRESUMEN
The current trend in prenatal diagnosis is that trisomy screening is being moved to the first trimester and ultrasonographic nuchal translucency measurement is included in risk calculation. It is likely that biochemical screening in the second trimester will gradually be given up. In Eastern and Northern Finland, during the year 1999 we offered first-trimester ultrasonographic and serum screening for trisomy 21, with measurements of maternal serum PAPP-A and beta-hCG. A total of 2515 pregnant women participated in the screening, yielding the detection of eight foetuses with Down's syndrome. Six affected foetuses (75%) were detected by means of first-trimester serum screening. Since we were in the phase of collecting data for the Finnish medians for PAPP-A and beta-hCG, the women were not given the estimates of risk for trisomy 21. Only 1602 of the 2515 enrolled women had the combination of first-trimester ultrasonographic and serum screening performed, and in that group there were five foetuses with Down's syndrome. The combination ultrasonographic and serum approach yielded a Down's syndrome detection rate of 80% (four out of five) with a 5% false positive rate, whereas in nuchal translucency based-screening the detection rate was 60%, with a 5% false positive rate.
Asunto(s)
Gonadotropina Coriónica Humana de Subunidad beta/sangre , Síndrome de Down/diagnóstico por imagen , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Primer Trimestre del Embarazo , Proteína Plasmática A Asociada al Embarazo/biosíntesis , Diagnóstico Prenatal , Adulto , Reacciones Falso Positivas , Femenino , Finlandia , Humanos , Madres , Embarazo , Reproducibilidad de los Resultados , UltrasonografíaRESUMEN
Fragile X syndrome is the second leading cause of mental retardation after Down syndrome. Most women carriers of the fragile X mutation are unaware of their condition. We critically evaluated whether screening pregnant women at low risk for FMR1 mutation would be feasible as a routine part of antenatal care in general practice. We also studied acceptance and attitudes to gene testing. From July 1995 until December 1996, a carrier test was offered at the Kuopio City Health Centre free of charge to all pregnant women in the first trimester following counselling given by midwives on fragile X syndrome. All women found to be carriers of FMR1 gene mutations underwent detailed genetic counselling and were offered prenatal testing. Attitudes towards the gene test were elicited by questionnaire. Most pregnant women (85%) elected to undertake the gene test. Six women were found to be carriers (a rate of 1 in 246), and all subsequently accepted prenatal testing. Three foetuses had a normal FMR1 gene, one had a large premutation, one a 'size mosaic' mutation pattern, and another a full mutation. This observational and interventional study demonstrates that antenatal screening provides an effective way of identifying carriers and incorporating prenatal testing into this process.
Asunto(s)
Síndrome del Cromosoma X Frágil/genética , Pruebas Genéticas , Discapacidad Intelectual/genética , Mutación , Proteínas del Tejido Nervioso/genética , Diagnóstico Prenatal , Proteínas de Unión al ARN , Estudios de Factibilidad , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Conocimientos, Actitudes y Práctica en Salud , Humanos , EmbarazoRESUMEN
Alzheimer's disease (AD) is a complex neurodegenerative disorder, for which several disease-associated loci have been located on different chromosomes. We have used a population-based linkage disequilibrium mapping approach in order to find potential AD-associated loci on chromosome 13. To avoid population stratification, late onset AD patients and age-matched controls were carefully chosen from the same geographical area in Eastern Finland, where the population is mainly descended from a small group of original founders. During the initial screening with chromosome 13-specific microsatellite markers, tetranucleotide marker D13S787 was found to be in linkage disequilibrium in the 13q12 region. Screening this region with additional microsatellite markers revealed that marker D13S292 was also significantly associated with AD. Stratification of the AD patients and controls into groups according to apolipoprotein E, sex, and familial/sporadic status indicated that the 13q12 locus was associated with female familial AD patients regardless of ApoE genotype. Based on the physical data from the region 13q12, markers D13S292 and D13S787 were estimated to reside in a 810kb long YAC clone 754h7 together with two infant brain-derived ESTs and the H,K-ATPase alpha-subunit protein gene (ATP1AL1). The localisation of these sequences at the linkage disequilibrium region suggests that they may be candidate genes involved in a sex-specific effect during development of AD.
Asunto(s)
Edad de Inicio , Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 13 , Desequilibrio de Ligamiento , Anciano , Alelos , Apolipoproteínas E/genética , Femenino , Finlandia/epidemiología , Pruebas Genéticas , Genotipo , Haplotipos , Humanos , Masculino , Repeticiones de MicrosatéliteRESUMEN
In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.
