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J Sequeiros

Publications and source records attributed to J Sequeiros.

At least 19 recordsLinked to original sources
PubMed2007

Depressive symptoms in Machado-Joseph disease (SCA3) patients and their relatives.

OBJECTIVES: It was the aim of this study to determine the depression scores of Machado-Joseph disease (MJD) patients, their spouses, and individuals at 50% risk for MJD, and second, to verify the existence of a correlation between depressive symptoms and the degree of motor incapacitation. SUBJECTS AND METHODS: Two hundred and forty-six individuals aged > or =18 years were studied: 79 MJD patients (group 1), 43 spouses of MJD patients (group 2), 80 individuals at risk for MJD (group 3), and a control group (group 4) composed of 44 patients with multiple sclerosis (MS). The following two tools were applied: the Beck Depression Inventory and the Barthel index of physical incapacitation, both in an adapted Brazilian Portuguese version. RESULTS: Moderate to severe depressive scores were found in 33.5% of patients in the MJD families, in 16.3% of the spouses, and in 6.3% of the individuals at risk. This linear reduction between MJD family members was statistically significant (p < 0.0001, ANOVA). Depressive scores were also associated with age and the female sex. A direct correlation between Beck Depression Inventory scores and motor incapacitation was found in MJD patients (r = 0.507, Pearson correlation, p < 0.0001). Although the depressive symptoms in the control group with MS were higher than those found in MJD patients (59% of MS patients showed moderate to severe scores), depression did not correlate with physical incapacitation, age, or education attainment in the MS group. CONCLUSIONS: Depressive symptoms are rather common in MJD patients and in their spouses (caregivers). In this condition, depression seemed to be more reactive than primarily related to the disease process itself.

Adult↗
PubMed2006

Psychological aspects of pre-symptomatic testing for Machado-Joseph disease and familial amyloid polyneuropathy type I.

Machado-Joseph disease [MJD, also spinocerebellar ataxia type 3 (SCA3)] and familial amyloid polyneuropathy type I (FAP-I or ATTR V30M) are neurodegenerative disorders, inherited in an autosomal dominant fashion, which have a high prevalence in Portugal, probably due to a founder effect. MJD and FAP-I are late-onset diseases, with symptoms emerging usually during adulthood. CGPP, which is the national reference centre for these disorders, has a genetic lab that offers diagnostic, pre-symptomatic and prenatal testing and an outpatient clinic to counsel and follow relatives at risk for hereditary ataxias, FAP-I and Huntington disease (HD). The present work is a review of our 10-year experience with psychological counselling of individuals at risk for MJD and FAP-I. Persons at risk for FAP-I may show a better response to pre-symptomatic testing than those who are at risk for MJD and HD because of the availability of liver transplantation, which may improve their health and life expectancy. Psychological well-being and specific distress of MJD and FAP-I test applicants, before undergoing genetic testing (baseline level) and 3 to 6 months after disclosure of test results, have shown a low level of change, both in identified carriers and non-carriers. A major goal of psychological characterization of at-risk individuals for MJD and FAP-I is to determine the factors that influence the uptake of genetic testing.

Amyloid Neuropathies, Familial↗
PubMed2005

Population genetics of wild-type CAG repeats in the Machado-Joseph disease gene in Portugal.

OBJECTIVE: To gain insights on the molecular mechanisms of mutation that led to the emergence of expanded alleles in the MJD gene, by studying the behavior of wild-type alleles and testing the association of its distribution with the representation of the disease. METHODS: The number of CAG motifs in the MJD gene was determined in a representative sample of 1000 unrelated individuals. Associations between the repeat size and the epidemiological representation of MJD were tested. RESULTS: The allelic profile of the total sample was in the normal range (13-41 repeats), with mode (CAG)23. No intermediate alleles were present. Allelic size distribution showed a negative skew. The correlation between the epidemiological representation of MJD in each district and the frequency of small, medium and large normal alleles was not significant. Further correlations performed grouping the districts also failed to produce significant results. CONCLUSIONS: The absence of association between the size of the repeats and the representation of MJD demonstrates that prevalence is not an indirect reflection of the frequency of large normal alleles. Globally the results obtained are in accordance with a model that postulates the occurrence of a few mutations on the basis of most of the MJD cases worldwide.

Ataxin-3↗
PubMed2005

Neuroferritinopathy: missense mutation in FTL causing early-onset bilateral pallidal involvement.

The authors identified a missense mutation in the FTL gene (474G>A; A96T) in a 19-year-old man with parkinsonism, ataxia, corticospinal signs, mild nonprogressive cognitive deficit, and episodic psychosis. This mutation was also present in his asymptomatic mother and younger brother, who had abnormally low levels of ferritin in the serum. The patient and his mother displayed bilateral involvement of the pallidum.

Adult↗
PubMed2003

A whole genome screen for association with multiple sclerosis in Portuguese patients.

Multiple sclerosis (MS) is common in Europe affecting up to 1:500 people. In an effort to identify genes influencing susceptibility to the disease, we have performed a population-based whole genome screen for association. In this study, 6000 microsatellite markers were typed in separately pooled DNA samples from MS patients (n=188) and matched controls (n=188). Interpretable data was obtained from 4661 of these markers. Refining analysis of the most promising markers identified 10 showing potential evidence for association.

