RESUMO
Familial hemiplegic migraine type 1, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) are allelic disorders associated with mutations in the CACNA1A gene, which encodes the alpha1 subunit of the P/Q-type calcium channel (Ca(V)2.1). SCA6 and EA2 share a number of clinical features, such as prominent cerebellar involvement and good response to acetazolamide therapy. However, while SCA6 develops as a late-onset, progressive ataxia, EA2 has an earlier, and episodic, onset. We report on two sisters with a heterogeneous clinical phenotype. The first developed progressive cerebellar ataxia after age 30, without noticeable episodes of vertigo or headache. A 1 year trial with acetazolamide did not produce significant results. The other reported episodes of vertigo, headache and gait imbalance since late childhood, with good response to acetazolamide, before developing moderate chronic cerebellar ataxia. Brain MRI showed cerebellar atrophy, especially in the vermis, in both patients. Direct sequencing of CACNA1A identified a heterozygous 1360G>A mutation in exon 11 resulting in the substitution of alanine for threonine at residue 454 (p.Ala454Thr). This is the first description of a change residing in the cytoplasmic I-II loop associated with a clinical phenotype.
Assuntos
Canais de Cálcio/genética , Predisposição Genética para Doença/genética , Mutação Puntual/genética , Degenerações Espinocerebelares/genética , Acetazolamida/uso terapêutico , Idade de Início , Substituição de Aminoácidos/genética , Inibidores da Anidrase Carbônica/uso terapêutico , Cerebelo/metabolismo , Cerebelo/patologia , Cerebelo/fisiopatologia , Análise Mutacional de DNA , Progressão da Doença , Éxons/genética , Feminino , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Degenerações Espinocerebelares/tratamento farmacológico , Degenerações Espinocerebelares/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND: A complicated form of recessive hereditary spastic paraplegias (HSPs) with thin corpus callosum (TCC) was first described in Japan, and most of the Japanese families showed linkage to chromosome 15q13-15. A recessive HSP locus (SPG11) has also been mapped to chromosome 15q13-15 in Italian and North American families with and without TCC, and it overlaps the region identified in the Japanese families. OBJECTIVE: To study clinically and genetically 12 Italian families with HSP and TCC. METHODS: The authors investigated 18 affected and 30 healthy individuals from 12 unrelated Italian families with recessive HSP-TCC. Clinical, neurophysiologic, and neuroradiologic studies were undertaken. All patients were negative for SPG7 mutations. Genetic linkage analyses were carried out with polymorphic DNA markers on 15q13-15. RESULTS: Five families were consistent with linkage, thus defining a 19.8-cM region between markers D15S1007 and D15S978, encompassing the SPG11 interval. In one consanguineous family, linkage could be firmly excluded, confirming genetic heterogeneity. Two families appeared not linked to the region, but this could not be firmly proved because of the small family size. The remaining four families were uninformative for linkage purposes. CONCLUSION: HSP-TCC is common in Italy. The phenotype is fairly homogeneous and is associated with impaired cognition. There are at least two loci for HSP-TCC, one of which is on chromosome 15q13-15.
Assuntos
Corpo Caloso/patologia , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Criança , Cromossomos Humanos Par 15/genética , Consanguinidade , Feminino , Genes Recessivos , Haplótipos , Humanos , Itália , Escore Lod , Masculino , Linhagem , Paraplegia Espástica Hereditária/patologiaRESUMO
The authors report on a novel frameshift mutation (c.1688insA) in the SPG3A gene resulting in premature translation termination of the gene product atlastin. These data add a new variant to the second disease gene in autosomal dominant hereditary spastic paraplegia (ADHSP) and lend definitive support to its causative role. By combining direct testing of SPAST and SPG3A, at least 50% of ADHSP families can now receive appropriate genetic diagnosis.
Assuntos
Mutação da Fase de Leitura/genética , GTP Fosfo-Hidrolases/genética , Paraplegia Espástica Hereditária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA/análise , DNA/genética , Elementos de DNA Transponíveis/genética , Feminino , Proteínas de Ligação ao GTP , Frequência do Gene , Genes Dominantes/genética , Humanos , Itália , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Linhagem , Paraplegia Espástica Hereditária/patologiaRESUMO
Hereditary Spastic Paraplegias (HSPs) are heterogeneous neurodegenerative disorders whose etiopathogenesis is still unclear. The identification of pathogenic mutations in a gene (SPG7) encoding a mitochondrial metalloprotease suggested that oxidative phosphorylation (OXPHOS) alterations might underlie HSP in a subgroup of patients. We performed clinical, morphological, biochemical, and molecular genetic studies in six HSP patients and in six sporadic patients to investigate OXPHOS in muscle biopsies. Complicated and pure forms were included in our study. Morphological alterations of the type seen in OXPHOS-related disorders were found in three patients. Five patients showed an isolated defect of complex I activity. No mutations in the SPG7 gene were detected. Our results suggest that OXPHOS defects in HSP patients are more common than previously believed.