Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
1.
Brain Res Bull ; 62(2): 137-41, 2003 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-14638387

RESUMEN

Previous research has demonstrated that longitudinal change in caudate volume could be observed over a period of 3 years in subjects with Huntington's disease (HD). The current pilot study was designed to determine whether measurement of caudate change on magnetic resonance imaging (MRI) is a feasible and valid outcome measure in an actual clinical trial situation. We measured caudate volumes on pre- and post-treatment MRI scans from 19 patients at two sites who were participating in CARE-HD (Co-enzyme Q10 and Remacemide: Evaluation in Huntington's Disease), a 30-month clinical trial of remacemide and co-enzyme Q(10) in symptomatic patients with HD. Results from this pilot study indicated that decrease in caudate volume was significant over time. Power analysis indicated that relatively small numbers of subjects would be needed in clinical trials using caudate volume as an outcome measure. Advantages and disadvantages of using MRI caudate volume as an outcome measure are presented. We recommend the adoption of quantitative neuroimaging of caudate volume as an outcome measure in future clinical trials for treatments of HD.


Asunto(s)
Núcleo Caudado/patología , Enfermedad de Huntington/patología , Imagen por Resonancia Magnética , Ubiquinona/análogos & derivados , Acetamidas/uso terapéutico , Antioxidantes/uso terapéutico , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/efectos de los fármacos , Coenzimas , Humanos , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/tratamiento farmacológico , Estudios Longitudinales , Masculino , Fármacos Neuroprotectores/uso terapéutico , Pruebas Neuropsicológicas , Proyectos Piloto , Radiografía , Resultado del Tratamiento , Ubiquinona/uso terapéutico
2.
Clin Genet ; 64(4): 300-9, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12974735

RESUMEN

The promise of genetic medicine is to provide information, based on genotype, to persons not yet sick about their risk of future illness. However, little is known of the long-term psychological effects for asymptomatic persons learning their risk of having a serious disease. Predictive genetic testing for Huntington's disease (HD) has been offered for the longest time for any disease. In the present study, the psychological consequences of predictive testing were assessed prospectively in individuals at risk for HD during seven visits over 5 years. Questionnaires of standard measures of psychological distress (the General Severity Index of the Symptom Check List-90-Revised), depression (the Beck Depression Inventory), and general well-being (the General Well-Being Scale) were administered to the participants. A significant reduction in psychological distress was observed for both result groups throughout 2 years (p < 0.001) and at 5 years (p = 0.002). Despite the overall improvement of the psychological well-being, 6.9% (14 of 202) of the participants experienced an adverse event during the first 2 years after predictive testing that was clinically significant. The frequency of all defined adverse events in the participants was 21.8%, with higher frequency in the increased risk group (p = 0.03) and most occurring within 12 months of receiving results.


Asunto(s)
Asesoramiento Genético , Pruebas Genéticas/psicología , Enfermedad de Huntington/diagnóstico , Estrés Psicológico/psicología , Adulto , Análisis de Varianza , Síntomas Conductuales/psicología , Estudios de Cohortes , Demografía , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Pruebas Psicológicas , Factores de Tiempo
3.
Clin Genet ; 63(6): 462-75, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12786753

RESUMEN

Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.


Asunto(s)
Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Diagnóstico Prenatal , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Canadá , Femenino , Humanos , Masculino , Persona de Mediana Edad , Embarazo , Estudios Retrospectivos , Expansión de Repetición de Trinucleótido
4.
Am J Med Genet A ; 119A(3): 279-82, 2003 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-12784292

RESUMEN

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.


Asunto(s)
Enfermedad de Huntington/genética , Repeticiones de Trinucleótidos , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Humanos , Persona de Mediana Edad , New England , Probabilidad , Tasa de Supervivencia
6.
Clin Genet ; 60(3): 198-205, 2001 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11595021

RESUMEN

The advent of the direct mutation test for Huntington disease (HD) has made it possible to identify a previously unrecognized symptomatic population of HD, including those with an atypical presentation or patients without a family history of HD. The present study investigated the uptake of this test in the province of British Columbia (BC), Canada and assessed the incidence rate and rate of identification of new mutations for HD. All symptomatic individuals residing in BC who were referred for the genetic test for HD between 1993 and 2000 (n=205) were analyzed for CAG expansion, baseline demographics and clinical data, and a family history of HD. A total of 141 (or 68.8%) had a CAG expansion > or =36. Of these, almost one-quarter (24.1%) did not have a family history of HD. An extensive chart review revealed that 11 patients (or 7.8%) had reliable information on both parents (who lived well into old age) and therefore possibly could represent new mutations for HD. This indicates a three to four times higher new mutation rate than previously reported. Our findings also show that the yearly incidence rate for HD was 6.9 per million, which is two times higher than previous incidence studies performed prior to the identification of the HD mutation. We also identified five persons with a clinical presentation of HD but without CAG expansion (genocopies) (2.4%).