Adolescent↗
PubMed2003

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

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.

Age of Onset↗
PubMed2003

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

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.

Adolescent↗
PubMed2002

Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus.

BACKGROUND: Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood. OBJECTIVE: To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA. PATIENTS AND METHODS: We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification. RESULTS: Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. CONCLUSIONS: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)(n) expansions at the TBP gene may cause SCA17.

Adenine↗
PubMed2001

Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity.

Ataxia with oculomotor apraxia (AOA) is characterized by early-onset cerebellar ataxia, ocular apraxia, early areflexia, late peripheral neuropathy, slow progression, severe motor handicap, and absence of both telangiectasias and immunodeficiency. We studied 13 Portuguese families with AOA and found that the two largest families show linkage to 9p, with LOD scores of 4.13 and 3.82, respectively, at a recombination fraction of 0. These and three smaller families, all from northern Portugal, showed homozygosity and haplotype sharing over a 2-cM region on 9p13, demonstrating the existence of both a founding event and linkage to this locus, AOA1, in the five families. Three other families were excluded from this locus, demonstrating nonallelic heterogeneity in AOA. Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA), so far described only in Japan, is characterized by marked cerebellar atrophy, peripheral neuropathy, mental retardation, and, occasionally, oculomotor apraxia. Two unrelated Japanese families with EOCA-HA were analyzed and appeared to show linkage to the AOA1 locus. Subsequently, hypoalbuminemia was found in all five Portuguese patients with AOA1 with a long disease duration, suggesting that AOA1 and EOCA-HA correspond to the same entity that accounts for a significant proportion of all recessive ataxias. The narrow localization of AOA1 should prompt the identification of the defective gene.

Alleles↗
PubMed2001

Improvement in the molecular diagnosis of Machado-Joseph disease.

BACKGROUND: Direct detection of the gene mutation allows for the confirmation of the clinical diagnosis of Machado-Joseph disease (MJD), the most frequent cause of autosomal dominant spinocerebellar ataxia worldwide. OBJECTIVE: To address the main difficulties in our national MJD predictive testing program. The first was the emergence of intermediate alleles, for which it is not yet possible to determine whether they will cause disease. The second was the issue of homoallelism, ie, homozygosity for 2 normal alleles with exactly the same (CAG)(n) length, which occurs in about 10% of all test results. METHODS: A large pedigree with 1 affected patient carrying a 71 and a 51 CAG repeat and 2 asymptomatic relatives carrying the 51 CAG repeat and normal-size alleles underwent clinical and molecular studies. Intragenic haplotypes for these alleles were determined. A representative sample of the healthy population in the region was obtained to assess the distribution of the normal (CAG)(n) length. We established the genotype for 4 intragenic polymorphisms in the gene for MJD (MJD1) in 21 homoallelic individuals, to distinguish their 2 normal chromosomes. In addition, we developed a new Southern blot method to completely exclude cases of nonamplification of expanded alleles in the homoallelic individuals. RESULTS: The study of the family in which the 51 CAG repeat was found suggests that the allele is apparently not associated with disease. These intermediate alleles were not present in a large sample of the healthy population from the same region. Intragenic polymorphisms allowed distinction of the 2 different normal alleles in all cases of homoallelism. The absence of an expanded allele was also confirmed by Southern blot. CONCLUSIONS: We propose an improved protocol for molecular testing for MJD. These strategies, developed to overcome the practical difficulties mostly in the presymptomatic and prenatal diagnosis of MJD, should prove useful for other polyglutamine-related disorders.

Adult↗
PubMed2001

Recessive ataxia with ocular apraxia: review of 22 Portuguese patients.

BACKGROUND: The recessive ataxias are a heterogeneous group of neurodegenerative disorders characterized by cerebellar ataxia associated with a number of different neurologic, ophthalmologic, or general signs. They are often difficult to classify in clinical terms, except for Friedreich ataxia, ataxia-telangiectasia, and a relatively small group of rare conditions for which the molecular basis has already been defined. OBJECTIVES: To study the clinical presentation and to define diagnostic criteria in a group of Portuguese patients with ataxia and ocular apraxia, an autosomal recessive form without the essential clinical and laboratory features of ataxia-telangiectasia. PATIENTS AND METHODS: We reviewed 22 patients in 11 kindreds, identified through a systematic survey of hereditary ataxias being conducted in Portugal. RESULTS: Age at onset ranged from 1 to 15 years, with a mean of 4.7 years. The duration of symptoms at the time of last examination varied from 5 to 58 years. All patients presented with progressive cerebellar ataxia, the characteristic ocular apraxia, and a peripheral neuropathy. Associated neurologic signs included dystonia, scoliosis, and pes cavus. Magnetic resonance imaging was performed in 16 patients, all of whom showed cerebellar atrophy. CONCLUSIONS: Ataxia with ocular apraxia may be more frequent than postulated before, and may be identified clinically using the following criteria: (1) autosomal recessive transmission; (2) early onset (for most patients in early childhood); (3) combination of cerebellar ataxia, ocular apraxia, and early areflexia, with later appearance of the full picture of peripheral neuropathy; (4) absence of mental retardation, telangiectasia, and immunodeficiency; and (5) the possibility of a long survival, although with severe motor handicap.