Asunto(s)
Neoplasias de la Mama/genética , Efecto Fundador , Genes BRCA1/genética , Mutación/genética , Proteínas de Neoplasias/genética , Neoplasias Ováricas/genética , Factores de Transcripción/genética , Adulto , Anciano , Proteína BRCA2 , Neoplasias de la Mama/patología , Familia , Femenino , Finlandia/epidemiología , Genotipo , Haplotipos , Humanos , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/patología , Fenotipo , Factores de Tiempo , Factores de Transcripción/metabolismoRESUMEN
Apolipoprotein E (ApoE) epsilon 4 allele is a risk factor for late-onset Alzheimer's disease (AD) and proposed to have a direct impact on cholinergic function in AD. Slowing of the EEG is characteristic in AD and the cholinergic system has an important role in modulating EEG. Fifty-eight AD patients at the early stage of the disease and 34 age- and sex-matched controls were studied using the quantitative EEG recorded from T6-O2 derivation. AD patients were divided into two subgroups: a) according to the ApoE allele (2 epsilon, 1 epsilon 4, and 0 epsilon 4) and b) according to familial aggregation. AD subgroups did not differ in clinical severity or duration of dementia. The AD patients with the epsilon 4 allele had higher relative theta amplitude and lower relative beta amplitude than controls and patients without the epsilon 4 allele. The peak frequencies were lower in all AD subgroups compared to controls. In conclusion, we found a tendency towards more pronounced EEG slowing in AD patients carrying the epsilon 4 allele. The minor differences in EEG may suggest differences in the degree of the cholinergic deficit in these subgroups.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Apolipoproteínas E/genética , Anciano , Alelos , Enfermedad de Alzheimer/genética , Electroencefalografía , Femenino , Humanos , Masculino , Polimorfismo GenéticoRESUMEN
A recent report suggested that brains of Alzheimer patients homozygous for APOE epsilon 4 show increased amyloid pathology compared to APOE epsilon 3 homozygotes. We studied APOE allele frequencies in 73 AD patients and 38 controls. We also investigated relation of APOE genotypes to beta/A4 immunopositive plaques, cerebrovascular beta/A4 deposition, neurons expressing paired helical filaments (PHFs), and synaptophysin-like immunopositivity in 22 neuropathologically verified AD patients. We also correlated APOE genotypes of definite AD patients to beta/A4 immunoreactivity in dermal vessel walls detected in lifetime skin biopsy samples. APOE allele epsilon 4 frequency was increased in AD compared to nondemented controls (0.37 vs. 0.11; p = 0.006). The number of beta/A4 immunoreactive plaques, PHFs-containing neurons, the degree of cerebrovascular beta/A4 deposition or synaptophysin-like immunoreactivity did not differ significantly in AD patients with or without epsilon 4. beta/A4 deposition in dermal vessel walls was more frequent in definite AD patients with epsilon 4 (43%) than in patients without epsilon 4 (22%). However, the difference did not reach the statistical significance.
Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Análisis de Varianza , Vasos Sanguíneos/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Encéfalo/patología , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Ovillos Neurofibrilares/metabolismo , Neuronas/metabolismo , Piel/irrigación sanguínea , Sinapsis , Sinaptofisina/metabolismo , Proteínas tau/metabolismoRESUMEN
BACKGROUND: AD is a complex neurodegenerative disorder comprising several disease-associated chromosome loci. To find novel susceptibility genes for late-onset AD, a population-based genome-wide search using linkage disequilibrium (LD) mapping approach has been performed. METHOD: Forty-seven patients with late-onset AD and 51 age-matched control subjects were carefully chosen from the same geographic area in eastern Finland, where the population is descended mainly from a small group of original founders. These subjects were initially genotyped with 366 polymorphic microsatellite markers, and a follow-up analysis was performed with additional microsatellite markers for those chromosome loci found to be associated with AD. RESULTS: Initial genome-wide screening revealed 21 chromosomal loci significantly associated with AD in addition to the 13q12 locus described previously. Subsequent comparison of single-allele frequencies of the microsatellite markers in the AD and control groups indicated the presence both of possible risk alleles (odds ratio [OR] > 1) and of possible protective alleles (OR < 1). Screening of the LD regions with additional microsatellite markers revealed seven chromosomal loci where more than one microsatellite marker was associated with AD (1p36.12, 2p22.2, 3q28, 4p13, 10p13, 18q12.1, and 19p13.3) in addition to the 13q12 locus. CONCLUSIONS: These genome-wide LD screening data suggest that several AD-associated chromosomal loci exist, which may encompass novel susceptibility genes for late-onset AD. Therefore, extensive screening of the genes located in the vicinity of these LD regions is necessary to elucidate their role in AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Desequilibrio de Ligamiento , Edad de Inicio , Anciano , Anciano de 80 o más Años , Apolipoproteína E4 , Apolipoproteínas E/genética , Femenino , Finlandia , Efecto Fundador , Genoma Humano , Haplotipos , Humanos , Modelos Logísticos , Masculino , Repeticiones de Microsatélite , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Alzheimer's disease (AD) is a heterogeneous entity presenting as sporadic and familial disease. In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (> or = 65 years), familial late-onset (FLO) (> or = 65 years), sporadic early-onset (SEO) (<65 years), and familial early-onset (FEO) (<65 years) patients and into three subgroups according to their ApoE genotype zero epsilon4, one epsilon4, and two epsilon4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon4++ allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon4 alleles had earlier age at onset of dementia than those with no epsilon4 allele (63 +/- 9 versus 68 +/- 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon4 allele in the delayed list learning (p<0.05) and from those with zero epsilon4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon4 allele.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Apolipoproteínas E/genética , Pruebas Neuropsicológicas , Polimorfismo Genético , Edad de Inicio , Anciano , Alelos , Enfermedad de Alzheimer/psicología , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 21 , Cognición , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Memoria , Persona de Mediana Edad , Factores Socioeconómicos , Percepción Espacial , HablaRESUMEN
An increased frequency of apolipoprotein E E4 allele has been reported in patients with late onset Alzheimer's disease. Apolipoprotein E participates in the transport of cholesterol and other lipids and interferes with the growth and regeneration of both peripheral and central nervous system tissues during development and after injury. Apolipoprotein E is also implicated in synaptogenesis. Apolipoprotein E isoforms differ in binding to amyloid-beta-protein and tau protein in vitro. Here, we wanted to study the effect of apolipoprotein E genotype on the magnitude of damage in the hippocampus, where a marked synapse loss exists in Alzheimer's disease. We measured by magnetic resonance imaging the volumes of the hippocampus, amygdala, and frontal lobes in the three Alzheimer subgroups: patients with 2, 1 or 0 E4 alleles. We also investigated the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions of these Alzheimer subgroups. All Alzheimer patients were at early stage of the disease. We found that Alzheimer patients with E4/4 genotype (N = 5) had smaller volumes of the hippocampus and the amygdala than those with E3/4 (N = 9) and those with E3/3 or E2/3 (N = 12). The difference was significant for the right hippocampus (-54% of control) and the right amygdala (-37% of control). The volumes of the frontal lobes were similar across the Alzheimer subgroups. The patients with E4/4 also showed lowest scores on delayed memory tests and differed from E3/3, 3/2 patients in the list learning test (< 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Amígdala del Cerebelo/patología , Apolipoproteínas E/genética , Lóbulo Frontal/patología , Hipocampo/patología , Anciano , Enfermedad de Alzheimer/psicología , Cognición/fisiología , Enzimas de Restricción del ADN , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria/fisiología , Reacción en Cadena de la PolimerasaRESUMEN
Fragile X is the most common inherited form of mental retardation, having an incidence of one in 1,250 males. The fragile X syndrome results from amplification of the CGG repeat found in the fragile X mental retardation-1-gene (FMR-1). This CGG repeat shows length variation in normal individuals and is increased significantly in both carriers and patients. Non-retarded carriers of both sexes can be detected reliably only by direct DNA analysis of the fra(X) mutation. Here we investigate fragile X families using the intragenic probes St.B 12.3 and St.B 12.3 XX (J-L Mandel). Fragile X syndrome could be verified in 51 families of the population of 900,000 in East-Finland during 1989-92. The index cases of the syndrome were found by the help of health care personnel, 463 relatives of these families consented to be tested for the mutation of the FMR-1 gene. Ninety-three relatives with the full mutation and 127 healthy carriers with the premutation of the fragile X syndrome were diagnosed. In addition, 28 decreased males were obligate carriers. During the year 1992 prenatal diagnosis for fragile X was carried out in nine pregnancies. For understanding of the occurrence of fragile X syndrome and for better prevention of this syndrome in next generations, systematic genetic counseling and carrier screening in these families is essential.
