RESUMO
BACKGROUND: Hyperhomocysteinemia is frequently observed in alcohol-dependent subjects, in particularly in those with marked withdrawal symptoms. The common C677T transition on the methylenetetrahydrofolate reductase (MTHFR) gene influences homocysteinemia. Our objective was to study the prevalence of the MTHFR C677T polymorphism in alcohol-dependent subjects and the influence of this polymorphism on symptoms associated with alcoholism. METHODS: MTHFR C677T polymorphism was determined in 93 control subjects and 242 alcohol-dependent subjects. Serum homocysteine, folate and vitamin B12 levels together with hepatic biological parameters were determined in the control and alcohol-dependent subjects. RESULTS: Hyperhomocysteinemia is frequently observed in alcohol-dependent subjects, particularly in those with marked withdrawal symptoms. Alcohol-dependent subjects showed a significant decrease in MTHFR 677TT prevalence (9%, 21/242) compared to controls (18%, 17/93) (p<0.02). The relative risk estimated as an odds ratio for alcoholism in subjects with the TT genotype is 0.42 (odd ratio 95% confidence interval, 0.21-0.83). Moreover, drinkers with TT genotype presented lower values for markers of alcohol misuse (p<0.05), better liver function tests, a lower frequency of relapses and no marked withdrawal symptoms as assessed by the Lesch typology. CONCLUSION: MTHFR 677TT genotype could play a protective role against alcohol dependence. Moreover, when subjects with MTHFR 677TT genotype become dependent to alcohol, they seem to constitute a subgroup of alcoholic patients with a decreased risk for developing neurotoxic withdrawal symptoms and hepatic toxicity.
Assuntos
Alcoolismo/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético/genética , Consumo de Bebidas Alcoólicas/genética , Neuropatia Alcoólica/genética , Alcoolismo/sangue , Alcoolismo/enzimologia , Grupos Controle , Feminino , Ácido Fólico/sangue , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/genética , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/genética , Hepatopatias Alcoólicas/genética , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Risco , Vitamina B 12/sangueRESUMO
Ataxia oculomotor apraxia type 1 (AOA1) is the most common form of autosomal recessive ataxia in Japan, and the second in Portugal after Friedreich ataxia. AOA1 is typically characterized by early-onset cerebellar ataxia, oculomotor apraxia, hypoalbuminemia, hypercholesterolemia and late axonal sensori-motor neuropathy. AOA1 is associated with the aprataxin gene (APTX) encoding a protein involved in DNA repair. We characterized a novel homozygous missense mutation of APTX in a 34 year-old female patient born from consanguineous parents. The mutation, a Val230Gly caused by a c.689 T>G substitution, involved the histidine-triad (HIT) domain of the protein, affected a phylogenetically conserved amino acid and was absent in the control population. We described the clinical and neurophysiological features, the findings at structural and functional brain imaging, and the pathological picture of the sural nerve biopsy. The report emphasized the genetical and phenotypical heterogeneity of AOA1 by demonstrating atypical features such as absence of oculomotor apraxia and signs of pyramidal involvement. Expression studies by Western blotting on fibroblasts demonstrated that the homozygous Val230Gly mutation was associated with decreased levels of APTX indicating a loss-of-function mechanism.
Assuntos
Apraxias/genética , Ataxia Cerebelar/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Mutação/genética , Proteínas Nucleares/genética , Transtornos da Motilidade Ocular/genética , Adulto , Neuropatia Alcoólica/genética , Neuropatia Alcoólica/patologia , Neuropatia Alcoólica/fisiopatologia , Substituição de Aminoácidos , Apraxias/metabolismo , Apraxias/fisiopatologia , Atrofia/genética , Atrofia/patologia , Atrofia/fisiopatologia , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Consanguinidade , Análise Mutacional de DNA , Eletroencefalografia , Feminino , Testes Genéticos , Genótipo , Humanos , Imageamento por Ressonância Magnética , Mutação de Sentido Incorreto/genética , Transtornos da Motilidade Ocular/metabolismo , Transtornos da Motilidade Ocular/fisiopatologia , Linhagem , Fenótipo , Tomografia por Emissão de PósitronsRESUMO
Persons who have the Glu-487-->Lys mutation (single nucleotide polymorphism) of the aldehyde dehydrogenase-2 (ALDH2) gene have less ability to metabolize the alcohol breakdown product acetaldehyde. In order to clarify whether acetaldehyde is associated with the pathogenesis of alcoholic polyneuropathy, we compared nerve conduction data as well as clinical signs and symptoms of neuropathy between alcoholics with ALDH2*2 (Lys-487) heterozygotes and those with ALDH2*1 (Glu-487) homozygotes. Alcoholics with ALDH2*2 heterozygotes showed significantly lower sensory nerve action potential amplitudes of the sural and median nerves than those with ALDH2*1 homozygotes, suggesting that the accumulation of acetaldehyde due to ALDH2 inactivity is associated with alcoholic polyneuropathy.
Assuntos
Neuropatia Alcoólica/genética , Aldeído Desidrogenase/genética , Polimorfismo Genético , Potenciais de Ação/fisiologia , Aldeído-Desidrogenase Mitocondrial , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Ácido Glutâmico/genética , Humanos , Lisina/genética , Masculino , Pessoa de Meia-Idade , Condução Nervosa/genética , Condução Nervosa/fisiologia , Nervos Periféricos/fisiopatologia , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
An improved differential display technique was used to search for changes in gene expression in the superior frontal cortex of alcoholics. A cDNA fragment was retrieved and cloned. Further sequence of the cDNA was determined from 5' RACE and screening of a human brain cDNA library. The gene was named hNP22 (human neuronal protein 22). The deduced protein sequence of hNP22 has an estimated molecular mass of 22.4 kDa with a putative calcium-binding site, and phosphorylation sites for casein kinase II and protein kinase C. The deduced amino acid sequence of hNP22 shares homology (from 67% to 42%) with four other proteins, SM22alpha, calponin, myophilin and mp20. Sequence homology suggests a potential interaction of hNP22 with cytoskeletal elements. hNP22 mRNA was expressed in various brain regions but in alcoholics, greater mRNA expression occurred in the superior frontal cortex, but not in the primary motor cortex or cerebellum. The results suggest that hNP22 may have a role in alcohol-related adaptations and may mediate regulatory signal transduction pathways in neurones.
