Asunto(s)
Hiperinsulinismo Congénito/complicaciones , Complicaciones de la Diabetes/complicaciones , Enfermedades del Recién Nacido , Cooperación Internacional , Neoplasias/epidemiología , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Humanos , Incidencia , Lactante , Recién Nacido , Persona de Mediana Edad , Proyectos Piloto , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Fanconi-Bickel syndrome (FBS) is a rare disorder of glucose transport caused by autosomal recessive mutations in GLUT2. Clinically, FBS results in growth failure, hepatomegaly, renal Fanconi syndrome, and abnormal glucose homeostasis. We report a 23 month old female with FBS characterized by more severe and refractory hypoglycemia than typically seen in this disorder. Although previous reports indicate that FBS patients have diminished insulin secretion, our patient showed evidence of hyperinsulinism (HI). Sequence analysis showed that the patient was homozygous for a known null mutation in GLUT2, confirming the clinical diagnosis of FBS. Parental genotyping showed that the mother was heterozygous for the GLUT2 mutation, while the father was wild type. Tandem repeat marker analysis showed that the patient inherited the GLUT2 mutation via maternal isodisomy of chromosome 3. Further molecular testing showed that the patient was heterozygous for a mutation in ABCC8, a known cause of congenital HI. We discuss the patient's biochemical responses in light of the molecular findings.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Cromosomas Humanos Par 3/genética , Enfermedad del Almacenamiento de Glucógeno/patología , Mutación , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio/genética , Receptores de Droga/genética , Secuencia de Bases , Análisis Mutacional de ADN , Glucosa/metabolismo , Transportador de Glucosa de Tipo 2/genética , Enfermedad del Almacenamiento de Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Humanos , Lactante , Insulina/metabolismo , Secreción de Insulina , Madres , Receptores de Sulfonilureas , Síndrome , Disomía UniparentalRESUMEN
Phenylalanine loading has been proposed as a diagnostic test for autosomal dominant DRD (dopa-responsive dystonia), and recently, a phenylalanine/tyrosine (phe/tyr) ratio of 7.5 after 4 h was reported as diagnostic of DRD. To test the utility of this test in another sample with DRD, we administered an oral challenge of phenylalanine (100 mg/kg) to 11 individuals with DRD and one non-manifesting gene carrier. Only 6/12 had a 4 h phe/tyr ratio of greater than 7.5, suggesting that additional parameters must be set to avoid missing the diagnosis of DRD, including the need for the plasma phenylalanine to reach a minimum level 600 in order for the test to be valid. We propose that in cases where this minimum plasma phenylalanine level is not reached, plasma tetrahydrobiopterin should be measured or alternatively other symptomatic family members should be screened.
Asunto(s)
Trastornos Distónicos/diagnóstico , Fenilalanina , Tirosina , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Cartilla de ADN , Estudios de Evaluación como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenilalanina/administración & dosificación , Fenilalanina/sangre , Fenilalanina Hidroxilasa/genética , Análisis de Secuencia de ADN , Factores de Tiempo , Tirosina/sangreRESUMEN
Dystonia is a movement disorder involving sustained muscle contractions and abnormal posturing with a strong hereditary predisposition and without a distinct neuropathology. In this study the TOR1A (DYT1) gene was screened for mutations in cases of early onset dystonia and early onset parkinsonism (EOP), which frequently presents with dystonic symptoms. In a screen of 40 patients, we identified three variations, none of which occurred in EOP patients. Two infrequent intronic single base pair (bp) changes of unknown consequences were found in a dystonia patient and the mother of an EOP patient. An 18-bp deletion (Phe323_Tyr328del) in the TOR1A gene was found in a patient with early onset dystonia and myoclonic features. This deletion would remove 6 amino acids close to the carboxy terminus, including a putative phosphorylation site of torsinA. This 18-bp deletion is the first additional mutation, beyond the GAG-deletion (Glu302/303del), to be found in the TOR1A gene, and is associated with a distinct type of early onset dystonia.
Asunto(s)
Proteínas Portadoras/genética , Distonía Muscular Deformante/genética , Chaperonas Moleculares , Enfermedad de Parkinson/genética , Polimorfismo Genético , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Cartilla de ADN , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Eliminación de SecuenciaRESUMEN
Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.