Asunto(s)
Enfermedades Fetales/diagnóstico , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Diagnóstico Prenatal/psicología , Femenino , Finlandia , Síndrome del Cromosoma X Frágil/psicología , Tamización de Portadores Genéticos , Asesoramiento Genético/psicología , Humanos , Masculino , Aceptación de la Atención de Salud , EmbarazoRESUMEN
The pathogenesis of Fragile-X syndrome is a consequence of absence of the FMR1 gene product associated with expansion of the CGG repeat and abnormal methylation of this and a CpG island 250 bp proximal to the CGG repeat located at exon 1 in the FMR1 gene. While this is usually the case, some suspected Fragile-X syndrome patients have been described with a mutation other than CGG expansion. We describe here an affected Fragile-X male, who was found to be mosaic of a full mutation of the CGG expansion and a deletion in the FMR1 gene. The patient's phenotype is probably mainly due to the effect of the full mutation of the repeat sequence. Thus, the influence of the deletion is difficult to evaluate.
Asunto(s)
Síndrome del Cromosoma X Frágil/genética , Proteínas del Tejido Nervioso/genética , Proteínas de Unión al ARN , Eliminación de Secuencia , Secuencia de Bases , Cartilla de ADN , Sondas de ADN , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Humanos , Masculino , Persona de Mediana Edad , Mosaicismo , Proteínas del Tejido Nervioso/deficiencia , Núcleo Familiar , Linaje , Reacción en Cadena de la Polimerasa , Repeticiones de TrinucleótidosRESUMEN
The apparent associations between fragile X mutations and nearby microsatellites may reflect both founder effects and microsatellite instability. To gain further insight into their relative contributions, we typed a sample of 56 unrelated control and 37 fragile X chromosomes from an eastern Finnish population for FMR1 CGG repeat lengths, AGG interspersion patterns, DXS548, FRAXAC1, FRAXE and a new polymorphic locus, Alu-L. In the controls, the most common FMR1 allele was 30 repeats with a range of 20 to 47 and a calculated heterozygosity of 88%. A strong founder effect was observed for locus DXS548 with 95% of fragile X chromosomes having the 21 CA repeat (196 bp) allele compared to 17% of controls, while none of the fragile X but 69% of controls had the 20 repeat allele. Although the FRAXAC1 locus is much closer than DXS548 to FMR1 (7 kb vs. 150 kb), there was no significant difference between fragile X and control FRAXAC1 allele distributions. The FRAXE repeat, located 600 kb distal to FMR1, was found to show strong linkage disequilibrium as well. A newly defined polymorphism, Alu-L, located at approximately 40 kb distal to the FMR1 repeat, showed very low polymorphism in the Finnish samples. Analysis of the combined loci DXS548-FRAXAC1-FRAXE showed three founder haplotypes. Haplotype 21-19-16 was found on 27 (75%) of fragile X chromosomes but on none of controls. Three (8.4%) fragile X chromosomes had haplotypes 21-19-15, 21-19-20, and 21-19-25 differing from the common fragile X haplotype only in FRAXE. These could have arisen by recombination or from mutations of FRAXE. A second haplotype 21-18-17 was found in four (11.1%) fragile X chromosomes but only one (1.9%) control. This may represent a more recent founder mutation. A third haplotype 25-21-15, seen in two fragile X chromosomes (5.6%) and one (1.9%) control, was even less common and thus may represent an even more recent mutation or admixture of immigrant types. Analysis of the AGG interspersions within the FMR1 CGG repeat showed that 7/8 premutation chromosomes lacked an AGG whereas all controls had at least one AGG. This supports the hypothesis that the mutation of AGG to CGG leads to repeat instability and mutational expansion.
