RESUMEN
Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.
Asunto(s)
Demencia/genética , Mutación , Trastornos Parkinsonianos/genética , Proteínas tau/genética , Adulto , Sustitución de Aminoácidos , Conducta , Encéfalo/patología , Trastornos del Conocimiento/etiología , Cisteína , Demencia/metabolismo , Demencia/patología , Demencia/psicología , Humanos , Masculino , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/psicología , Linaje , Personalidad , Fenotipo , Isoformas de Proteínas/metabolismo , Treonina , Proteínas tau/metabolismoRESUMEN
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15-29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.
Asunto(s)
Fumarato Hidratasa/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias/genética , Adolescente , Adulto , Factores de Edad , Anciano , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/genética , Estudios de Cohortes , Femenino , Finlandia , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Leiomiomatosis/diagnóstico , Leiomiomatosis/genética , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Fenotipo , Factores de RiesgoRESUMEN
Microsatellite (MS) instability occurs in tumors with DNA mismatch repair (MMR) deficiencies but is typically absent in adjacent normal tissue. However, MS mutations have been observed in normal tissues from rare individuals with congenital MMR deficiencies. Autopsy tissues from a 4-year-old with congenital MMR deficiency (MLH1-/-) were examined for MS mutations. Insertions and deletions were observed in CA-repeat MS loci. Approximately 0.26 to 1.4 mutations per MS locus per cell were estimated to be present in normal heart, lymph node, kidney, and bladder epithelium. These findings illustrate that phenotypically normal MMR-deficient cells commonly accumulate MS mutations. Loss of MMR and the accumulation of some MS mutations may occur early in MMR-deficient tumor progression, even before a gatekeeper mutation.
Asunto(s)
Disparidad de Par Base , Reparación del ADN/genética , Repeticiones de Microsatélite/genética , Proteínas Adaptadoras Transductoras de Señales , Neoplasias Encefálicas/genética , Proteínas Portadoras , Preescolar , ADN/genética , ADN/aislamiento & purificación , Femenino , Glioma/genética , Humanos , Homólogo 1 de la Proteína MutL , Mutación , Proteínas de Neoplasias/genética , Proteínas NuclearesRESUMEN
OBJECTIVES: The aim of this study was to assess the occurrence of the two most commonly encountered mitochondrial DNA (mtDNA) deletions in the hearts of patients with idiopathic dilated cardiomyopathy. BACKGROUND: The mutation frequency of mtDNA is high, and sporadic cases of cardiomyopathies associated with mtDNA deletions have been described. Reports of increases in mtDNA deletions with advancing age also exist. METHODS: We studied 15 consecutive patients with typical signs of idiopathic dilated cardiomyopathy, without a family history, together with 16 control hearts obtained at autopsy from patients who died of noncardiac causes. The patients underwent both right and left heart catheterization, during which endomyocardial biopsy samples were taken. The mtDNA in these samples and in the control hearts was analyzed by the polymerase chain reaction technique for the occurrence and proportion of 5- and 7.4-kilobase (kb) deletions (Cambridge sequence map positions from nucleotides 8469 to 13447 and 8637 to 16084, respectively). RESULTS: The 5-kb mtDNA deletion was observed in the hearts of all of the patients with idiopathic dilated cardiomyopathy, accounting for 0.32 +/- 0.05% (mean +/- SEM) of the total mtDNA. The 7.4-kb deletion was found in 7 of the 15 patients with idiopathic dilated cardiomyopathy and comprised 0.28 +/- 0.08% of the total. The 5- and 7.4-kb deletions were detected in 12 and 9 control hearts, respectively, quantitatively similar to the patients with idiopathic dilated cardiomyopathy. A sigmoidal age dependency of the mtDNA deletions was found both in the patients with cardiomyopathy and in the control hearts, but after elimination of the confounding age variable, there was no difference between these groups. CONCLUSIONS: Because of the similarity of the age-dependent increase in the frequency of mtDNA deletions in cardiomyopathic and control hearts, the deletions have no causal relation with idiopathic dilated cardiomyopathy. The present results confirm the notion of an increase in mtDNA deletions with advancing age and show that endomyocardial tissue sampling is a feasible method for detecting mtDNA defects in affected hearts.
