Showing papers by "Isabel Silveira published in 2003"

Phenotypes of Spinocerebellar Ataxia Type 6 and Familial Hemiplegic Migraine Caused by a Unique CACNA1A Missense Mutation in Patients From a Large Family

Abstract: Background:Different mutations in the1A-subunit of thebrainP/Q-typecalciumchannelgene(CACNA1A)are responsibleforfamilialhemiplegicmigraine(FHM),episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). Missense and splice site mutations have been found in FHM and episodic ataxia type 2, respectively, whereas a CAG repeat in the CACNA1A gene was found expanded in patients with SCA6. Objective: To identify the disease causing mutation in a large family of patients with phenotypes of hemiplegic migraine with or without cerebellar signs or permanent cerebellar ataxia without migraine inherited in a dominant manner. Patients and Methods: We examined 15 patients from a large family identified through a systematic survey of hereditary ataxias being conducted in Portugal. Linkage analysis was performed with CACNA1A gene markers, and mutation analysis was performed by single strand conformational polymorphism analysis and sequencing. Results: Genetic linkage analysis with CACNA1A intragenic markers showed positive LOD scores. The maximal LOD score was obtained with the polymorphic CAG repeat (Zmax=4.47, =0). By single-strand conformational polymorphismanalysis,ashiftinexon13oftheCACNA1A genewasdetectedinallpatients.AG-to-Asubstitutionwas thenidentified,resultinginanarginine-to-glutaminechange at codon 583 of this calcium channel 1A-subunit. Conclusions:Thedisease-causingmutationinthisfamily was identified, showing that a unique mutation in the CACNA1A gene causes several phenotypes, including those of SCA6 and FHM, thus suggesting that SCA6 and FHM are not only allelic diseases but are the same disorder with a large phenotypic variability. Arch Neurol. 2003;60:610-614

Use of fluoxetine for treatment of Machado-Joseph disease: an open-label study.

Abstract: Context – Machado-Joseph Disease (MJD/SCA3) is an autosomal dominant spinocerebellar degeneration that evolves to disability and death. Experimental data have shown that serotonin is an important cerebellar neurotransmitter and that impairment of the serotoninergic cerebellar system can induce cerebellar ataxia. Objectives – To evaluate the efficacy of fluoxetine, a serotonin reuptake inhibitor, in treating neurologic dysfunction in patients with MJD. Patients and methods – Thirteen MJD patients were treated with fluoxetine (20 mg/day) and were followed-up for 6 weeks. Outcome measures included functional capacity, standardized neurologic and cognitive ratings. The Montgomery-Asberg depression rating scale was used to control depressive symptoms. Results – There was no significant improvement in motor abilities after 6 weeks of treatment. Conclusions – These results suggest that fluoxetine has no benefit in motor function of patients with MJD/SCA3.

A novel R1347Q mutation in the predicted voltage sensor segment of the P/Q‐type calcium‐channel α1A‐subunit in a family with progressive cerebellar ataxia and hemiplegic migraine

