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J Sequeiros

Publications and source records attributed to J Sequeiros.

At least 37 records · Page 2Linked to original sources
PubMed2000

Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single-base-pair polymorphisms (A(669)TG/G(669)TG, C(987)GG/G(987)GG, and TAA(1118)/TAC(1118)). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD.

Alleles↗
PubMed2000

CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation.

Machado-Joseph disease (MJD) is one of several disorders caused by the expansion of a coding CAG repeat (exp-CAG). The presence of intranuclear inclusions (INIs) in patients and cellular models of exp-CAG-associated diseases has lead to a nuclear toxicity model. Similar INIs are found in oculopharyngeal muscular dystrophy, which is caused by a short expansion of an alanine-encoding GCG repeat. Here we propose that transcriptional or translational frameshifts occurring within expanded CAG tracts result in the production and accumulation of polyalanine-containing mutant proteins. We hypothesize that these alanine polymers deposit in cells forming INIs and may contribute to nuclear toxicity. We show evidence that supports our hypothesis in lymphoblast cells from MJD patients, as well as in pontine neurons of MJD brain and in in vitro cell culture models of the disease. We also provide evidence that alanine polymers alone are harmful to cells and predict that a similar pathogenic mechanism may occur in the other CAG repeat disorders.

Amino Acid Sequence↗
PubMed2000

High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles.

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of late-onset, neurodegenerative disorders for which 10 loci have been mapped (SCA1, SCA2, SCA4-SCA8, SCA10, MJD, and DRPLA). The mutant proteins have shown an expanded polyglutamine tract in SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA; a glycine-to-arginine substitution was found in SCA6 as well. Recently, an untranslated (CTG)n expansion on chromosome 13q was described as being the cause of SCA8. We have now (1) assessed the repeat size in a group of patients with ataxia and a large number of controls, (2) examined the intergenerational transmission of the repeat, and (3) estimated the instability of repeat size in the sperm of one patient and two healthy controls. Normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15-21 CTGs), intermediate (22-37 CTGs), and large (40-91 CTGs) alleles; large alleles accounted for only0.7% of all normal-size alleles. No expanded alleles (>/=100 CTGs) were found in controls. Expansion of the CTG tract was found in five families with ataxia; expanded alleles (all paternally transmitted) were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in one patient, the expanded allele (152 CTGs) had mostly contraction in size (often into the normal range); in the sperm of two normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, our results show (1) no overlapping between control (15-91) and pathogenic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus.

Adolescent↗
PubMed1999

Living with Machado-Joseph disease in a small rural community of the Tagus valley.

OBJECTIVES: In the context of our national program of predictive testing for Machado-Joseph disease (MJD), we have studied in a small rural community (1) discourses about the illness by individuals at risk and patients, and (2) how individuals at risk and patients plan to cope with the familial illness. METHODS: We used qualitative methods, beginning with a group interview of individuals at risk, and followed by in-depth interviews (about 1 hour long) of at-risk and affected individuals, in their homes. The latter interviews were subjected to a content analysis. RESULTS: The coexistence of two contradictory discourses about MJD (a scientific and a folk one) was found consistently among all individuals. The main metaphor was that of the 'drunkard'. Knowledge about a precise diagnosis of their disease produced relief and hope, because it provided evidence that affected individuals were not drunkards. CONCLUSIONS: The understanding of beliefs about the disease and its social representation is essential in planning effective genetic and psychological counseling.

Journal Article↗
PubMed1999

Two pairs of proven monozygotic twins discordant for familial amyloid neuropathy (FAP) TTR Met 30.

Twin studies are an important tool in medical genetics for the evaluation of the relative roles of genetic and non-genetic factors in several diseases. Familial amyloidotic polyneuropathy type I (FAP-I), TTR Met 30, was present in two sets of proven monozygotic (MZ) twins, one from Majorca and the other from Portugal. Monozygosity was established by analysis of DNA polymorphisms. Both pairs were discordant for age at onset and some clinical manifestations of FAP-I. We reviewed the differences in age at onset and clinical features in both sets and in two other pairs of presumed MZ twins with FAP-I and compared them with those in MZ twin pairs with other Mendelian disorders, such as neurofibromatosis type 1, Huntington's disease, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. We conclude that, in addition to the postulated modifying genes, there must be a significant contribution from non-genetic factors to the phenotypic variability of FAP-I (age at onset and clinical expression), either because of environmental differences or stochastic events during (or after) the twinning process.

Adult↗
PubMed1998

Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families.

The spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. To date, eight different loci causing SCA have been identified: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA6, SCA7, and dentatorubropallidoluysian atrophy (DRPLA). Expansion of a CAG repeat in the disease genes has been found in five of these disorders. To estimate the relative frequencies of the SCA1, DRPLA, MJD, SCA2, and SCA6 mutations among Portuguese ataxia patients, we collected DNA samples from 48 ataxia families and performed polymerase chain reaction (PCR) amplification of the CAG repeat mutations on chromosomes 6p, 12p, 14q, 12q, and 19p, respectively. Fifty-five individuals belonging to 34 dominant families (74%) had an expanded CAG repeat at the MJD gene. In five individuals from two kindreds with a dominant pattern of inheritance (4%), an expanded CAG repeat at the SCA2 gene was found. In MJD patients, the normal allele size ranged from 13 to 41, whereas the mutant alleles contained 65 to 80 repeats. For the SCA2 patients, normal alleles had 22 or 23, while expanded alleles had between 36 and 47 CAG units. We did not find the SCA1, DRPLA, or SCA6 mutations in our group of families. The MJD mutation remains the most common cause of SCA in Portugal, while a small number of cases are caused by mutations at the SCA2 gene, and 22% are due to still unidentified genes.

Adolescent↗
PubMed1998

Prenatal diagnosis of Machado-Joseph disease by direct mutation analysis.

MJD is the most frequent dominant ataxia and an incapacitating disorder. Onset is most frequently during the reproductive years, and genetic counseling is its only means of prevention. The causative mutation--an expansion of a (CAG)n on chromosome 14q32.1--can now be directly detected. We now report the first two cases of prenatal diagnosis (PND). The first presented as a simultaneous request for predictive testing and PND at 14 weeks of pregnancy. Owing to time constraints, we performed a full protocol of counseling with shorter inter between sessions, while psycho-social evaluation of the other parent obstetric consults were also begun. We ensured that the couple wished termination if the fetus was a carrier, to avoid a presymptomatic test for the unborn child. We were thus able to deliver test results two weeks before PND. As the fetus carried an expanded allele (77 CAGs) inherited from his father, termination was performed and the couple received counselling, psychological and social support. The second case was the fetus of a carrier-mother that was diagnosed as non-carrier, also after amniocentesis.

Adult↗
PubMed1996

Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease.

BACKGROUND: Machado-Joseph disease (MJD) is a type of autosomal dominant spinocerebellar ataxia for which molecular diagnosis is available. We identified 4 families segregating the MJD mutation in which no unequivocal clinical diagnosis could be established prior to molecular testing. Ethnic background, clinical, and molecular characteristics of 19 individuals carrying the MJD mutation in these 4 families were compared with a group of 32 Portuguese families who were clinically diagnosed as having MJD and were found to carry the MJD mutation. RESULTS: Several factors seemed to have an impact in the accuracy of the clinical diagnosis, such as ethnic origin; the number of affected individuals available for examination in each family; the absence of patients showing specific clinical features, such as extrapyramidal signs; and the size of the expanded CAG repeat in the MJD gene. CONCLUSION: Since the recognition of MJD based solely on clinical grounds might sometimes be misleading, a search for the MJD mutation should be performed in patients with a clinical diagnosis of spinocerebellar degeneration.

Adult↗
PubMed1996

Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease.

Spinocerebellar ataxia type 1 and Machado-Joseph disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these diseases, somatic mosaicism, the result of mitotic instability of the CAG repeat, could be the basis for specificity of neurodegeneration; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado-Joseph disease; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined: The cerebellar cortex showed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosaicism, similar in spinocerebellar ataxia type 1 and Machado-Joseph disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.

Age of Onset↗
PubMed1996

Linkage disequilibrium analysis in Machado-Joseph disease patients of different ethnic origins.

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration originally described in families of Portuguese-Azorean ancestry. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised. To test this possibility we have conducted a linkage disequilibrium study of markers segregating with the MJD1 locus in a total of 64 unrelated families of different geographical origins. Significant association was detected between the MJD1 locus and marker alleles at loci D14S280, D14S1050 and D14S81. All affected individuals, except one Chinese family, had allele 3 (237 bp) at D14S280. This finding is consistent with a founder effect in our MJD population. However, distinct haplotypes were observed in patients originating from the two Azorean islands showing the highest disease prevalence; therefore, the possible existence of more than one founder mutation can not be excluded with the markers currently available.

Alleles↗
PubMed1996

Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients.

The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders varying in both clinical manifestations and mode of inheritance. Six different genes causing autosomal dominant SCA are mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA type 1 (SCA1), MJD, and DRPLA. We determine the frequency of the SCA1, DRPLA, and MJD mutations in a large group of unrelated SCA patients with various patterns of inheritance and different ethnic backgrounds. We studied 92 unrelated SCA patients. The frequency of the SCA1 mutation was 3% in the overall patient group and 10% in the non-Portuguese dominantly inherited SCA subgroup. We found that DRPLA mutation in only one Japanese patient, who was previously diagnosed with this disease. We identified the MJD mutation in 41% of the overall patient group, which included 38 autosomal dominant kindreds of Portuguese origin; the frequency of the MJD mutation among the non-Portuguese dominantly inherited cases was 17%. These results suggest that SCA may be occasionally caused by the SCA1 mutation and rarely caused by the DRPLA mutation and that, to date, the MJD mutation seems to be the most common cause of dominantly inherited SCA. Finally, our results suggest that recessively inherited cases of SCA are not caused by the known trinucleotide repeat expansions.

