RESUMEN
Risperidone blood levels were measured every 2 weeks after initiation of therapy in 24 refractory chronic schizophrenic patients referred to a locked, skilled nursing facility for long-term treatment. Blood levels were assessed on 285 occasions over a 1- to 16-month treatment program. Drug plasma level increases peaked by 2 months for risperidone at 334% and by 6 months for 9-hydroxy-risperidone at 104% over the baseline levels. Total blood levels (risperidone plus 9-hydroxy-risperidone) peaked at 111% increase at 6 months and then declined 8% per month to 12 months, stabilizing at a value 31% higher than the initial value. Significant dose to blood level interindividual variation was noted. Considerable blood level variation was evident in single blood level sample determinations. The results suggest the value of risperidone blood levels, consideration of reduction of initial recommended starting dosages, and a need to optimize risperidone dosage approaches individually to patients.
Asunto(s)
Antipsicóticos/sangre , Antipsicóticos/uso terapéutico , Risperidona/sangre , Risperidona/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Haloperidol levels in blood were measured monthly in 43 refractory chronic schizophrenic patients referred to a locked skilled nursing facility for long-term treatment. Gross toxic side effects (seizures, catatonia, confusion) and Neuroleptic Induced Deficit Syndrome in conjunction with blood levels over 30 ng/ml were identified in 13 of our 43 patients. Blood level reductions contributed to a reduction of side effects and clinical improvement and led to the expedited discharge of 6 of these 13 patients of the toxic subgroup. Considerable blood level variation was evident in single samples, and four levels appeared necessary to develop confidence for accuracy. Significant dose to blood level interindividual variability was identified, thereby bringing into question fixed-dose approaches to patients. The results strongly suggest the utility of haloperidol blood levels in the clinical setting.
Asunto(s)
Antipsicóticos/efectos adversos , Haloperidol/efectos adversos , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Administración Oral , Adulto , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacocinética , Disponibilidad Biológica , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Femenino , Haloperidol/administración & dosificación , Haloperidol/farmacocinética , Humanos , Cuidados a Largo Plazo , Masculino , Tasa de Depuración Metabólica/fisiología , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Psicosis Inducidas por Sustancias/sangre , Psicosis Inducidas por Sustancias/diagnóstico , Psicosis Inducidas por Sustancias/psicología , Esquizofrenia/sangreRESUMEN
The fragile X syndrome is the result of amplification of a CGG trinucleotide repeat in the FMR1 gene and anticipation in this disease is caused by an intergenerational expansion of this repeat. Although regression of a CGG repeat in the premutation range is not uncommon, regression from a full premutation (> 200 repeats) or premutation range (50-200 repeats) to a repeat of normal size (< 50 repeats) has not yet been documented. We present here a family in which the number of repeats apparently regressed from approximately 110 in the mother to 44 in her daughter. Although the CGG repeat of the daughter is in the normal range, she is a carrier of the fragile X mutation based upon the segregation pattern of Xq27 markers flanking FMR1. It is unclear, however, whether this allele of 44 repeats will be stably transmitted, as the daughter has as yet no progeny. Nevertheless, the size range between normal alleles and premutation alleles overlap, a factor that complicates genetic counseling.