Asunto(s)
Cardiomiopatía Dilatada/genética , ADN Mitocondrial/genética , Eliminación de Gen , Adulto , Factores de Edad , Cardiomiopatía Dilatada/patología , Estudios de Casos y Controles , Mapeo Cromosómico , Endocardio/ultraestructura , Femenino , Humanos , Modelos Logísticos , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
The placenta is responsible for the production of progesterone (P) and estrogens during human pregnancy. In this study, the expression of several key steroidogenic enzymes was investigated in different cell types of human placenta during early and mid-gestation by in situ hybridization. 3Beta-hydroxysteroid dehydrogenase type 1 (3beta-HSD1), P450 aromatase (P450arom) and 17beta-hydroxysteroid dehydrogenase type 1 (17HSD1) were expressed abundantly in syncytiotrophoblast (ST) cells. These three enzymes were also detected in some column cytotrophoblast (CCT) cells. 17HSD5 was found in intravillous stromal (IS) cells in low levels, suggesting that androgens may be synthesized and metabolized in the placenta. 17HSD7 was found in all types of placental cells. Moreover, 17HSD2 was localized in IS cells. The expression level of 17HSD2 gradually increased during pregnancy weeks 7-16, concurrently with the androgen production by the male fetus. The present study provides evidence that CCT and IS cells participate in P and estrogen biosynthesis, in addition to ST cells. 17HSD2 also converts 20alpha-dihydroprogesterone (20-OH-P) to P, whereas 17HSD5 and 17HSD7 inactivate P. Therefore, the action of 3beta-HSD1 and 17HSD2 on P biosynthesis in the placenta is countered by 17HSD5 and 17HSD7, which may provide an optimal level of P for the maintenance and progression of pregnancy.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , 3-Hidroxiesteroide Deshidrogenasas/genética , Aromatasa/genética , Placenta/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Andrógenos/biosíntesis , Estrógenos/biosíntesis , Femenino , Feto/metabolismo , Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Placenta/citología , Placentación , Embarazo , Progesterona/biosíntesisRESUMEN
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by cerebral symptoms, but peripheral nerve or muscle involvement has not been reported. We describe a patient who had a stereotypic clinical presentation of CADASIL and, in addition, myopathy with ragged-red fibers, suggesting a mitochondrial disorder. Therefore we determined the nucleotide sequence in the entire coding region of the patient's mtDNA by conformation-sensitive gel electrophoresis and sequencing. Sequence of the exon 4 in the Notch3 gene was determined in a similar fashion. We found that the patient had myopathy with ragged-red fibers, and ultrastructural examination revealed mitochondrial aberrations. CADASIL was due to an R133C mutation in Notch3; in addition, we found a novel mutation 5650G>A in the tRNAAla gene in mtDNA. The mutation was heteroplasmic, with the proportions of the mutant genome being 99% in muscle, 96% in the buccal epithelium, 95% in the skin, and 65% in the blood. The absence of the mutation in a maternal cousin four times removed indicated that it was new in the pedigree. We suggest that the mtDNA mutation is pathogenic, as it was associated with a relevant clinical phenotype, it was not found among controls, and it altered a structurally important segment in the amino acid acceptor stem in the tRNAAla. Furthermore, its absence in nine patients from five families with R133C suggests that its relationship with the Notch3 mutation is coincidental.
