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1.
Ultramicroscopy ; 200: 139-148, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30925259

RESUMO

Competitive mechanisms contribute to image contrast from dislocations in annular dark-field scanning transmission electron microscopy (ADF-STEM). A clear theoretical understanding of the mechanisms underlying the ADF-STEM contrast is therefore essential for correct interpretation of dislocation images. This paper reports on a systematic study of the ADF-STEM contrast from dislocations in a GaN specimen, both experimentally and computationally. Systematic experimental ADF-STEM images of the edge-character dislocations reveal a number of characteristic contrast features that are shown to depend on both the angular detection range and specific position of the dislocation in the sample. A theoretical model based on electron channelling and Bloch-wave scattering theories, supported by numerical simulations based on Grillo's strain-channelling equation, is proposed to elucidate the physical origin of such complex contrast phenomena.

2.
J Neurol ; 264(1): 139-151, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27844165

RESUMO

Antibodies against conformation-dependent epitopes of myelin-oligodendrocyte-glycoprotein (MOG-abs) are present in subgroups of neuromyelitis optica spectrum disorder (NMOSD), recurrent optic neuritis (rON), multiple sclerosis (MS), and anti-NMDAR encephalitis. Using optical coherence tomography (OCT) we assessed whether MOG-abs might serve as potential marker of retinal axonal degeneration. We investigated a clinically heterogeneous cohort of 13 MOG-abs-positive patients (4 MOG-abs-positive rON, 4 MOG-abs-positive adult MS, 3 MOG-abs-positive relapsing encephalomyelitis, 2 MOG-abs-positive aquaporin-4-abs-negative NMOSD). As controls, we studied 13 age, sex and ON episode(s)-matched MOG-abs and aquaporin-4-abs-negative (AQP4-abs-negative) MS patients and 13 healthy controls (HC). In addition, we investigated 19 unmatched AQP4-abs-positive MOG-abs-negative NMOSD subjects. Considering all eyes, global pRNFL [in µm, mean (SD)] was significantly reduced in MOG-abs-positive patients [72.56 (22.71)] compared to MOG-abs-negative MS [80.81 (13.55), p = 0.0128], HCs [103.54 (8.529), p = 0.0014] and NMOSD [88.32 (18.43), p = 0.0353]. Non ON eyes from MOG-abs-positive subjects showed significant subclinical atrophy of temporal pRNFL quadrants. Microcystic macular edema (MME) was observed only in eyes of MOG-abs-positive (24%) and AQP4-abs-positive NMOSD (5.6%), but not in MOG-abs-negative MS or HC (p < 0.01). MOG-abs may serve as potential marker of retinal degeneration. Specifically, MOG-abs-related OCT features predominate in temporal pRNFL quadrants (resembling the MS retinal pattern), might be more severe than AQP4-abs-positive NMOSD, indicate subclinical pathology, and may be associated with MME.


Assuntos
Autoanticorpos/sangue , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/diagnóstico por imagem , Neurite Óptica/imunologia , Retina/diagnóstico por imagem , Adulto , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico por imagem , Encefalite Antirreceptor de N-Metil-D-Aspartato/imunologia , Aquaporina 4/imunologia , Biomarcadores/metabolismo , Encefalomielite/diagnóstico por imagem , Encefalomielite/imunologia , Feminino , Seguimentos , Humanos , Edema Macular/diagnóstico por imagem , Edema Macular/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/imunologia , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/imunologia , Nervo Óptico/diagnóstico por imagem , Tomografia de Coerência Óptica
4.
Neurology ; 74(10): 839-45, 2010 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-20211908