Asunto(s)
Síndrome del Cromosoma X Frágil/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Proteínas de Unión al ARN , Secuencias Repetitivas de Ácidos Nucleicos/genética , Alelos , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Haplotipos , Heterocigoto , Humanos , Masculino , LinajeRESUMEN
BACKGROUND: At least half of the cases of profound deafness of early onset are caused by genetic factors, but few of the genetic defects have been identified. This is particularly true of the most common hereditary forms of deafness, which occur in the absence of any associated syndrome. METHODS: We studied a large Indonesian family in which hearing loss was inherited in an autosomal dominant pattern. The hearing loss first affects the high frequencies during the teens or 20s and becomes profound within 10 years. To locate the responsible gene, we performed genetic-linkage analysis, using microsatellite markers distributed over the entire genome. We then performed linkage analyses in an American family and a Dutch family with similar patterns of hereditary hearing loss. RESULTS: In the extended Indonesian family, a gene linked to deafness mapped to chromosome 1p, with a multipoint lod score of more than 7. In the American family, deafness was linked to the same locus on chromosome 1p, with a multipoint lod score of more than 5. In the Dutch family, however, this locus was ruled out. The flanking markers D1S255 and D1S211 defined a region of 6 cM on chromosome 1p that is likely to contain the gene associated with deafness in the first two families. CONCLUSIONS: In some families with early-onset autosomal dominant hearing loss, the responsible gene is on chromosome 1p.
Asunto(s)
Cromosomas Humanos Par 1 , Ligamiento Genético , Pérdida Auditiva Sensorineural/genética , Adolescente , Adulto , Niño , Preescolar , ADN , Femenino , Genes Dominantes , Pérdida Auditiva Sensorineural/etnología , Humanos , Indonesia , Escala de Lod , Masculino , Persona de Mediana Edad , Países Bajos , Linaje , Reacción en Cadena de la Polimerasa , Estados UnidosRESUMEN
Eleven patients with tardive dyskinesia were treated in a double-blind study of vitamin E or placebo for 12 weeks. Abnormal Involuntary Movement Scale (AIMS) ratings were performed before and after treatment. Patients receiving vitamin E showed a significant reduction in their AIMS scale score, but patients receiving placebo showed no significant change. Vitamin E had a helpful effect even for patients whose tardive dyskinesia was mild and long-term.
Asunto(s)
Discinesia Inducida por Medicamentos/tratamiento farmacológico , Vitamina E/uso terapéutico , Adulto , Anciano , Atención Ambulatoria , Método Doble Ciego , Discinesia Inducida por Medicamentos/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Examen Físico , Placebos , Índice de Severidad de la EnfermedadRESUMEN
Fragile X syndrome is characterized at the molecular level by amplification of a (CGG)n repeat and hypermethylation of a CpG island preceeding the open reading frame of the fragile X gene (FMR-1) located in Xq27.3. Anticipation in this syndrome is associated with progressive amplification of the (CGG)n repeat from a premutation to a full mutation through consecutive generations. Remarkably, expansion of the premutation to the full mutation is strictly maternal. To clarify this parental influence we studied FMR-1 in sperm of four male fragile X patients. This showed that only the premutation was present in their sperm, although they had a full mutation in peripheral lymphocytes. This might suggest that expansion of the premutation to the full mutation in FMR-1 does not occur in meiosis but in a postzygotic stage.
Asunto(s)
Síndrome del Cromosoma X Frágil/genética , Amplificación de Genes , Modelos Genéticos , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas de Unión al ARN , Secuencias Repetitivas de Ácidos Nucleicos , Espermatozoides/química , Análisis Mutacional de ADN , Desarrollo Embrionario y Fetal/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Humanos , Linfocitos/química , Masculino , Meiosis , Metilación , Sistemas de Lectura Abierta , Reacción en Cadena de la Polimerasa , Caracteres SexualesRESUMEN
Fucosidosis is a rare, autosomal recessive, lysosomal storage disorder caused by a severe deficiency of alpha-L-fucosidase in all tissues. We have conducted a review of fucosidosis, compiling data from published reports and an international questionnaire survey. Seventy-seven patients affected with fucosidosis of which 19 had not been reported before have been identified. A major aim of the present study was to define the natural history of fucosidosis. The clinical picture of fucosidosis consists of progressive mental (95%) and motor (87%) deterioration, coarse facies (79%), growth retardation (78%), recurrent infections (78%), dysostosis multiplex (58%), angiokeratoma corporis diffusum (52%), visceromegaly (44%), and seizures (38%). Whereas the original fucosidosis patients described by Durand et al. (J. Pediatr 75:665-674, 1969) were decerebrate and died before age 5 years, most fucosidosis patients have a slower course of degeneration. Mortality before age 5 years was observed in only 7 patients (9%), whereas 36 patients (64%) reached the second decade. We did not find evidence for the existence of clinical heterogeneity with a rapidly progressive type I and a slowly progressive type II fucosidosis as suggested in the literature. Instead, there seems to exist a wide continuous clinical spectrum. At the biochemical level no heterogeneity in residual fucosidase enzyme activity or cross-reacting immunoreactive fucosidase protein was observed. At the DNA level at least 4 different mutations must be responsible for fucosidosis. These genotypic differences however do not explain the observed phenotypic differences.