Asunto(s)
Cromosomas Humanos Par 7/genética , Distonía/genética , Ligamiento Genético/genética , Mioclonía/genética , Mapeo Cromosómico , Cromosomas Humanos Par 11/genética , Exones/genética , Femenino , Marcadores Genéticos/genética , Humanos , Escala de Lod , Masculino , Linaje , Receptores de Dopamina D2/genética , Recombinación Genética/genética , Programas InformáticosAsunto(s)
Conflicto Psicológico , Consultores/psicología , Toma de Decisiones , Eticistas , Consultoría Ética , Ética Clínica , Ética Médica , Familia/psicología , Negociación/métodos , Negociación/psicología , Rol del Médico , Rol Profesional , Adolescente , Adulto , Directivas Anticipadas , Anciano , Anciano de 80 o más Años , Eutanasia Pasiva , Femenino , Humanos , Lactante , Perfil Laboral , Masculino , Inutilidad Médica , Persona de Mediana Edad , Defensa del Paciente , Privación de TratamientoRESUMEN
Early-onset idiopathic torsion dystonia (ITD) is an autosomal dominant hyperkinetic movement disorder with incomplete penetrance, associated with a 3 base-pair deletion in the DYT1 gene on chromosome 9q34. To determine the metabolic substrates of brain dysfunction in DYT1 dystonia, we scanned 7 nonmanifesting and 10 affected DYT1 carriers and 14 normal volunteers with [18F]fluorodeoxyglucose and positron emission tomography. We found that DYT1 dystonia is mediated by the expression of two independent regional metabolic covariance patterns. The first pattern, identified in an analysis of nonmanifesting gene carriers was designated movement free (MF). This abnormal pattern was characterized by increased metabolic activity in the lentiform nuclei, cerebellum, and supplementary motor areas. The MF pattern was present in DYT1 carriers with and without clinical manifestations and persisted in DYT1 dystonia patients in whom involuntary movements were suppressed by sleep. The second pattern, identified in an analysis of affected gene carriers with sustained contractions at rest, was designated movement related (MR). This pattern was characterized by increased metabolic activity in the midbrain, cerebellum, and thalamus. The expression of the MR pattern was increased in waking DYT1 patients with sustained dystonia, compared with DYT1 carriers who were unaffected or who had dystonia only on action, as well as normal controls. MR subject scores declined significantly with sleep in affected DYT1 patients but not in normal controls. These findings indicate the penetrance of the DYT1 gene is considerably greater than previously assumed. ITD is mediated through the interaction of functional brain networks relating separately to gene status and to abnormal movement.
Asunto(s)
Encéfalo/fisiología , Proteínas Portadoras/genética , Distonía Muscular Deformante/fisiopatología , Chaperonas Moleculares , Red Nerviosa/fisiología , Adolescente , Adulto , Anciano , Encéfalo/metabolismo , Mapeo Encefálico , Distonía Muscular Deformante/etiología , Distonía Muscular Deformante/genética , Femenino , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/genética , Trastornos del Movimiento/fisiopatología , Vías Nerviosas/fisiología , Sueño , Tomografía Computarizada de Emisión , VigiliaRESUMEN
Rapid-onset dystonia-parkinsonism (RDP), first described in a large Midwestern family, is now reported in a second, apparently unrelated, family in which four individuals have this same syndrome. All four developed sudden onset of dysarthria, dysphagia, severe dystonic spasms, bradykinesia, and postural instability over less than 1 hour to a few days. Three of the four had stable limb dystonia for several years preceding the onset of combined dystonia-parkinsonism. Treatment with levodopa/carbidopa provided little benefit. We propose diagnostic criteria for RDP and further define the spectrum of this unusual disease.
Asunto(s)
Distonía/genética , Enfermedad de Parkinson/genética , Adolescente , Adulto , Niño , Distonía/fisiopatología , Femenino , Humanos , Masculino , Enfermedad de Parkinson/fisiopatología , Linaje , Síndrome , Factores de TiempoRESUMEN
PURPOSE: The purpose of this study was to determine whether patients and their families found ethics consultations to be helpful and whether they were satisfied with the treatment decisions that were made in those cases where ethics consultation was requested. METHODS: Interviews were conducted with each patient (or surrogate) concerning whom an ethics consultation had been provided during a 1-year period at Loma Linda University Medical Center, excepting those who met exclusion criteria. The interview was done by telephone a few weeks after hospital discharge. It included multiple choice and open-ended questions. A content analysis was done on the solicited and spontaneous comments. RESULTS: Eighty-six ethics consultations were provided and interviews were completed for 56 of them (65%). Fifty-seven percent of interviewees found the ethics consultation to have been helpful, and only 4% found them to have been detrimental. Interviewees were more likely to have found the consultation helpful when they perceived that it had resulted in a significant change in treatment, and were less likely to have found it helpful when the patients were more seriously ill. In addition, 77% were satisfied with the treatment decisions made, and 11% showed some degree of dissatisfaction. CONCLUSIONS: Patients and families found ethics consultation provided by clinical ethicists at Loma Linda University Medical Center to be helpful in a majority of instances, and rarely found them detrimental. Based on an analysis of their comments, we believe ethics consultations were perceived as helpful in 7 ways: increased clinical clarity, increased moral or legal clarity, motivation to do what they believe is right, facilitation of the process of decision-making, implementation of a decision, interpretation of technical language, and consolation and support.
Asunto(s)
Toma de Decisiones , Eticistas , Consultoría Ética , Ética Médica , Familia , Satisfacción del Paciente , Derivación y Consulta , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Evaluación como Asunto , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The role of male pheromones in estrous cyclicity was studied in mice selected for different reproductive traits. When females are exposed to males of their own strain, estrous cycles are highly regular in females selected for increased embryo survival (line E). In contrast, cycle regularity is reduced by exposure of line E females to males from a strain characterized by irregular estrous cycles (line CN-). To investigate the inhibition of estrous cyclicity and the role of androgen in this phenomenon, line E females were housed in the olfactory presence of E males and later rehoused with one of the following: intact or castrated males of line E (homogenotypic condition) or line CN-heterogenotypic condition) or castrated CN- males provided with testosterone replacement. A final exposure to homogenotypic (line E) males was provided. Estrous cyclicity was decreased when line E females were rehoused with intact or castrated CN- males. Metestrus was prolonged by intact CN- males, whereas diestrus was prolonged in the presence of castrated CN- males. Androgen treatment did not enable castrated CN- males to prolong metestrus. These results demonstrate that: 1) heterogenotypic pheromones inhibit estrous cyclicity in line E; and 2) the inhibitory influence of line CN- males on line E estrous cyclicity is mediated by factors in addition to or other than testosterone.
Asunto(s)
Estro/fisiología , Feromonas/fisiología , Animales , Femenino , Genotipo , Masculino , Ratones , Ratones Endogámicos , Orquiectomía , Especificidad de la Especie , Testículo/fisiología , Testosterona/fisiologíaRESUMEN
Reproductive hormone secretion and ovarian LH receptor content were studied during the oestrous cycle of mice that differed in fertility after genetic selection. Strain variation in the secretory pattern of progesterone was observed along with differences in the timing and magnitude of prolactin release. Scatchard analysis showed similar affinities of the LH receptor for hCG in strains with increased or decreased reproductive performance, with a single order of binding sites during both pro-oestrus and dioestrus. The number of unoccupied LH receptors during pro-oestrus was greatest in mice with increased reproductive performance. These results provide evidence that trait selection can change gonadotrophin receptor concentration and the dynamics of hormone secretion during the oestrous cycle of the mouse.
Asunto(s)
Estro/metabolismo , Fertilidad/fisiología , Hormonas Esteroides Gonadales/metabolismo , Animales , Gonadotropina Coriónica/metabolismo , Femenino , Fertilidad/genética , Genotipo , Ratones , Ratones Endogámicos , Ovario/metabolismo , Progesterona/metabolismo , Prolactina/metabolismo , Receptores de HL/metabolismoRESUMEN
The results of segregation analysis applied to a family study of idiopathic torsion dystonia in Ashkenazi Jews are reported. The study is based on 43 probands (with age at onset prior to 27 years) from 42 nuclear families; pedigrees were extended systematically through all available first- and second-degree relatives, who were directly examined and videotaped. Final diagnoses were based on exam information and blinded videotape review. Segregation analysis demonstrated that the data are consistent with autosomal dominant inheritance with 30% penetrance. Recessive and polygenic inheritance were strongly rejected. There was no evidence for sporadic cases or new mutations. The high incidence and dominant inheritance of early-onset idiopathic torsion dystonia in Ashkenazi Jews suggests genetic homogeneity within this population, making it especially useful for linkage studies of this disorder.