RESUMO

BACKGROUND: The pleiotropic effects of riluzole may antagonize common mechanisms underlying chronic cerebellar ataxia, a debilitating and untreatable consequence of various diseases. METHODS: In a randomized, double-blind, placebo-controlled pilot trial, 40 patients presenting with cerebellar ataxias of different etiologies were randomly assigned to riluzole (100 mg/day) or placebo for 8 weeks. The following outcome measures were compared: proportion of patients with a decrease of at least 5 points in the International Cooperative Ataxia Rating Scale (ICARS) total score after 4 and 8 weeks compared with the baseline score; mean changes from the baseline to posttreatment ICARS (total score and subscores at 8 weeks); and occurrence of adverse events. RESULTS: Riluzole and placebo groups did not differ in baseline characteristics. The number of patients with a 5-point ICARS drop was significantly higher in the riluzole group than in the placebo group after 4 weeks (9/19 vs 1/19; odds ratio [OR] = 16.2; 95% confidence interval [CI ] 1.8-147.1) and 8 weeks (13/19 vs 1/19; OR = 39.0; 95% CI 4.2-364.2). The mean change in the riluzole group ICARS after treatment revealed a decrease (p < 0.001) in the total score (-7.05 [4.96] vs 0.16 [2.65]) and major subscores (-2.11 [2.75] vs 0.68 [1.94] for static function, -4.11 [2.96] vs 0.37 [2.0] for kinetic function, and -0.74 [0.81] vs 0.05 [0.40] for dysarthria). Sporadic, mild adverse events occurred. CONCLUSIONS: These findings indicate the potential effectiveness of riluzole as symptomatic therapy in diverse forms of cerebellar ataxia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that riluzole reduces, by at least 5 points, the ICARS score in patients with a wide range of disorders that cause cerebellar ataxia (risk difference 63.2%, 95% CI 33.5%-79.9%).


Assuntos
Ataxia Cerebelar/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Adulto , Idoso , Intervalos de Confiança , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Avaliação de Resultados em Cuidados de Saúde , Projetos Piloto , Índice de Gravidade de Doença , Adulto Jovem
5.
Cancer Gene Ther ; 15(2): 108-14, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17992201

RESUMO

A recently developed, adaptive constant-current electroporation technique was used to immunize mice with an intramuscular injection of plasmid coding for the extracellular and transmembrane domains of the product of the rat neu(664V-E) oncogene protein. In wild-type BALB/c mice, plasmid electroporation at lower current settings elicits higher antibody titers, a strong cytotoxic response and completely protects all mice vaccinated with 10, 25 and 50 microg of plasmid against a lethal challenge of rat neu+ carcinoma cells. BALB/c mice transgenic for the transforming rat neu(664V-E) (ErbB-2, Her-2/neu) oncogene (BALB-neuT(664V-E)) develop an invasive mammary gland carcinoma by 20 weeks of age. Remarkably, when transgenic BALB-neuT(664V-E) mice were vaccinated at a 10- week interval with 50 microg of plasmid with 0.2 A electroporation, mice remained tumor free for more than a year. A single administration of plasmid associated with electroporation was enough to markedly delay carcinogenesis progression in mice with multiple microscopic invasive carcinomas, and keep about 50% of mice tumor free at one year of age. Thus, vaccination using a clinically relevant dose of plasmid encoding the extracellular and transmembrane domains of the neu oncogene delivered by electroporation prevents long-term tumor formation. These improvements in the efficacy of this cancer vaccine regimen vastly increase its chances for clinical success.


Assuntos
Vacinas Anticâncer/imunologia , Eletroporação , Técnicas de Transferência de Genes , Predisposição Genética para Doença , Terapia Genética/métodos , Neoplasias Mamárias Experimentais/terapia , Vacinas de DNA/imunologia , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Feminino , Glicoproteínas/administração & dosagem , Glicoproteínas/genética , Glicoproteínas/imunologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Invasividade Neoplásica , Plasmídeos , Ratos , Receptor ErbB-2 , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética
6.
Br J Cancer ; 93(11): 1250-6, 2005 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-16265350

RESUMO

This paper illustrates the efficacy of DNA vaccination through electroporation in the prevention of oral transplantable carcinoma in Syrian hamsters. At 21 and 7 days before tumour challenge, 19 hamsters were vaccinated with plasmids coding for the extracellular and transmembrane domains of rat HER-2 receptor (EC-TM plasmids), whereas 19 control hamsters were injected intramuscularly with the empty plasmid. Immediately following plasmid injection, hamsters of both groups received two square-wave 25 ms, 375 V cm(-1) electric pulses via two electrodes placed on the skin of the injection area. At day 0, all hamsters were challenged in the submucosa of the right cheek pouch with HER-2-positive HCPC I cells established in vitro from an 7,12-dimethylbenz[a]anthracene-induced oral carcinoma. This challenge gave rise to HER-2-positive buccal neoplastic lesions in 14 controls (73.37%), compared with only seven (36.8%, P<0.0027) vaccinated hamsters. In addition, the vaccinated hamsters displayed both a stronger proliferative and cytotoxic response than the controls and a significant anti-HER-2 antibody response. Most of the hamsters that rejected the challenge displayed the highest antibody titres. These findings suggest that DNA vaccination may have a future in the prevention of HER-2-positive human oral cancer.