Asunto(s)
Fucosidosis/genética , Conformación de Carbohidratos , Secuencia de Carbohidratos , ADN/análisis , Fucosidosis/epidemiología , Fucosidosis/patología , Humanos , Datos de Secuencia Molecular , Mutación , LinajeRESUMEN
The loci DNF15S1 and DNF15S2 are members of a small repetitive sequence family at discrete chromosomal locations, namely, 1p36 and 3p21, respectively. Studies of the structure, arrangement, and interrelations of the family suggest that the single copy on chromosome 3 is the original member and that this gave rise to the several members on chromosome 1 by transposition, partial duplication, and amplification. Several restriction fragment length polymorphisms have been discovered at the DNF15S1 locus and these have been assigned to the different subfamilies of the repeat at this locus. The existence of these RFLPs, and the nonallelic restriction site variation also found in this sequence family, suggests that transposition and amplification occurred as discrete events. We sequenced across the ancient junction between chromosomes 1 and 3 and noted features which might explain the mechanics of the transposition and amplification events.
Asunto(s)
Cromosomas Humanos Par 1 , Cromosomas Humanos Par 3 , Amplificación de Genes , Recombinación Genética , Secuencias Repetitivas de Ácidos Nucleicos , Secuencia de Bases , Densitometría , Variación Genética , Humanos , Datos de Secuencia Molecular , Familia de Multigenes , Conformación de Ácido Nucleico , Hibridación de Ácido Nucleico , Polimorfismo de Longitud del Fragmento de Restricción , Mapeo Restrictivo , Homología de Secuencia de Ácido NucleicoRESUMEN
Fucosidosis is an autosomal recessive lysosomal storage disease due to a deficiency of alpha-L-fucosidase activity in tissues and body fluids. Exponentially growing lymphoid cell cultures from four fucosidosis patients had 2.7-fold to 15.6-fold less extracellular alpha-L-fucosidase protein and 28.8-fold to 144.0-fold less intracellular alpha-L-fucosidase protein with negligible catalytic activity, compared to the mean of 19 control cultures. The percentage of total alpha-L-fucosidase protein released extracellularly by cultures from the four patients was 64 to 85%, compared to 35 +/- 9% for control cultures. Intracellular and extracellular enzyme forms in fucosidosis and control cell lines were glycoproteins containing polypeptide chains of Mr = 52,000. During a 1.5-hr pulse-label with 35S-methionine, alpha-L-fucosidase was synthesized by control cells and two fucosidosis cell lines as an intracellular form with Mr = 58,000. During a subsequent 21-hr chase with unlabeled methionine, mutant enzyme was almost entirely processed to an extracellular form with Mr = 62,000. In contrast, only 25-30% of control enzyme was processed to an extracellular form (Mr = 62,000), with the remainder retained intracellularly (Mr = 60,000). In the other two fucosidosis cell lines, alpha-L-fucosidase was synthesized as an intracellular form with Mr = 56,000 that was processed to an extracellular form with Mr = 60,000. In summary, the fucosidosis mutation(s) affected the catalytic activity, quantity, and extracellular release of alpha-L-fucosidase as expressed by lymphoid cells.