Asunto(s)
Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/genética , Expansión de Repetición de Trinucleótido , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Anciano , Colombia Británica , Niño , Preescolar , Salud de la Familia , Padre , Femenino , Humanos , Enfermedad de Huntington/diagnóstico , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Modelos Genéticos , Madres , Mutación , Análisis de Secuencia de ADN , Factores Sexuales , Factores de Tiempo
7.
Am J Med Genet ; 105(5): 399-403, 2001 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-11449389

RESUMEN

In order to provide data relevant to a search for modifying genes for age of onset in Huntington disease, we examined the relationship between CAG number and age of onset in a total of 370 individuals from 165 siblingships, in two cohorts of siblings with Huntington disease: an American group of 144 individuals from 64 siblingships, and a Canadian population of 255 individuals from 113 siblingships. Using a logarithmic model to regress the age of onset on the number of CAG triplets, we found that CAG number alone accounted for 65%-71% of the variance in age of onset. The siblingship an individual belonged to accounted for 11%-19% of additional variance. This adds to the previous evidence that there are familial modifiers of the age of onset, independent of the CAG number. Such modifiers may consist of additional genes, which could be the target of a linkage study. A linkage study is feasible with the cooperation of a number of major centers and may be made more efficient by concentrating on sibling pairs that are highly discordant for age of onset.


Asunto(s)
Enfermedad de Huntington/genética , Edad de Inicio , Estudios de Cohortes , ADN/genética , Salud de la Familia , Femenino , Humanos , Enfermedad de Huntington/patología , Masculino , Repeticiones de Trinucleótidos/genética
8.
Am J Hum Genet ; 68(2): 373-85, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11225602

RESUMEN

We describe a new approach for analysis of the epidemiology of progressive genetic disorders that quantifies the rate of progression of the disease in the population by measuring the mutational flow. The framework is applied to Huntington disease (HD), a dominant neurological disorder caused by the expansion of a CAG-trinucleotide sequence to >35 repeats. The disease is 100% penetrant in individuals with > or = 42 repeats. Measurement of the flow from disease alleles provides a minimum estimate of the flow in the whole population and implies that the new mutation rate for HD in each generation is > or = 10% of currently known cases (95% confidence limits 6%-14%). Analysis of the pattern of flow demonstrates systematic underascertainment for repeat lengths <44. Ascertainment falls to <50% for individuals with 40 repeats and to <5% for individuals with 36-38 repeats. Clinicians should not assume that HD is rare outside known pedigrees or that most cases have onset at age <50 years.


Asunto(s)
Frecuencia de los Genes , Enfermedad de Huntington/genética , Mutación/genética , Adolescente , Adulto , Edad de Inicio , Alelos , Salud de la Familia , Femenino , Genética de Población , Humanos , Funciones de Verosimilitud , Masculino , Persona de Mediana Edad , Modelos Genéticos , Datos de Secuencia Molecular , Expansión de Repetición de Trinucleótido/genética , Repeticiones de Trinucleótidos/genética
9.
Am J Psychiatry ; 157(12): 1955-9, 2000 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11097960

RESUMEN

OBJECTIVE: The mutation responsible for Huntington's disease is an elongated and unstable trinucleotide (CAG) repeat on the short arm of chromosome 4. Psychotic symptoms are more common in patients with Huntington's disease than in the general population. This study explored the relationship of psychosis in Huntington's disease patients with the number of CAG repeats and family history of psychosis. METHOD: Forty-four patients with Huntington's disease, 22 with and 22 without psychotic symptoms, were recruited from two university-affiliated medical genetics clinics in Seattle and Vancouver, B.C. Psychiatric assessments of the subjects were made through chart review, and diagnoses were validated by structured interviews in a subset of patients. The demographic and clinical characteristics of the psychotic and nonpsychotic patients were compared. RESULTS: The two groups did not differ in demographic and clinical characteristics, except that subjects with psychosis were significantly more likely than nonpsychotic subjects to have a first-degree relative with psychosis. In eight of nine families in which Huntington's disease probands with psychosis had a first-degree relative with psychosis, the relative's psychosis co-occurred with Huntington's disease. In the Huntington's disease probands with psychosis, the onset of psychosis correlated with the onset of the neurological symptoms of Huntington's disease, and the age at onset of psychosis was lower in probands with a higher number of CAG repeats. CONCLUSIONS: Patients with Huntington's disease and psychotic symptoms may have a familial predisposition to develop psychosis. This finding suggests that other genetic factors may influence susceptibility to a particular phenotype precipitated by CAG expansion in the Huntington's disease gene.