Asunto(s)
ADN Mitocondrial , Demencia por Múltiples Infartos/genética , Enfermedades Musculares/genética , Mutación , Proteínas Proto-Oncogénicas/genética , Receptores de Superficie Celular , Secuencia de Bases , Encéfalo/patología , Clonación Molecular , Exones , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Músculos/ultraestructura , Conformación de Ácido Nucleico , Fenotipo , Reacción en Cadena de la Polimerasa , ARN de Transferencia de Alanina/genética , Receptor Notch3 , Receptores NotchRESUMEN
Although characterized by a highly variable phenotype and multiple genetic alterations, glioblastomas are considered monoclonal in origin. We here report on a 64-yr-old patient who developed a second glioblastoma in the left frontal lobe 10 yr after surgical resection of a glioblastoma of right frontal lobe. The first tumor contained 2 p53 mutations, in codon 213 (CGA-->TGA, Arg-->stop) and codon 306 (CGA-->TGA, Arg-->stop), further, 1 missense PTEN mutation (codon 257, TTC-->TTA, Phe-->Leu) and a silent PTEN mutation (codon 154, TTC-->TTT, Phe-->Phe). The second glioblastoma also contained multiple, but different mutations: p53 mutations in codons 158 (CGC-->CAC, Arg-->His) and 273 (CGT-->TGT, Arg-->Cys), and a PTEN mutation in codon 233 (CGA-->TGA, Arg-->Stop). Both neoplasms had a homozygous p16 deletion. The discordant pattern of mutations indicates that the second glioblastoma was not a recurrence but an independent second glioblastoma. The presence in these neoplasms of multiple mutations in tumor suppressor genes suggests the involvement of a novel disease mechanism but there was no indication of a DNA mismatch repair deficiency or of an inherited tumor syndrome.
Asunto(s)
Glioblastoma/genética , Glioblastoma/patología , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 19/genética , Análisis Mutacional de ADN , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/patología , Glioblastoma/diagnóstico por imagen , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid-Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N-terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid-lipofuscinosis with an exceptionally protracted course.
Asunto(s)
Epilepsia Tónico-Clónica/clasificación , Lipofuscinosis Ceroideas Neuronales/clasificación , Adulto , Electroforesis en Gel Bidimensional , Epilepsia Tónico-Clónica/genética , Epilepsia Tónico-Clónica/metabolismo , Epilepsia Tónico-Clónica/patología , Humanos , Inmunohistoquímica , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Lipofuscinosis Ceroideas Neuronales/metabolismo , Lipofuscinosis Ceroideas Neuronales/patología , LinajeRESUMEN
GATA-4 is a highly conserved transcription factor that plays a critical role in regulating embryonic morphogenesis and cellular differentiation. Given the emerging role of GATA-4 in the development and function of murine gonads, we have now studied its role in human testis. We find that GATA-4 is expressed from early human fetal testicular development to adulthood. This transcription factor is evident in Sertoli cells through fetal and postnatal development. Expression of GATA-4 in Sertoli cells peaks at 19-22 weeks gestation at the time of high circulating fetal FSH. In Leydig cells, GATA-4 is expressed during fetal period and after puberty, coinciding with the periods of active androgen synthesis in the testis; this suggests a link between GATA-4 and steroidogenesis. Also, fetal germ cells and prepubertal spermatogonia express GATA-4, and it is down-regulated in these cells after puberty. As hormonal regulation of GATA-4 in human testis was not possible to study directly, we used testicular samples from patients who had endocrine abnormalities or were hormonally treated. Testicular expression of GATA-4 in hCG-treated cryptorchidism does not differ from that in controls. In androgen resistance, GATA-4 expression in Sertoli and germ cells is weak or totally absent. GATA-4 protein is abundantly present in Sertoli and Leydig cell tumors, suggesting a relationship to tumorigenesis or tumor progression in somatic cell-derived testicular neoplasms.
