RESUMO
Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.
Assuntos
Acetiltransferases/genética , Metabolismo dos Lipídeos/genética , Mutação/genética , Ataxias Espinocerebelares/genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Animais , Ácido Araquidônico/sangue , Cerebelo/patologia , Ácidos Docosa-Hexaenoicos/sangue , Retículo Endoplasmático/metabolismo , Elongases de Ácidos Graxos , Feminino , Ligação Genética , Genótipo , Complexo de Golgi/metabolismo , Haplótipos , Humanos , Itália , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem , Células de Purkinje/citologiaRESUMO
Enterovirus meningitis is well documented in children. However, there is a paucity of reports in adults, despite the availability of genome detection (RT-PCR) in cerebrospinal fluid (CSF), which provides a rapid and reliable diagnosis. The clinical course and management of 30 cases of entero-virus proven meningitis prospectively diagnosed between August 1999 and November 2000 in immunocompetent adults were analysed, and laboratory and clinical strategies evaluated. Patient age ranged between 17 and 43 (median 29). The analysis of clinical, biological, and epidemiological data showed the difficulty of recognising enterovirus meningitis in adults. Characteristic symptoms were either inconstant (the association of fever/headache/stiff neck) or misleading (the presence of vesicular lesions). CSF data showed moderate pleocytosis but a predominance of lymphocytes in only 12/27 (44%) patients. An epidemiological background was present in 10/30 (33%) patients, but 10/30 (33%) patients were admitted during cold months. Consequently, although the detection of enterovirus genome in CSF was positive in all cases, the results were communicated within a median of 6 days [2-9] after admission, mainly because the aetiology was not considered early enough. Management of patients varied between departments and between individual physicians, with measures ranging from computed tomography (33%) to the prescription of aciclovir (20%) or antibiotics (53%). Enterovirus meningitis should not be underestimated in adults. Management could be improved and standardised, and costs reduced by more systematic year-round use of enterovirus RT-PCR in meningitis, provided results are rapid.