Asunto(s)
Familia , Enfermedad de Huntington/diagnóstico , Trastornos Psicóticos/epidemiología , Repeticiones de Trinucleótidos/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Causalidad , Cromosomas Humanos Par 4/genética , Comorbilidad , Femenino , Genotipo , Humanos , Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/genética , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/genética
10.
Neurology ; 53(5): 1000-11, 1999 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-10496259

RESUMEN

OBJECTIVE: To assess the efficacy of lamotrigine, a novel antiepileptic drug that inhibits glutamate release, to retard disease progression in Huntington disease (HD). BACKGROUND: Excitatory amino acids may cause selective neuronal death in HD, and lamotrigine may inhibit glutamate release in vivo. METHODS: A double-blinded, placebo-controlled study was conducted of 64 patients with motor signs of less than 5 years' duration who were randomly assigned to either placebo or lamotrigine and assessed at 0 (baseline), 12, 24, and 30 months. The primary response variable was total functional capacity (TFC) score. Secondary response variables included the quantified neurological examination and a set of cognitive and motor tests. Repeated fluorodeoxyglucose measurements of regional cerebral metabolism using PET also were included. RESULTS: Fifty-five patients (28 on lamotrigine, 27 on placebo) completed the study. Neither the primary response variable nor any of the secondary response variables differed significantly between the treatment groups. Both the lamotrigine and the placebo group deteriorated significantly on the TFC, in the lamotrigine group by 1.89 and the placebo group by 2.11 points. No effect of CAG size on the rate of deterioration could be detected. CONCLUSIONS: There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Enfermedad de Huntington/tratamiento farmacológico , Triazinas/uso terapéutico , Adulto , Encéfalo/diagnóstico por imagen , Método Doble Ciego , Femenino , Humanos , Enfermedad de Huntington/psicología , Lamotrigina , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Factores de Tiempo , Tomografía Computarizada de Emisión
11.
Clin Genet ; 55(3): 198-202, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10334474

RESUMEN

We have developed a sequence-specific internal DNA size standard for the accurate determination of the number of CAG repeats in the Huntington disease (HD) gene by cloning key fragments (between 15 and 64 CAG repeats) of the HD gene. These fragments, pooled to produce a sequence-specific DNA ladder, enabled us to observe the true number of CAG repeats directly, with no need for calculations. Comparison of the calculated numbers of CAG repeats in the HD gene using this sequence-specific DNA standard with a commercially available standard (GENESCAN-500 TAMRA) showed that the latter underestimated the number of CAG repeats by three when analyzed by capillary electrophoresis on the ABI 310 Genetic Analyzer (POP4 polymer). In contrast, the use of the same standard overestimated the number of CAG repeats by one when the samples were analyzed by denaturing polyacrylamide electrophoresis on ABI 377 DNA Sequencer (6% denaturing polyacrylamide gel). This suggests that our sequence-specific standard provides greater accuracy for the determination of the true number of CAG repeats in the HD gene than commercially available standards. The sequence-specific standard can be radioactively labeled and successfully replace conventional DNA size standards when analyzing polymerase chain reaction (PCR)-amplified HD alleles by denaturing polyacrylamide electrophoresis.


Asunto(s)
ADN/normas , Enfermedad de Huntington/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Repeticiones de Trinucleótidos/genética , Alelos , Autorradiografía , Calibración , ADN/genética , Humanos , Proteína Huntingtina , Marcaje Isotópico , Estándares de Referencia
12.
Am J Hum Genet ; 64(5): 1293-304, 1999 May.
Artículo en Inglés | MEDLINE | ID: mdl-10205260