Asunto(s)
Efecto Fundador , Síndrome del Cromosoma X Frágil/genética , Mutación , Proteínas de Unión al ARN , Finlandia , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Frecuencia de los Genes , Haplotipos , Humanos , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/genética , Polimorfismo Genético , Repeticiones de TrinucleótidosRESUMEN
FRAXE is a fragile site located at Xq27-8, which contains polymorphic triplet GCC repeats associated with a CpG island. Similar to FRAXA, expansion of the GCC repeats results in an abnormal methylation of the CpG island and is associated with a mild mental retardation syndrome (FRAXE-MR). We surveyed the GCC repeat alleles of FRAXE from 3 populations. A total of 665 X chromosomes including 416 from a New York Euro-American sample (259 normal and 157 with FRAXA mutations), 157 from a Chinese sample (144 normal and 13 FRAXA), and 92 from a Finnish sample (56 normal and 36 FRAXA) were analyzed by polymerase chain reaction. Twenty-seven alleles, ranging from 4 to 39 GCC repeats, were observed. The modal repeat number was 16 in the New York and Finnish samples and accounted for 24% of all the chromosomes tested (162/665). The modal repeat number in the Chinese sample was 18. A founder effect for FRAXA was suggested among the Finnish FRAXA samples in that 75% had the FRAXE 16 repeat allele versus only 30% of controls. Sequencing of the FRAXE region showed no imperfections within the GCC repeat region, such as those commonly seen in FRAXA. The smaller size and limited range of repeats and the lack of imperfections suggests the molecular mechanisms underlying FRAXE triplet mutations may be different from those underlying FRAXA.
Asunto(s)
Síndrome del Cromosoma X Frágil/genética , Discapacidad Intelectual/genética , Repeticiones de Trinucleótidos , Cromosoma X , Alelos , Secuencia de Bases , China , Mapeo Cromosómico , Cartilla de ADN , Etnicidad , Europa (Continente)/etnología , Finlandia , Humanos , Datos de Secuencia Molecular , New York , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , SíndromeRESUMEN
OBJECTIVE: To evaluate the association between velamentous cord insertion and adverse pregnancy outcome in singleton pregnancies, and to assess the diagnostic usefulness of nonstress testing (NST) and Doppler ultrasound in this condition. METHODS: We retrospectively reviewed 12,750 consecutive singleton, chromosomally normal pregnancies from July 1989 through December 1993 at the University Hospital of Kuopio, Finland. Of these, 216 were complicated by velamentous umbilical cord insertion, whereas the remaining 12,534 were normal controls. Using multiple regression analysis, we evaluated the risks by noting adverse infant outcomes: low birth weight (LBW), small for gestational age (SGA), preterm delivery, fetal death, admission to a specific infant care unit, low Apgar scores, neonatal acidemia, and abnormal intrapartum fetal heart rate (FHR) patterns. At prenatal visits, NST and Doppler ultrasound examinations were carried out as a routine part of obstetric care. RESULTS: Even after we controlled for confounding factors, velamentous umbilical cord insertion was associated with higher risk of LBW (odds ratio [OR] 2.32), SGA (OR 1.54), preterm delivery (OR 2.12), low Apgar scores at 1 and 5 minutes (ORs 1.76 and 2.47, respectively), and abnormal intrapartum FHR pattern (OR 1.59). Only 5% of the patients with abnormal insertion showed pathologic NST results at prenatal visits. Ultrasonographic examination was carried out on 80 patients with velamentous umbilical cord insertion as a routine part of obstetric care, and in only one case was direct visualization of the abnormal insertion successful. After we excluded pregnancies with preeclampsia, abnormal umbilical artery Doppler velocimetry was found in none of the cases examined (n = 48). CONCLUSION: There were substantial differences in pregnancy outcome measures between the subjects with velamentous umbilical cord insertion and controls. Current antepartum methods of tracing uteroplacental problems are not effective in the prenatal detection of abnormal insertion. Therefore, in future studies, the use of other diagnostic tools, such as color Doppler imaging of cord insertion, should be evaluated in high-risk pregnancies followed-up because of fetal growth restriction.
Asunto(s)
Complicaciones del Embarazo/diagnóstico por imagen , Resultado del Embarazo , Ultrasonografía Prenatal , Cordón Umbilical/diagnóstico por imagen , Adolescente , Adulto , Femenino , Humanos , Modelos Logísticos , Oportunidad Relativa , Embarazo , Estudios Retrospectivos , Cordón Umbilical/embriologíaRESUMEN
Sixteen pregnancies of 12 women with a previous child affected with the Meckel syndrome were monitored by ultrasonic scanning and amniotic fluid alpha-fetoprotein (AFP) assay. Second-trimester AFP testing in 14 pregnancies detected 1 of 2 affected fetuses, and was normal in all 12 pregnancies in which the child was normal. It is concluded that measurement of amniotic fluid AFP is helpful for Meckel syndrome only when there is an associated open neural tube defect. The importance of extremely careful ultrasonography is emphasized.