Assuntos
Carcinoma de Células Escamosas/imunologia , Neoplasias Bucais/imunologia , Receptor ErbB-2/imunologia , Vacinas de DNA/imunologia , Animais , Formação de Anticorpos , Vacinas Anticâncer/imunologia , Carcinoma de Células Escamosas/prevenção & controle , Proliferação de Células , Cricetinae , Eletroporação , Masculino , Mesocricetus , Neoplasias Bucais/prevenção & controle , Transplante Heterólogo
8.
Neurol Sci ; 25 Suppl 4: S356-60, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15727233

RESUMO

In the past few years, magnetic resonance imaging (MRI) has become increasingly relevant in the diagnosis of multiple sclerosis (MS). Yet, the specificity of MR is limited. Atypical forms of MS and other diseases of the central nervous system may show similar patterns in MR. We briefly discuss the MR findings of the main MS-like diseases. Correct differential diagnosis can be carried out by combining the MR findings with clinical and laboratory findings.


Assuntos
Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico , Mapeamento Encefálico , Neoplasias Encefálicas/patologia , Doenças Desmielinizantes/patologia , Diagnóstico Diferencial , Humanos , Exame Neurológico , Sensibilidade e Especificidade , Doenças Vasculares/patologia
9.
Neurology ; 58(9): 1409-11, 2002 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-12011292

RESUMO

Interferon (IFN)-beta1a induction of neopterin and beta2-microglobulin (beta2-MG) were evaluated over 1 year in patients with MS. Neopterin and beta2-MG levels peaked 24 to 48 hours after weekly injections of IFNbeta1a over the entire study period. Predose levels of neopterin decreased significantly, consistent with a long-term decrease in IFNgamma expression and macrophage activation during IFNbeta-1a treatment. Predose levels of beta2-MG increased, the significance of which is as yet unclear.


Assuntos
Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Neopterina/sangue , Microglobulina beta-2/sangue , Adulto , Análise de Variância , Feminino , Seguimentos , Humanos , Interferon beta-1a , Modelos Lineares , Masculino , Recidiva , Tempo
10.
Eur J Gynaecol Oncol ; 23(2): 123-6, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12013107

RESUMO

Ultrasound is a diagnostic method suitable for first level screening of ovarian cancer. The results in 4350 patients confirmed that ultrasound examination, both transabdominal and transvaginal, can be considered quite satisfactory because the sensibility was 100%.


Assuntos
Programas de Rastreamento , Neoplasias Ovarianas/diagnóstico , Abdome , Feminino , Humanos , Incidência , Itália/epidemiologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/terapia , Sensibilidade e Especificidade , Ultrassonografia , Vagina
11.
Cancer Res ; 61(7): 2809-12, 2001 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-11306448

RESUMO

With a slight asynchronous but consistent progression, all of the mammary glands of female BALB/c mice transgenic for the transforming rat HER-2/neu oncogene progress to atypical hyperplasia and to invasive carcinoma. Previous studies have shown that chronic administration of interleukin (IL) 12 started at the 2nd week of age hampers this progression because of its ability to inhibit tumor angiogenesis and activate a nonspecific immune response. Here we show that a similar inhibition is achieved when 7-week-old mice with fully blown atypical hyperplasia receive a weekly injection of 100 ng IL-12 for 16 times. This lower-dose and later IL-12 administration induces high and sustained levels of serum IFN-gamma equivalent to those elicited by more frequent administrations. A lower-dose and less toxic treatment may thus be envisaged as a possible option in the management of preneoplastic mammary lesions.


Assuntos
Genes erbB-2/genética , Interleucina-12/farmacologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/prevenção & controle , Animais , Relação Dose-Resposta a Droga , Feminino , Hiperplasia/patologia , Interferon gama/biossíntese , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Transgênicos
12.
Am J Hum Genet ; 68(3): 759-64, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11179022

RESUMO

Familial hemiplegic migraine, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the alpha(1A) subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype-that is, T-->C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human alpha(1A-2) subunit, together with human beta(4) and alpha(2)delta subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.