Adolescent↗
PubMed2001

Neurologic findings in Machado-Joseph disease: relation with disease duration, subtypes, and (CAG)n.

CONTEXT: Machado-Joseph disease (MJD), an autosomal dominant spinocerebellar degeneration caused by an expanded CAG repeat on chromosome 14q32.1, is a heterogeneous disorder for clinical manifestations. The reasons for the wide range of neurologic findings in this disease are poorly understood. OBJECTIVE: To explain part of this heterogeneity through the association of the neurologic findings with sex, disease duration, age of onset, clinical type, and size of CAG repeat expansion. DESIGN: A case-control study. SETTING: Ambulatory care. PATIENTS: A consecutive sample of 62 patients with MJD. MAIN OUTCOME MEASURE: Neurologic signs. RESULTS: A direct relationship was found between the disease duration and severity of gait and limb ataxia, dysarthria, dysphagia, fasciculations, pyramidal syndrome, and ophthalmoplegia (P<.02). The most severe forms of nuclear ophthalmoplegia were associated with type 1 MJD, whereas those of supranuclear ophthalmoplegia were associated with type 3 MJD (P<.001). It was also found that higher mean (CAG)(n) lengths were associated with worse degrees of the pyramidal syndrome and dystonia (P<.001). The presence and severity of nystagmus, eyelid retraction, rigidity and/or bradykinesia, and optic atrophy were not clearly associated with any of the predictive variables under study. CONCLUSIONS: Disease duration can explain part of the heterogeneity of ataxia, dysarthria, dysphagia, fasciculations, pyramidal syndrome, and ophthalmoplegia, in MJD. Type 1 MJD was positively associated with nuclear ophthalmoplegia; type 3 MJD was positively associated with supranuclear ophthalmoplegia. Higher mean CAG lengths were found to correlate with the pyramidal syndrome and dystonia. Nystagmus, eyelid retraction, rigidity and/or bradykinesia, and optic atrophy were hardly attributable to any known reason or variable.

Adult↗
PubMed2001

A survey of spinocerebellar ataxia in South Brazil - 66 new cases with Machado-Joseph disease, SCA7, SCA8, or unidentified disease-causing mutations.

BACKGROUND: The autosomal dominant spinocerebellar ataxias (SCAs) are a clinical and genetically heterogeneous group of debilitating, neurodegenerative diseases, related to fourteen different loci - SCAs 1, 2, 4, 5, 6, 7, 8, 10, 11,12,13 and 14, Machado-Joseph disease (MJD/SCA 3), and DRPLA. OBJECTIVES: (1) To verify the frequency of SCA1, SCA2, MJD, DRPLA, SCA6, SCA7 and SCA8 in a series of new SCA patients from South Brazil and (2) to compare their molecular and clinical characteristics with other patients previously described. METHODS: Sixty-six cases were included in the present study: 52 were familial and 14 sporadic. Molecular analysis of the trinucleotide repeat loci were performed according to methods in the literature. RESULTS: 92% of families with autosomal dominant inheritance segregated the MJD1 mutation,2% of families segregated the SCA7 mutation and 6% remained undiagnosed. Among 14 isolated cases, one showed the SCA8 mutation. Clinical and molecular findings were similar to those already described in the literature, but revealed (1) one SCA7 patient with eyelid retraction, a sign usually related to MJD; and (2) one sporadic case of SCA8. CONCLUSIONS: The proportion of MJD cases was very high, probably reflecting an Azorean founder effect. The estimated frequency of affected individuals with MJD, in our region, was 1.8 / 100,000, and of SCAs other than MJD, 0.2/100,000.

Adult↗
PubMed2001

Machado-Joseph disease in South Brazil: clinical and molecular characterization of kindreds.

OBJECTIVE: To examine the clinical, genetic, and molecular characteristics of a group of MJD patients recently identified in the southernmost state of Brazil, and compare these data with studies from the literature. METHODS: Some 62 individuals from 35 families, mostly of Azorean ancestry, had their clinical data and their MJD1 expanded regions examined. RESULTS: The present patients had an earlier age of onset, on average, than Portuguese-Azorean cases. Their survival, proportion of types, average anticipation, proportion of affected versus non-affected siblings, neurological signs and molecular findings are similar to those observed in patients previously described. Type 1 patients with male transmission showed worse anticipations than type 1 patients with female transmission. Patients with type 1 had also larger CAG expansions than other patients. CONCLUSIONS: The Brazilian origin seemed to affect the age of onset. We also noted that there were no differences other than the neurological between types 2 or 3, since both are similar in age of onset, disease duration and length of CAG repeats. We addressed the question of maintaining or not subtypes 2 and 3 separated, among patients with genetic and geographical backgrounds like the presented patients here.

Adolescent↗
PubMed2001

The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.

The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.

Amino Acid Sequence↗