Asunto(s)
Fucosidosis/genética , alfa-L-Fucosidasa/genética , Línea Celular , Femenino , Fucosidosis/enzimología , Humanos , Hidrólisis , Masculino , Mutación , Pruebas de Precipitina , alfa-L-Fucosidasa/biosíntesisRESUMEN
Recently, a subset of fucosidosis patients was identified in which the single EcoRI site in the open reading frame of the human cDNA encoding alpha-L-fucosidase was obliterated. We have employed the polymerase chain reaction technique to amplify alpha-L-fucosidase DNA from the five patients known to carry the EcoRI abnormality as well as four patients and two additional fucosidosis patients who do not carry the EcoRI abnormality. Sequence analysis of the amplified DNA has determined that the EcoRI site was destroyed by a C-T transition in the last position of the EcoRI site. This single base change results in the generation of a stop codon 120 base pairs upstream of the normal stop codon. In addition, we have determined that EcoRI cleavage of amplified DNA may be a useful diagnostic tool in the diagnosis of heterozygotes and in prenatal diagnosis of fetuses at risk for this disease.
Asunto(s)
Codón/genética , Fucosidosis/genética , Mutación , ARN Mensajero/genética , alfa-L-Fucosidasa/genética , Secuencia de Aminoácidos , Secuencia de Bases , Desoxirribonucleasa EcoRI , Desoxirribonucleasa HindIII , Femenino , Fucosidosis/enzimología , Humanos , Masculino , Datos de Secuencia Molecular , Sondas de Oligonucleótidos , Linaje , Reacción en Cadena de la Polimerasa , Valores de Referencia , Mapeo RestrictivoRESUMEN
The genetic locus for neurofibromatosis 1 (NF1) has recently been mapped to the pericentromeric region of chromosome 17. We have genotyped eight previously identified RFLP probes on 50 NF1 families to determine the placement of the NF1 locus relative to the RFLP loci. Thirty-eight recombination events in the pericentromeric region were identified, eight involving crossovers between NF1 and loci on either chromosomal arm. Multipoint linkage analysis resulted in the unique placement of six loci at odds greater than 100:1 in the order of pter-A10-41-EW301-NF1-EW207-CRI-L581-CRI-L946 -qter. Owing to insufficient crossovers, three loci--D17Z1, EW206, and EW203--could not be uniquely localized. In this region female recombination rates were significantly higher than those of males. These data were part of a joint study aimed at the localization of both NF1 and tightly linked pericentromeric markers for chromosome 17.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 17 , Ligamiento Genético , Marcadores Genéticos , Neurofibromatosis 1/genética , Humanos , Recombinación GenéticaRESUMEN
Human alpha-L-fucosidase is a lysosomal enzyme responsible for hydrolysis of alpha-L-fucoside linkages in fucoglycoconjugates. A single gene, FUCA 1, located on chromosome 1p34.1-1p36.1 encodes for alpha-L-fucosidase activity. To gain insight into the nature of the molecular defects leading to fucosidosis, we have characterized the genomic structure of FUCA 1. Restriction-endonuclease analysis suggests that at least seven exons dispersed over 22 kb are present in genomic FUCA 1. Two restriction-fragment-length polymorphisms (RFLPs) have been identified in the Caucasian population. The PvuII and BglI RFLPs each have two codominant alleles in Hardy-Weinberg equilibrium. Allele frequencies for the PvuII RFLP are .70/.30, and those for the BglI RFLP .63/.37. Both RFLPs are in strong linkage disequilibrium with each other, with a correlation coefficient of .94. The polymorphism information content (PIC) of the combined DNA markers is .38, high enough to be useful in the prenatal diagnosis of fucosidosis. The combined lod score for linkage between the fucosidosis mutation and FUCA 1 markers in two families was significant at a recombination fraction of 0. This suggests that the fucosidosis mutation resides in FUCA 1.