Assuntos
Canais de Cálcio/genética , Ataxia Cerebelar/genética , Cromossomos Humanos Par 19 , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Canais de Cálcio/química , Canais de Cálcio/fisiologia , Canais de Cálcio Tipo P/genética , Canais de Cálcio Tipo Q/genética , Linhagem Celular , Ataxia Cerebelar/classificação , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Potenciais da Membrana/fisiologia , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Técnicas de Patch-Clamp , Linhagem , Estrutura Secundária de Proteína , Subunidades Proteicas , Transfecção
13.
Invest Ophthalmol Vis Sci ; 40(11): 2520-7, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10509645

RESUMO

PURPOSE: To assess whether a correlation exists between optic nerve fiber layer (NFL) thickness and the retinal or visual pathway function in multiple sclerosis (MS) patients previously affected by optic neuritis. METHODS: Fourteen patients with a diagnosis of definite MS were examined. All had been affected by optic neuritis (MSON) with complete recovery of visual acuity (14 eyes included in study). These were compared with 14 eyes from 14 age-matched control subjects. NFL thickness was measured by optical coherence tomography (OCT). Three different measurements in each quadrant (superior, inferior, nasal, and temporal) were taken and averaged. The data in all quadrants (12 values averaged) were identified as NFL Overall, whereas the data obtained in the temporal quadrant only (3 values averaged) were identified as NFL Temporal. Retinal and visual pathway function was assessed by simultaneously recording pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) using high-contrast (80%) checkerboard stimuli subtending 15 minutes and 60 minutes of the visual arc (min arc) and reversed at the rate of two reversals per second. RESULTS: In MSON eyes there was a significant (P < 0.01) reduction in NFL thickness in both NFL Overall and NFL Temporal evaluations compared with the values observed in control eyes. PERG, (15-min arc checks) and VEP (15-min arc and 60-min arc checks), showed a significant (P < 0.01) delay in latency and reduction in amplitude. NFL Overall and NFL Temporal values were significantly correlated (P < 0.01) to the PERG P50 latency and P50 to N95 amplitude recorded with 15-min arc checks. No correlations (P > 0.01) between NFL values and the other electrophysiological data (PERG recorded with 60-min arc checks and VEP recorded with 15-min arc and 60-min arc checks) were found. CONCLUSIONS: There is a correlation between PERG changes and NFL thickness in MS patients previously affected by optic neuritis, but there is no correlation between VEP changes and NFL thickness.


Assuntos
Potenciais Evocados Visuais , Esclerose Múltipla/fisiopatologia , Fibras Nervosas/patologia , Nervo Óptico/patologia , Neurite Óptica/fisiopatologia , Retina/fisiopatologia , Vias Visuais/fisiopatologia , Adulto , Eletrorretinografia , Feminino , Humanos , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Neurite Óptica/complicações , Neurite Óptica/patologia , Tomografia/métodos
15.
Mult Scler ; 5(2): 121-5, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10335521

RESUMO

The aim of this study was to assess the frequency of organ- and nonorgan-specific autoantibodies in MS patients and evaluate whether the presence of autoantibodies is an indicator of disease activity and/or a prognosis factor. One hundred and five definite MS patients in different stages and with different course and 75 blood donors were tested for the autoantibodies TgA, TMA/TPO-A, PCA, ANA, aCl, SMA, AMA and ANCA. All patients were screened for the LAC. Autoantibodies to at least one autoantigen were found in 66.6% MS patients and in 13.3% controls (P < 0.001). The frequency of TgA, TMA/TPO-A, ANA, aCl and SMA was statistically higher in patients than in controls. Circulating ANCAs were found in seven MS, a never reported finding. An early onset of MS (< 20 years) was associated with a lower autoantibody frequency (P < 0.01) Primary and secondary progressive MS had a higher antibody frequency than relapsing-remitting (P < 0.05) or benign (P < 0.001) MS. Up to 86% of patients were autoantibody-positive during the acute stage, but only 30% of them remained positive during the remission stage (P < 0.001). A generalised immune dysregulation occurs in MS patients, mostly during the acute stages and in the progressive courses, involving activation of both autoreactive Th1-cells (mainly linked to CNS lesions) and B-cells via Th2 cells.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Antinucleares/sangue , Esclerose Múltipla/imunologia , Adolescente , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/imunologia , Músculo Liso/imunologia , Prognóstico
18.
Electroencephalogr Clin Neurophysiol ; 108(1): 73-9, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9474064