Abstract: To the Editor: The CACNA1A gene encodes the highly conserved brain-specific P/Q-type voltage-gated calcium-channel a1A-subunit, expressed mainly in the cerebellum. This channel mediates the entry of calcium ions into cells. This gene is involved in spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1), which have been considered as distinct clinical entities (1, 2). Recent studies have shown extensive clinical and genetic overlaps between these diseases (3–6). Here, we report a novel missense mutation, located in a region considered to be the voltage sensor of the P/Q-type calcium channel, responsible for both progressive cerebellar ataxia and hemiplegic migraine in all patients from one affected family. We ascertained a Portuguese family with both progressive cerebellar ataxia and hemiplegic migraine, during a population-based survey on hereditary ataxias (7). This family had three patients, two of whom were clinically examined, in two consecutive generations. The proband was a 32-year-old woman presenting with slowly progressive ataxia since her childhood. She experienced a 24-h coma, at the age of 18, after a car accident without head trauma. Magnetic resonance imaging study in this patient showed atrophy of the cerebellum. Nine years later, she had the first episode of hemiplegic migraine that occurred again at a later time. Her brother had the first symptoms at 11 years of age with hemiparesis and aphasia, triggered by physical effort. Hemiparesis and aphasia have recovered after 1week, whereas the signs of gait ataxia have persisted and slowly progressed. No headache was present. Their mother, already deceased, has never been clinically evaluated. We were told by her family members that she had attacks of hemiparesis and aphasia precipitated by physical effort, mainly during the summer season, since she was 11 years of age. By the age of 13, she began to exhibit signs of a slowly progressive ataxia. Mutation analysis of the CACNA1A gene in this family revealed a mobility variant at exon 25 in the two affected sibs but not in their healthy relatives. By direct sequencing, a G-to-A substitution at position 4315 was identified, which produces an arginine-to-glutamine change, at codon 1347, in the CACNA1A gene; this was not present in 100 control chromosomes from the Portuguese general population. This Arg1347 is evolutionarily conserved among a1A-subunits from other species such as Rattus norvegicus, Mus musculus, Drosophila melanogaster and Caenorhabditis elegans, as well as in other a1-subunits. Other mobility variants were detected in this family, indicative of several polymorphisms (Table 1). In the present study, we report a new mutation in the P/Q-type calcium-channel a1A-subunit gene, in a Portuguese family with both slowly progressive cerebellar ataxia and hemiplegic migraine. This mutation replaces a polar positively charged highly conserved arginine by a neutral glutamine, at codon 1347. The two previously described mutations R192Q (1) and R583Q (6, 8) are located in the S4-transmembrane segments of protein domains I and II, respectively (Fig. 1), which are considered to be the voltage sensor segments, both replacing highly conserved positively charged arginines by neutral glutamines. The missense mutation in this family is similar and is also located in the S4-transmembrane segment but of protein domain III. Functional studies performed in channels with the two previously Clin Genet 2004: 65: 70–72 Copyright # Blackwell Munksgaard 2004 Printed inDenmark. All rights reserved CLINICALGENETICS

Portuguese families with dentatorubropallidoluysian atrophy (DRPLA) share a common haplotype of Asian origin

Abstract: Dentatorubropallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by a variable combination of progressive ataxia, epilepsy, myoclonus, choreoathetosis and dementia. This disease is caused by a (CAG)n expansion in the DRPLA gene, on chromosome 12p13. DRPLA is prevalent in Japan, but several families of non-Japanese ancestry have already been published. To identify the origin of expanded alleles in Portuguese families with DRPLA, we studied two previously reported intragenic SNPs in introns 1 and 3, in addition to the CAG repeat of the DRPLA gene. The results showed that all four Portuguese DRPLA families shared the same haplotype, which is also common to that reported for Japanese DRPLA chromosomes. This haplotype is also the most frequent in Japanese normal alleles, whereas it was rare in Portuguese control chromosomes. Thus, our findings support that a founder DRPLA haplotype of Asian origin was introduced in Portugal, being responsible for the frequency of the disease in this country.

Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado-Joseph disease (SCA3) phenotype.

Abstract: Context – Machado–Joseph disease (MJD/SCA3) is an autosomal dominant cerebellar ataxia of adult onset. The variability in age at onset and the complex and heterogeneous neurologic findings indicate that MJD, caused by a major gene, is modulated by modifier factors. Objective – To study if the polymorphic CAG repeats at other loci (namely, SCA2, SCA6 and DRPLA) thus acted as modifier factors of this disease. Design – Case–control. Setting – Ambulatory care in a referral center. Patients – A convenience sample of 39 unrelated, Brazilian patients with MJD. Main outcome measures: age of onset, anticipation, clinical subtypes and neurological findings. Results – Fasciculations were associated with CAG repeat length of the long SCA2 allele (Mann–Whitney U-test, P < 0.03, after Bonferroni procedure). Other measures (age of onset, anticipation, clinical types and other neurological signs) were not associated with CAG repeat length of SCA2, SCA6 and DRPLA genes. Conclusions – The present results show that the CAG tract of SCA2 gene interferes with MJD phenotype. Further studies, with patients of other origins and with typing of other (CAG)n loci, are necessary.