Asunto(s)
Proteínas de Unión al ADN/biosíntesis , Enfermedades Testiculares/metabolismo , Testículo/crecimiento & desarrollo , Testículo/metabolismo , Factores de Transcripción/biosíntesis , Adulto , Antagonistas de Andrógenos/farmacología , Síndrome de Resistencia Androgénica/genética , Síndrome de Resistencia Androgénica/metabolismo , Northern Blotting , Western Blotting , Gonadotropina Coriónica/farmacología , Criptorquidismo/genética , Criptorquidismo/metabolismo , Proteínas de Unión al ADN/genética , Femenino , Factor de Transcripción GATA4 , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Inmunohistoquímica , Masculino , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/metabolismo , Enfermedades Testiculares/genética , Enfermedades Testiculares/patología , Testículo/patología , Factores de Transcripción/genéticaRESUMEN
The recent finding that a mutation in the FSH receptor gene causes ovarian dysgenesis prompted the present study to determine the phenotype caused by this mutation. Twenty-two patients with ovarian dysgenesis and a 566C-->T mutation in the FSH receptor gene (designated FSH-resistant ovaries or FSHRO) were compared with 30 clinically similar patients with ovarian dysgenesis (designated ODG) who did not have this mutation. The genealogical studies suggested a founder effect of the FSH receptor gene mutation in Finland. Clinically, both groups of patients were characterized by primary or early secondary amenorrhea, variable development of secondary sex characteristics, and high serum levels of FSH and LH. Notable differences were observed in median adult height (FSHRO patients were shorter) and the occurrence of follicles judged by transvaginal sonography (observed in 6 of 8 FSHRO vs. 1 of 11 ODG) and ovarian histology (present in all 9 FSHRO vs. 1 of 4 ODG). These findings suggest that a subset of ovarian dysgenesis patients with the FSH receptor mutation 566C-->T is pathogenetically distinct, possibly due to residual receptor activity, and that these patients can be tentatively identified by demonstrating the presence of ovarian follicles and confirmed by mutation analysis.
Asunto(s)
Mutación Puntual , Insuficiencia Ovárica Primaria/diagnóstico , Insuficiencia Ovárica Primaria/genética , Receptores de HFE/genética , Adolescente , Adulto , Amenorrea , Estatura , Análisis Mutacional de ADN , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Ovario/diagnóstico por imagen , Insuficiencia Ovárica Primaria/diagnóstico por imagen , UltrasonografíaRESUMEN
The majority of oocytes present in fetal ovaries are depleted before birth, and only about 400 will ovulate during the normal fertile life span. Studies on animals have shown that apoptosis is the mechanism behind oocyte depletion and follicular atresia. In the present study, we investigated the extent and localization of apoptosis in human fetal (aged 13-40 weeks) and adult ovaries. Furthermore, the expression of apoptosis-regulating proteins, bcl-2 and bax, and the relationship of transcription factor GATA-4 were studied. Apoptosis was found in ovarian follicles throughout fetal and adult life. During fetal development, apoptosis was localized mainly to primary oocytes and was highest between weeks 14-28, decreasing thereafter toward term. Expression of bcl-2 was observed only in the youngest fetal ovaries (weeks 13-14), and bax was present in the ovaries throughout the entire fetal period. In adult ovaries, apoptosis was detected in granulosa cells of secondary and antral follicles, and Bcl-2 and bax were expressed from primary follicles onwards. During fetal ovarian development, GATA-4 messenger RNA and protein were localized to the granulosa cells, with expression being highest in the youngest ovaries and decreasing somewhat toward term. The expression pattern of GATA-4 suggests that it may be involved in the mechanisms protecting granulosa cells from apoptosis from fetal to adult life. The results indicate that depletion of ovarian follicles in the human fetus occurs through intrinsic mechanisms of apoptosis in oocytes, and later in adult life the survival of growing follicles may be primarily determined by granulosa cell apoptosis.
Asunto(s)
Apoptosis , Proteínas de Unión al ADN/análisis , Folículo Ovárico/fisiología , Factores de Transcripción/análisis , Envejecimiento , Northern Blotting , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Femenino , Factor de Transcripción GATA4 , Edad Gestacional , Células de la Granulosa/química , Células de la Granulosa/citología , Humanos , Inmunohistoquímica , Hibridación in Situ , Oocitos/citología , Folículo Ovárico/embriología , Folículo Ovárico/crecimiento & desarrollo , Ovario/química , Ovario/citología , Ovario/embriología , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , ARN Mensajero/análisis , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Proteína X Asociada a bcl-2RESUMEN
We describe a family with three cases of "clinically incomplete mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome" in which heteroplasmic tRNA(Leu(UUR)) mutation at nucleotide 3243 of the mitochondrial DNA was present in three generations. The amount of mutant genome varied among tissues: it was 60% in the kidney, 72% in the cardiac muscle, and 91% in the liver of the female proband's affected brother and 63% in the kidney, 71% in the cardiac muscle, and 71% in the liver of the female proband's perinatally deceased son. The tRNA(Leu(UUR)) mutation was also carried by the siblings of the proband's affected mother. None of them had any clinical signs of MELAS syndrome. This syndrome has the new feature of being associated with adult-onset diabetes mellitus, neurosensory hearing loss, and short stature.