RESUMO

The aim of our work was to evaluate if an optic nerve involvement (multiple sclerosis patients previously affected by optic neuritis) may induce any change in visual evoked potential (VEP) after photostress response. VEP in basal conditions and after photostress were assessed in 10 patients with defined multiple sclerosis without a history of optic neuritis (MSWO); in 14 patients with defined multiple sclerosis previously affected by optic neuritis but with complete recovery of the visual acuity (MSON) and in 14 age-matched controls. In order to complete the investigation of the retinal function, Transient Pattern electroretinogram (PERG) and steady-state focal-ERG (counterphased gratings presented at 8 Hz in the macular region) were performed in MSON patients only. In MSWO eyes VEP parameters in basal condition and after photostress did not undergo significant changes compared to controls (ANOVA; P > 0.05). In MSON eyes we observed basal VEP with delayed P100 peak latency and reduced N75-P100 amplitude when compared with the control ones (P < 0.01). In MSON eyes the parameters of VEP after photostress underwent large changes and longer recovery time (RT) than in control and MSWO eyes (P < 0.01). In addition; in MSON eyes we found increased transient PERG P50 latency (P < 0.01) and reduced P50-N95 amplitude (P < 0.01); Focal-ERG (that displays a major component at 16 Hz; 2nd harmonic:2P) with reduced 2P amplitudes and delayed 2P phases (P < 0.01). Our results indicate that patients previously affected by optic neuritis present an abnormal VEP after photostress response and this may be ascribed predominantly to an involvement of the inner retinal layers as indicated by the concomitant impairment of PERG and focal-ERG responses.


Assuntos
Potenciais Evocados Visuais/fisiologia , Esclerose Múltipla/fisiopatologia , Neurite Óptica/fisiopatologia , Estimulação Luminosa , Adulto , Eletrorretinografia , Feminino , Humanos , Masculino , Esclerose Múltipla/complicações , Neurite Óptica/etiologia , Estresse Fisiológico
19.
Hum Mol Genet ; 6(11): 1973-8, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9302278

RESUMO

Point mutations of the CACNA1A gene coding for the alpha 1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive spinocerebellar ataxia, named SCA6. In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented. In one family, with a clinical diagnosis of EA2, a CAG23 repeat allele segregated in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In the second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an inter-generational allele size change showed that a CAG20 allele was associated with an EA2 phenotype and a CAG25 allele with progressive cerebellar ataxia. These results show that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported. A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.


Assuntos
Canais de Cálcio/genética , Ataxia Cerebelar/genética , Cromossomos Humanos Par 19 , Degenerações Espinocerebelares/genética , Repetições de Trinucleotídeos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Éxons , Feminino , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo
20.
Ann Hum Genet ; 60(5): 423-35, 1996 09.
Artigo em Inglês | MEDLINE | ID: mdl-8912795

RESUMO

An analysis of genetic fitness was performed in Huntington's Disease (HD) and Spinocerebellar Ataxia 1 (SCA1) families. Two partially overlapping samples were used: clinically defined HD and SCA1 patients from families ascertained in definite geographical areas, and molecularly typed carriers of HD and SCA1 mutations (CAG trinucleotide expansions). In both cases, a control group of normal relatives was used. HD and SCA1 patients born before 1915-20 had more children than normal controls. Carriers of HD and SCA1 mutations, all in the low/medium expansion range (37-49 and 47-54 CAG repeats respectively), had a higher number of children than controls up to more recent times (1935-1950). The reproduction of heterozygotes for large expansions could be analysed only in subjects born after 1950 and provided indirect evidence of a lower than normal number of children. The above results fit a model based on a differential fitness according to the degree of expansion. Such a model predicts that 1) up to relatively recently the frequency of alleles in the low/medium range has been maintained or even increased by the increased fitness of their carriers, as well as by new mutations, and 2) the frequency of large expansions, part of which are lost at each generation, is maintained through further expansions of alleles in the low/medium expansion range. The implications of such a model on linkage disequilibrium and the possible spread of these diseases in future generations are discussed.


Assuntos
Doença de Huntington/genética , Degenerações Espinocerebelares/genética , Repetições de Trinucleotídeos , Idade de Início , Características da Família , Feminino , Heterozigoto , Humanos , Doença de Huntington/mortalidade , Desequilíbrio de Ligação , Masculino , Modelos Genéticos , Degenerações Espinocerebelares/mortalidade , Fatores de Tempo
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