Brain Chemistry↗
PubMed1995

Genetic epidemiology of familial amyloidotic polyneuropathy (FAP)-type I in Póvoa do Varzim and Vila do Conde (north of Portugal).

Familial amyloidotic polyneuropathy (FAP-type I) was first described in Portugal by Andrade in 1952, a time when 54 among 64 patients (belonging to 25 families) originated from Póvoa do Varzim or its surrounding districts. Since then, a total of 1,233 patients, belonging to 489 pedigrees (so far unrelated), have been diagnosed at Centro de Estudos de Paramiloidose, Porto, Portugal. Although age-of-onset showed a wide range (17 to 78 years), 87% of these 1,233 patients developed symptoms before 40 years of age (mean 33.5, SD 9.4 years). Among all patients, 432 belong to 140 families originating from the area of Póvoa do Varzim/Vila do Conde, 330 of whom lived in that area at the time of diagnosis; age-of-onset was, on average, lower than in the overall group of patients (mean 31.1, SD 6.7 years), and no patient had onset after 57 years (versus 3.3% in the global sample). As in previous studies, women were found to have a later onset (33.7) than men (29.0) years. In 1991, the crude prevalence rate was 90.3 x 10(-5) (one in every 1,108 inhabitants), and the frequency of gene carriers was estimated to be 186 x 10(-5) (one in every 538); about 48.4% of these carriers had manifested symptoms by 1991. Female patients had a significantly higher number of children (mean 3.7, SD 2.6) than male patients (mean 2.7, SD 2.1) and the length of their reproductive period (mean 8.4, SD 5.8 yr) was also greater than for men (mean 5.6, SD 4.4 yr). Altogether, the 122 patients who ever reproduced contributed 457 children to the next generation, a mean fertility of 3.7. Further studies using a control groups may answer the question of whether this is the result of a specific high fertility of these patients or just their belonging to a population in natural expansion.

Adult↗
PubMed1994

Genetic linkage studies of Machado-Joseph disease with chromosome 14q STRPs in 16 Portuguese-Azorean kindreds.

Machado-Joseph disease (MJD) is a dominant multisystem degeneration found mostly among Azoreans and characterized by the adulthood onset of cerebellar, ocular, pyramidal, extrapyramidal, and/or peripheral signs. MJD has been recorded in many other populations, particularly in the United States and Japan. Using the microsatellite DNA polymorphisms (STRPs) D14S53, D14S55, D14S48, and D14S45, we found significantly positive lod scores in 16 Portuguese kindreds, suggesting that the MJD locus is linked to chromosome 14q in this population. Differences in age-at-onset and many untyped individuals seem to explain the lower lod scores. Using HOMOG, no evidence was found for heterogeneity with the five Japanese families in whom linkage was reported.

Adult↗
PubMed1987

Onset in the seventh decade and lack of symptoms in heterozygotes for the TTRMet30 mutation in hereditary amyloid neuropathy-type I (Portuguese, Andrade).

In a Portuguese-American family with hereditary amyloid neuropathy (familial amyloidotic polyneuropathy), onset was in the seventh decade in all affected relatives. Another unusual characteristic was their origin from the Portuguese island of Madeira. In spite of this, the mutant transthyretin (TTRMet30) (the same variant prealbumin that is the circulating precursor of AFP protein in the classic Portuguese patients) could be found in the propositus' plasma. In addition, three other asymptomatic relatives (ages 90, 73, and 48) were shown to carry the mutation. Late onset and incomplete penetrance, at a clinical level, raise problems for presymptomatic detection of mutant TTR, as these tend to cluster in families. When counseling asymptomatic heterozygotes, we must consider intra-familial correlation in age-of-onset, and the distribution of age-of-onset including age of unaffected heterozygotes. This family poses interesting questions regarding pathogenesis of this degenerative process and the influence of other genetic factors, such as modifiers, epistasis, and polymorphism of the TTR genes or their regulators. A cis-effect of a gene linked to the mutant gene, decreasing the synthesis of the mutant TTR and keeping a sufficient amount of the normal one in circulation, or producing some cofactor for TTR, could also explain late onset and apparently incomplete penetrance; the occasional finding of classic forms in these families would be the result of recombinatory events.

Age Factors↗
PubMed1986

Machado-Joseph disease in a Sicilian-American family.

Machado-Joseph disease (MJD) is an autosomal dominant motor system degeneration which was originally described in Portuguese-American families. Large pedigrees have been found on the east and west coasts of the United States in which 4 main syndromes are described. Type I disease presents with pyramidal and extrapyramidal findings usually in individuals in the second or third decades of life. Type II disease, which is the most common form of presentation, includes true cerebellar deficits associated with other motor features. Type III is late-onset in the fifth through the seventh decades of life presenting with pancerebellar deficits with motor and sensory polyneuropathy. A rare presentation is Type IV with parkinsonian features with mild cerebellar deficits and a distal motor sensory neuropathy or amyotrophy. A family is described here with typical MJD who are of Italian origin. It thus indicates a wider distribution of this gene which now clearly has entered a second Italian-American family.

Adolescent↗