RESUMO
BACKGROUND: Autosomal dominant cerebellar ataxia, currently denominated spinocerebellar ataxia (SCAs), represents a heterogeneous group of neurodegenerative disorders affecting the cerebellum and its connections. We describe the clinical and molecular findings in 16 patients originating from Malian families, who suffer from progressive cerebellar ataxia syndrome. METHODS AND RESULTS: Molecular analysis allows genetic profiles of SCA to be distinguished. In seven patients, SCA type 2 (CAG) mutation was expanded from 39 to 43 repeats. SCA type 7 (CAG) mutation was confirmed in six patients. Mutations were expanded from 49 to 59 repeats. In three patients, SCA type3 was diagnosed and CAG mutation was expanded to 73 repeats. CONCLUSIONS: Our data suggest that the most frequent types of SCA are SCA2 and SCA7. However, further studies are needed to confirm these preliminary results.
Assuntos
Predisposição Genética para Doença/genética , Mutação/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Mali/epidemiologia , Pessoa de Meia-Idade , Ataxias Espinocerebelares/classificaçãoRESUMO
We identified a family in Mali with two sisters affected by spastic paraplegia. In addition to spasticity and weakness of the lower limbs, the patients had marked atrophy of the distal upper extremities. Homozygosity mapping using single nucleotide polymorphism arrays showed that the sisters shared a region of extended homozygosity at chromosome 19p13.11-q12 that was not shared by controls. These findings indicate a clinically and genetically distinct form of hereditary spastic paraplegia with amyotrophy, designated SPG43.
Assuntos
Neurite do Plexo Braquial/genética , Cromossomos Humanos Par 19/genética , Loci Gênicos , Paraplegia Espástica Hereditária/genética , Adolescente , Idade de Início , Feminino , Homozigoto , Humanos , Mali , Linhagem , Polimorfismo de Nucleotídeo Único , Irmãos , Adulto JovemRESUMO
We studied a Malian family with parental consanguinity and two of eight siblings affected with late-childhood-onset progressive myoclonus epilepsy and cognitive decline, consistent with the diagnosis of Lafora disease. Genetic analysis showed a novel homozygous single-nucleotide variant in the NHLRC1 gene, c.560A>C, producing the missense change H187P. The changed amino acid is highly conserved, and the mutation impairs malin's ability to degrade laforin in vitro. Pathological evaluation showed manifestations of Lafora disease in the entire brain, with particularly severe involvement of the pallidum, thalamus, and cerebellum. Our findings document Lafora disease with severe manifestations in the West African population.
Assuntos
Proteínas de Transporte/genética , Doença de Lafora/genética , Mutação de Sentido Incorreto , Adolescente , Encéfalo/patologia , Criança , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Doença de Lafora/patologia , Doença de Lafora/fisiopatologia , Masculino , Mali , Linhagem , Polimorfismo de Nucleotídeo Único , Ubiquitina-Proteína Ligases , Adulto JovemRESUMO
Cysteine and its metabolites cysteine sulphinic acid (CSA) and taurine (TA) were shown to be toxic to human and rat neuronal cell lines. However, the mechanisms of action of CSA and TA appeared to be different. As MND/ALS patients have high plasma and CSF cysteine levels, they may have increased levels of neurotoxins in vivo, since cysteine was more toxic than CSA in the assay system used. Cysteic acid, homocysteic acid, BMAA and BOAA were also toxic to the cell lines used.
Assuntos
Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Enxofre/toxicidade , Animais , Linhagem Celular , Humanos , L-Lactato Desidrogenase/metabolismo , Neurônios/enzimologia , Ratos , Células Tumorais CultivadasRESUMO
We have previously reported an association of impaired S-oxidation with primary biliary cirrhosis. In order to confirm and further define this relationship, we retested S-oxidation capacity via three metabolic pathways and sulphation capacity via a fourth pathway. Metabolism of S-carboxymethyl-L-cysteine is polymorphic -20% of healthy individuals being poor S-oxidisers. We found 26% with primary biliary cirrhosis were poor S-oxidisers, compared with 36% with other liver disease and 25% of healthy controls. Differences were not statistically significant. S-oxidation of ranitidine is dependent upon flavin mono-oxygenases. We showed a non-significant trend toward less S-oxide in primary biliary cirrhosis and other liver disease, compared with healthy controls, with no significant difference between disease groups. Conversion of cysteine to sulphate depends predominantly on cysteine dioxygenase. Impaired activity may be reflected by decreased plasma sulphate and elevated cysteine. We found that the plasma cysteine: sulphate ratio was significantly elevated not only in primary biliary cirrhosis (p < 0.0001), but also in other liver disease (p < 0.0001), compared with healthy individuals. Sulphation capacity was studied by analysing paracetamol metabolism. Paracetamol sulphate and sulphate: glucuronide ratio were reduced in primary biliary cirrhosis compared with normal individuals, (p < 0.05). A trend towards less sulphate in primary biliary cirrhosis compared other liver disease was not significant (p = 0.42). We conclude that although sulphation and some sulphoxidation pathways are impaired in primary biliary cirrhosis, we can currently find no evidence to substantiate the hypothesis that primary biliary cirrhosis is a disease specifically associated with poor S-oxidation, as assessed via these metabolic pathways.
Assuntos
Carbocisteína/metabolismo , Cirrose Hepática Biliar/metabolismo , Sulfóxidos/metabolismo , Ésteres do Ácido Sulfúrico/metabolismo , Acetaminofen/metabolismo , Adulto , Estudos de Casos e Controles , Cisteína/sangue , Feminino , Humanos , Cirrose Hepática Biliar/sangue , Masculino , Pessoa de Meia-Idade , Oxirredução , Ranitidina/análogos & derivados , Ranitidina/metabolismo , Valores de Referência , Ésteres do Ácido Sulfúrico/sangueRESUMO
Analysis of plasma from MND/ALS patients has shown no significant differences in metabolism of cysteine derivatives, although a sub-set of the population has raised glutamate values. Cysteine dioxygenase was found to have reduced activity in vitro, consistent with previous findings of a high plasma cysteine/sulphate ratio.