RESUMEN
Autosomal dominant cerebellar ataxias (ADCAs) are a complex group of slowly progressive neurodegenerative disorders characterized by gait and stance ataxia, dysarthria and other symptoms of nervous system involvement. ADCA type I is the commonest form and is genetically heterogeneous; several loci have been identified. Spinocerebellar ataxia type 2 (SCA2) has been mapped to chromosome 12, with expanded cytosine-adenine-guanine (CAG) repeats being identified as the mutational cause of the disease. We investigated 15 families, all originating from mid-eastern Sicily, with ADCA type I; molecular studies performed in 12 families showed the SCA2 mutation to be present in 11 of them (91.6%) - the highest occurrence so far reported in the literature. The CAG repeat of the affected alleles varied between 34 and 44 repeats. Age at onset and repeat length revealed an inverse correlation. Mean age at onset was 37.32 +/- 16. 74 years, and occurred earlier in males than in females. There were no differences in mean CAG repeat units between the sexes. However, a higher instability of CAG repeats was observed for paternal transmission than for maternal transmission. Age at onset and anticipation were not related to parental transmission. Our data suggest that in SCA2 an unknown sex-linked factor may play a role in the modulation of toxic effects of the polyglutamine tract.
Asunto(s)
Ataxias Espinocerebelosas/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Niño , Cromosomas Humanos Par 12/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Sicilia , Repeticiones de TrinucleótidosRESUMEN
Seven different chromosomal loci, designated SCA1 to SCA7 (spinocerebellar ataxias), have been identified as responsible for autosomal dominant cerebellar ataxias. Five genes (SCA1, 2, 3, 6, 7) have been cloned to date and show a single type of mutation, an unstable expansion of a CAG repeat coding for a polyglutamine stretch in the corresponding protein. We describe an improved polymerase chain reaction assay, based on a touchdown protocol, for the diagnosis of spinocerebellar ataxia type 2. This method produces an efficient amplification of both normal and pathological alleles and no radioactive labelling is necessary to observe the amplification products. The pathological alleles are identified by a simple non-denaturing polyacrylamide electrophoretic separation followed by ethidium bromide staining. A comparison of this technique with previously reported methods confirmed its utility for the rapid molecular diagnosis of spinocerebellar ataxia type 2. We found that the spinocerebellar ataxia type 2 mutation is responsible for 88% of the examined autosomal dominant cerebellar ataxia type 1 families in our territory (eastern Sicily). With the rapid touchdown polymerase chain reaction method, the trinucleotide expansion was also observed in 2 ataxic patients without family history of the disease, suggesting the necessity for analysis of spinocerebellar ataxia type 2 expansion even in sporadic patients.
Asunto(s)
Salud de la Familia , Reacción en Cadena de la Polimerasa/métodos , Degeneraciones Espinocerebelosas/diagnóstico , Degeneraciones Espinocerebelosas/genética , Repeticiones de Trinucleótidos , Alelos , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Masculino , Mutación , LinajeRESUMEN
The occurrence of acute dystonic reactions was intensively monitored in a population of 646 patients, 379 males and 267 females, aged 18-87 years, consecutively admitted to different psychiatric units and treated with neuroleptics alone or in combination with anticholinergic drugs. Thirty-four patients experienced acute dystonic reactions yielding a total incidence of 5.3%. There was a tendency towards a higher frequency of dystonia in males than in females, and in young patients than in older ones. Patients without anticholinergic medication had a higher frequency of the reaction than those receiving anticholinergic drugs (8.5% vs. 2.8%; p < 0.02). Neuroleptic-induced dystonia was more common in patients treated with butyrophenones than in those receiving phenothiazines or substituted benzamides.
Asunto(s)
Antipsicóticos/efectos adversos , Distonía/epidemiología , Parasimpatolíticos/uso terapéutico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antipsicóticos/uso terapéutico , Distonía/inducido químicamente , Distonía/prevención & control , Femenino , Humanos , Masculino , Trastornos Mentales/tratamiento farmacológico , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
To evaluate the role of defective drug oxidation as a predisposing factor for neuroleptic-induced dystonic reactions, 26 patients who developed the reaction and 53 with no history of dystonia were phenotyped by the debrisoquine hydroxylation test. The percentage of poor debrisoquine metabolizers was similar in patients with dystonic reactions (11.5%) and in the control group (9.4%). These results suggest that there is no association between the individual's drug oxidative status and the occurrence of neuroleptic-induced dystonia.