Asunto(s)
Fucosidosis/genética , Genes , Ligamiento Genético , Mapeo Restrictivo , alfa-L-Fucosidasa/genética , Southern Blotting , Cromosomas Humanos Par 1 , Sondas de ADN , Fucosidosis/enzimología , Marcadores Genéticos , Humanos , Focalización Isoeléctrica , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Fucosidosis is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration and mental retardation. The disease results from deficient activity of alpha-L-fucosidase (E.C.3.2.1.51), a lysosomal enzyme that hydrolyzes fucose from fucoglycoconjugates. In an attempt to identify the mutation(s) that result(s) in fucosidosis, we performed Southern blot analysis of the structural gene encoding alpha-L-fucosidase (FUCA 1) in 23 patients affected with fucosidosis. In five patients Southern blot analysis showed obliteration of an EcoRI restriction site in the open reading frame of FUCA 1 encoding mature alpha-L-fucosidase. This abnormality was not observed in 80 controls, and it may be the basic defect responsible for fucosidosis in these patients. Both patients with the severe type I form of fucosidosis and patients with the less severe type II were shown to be homozygous for this presumed mutation. In the remaining 18 patients the EcoRI site obliteration, major-gene deletions, or insertions were not detected. This suggests that at least two different mutations are involved in fucosidosis. The heterogeneity found at the DNA level was not present at the protein level, as all fucosidosis patients investigated had low fucosidase protein (less than 6% of normal) and negligible fucosidase activity in fibroblasts and lymphoblastoid cell lines.
Asunto(s)
Fucosidosis/genética , Genes , Mutación , alfa-L-Fucosidasa/genética , Southern Blotting , Línea Celular , Sondas de ADN , Femenino , Fucosidosis/enzimología , Humanos , Masculino , Linaje , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Two families with five patients affected with fucosidosis are described. Within each family, both type I and type II fucosidosis are present. This suggests that environmental factors or "modifying genes" different from the fucosidase structural gene contribute to the phenotype of a fucosidosis patient.
Asunto(s)
Fucosidosis/genética , Genes , alfa-L-Fucosidasa/genética , Adulto , Niño , Preescolar , Humanos , Masculino , Mutación , Linaje , FenotipoRESUMEN
One neurofibrosarcoma from each of three patients with von Recklinghausen neurofibromatosis (VRNF) was studied for the expression of selected growth factor genes and oncogenes. Comparative analyses were also performed on four neurofibromas and skin, nerve and muscle specimens from one of the patients with neurofibrosarcoma, an autopsy kidney specimen from a fifth VRNF patient, and normal liver and term placenta specimens from healthy control subjects. Northern blot hybridization techniques were used to analyze the amounts and sizes of mRNA resulting from the expression of eight genes. Insulin-like growth factor I showed a moderate level of expression in normal nerve and lower expression in two neurofibrosarcomas. Insulin-like growth factor II was moderately to heavily expressed in all specimens, and differential splicing patterns were seen. Platelet-derived growth factor showed low levels of expression in all three neurofibrosarcomas, skin, nerve, muscle and normal liver, low to moderate levels of expression in the neurofibromas, and high expression in normal control placenta. Beta-nerve growth factor was expressed at low levels in two neurofibrosarcomas and skin, but was not seen in other specimens. N-myc showed a low level of expression in one neurofibrosarcoma and a neurofibroma, and a higher level of expression in a second neurofibrosarcoma (and in this same subject's skin and nerve). Tissue-type plasminogen activator showed moderate levels of expression in two neurofibrosarcomas and one neurofibroma, but it was not seen in skin, nerve, kidney and normal term placenta specimens.