Asunto(s)
ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Pérdida Auditiva Sensorineural/genética , Síndrome MELAS/genética , Mutación Puntual , ARN de Transferencia de Leucina/genética , Adulto , Secuencia de Bases , ADN Mitocondrial/aislamiento & purificación , Femenino , Humanos , Riñón/metabolismo , Masculino , Mitocondrias/metabolismo , Mitocondrias Cardíacas/metabolismo , Mitocondrias Musculares/metabolismo , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
Fetal development and tumor progression both require a complex system of extracellular matrix (ECM) synthesis and breakdown, which is mediated by, for instance, the matrix metalloproteinases (MMPs). Human metalloelastase (MMP-12) is an MMP, the expression of which has so far been documented in macrophages associated with atherosclerosis, wound repair, and certain cancers. In this study we first examined the expression of MMP-12 during human fetal development. By in situ hybridization MMP-12 transcripts were detected in chondrocytes of hypertrophic cartilage in vertebrae of the spinal column, in ribs, and in extremities undergoing ossification, beginning at the gestational age of 8 weeks. Also, periosteal cells expressed MMP-12 at 11 weeks. No expression of MMP-12 mRNA could be noted in other fetal tissues, including the skin, lungs, intestine, kidney, and liver. Expression of MMP-12 mRNA could not be detected in adult normal cartilage or osteosarcomas, but in chondrosarcomas both macrophages (8 of 19 samples) (identified by CD68 immunostaining) and chondrosarcoma cells (8 of 19) were positive. MMP-12 was also demonstrated in the tumors by western blotting and it was expressed in the same regions as MMP-13 mRNA. By immunostaining, MMP-12 mRNA colocalized with the protein in both fetal and chondrosarcoma specimens. Unlike basic fibroblast growth factor (bFGF) and transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) induced MMP-12 mRNA production in chondrosarcoma-derived HTB-94 cells. Our results suggest that MMP-12 plays an important role in ECM remodeling during fetal bone development and is induced when chondrocytes undergo malignant transformation.
Asunto(s)
Neoplasias Óseas/fisiopatología , Cartílago/embriología , Condrocitos/fisiología , Condrosarcoma/fisiopatología , Metaloendopeptidasas/genética , Cartílago/citología , Transformación Celular Neoplásica , Células Cultivadas , Condrocitos/citología , Condrocitos/efectos de los fármacos , Colagenasas/genética , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/fisiología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Macrófagos/enzimología , Metaloproteinasa 12 de la Matriz , Metaloproteinasa 13 de la Matriz , ARN Mensajero/análisis , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Anhidrotic ectodermal dysplasia (EDA) is characterized by defects in the development of teeth, hair, and sweat glands. To study the expression of the human gene defective in EDA in human fetal development (Weeks 6-23 of gestational age) and in adult tissues, in situ hybridization and immunohistochemistry were used. First signs of expression were detected at Week 8 in epidermis and in neuroectodermal cells. Starting at Week 12, osteoblasts and thymus were positive for EDA mRNA. Hair follicles expressed EDA mRNA from 18 weeks. The presence of the EDA protein coincided with mRNA expression in the tissues examined. The expression pattern of the EDA gene is consistent with typical involvement of the skin in the syndrome. However, the expression is not limited to the ectodermal tissues and many sites of expression are not obviously reflected in the clinical features of the syndrome.
Asunto(s)
Huesos/metabolismo , Sistema Nervioso Central/metabolismo , Displasia Ectodérmica/genética , Piel/metabolismo , Timo/metabolismo , Adulto , Huesos/citología , Huesos/embriología , Sistema Nervioso Central/embriología , Displasia Ectodérmica/metabolismo , Folículo Piloso/embriología , Folículo Piloso/metabolismo , Humanos , Inmunohistoquímica , Hibridación in Situ , ARN Mensajero/análisis , Sistema Respiratorio/metabolismo , Piel/embriología , Timo/embriología , Factores de Tiempo , Distribución TisularRESUMEN
OBJECTIVES: To assess the frequency of mitochondrial abnormalities in muscle histology, defects in respiratory chain enzyme activities, and mutations in mitochondrial DNA (mtDNA) in children with unexplained psychomotor retardation in the population of Northern Finland. BACKGROUND: The frequency of mitochondrial diseases among patients with childhood encephalopathies and myopathies is not known. Frequencies are difficult to estimate because the clinical presentation of these disorders is variable. METHODS: A total of 116 consecutive patients with undefined encephalopathies and myopathies were enrolled during a 7-year period in a hospital serving as the only neurologic unit for a pediatric population of 97 609 and as the only tertiary level neurologic unit for a pediatric population of 48 873. Biochemical and morphologic investigations were performed on muscle biopsy material, including oximetric and spectrophotometric analyses of oxidative phosphorylation, histochemistry, electron microscopy, and molecular analysis of mtDNA. RESULTS: Ultrastructural changes in the mitochondria were the most common finding in the muscle biopsies (71%). Ragged-red fibers were found in 4 cases. An oxidative phosphorylation defect was found in 26 children (28%), complex I (n = 15) and complex IV (n = 13) defects being the most common. Fifteen percent of patients (n = 17/116) with unexplained encephalomyopathy or myopathy had a probable mitochondrial disease. Common pathogenic mutations were found in the mtDNA of only 1 patient (.9%). CONCLUSIONS: The common known mutations in mtDNA are rarely causes of childhood encephalomyopathies, which is in contrast to the considerable frequency of the common MELAS mutation observed among adults in the same geographical area. Biochemically and morphologically verified mitochondrial disorders were nevertheless common among the children, making the analysis of a muscle biopsy very important for clinical diagnostic purposes.
Asunto(s)
Encefalomiopatías Mitocondriales/epidemiología , Adolescente , Adulto , Biopsia , Niño , Preescolar , Estudios Transversales , ADN Mitocondrial/genética , Femenino , Finlandia/epidemiología , Frecuencia de los Genes/genética , Genética de Población , Humanos , Lactante , Síndrome MELAS/epidemiología , Síndrome MELAS/genética , Síndrome MELAS/patología , Masculino , Microscopía Electrónica , Mitocondrias Musculares/patología , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/patología , Músculo Esquelético/patología , Estudios ProspectivosRESUMEN
We describe 16 cases of a lethal syndrome with multiple congenital contractures from ten families. The main clinical findings included intrauterine growth retardation with marked fetal hydrops, multiple contractures, and facial abnormalities, especially micrognathia. At autopsy, pulmonary hypoplasia and muscular atrophy were present. There was a paucity of anterior horn motor neurons in the four studied cases. We think that the cases represent the same clinical entity, probably caused by homozygosity of an autosomal recessive gene. The syndrome resembles the Pena-Shokeir I syndrome, but seems to differ in some respects, including length of survival and presence of hydrops. Prenatal diagnosis of this syndrome is possible after the 16th week of pregnancy with ultrasound.
Asunto(s)
Contractura/genética , Contractura/congénito , Contractura/diagnóstico , Edema/genética , Femenino , Genes Letales , Genes Recesivos , Humanos , Recién Nacido , Masculino , Embarazo , Diagnóstico Prenatal , SíndromeRESUMEN
In a routine cytogenetic investigation of the outpatients of a hospital for the mentally retarded, a 26-year-old women with a presumptive interstitial deletion of the short arm of one of the X chromosomes was found. The same aberration was found in her phenotypically normal mother and in one of her four sisters, all phenotypically normal. By GTG- and QFQ-banding methods, the deletion was interpreted to involve the entire band Xp21 and adjacent parts of p11 and p22. The karyotype is written 46,X,del(X)(pter leads to p22::p11 leads to qter). By autoradiography and Bud R acridine orange technique, the deleted X was the late replicating one in all three affected persons. The deletion apparently causes shortness of stature but no other phenotypic symptoms or signs. Hence a gene or genes controlling stature is located in band Xp21 or regions immediately adjacent to this band. Since the absence of this region does not cause streak gonads, it does not contain genes controlling the formation of the ovaries. This appears to be the first example of a heritable chromosome deletion compatible with a normal phenotype and reproduction.
Asunto(s)
Deleción Cromosómica , Cromosomas Sexuales , Cromosoma X , Adulto , Peso Corporal , Mapeo Cromosómico , Femenino , Genes , Ligamiento Genético , Humanos , Discapacidad Intelectual/genética , Persona de Mediana Edad , Ovario/embriología , LinajeRESUMEN
We present 14 familial cases from five Finnish families affected with a life-threatening congenital diaphragmatic defect (CDD) and review data on 53 previously published familial cases. CDD occurred in three sibs and their half brother's son, and probably in all four offspring of parents consanguineous as both first and second cousins. In the remaining three Finnish families and in the vast majority of the previously reported familial cases, only two sibs were affected. Two thirds of those affected were males both in the Finnish and the overall series. Pedigree data, delayed fusion of the diaphragm as the primary pathogenetic mechanism, varying anatomical structure of the defective hemidiaphragm, association with other congenital anomalies, and data on animal experiments are more in accordance with multifactorial determination than with recessive inheritance. This does not exclude other genetic causes in some familial cases. The recurrence risk for sibs after one affected sib is about 2%. As the prognosis, especially in familial cases of CDD has remained grave, the development of fetal surgical treatment is desirable. This emphasizes the future role of prenatal diagnosis by ultrasound.
Asunto(s)
Hernias Diafragmáticas Congénitas , Diagnóstico Prenatal , Consanguinidad , Diafragma/anomalías , Femenino , Finlandia , Genes Recesivos , Asesoramiento Genético , Hernia Diafragmática/genética , Humanos , Recién Nacido , Masculino , Linaje , Pronóstico , RiesgoRESUMEN
We performed a neuropathological study on 5 fetuses with an autosomal recessive, lethal syndrome of congenital contractures diagnosed by fetal hydrops on ultrasonography. The fetuses showed a typical pattern of malpositioning of hips and knees with occasional pterygia of the neck and elbows. The muscles were hypoplastic and the spinal cords showed severe thinning, most markedly affecting the ventral half. A total loss of axons in the ventral and lateral funiculi, subtotal loss of anterior horn motor neurons with accompanying astrocytosis and astrogliosis, and similar but less severe changes at the brain stem level suggested a degenerative rather than a dysmorphogenetic mechanism. Sensory nuclei and pathways were distinctly less severely affected, if at all. The findings further delineate this condition as a genetically and pathoanatomically distinct autosomal recessive syndrome.
Asunto(s)
Anomalías Múltiples/patología , Contractura/patología , Enfermedades Fetales/patología , Anomalías Múltiples/genética , Tronco Encefálico/patología , Contractura/genética , Femenino , Enfermedades Fetales/genética , Movimiento Fetal , Humanos , Masculino , Músculos/patología , Nervios Periféricos/patología , Embarazo , Médula Espinal/patología , SíndromeRESUMEN
We describe a 22-year-old woman with primary amenorrhea, bilateral gonadoblastomas, and short stature (148.0 cm), but no other signs of the Ullrich-Turner syndrome. There were three cell lines identified in peripheral blood lymphocytes - 45,X (30%), 46,XY (60%), and 46,X,tan dic(Y) (10%). Cells cultured from gonadal biopsies showed only the 45,X karyotype. However, frozen sections of the biopsies showed frequent single and rare double-Y-chromatin bodies. Lymphocytes were H-Y antigen-negative. This previously undescribed structurally abnormal chromosome probably consists of two Y chromosomes attached end-to-end in a tandem translocation. One of the centromeres forms the primary (functional) constriction, the other being detectable only as C-positive material on each chromatid, so presumably inactive. The discrepancy between the presence of Y-chromatin in frozen sections of the gonads and its absence from karyotype in gonadal cultures is indicative of cell selection in tissue culture. Finally, the case confirms the high risk of gonadoblastoma in women with a Y chromosome, even in the absence of H-Y antigen.