Asunto(s)
Distonía Muscular Deformante/genética , Genes Dominantes , Judíos/genética , Modelos Genéticos , Adolescente , Adulto , Niño , Preescolar , Humanos , Lactante , Persona de Mediana EdadRESUMEN
The transition from early (E) to late (L) histone gene expression in developing sea urchin (Strongylocentrotus purpuratus) embryos was examined for H2B, H3, and H4 mRNAs by in situ hybridization of class-specific probes. Hybridization patterns indicate that the shift from E to L mRNAs occurs gradually and simultaneously in all blastomeres. Thus, during the transition the ratio of L to E mRNAs is similar in most cells. This suggests that no sudden changes in histone composition occur in individual cells which might be related to alterations in gene expression associated with differentiation of cell lineages. Around the midpoint of the transition, clusters of cells progressively appear which contain little, if any, E or L histone mRNA. This modulation of expression is coordinated for the three late genes examined because most individual cells contain either high or low levels of all three mRNAs. At blastula stage these clusters of unlabeled cells appear to be randomly distributed throughout the embryo. Subsequently the unlabeled regions expand and are found predominantly in aboral ectoderm as these cells cease to divide. Thus, the L/E histone mRNA ratio is not differentially regulated in diverse cell lineages, and the major differences in total histone mRNA content among individual cells may be related to cell cycle and/or the cessation of division.
Asunto(s)
Embrión no Mamífero/análisis , Regulación de la Expresión Génica , Histonas/genética , ARN Mensajero/análisis , Animales , Autorradiografía , Secuencia de Bases , Hibridación de Ácido Nucleico , Erizos de Mar , Distribución TisularRESUMEN
We have used in situ hybridization and RNA blotting analysis to compare the timing of accumulation of poly(A) and alpha-subtype histone mRNA during oogenesis in the sea urchin Strongylocentrotus purpuratus. In situ hybridization with 3H-poly(U) shows that the content of poly(A) in the developing oocyte increases four- to sixfold during vitellogenesis, implying a similar increase for polyadenylated maternal RNAs. In contrast, both RNA blotting and in situ hybridization demonstrate that there is little, if any, alpha-subtype histone mRNA in large oocytes. These results suggest that these maternal mRNAs accumulate in the pronucleus of the haploid egg after completion of meiotic maturation where they are stored until their release during the breakdown of the pronucleus during prophase.
Asunto(s)
Histonas/genética , Oocitos/metabolismo , Oogénesis , ARN Mensajero/metabolismo , Animales , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Femenino , Hibridación de Ácido Nucleico , Plásmidos , Poli A/metabolismo , Erizos de MarRESUMEN
Asymmetric RNA probes, which contain only the mRNA coding strand, provide a large increase in hybridization efficiency in situ over that observed with either symmetric (both strands represented) RNA or DNA probes. Asymmetric RNA probes are synthesized in vitro by transcription from recombinants formed between sequences encoding sea urchin mRNAs and the transcription vector R7 delta 7. Using a probe representing early variant histone mRNA sequences we have characterized hybridization to sections of sea urchin embryos with respect to thermal stability of the hybrids formed, optimum temperature, effect of sequence divergence on hybrid thermal stability, and dependence of the hybridization signals on probe concentration and hybridization time. Estimates from the observed signals indicate that a large fraction of target RNAs is both retained in sections and hybridized with probe at saturation. Coupled with measurements of nonspecific background binding of heterologous probes, these data indicate that the method has sufficient sensitivity to detect many moderately abundant mRNAs (20-75 molecules per cell in the 1500-cell pluteus). In situ hybridizations to embryos at different developmental stages show that while histone mRNAs are uniformly distributed in cleaving embryos, different cell lineages of older embryos show large differences in accumulation of these mRNAs.
Asunto(s)
Histonas/genética , Hibridación de Ácido Nucleico , ARN Mensajero/metabolismo , Erizos de Mar/embriología , Animales , ADN Recombinante , Estabilidad de Medicamentos , Calor , Cinética , Ácidos Nucleicos Heterodúplex , Plásmidos , Transcripción GenéticaRESUMEN
Previous studies demonstrated that the pronucleus of the unfertilized sea urchin egg contains a high concentration of transcripts complementary to the early histone repeat unit (D. L. Venezky, L. M. Angerer, and R. C. Angerer (1981). Cell 24, 385-391.) In this paper, in situ hybridization techniques of improved sensitivity are used to show that these nuclear RNAs include authentic histone mRNA but not spacer-complementary sequences. It is estimated that most early-variant histone mRNA contained in the egg is, in fact, restricted to the pronucleus. These mRNAs are released to the cytoplasm at the time of nuclear breakdown of first cleavage and rapidly distribute throughout the cytoplasm.