Asunto(s)
Sustancias de Crecimiento/metabolismo , Neurofibroma/metabolismo , Neurofibromatosis 1/metabolismo , Oncogenes , Neoplasias Cutáneas/metabolismo , Somatomedinas/metabolismo , Northern Blotting , Femenino , Humanos , Masculino , Neurofibroma/genética , Neurofibromatosis 1/genética , Neoplasias Cutáneas/genética , Activador de Tejido Plasminógeno/metabolismoRESUMEN
Genotyping, using plasma proteins or DNA polymorphisms or both, was carried out on 30 families selected through probands with Von Recklinghausen disease. The data provide additional evidence for the exclusion of loci on chromosomes 3 and 5, and chromosome arms 1q, 2p, 4p, 4q, 6q, 7p, 9q, 11p, 11q, and 14q. There was no evidence for genetic heterogeneity at D1S1 (DNF15S2) on chromosome arm 3p, using the Morton test for heterogeneity.
Asunto(s)
Neurofibromatosis 1/genética , Proteínas Sanguíneas/genética , ADN/genética , Ligamiento Genético , Marcadores Genéticos , Humanos , Polimorfismo GenéticoRESUMEN
Apolipoprotein E is expressed in neurofibrosarcoma and Schwannoma cell cultures derived from two patients with different types of neurofibromatosis, but not in six cell cultures derived from the benign neurofibromatosis neurofibromas. In addition, a cell culture derived from a nonneurofibromatosis human malignant astrocytoma showed apolipoprotein E expression. Although all cells in either the neurofibrosarcoma or Schwannoma cultures appeared morphologically similar (suggesting homogeneity), apolipoprotein E was immunochemically detected in the perinuclear region of only half of the cells. Thus, production of apolipoprotein E in neurofibromatosis-associated neurofibroma tumors may be a marker for a specific subclass of transformed cells. The expression of apolipoprotein E in glial cell neoplasms is possibly related to an alteration in their lipid metabolism.
Asunto(s)
Apolipoproteínas E/biosíntesis , Neoplasias Encefálicas/metabolismo , Neurilemoma/metabolismo , Neurofibroma/metabolismo , Neurofibromatosis 1/metabolismo , Adulto , Astrocitoma/metabolismo , Precipitación Química , Niño , Electroforesis en Gel de Poliacrilamida , Femenino , Técnica del Anticuerpo Fluorescente , Histocitoquímica , Humanos , Técnicas In Vitro , Masculino , Microscopía de Contraste de Fase , Persona de Mediana EdadRESUMEN
Human alpha-L-fucosidase, a lysosomal enzyme, hydrolyzes alpha-L-fucose from glycolipids and glycoproteins. Its activity is deficient in human fucosidosis an autosomal recessive disease. In order to understand the molecular basis of this lysosomal storage disorder we have cloned several cDNAs coding for human alpha-L-fucosidase from a human hepatoma and a human liver cDNA library constructed in lambda gt11. Compiling the cDNA sequences of these clones we have identified 1,829 base pairs (bp) encoding human alpha-L-fucosidase. This includes an open reading frame of 1,172 bp, a consensus polyadenylation signal AAT AAA and a poly(A)+ tail. The sequence is incomplete at the 5'-end, and clones encoding the amino terminus of the native protein, the propeptide and leader signal have not yet been isolated. The open reading frame encodes for 390 amino acids with a calculated Mr of 45,557. This represents 78-95% of the mature processed alpha-L-fucosidase. The availability of these cDNA clones has enabled us to map the structural gene for alpha-L-fucosidase to chromosome 1p34.1-1p36.1 by Southern blot analysis of DNA from human-rodent somatic cell hybrids and by in situ hybridization. Furthermore, a Pvu II restriction fragment length polymorphism (RFLP) has been identified at the human alpha-L-fucosidase gene locus. Analysis of mRNA by Northern blotting gives a major species of 2.25 kb. In 4 patients with fucosidosis no mRNA signal was detected and Western blots gave no immunoreactive enzyme. Southern blotting after Eco RI digestion in two fucosidosis families revealed a banding abnormality (extra 6-kb band).(ABSTRACT TRUNCATED AT 250 WORDS)