RESUMEN

Prior to the implementation of predictive-testing programs for Huntington disease (HD), significant concern was raised concerning the likelihood of catastrophic events (CEs), particularly in those persons receiving an increased-risk result. We have investigated the frequency of CEs-that is, suicide, suicide attempt, and psychiatric hospitalization-after an HD predictive-testing result, through questionnaires sent to predictive-testing centers worldwide. A total of 44 persons (0.97%) in a cohort of 4,527 test participants had a CE: 5 successful suicides, 21 suicide attempts, and 18 hospitalizations for psychiatric reasons. All persons committing suicide had signs of HD, whereas 11 (52.4%) of 21 persons attempting suicide and 8 (44.4%) of 18 who had a psychiatric hospitalization were symptomatic. A total of 11 (84.6%) of 13 asymptomatic persons who experienced a CE during the first year after HD predictive testing received an increased-risk result. Factors associated with an increased risk of a CE included (a) a psychiatric history

Asunto(s)
Pruebas Genéticas/psicología , Salud Global , Hospitalización/estadística & datos numéricos , Enfermedad de Huntington/psicología , Trastornos Mentales/epidemiología , Suicidio/estadística & datos numéricos , Estudios de Cohortes , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Trastornos Mentales/genética , Intento de Suicidio/estadística & datos numéricos
13.
Am J Hum Genet ; 63(5): 1431-8, 1998 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9792871

RESUMEN

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor disturbance, cognitive loss, and psychiatric manifestations. The disease is associated with a CAG trinucleotide-repeat expansion in the Huntington gene (IT15) on chromosome 4p16.3. One family with a history of HD was referred to us initially for predictive testing using linkage analysis. However, the chromosome 4p region was completely excluded by polymorphic markers, and later no CAG-repeat expansion in the HD gene was detected. To map the disease trait segregating in this family, whole-genome screening with highly polymorphic dinucleotide-, trinucleotide-, and tetranucleotide-repeat DNA markers was performed. A positive LOD score of 3.01 was obtained for the marker D20S482 on chromosome 20p, by two-point LOD-score analysis with the MLINK program. Haplotype analysis indicated that the gene responsible for the disease is likely located in a 2.7-cM region between the markers D20S193 and D20S895. Candidate genes from the mapping region were screened for mutations.


Asunto(s)
Cromosomas Humanos Par 20 , Enfermedad de Huntington/genética , Enfermedades Neurodegenerativas/genética , Repeticiones de Trinucleótidos , Adulto , Edad de Inicio , Atrofia , Encéfalo/patología , Mapeo Cromosómico , Cromosomas Humanos Par 4 , Femenino , Marcadores Genéticos , Genotipo , Humanos , Enfermedad de Huntington/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/patología , Linaje , Suecia
14.
Fam Pract ; 8(1): 23-7, 1991 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-1828446

RESUMEN

Ten persons with a 50% risk of inheriting Huntington's disease were interviewed in depth about experiences of the disease with special regard to their attitude to a predictive test. The persons showed great interest, concern and worry about a test: six were generally positive while four were negative or uncertain. Every interview had a very personal character and early life experiences seemed to have a determinative influence on the attitude to the test. Persons who were without symptoms of the disease and had passed the mean age of onset within the family (usually older individuals) were largely enthusiastic about a test, as were those with slight and undetermined symptoms. Younger persons, especially those with a qualitatively good contact with the affected parent, seemed to be less interested. Contradictions during the interview were more common among those positive to testing and an ambivalence among many was reflected in a tendency towards changing opinions over time.


Asunto(s)
Actitud Frente a la Salud , Pruebas Genéticas/psicología , Enfermedad de Huntington/psicología , Adulto , Femenino , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/epidemiología , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Suecia/epidemiología , Incertidumbre
16.
Clin Genet ; 32(5): 289-94, 1987 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-2961484

RESUMEN

Two Swedish families with Huntington's disease (HD) have been investigated for linkage with G8 (D4S10). In one family from northern Sweden (Family 1) 48 family members were examined, and in another family from the southwestern part of Sweden (Family 2) 14 family members were examined. The lod scores were 1.531 for Family 1 and 2.057 for Family 2, and the combined lod score was 3.59. The HD gene was segregating with the haplotype C in Family 1 and with haplotype A in Family 2. The predictive value of the test was obvious. Before the testing with the G8 probe, 84.2% of the family members in Family 1 had a theoretical risk of 25% or 50% of having the HD gene. After the testing with the G8 probe, only 23.7% of the family members remained at the same risk, and it could also be certified that 63.2% had no or little risk of having the HD gene. Only one asymptomatic person was predicted to have HD.


Asunto(s)
Ligamiento Genético , Haplotipos , Enfermedad de Huntington/genética , Escala de Lod , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Suecia
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA