José Barros

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.

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.

First Mutation in the Voltage-Gated Nav1.1 Subunit Gene SCN1A with Co-Occurring Familial Hemiplegic Migraine and Epilepsy

Almost all mutations in the SCN1A gene, encoding the α1 subunit of neuronal voltage-gated Nav1.1 sodium channels, are associated with severe childhood epilepsy. Recently, two mutations were identified in patients with pure familial hemiplegic migraine (FHM). Here, we identified a novel SCN1A L263V mutation in a Portuguese family with partly co-segregating hemiplegic migraine and epilepsy. The L263V mutation segregated in five FHM patients, three of whom also had epileptic attacks, occurring independently from their hemiplegic migraine attacks. L263V is the first SCN1A mutation associated with FHM and co-occurring epilepsy in multiple mutation carriers, and is the clearest molecular link between migraine and epilepsy thus far. The results extend the clinical spectrum associated with SCN1A mutations and further strengthen the molecular evidence that FHM and epilepsy share, at least in part, similar molecular pathways.

Hereditary ataxia and spastic paraplegia in Portugal: a population-based prevalence study.

IMPORTANCE Epidemiological data on hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are scarce. OBJECTIVE To present the prevalence and distribution of HCA and HSP in Portugal. DESIGN AND SETTING Population-based, nationwide, systematic survey, from January 1, 1994, through April 15, 2004, in Portugal. PARTICIPANTS Multiple sources of information were used (review of clinical files, active collaboration of neurologists and geneticists, and investigation of affected families), but the main source was active collaboration of general practitioners. Patients were examined by the same team of neurologists, using homogeneous inclusion criteria. The clinical data were registered, and all families were genetically tested. RESULTS Overall, 1336 patients from a population of 10,322 million were diagnosed as having HCA or HSP, a prevalence of 12.9 per 100,000 population. Hereditary cerebellar ataxia was more prevalent (prevalence, 8.9 per 100,000 population; 5.6 for dominant and 3.3 for recessive ataxias) than HSP (prevalence, 4.1 per 100,000 population; 2.4 for dominant and 1.6 for recessive). Machado-Joseph disease (spinocerebellar ataxia type 3) (prevalence, 3.1 per 100,000 population), Friedreich ataxia (prevalence, 1.0 per 100,000 population), and ataxia with oculomotor apraxia (prevalence, 0.4 per 100,000 population) were the most frequent HCAs. Spastic paraplegia types 4 (prevalence, 0.91 per 100,000 population), 3 (prevalence, 0.14 per 100,000 population), and 11 (prevalence, 0.26 per 100,000 population) were the most prevalent HSPs. CONCLUSIONS AND RELEVANCE This population-based survey covered all the Portuguese territory and mobilized most general practitioners and health centers. To our best knowledge, this survey was the largest ever performed for HCA and HSP. Prevalence of autosomal dominant ataxias was high, particularly for Machado-Joseph disease (spinocerebellar ataxia type 3). The genetic cause has not been identified in 39.7% of the patients studied.

Cross-Cultural Variations in Attitudes Toward Love

Using the Love Attitude Scale, the first objective of this study was to examine the extent to which Lee’s six-factor colors of love model was able to account for data gathered across a large number of countries in Africa, Asia, South America, and Europe. Confirmatory factor analyses showed that the structure postulated by Lee could be applied across multiple cultures. The second objective was to study possible cross-cultural variations in attitudes related to love. The hypotheses were that (a) factors involving strong personal feelings, such as mania, Eros, and agape, would be largely free of cultural influences and (b) factors involving strict social rules, and consequently low affects, such as Pragma, Storge, and Ludus, would be dependent on cultural influences. Each of these hypotheses was well supported by the data.

Psychosocial Concomitants of Loneliness Among Students of Cape Verde and Portugal

Abstract This research is an examination of the relationship between loneliness and a number of psychosocial variables (e.g., affective state, cultural issues, gender, age) among adolescents and young adults from Cape Verde and Portugal. Two studies are presented. The participants in the first study were 285 adolescents from Cape Verde and 202 from Portugal, and in the second study there were 134 college students from Cape Verde and 112 from Portugal. The following instruments were administered to all the participants in both studies: The Revised UCLA Loneliness Scale (D. Russell, L. Peplau, & C. Cutrona, 1980), the Neuroticism Scale (J. Barros, 1999), the Optimism Scale (J. Barros, 1998), the Social Anxiety subscale (A. Fenigstein, M. Scheier, & A. Buss, 1975), and the Satisfaction With Life Scale (E. Diener, R. Emmons, R. Larsen, & S. Griffin, 1985). No ethnic or gender differences were found for loneliness between the two groups. For both groups, the most prominent predictors of loneliness were neuroticism and dissatisfaction with life. However, as expected, the adolescent group recorded higher scores for loneliness than did the college students.

BDNF and CGRP interaction: implications in migraine susceptibility.

Objectives: Migraine pathophysiology involves several pathways. Our aims were to explore a possible role of the brain-derived neurotrophic factor gene (BDNF) in migraine susceptibility; to study, for the first time, the calcitonin gene-related peptide gene (CGRP); and a possible interaction between the two. Methods: Using a case-control approach, four tagging single nucleotide polymorphisms (SNPs) (rs7124442, rs6265, rs11030107, and rs2049046) of BDNF and one tagging SNP—rs1553005—of CGRP were analyzed in 188 cases and 287 controls. A multivariable logistic regression was performed, adjusting for gender. Allelic and haplotypic frequencies were estimated. Interaction was assessed by a stepwise multivariable-logistic regression and confirmed by a multifactor dimensionality reduction analysis. Results: No significant main effects were found; however, a significant interaction was found between BDNF and CGRP, showing an increased risk for the AT-genotype of rs2049046 and the GC-genotype of rs1553005 (odds ratio = 1.88, 95% confidence interval: 1.20–2.93) for migraineurs. Conclusion: Our data support the hypothesis of an interaction between BDNF and CGRP in migraine susceptibility that should be further explored.

Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency

Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from reduced coenzyme Q to cytochrome c. Low biochemical activity of CIII is not a frequent etiology in disorders of oxidative metabolism and is genetically heterogeneous. Recently, mutations in the human tetratricopeptide 19 gene (TTC19) have been involved in the etiology of CIII deficiency through impaired assembly of the holocomplex. We investigated a consanguineous Portuguese family where four siblings had reduced enzymatic activity of CIII in muscle and harbored a novel homozygous mutation in TTC19. The clinical phenotype in the four sibs was consistent with severe olivo–ponto–cerebellar atrophy, although their age at onset differed slightly. Interestingly, three patients also presented progressive psychosis. The mutation resulted in almost complete absence of TTC19 protein, defective assembly of CIII in muscle, and enhanced production of reactive oxygen species in cultured skin fibroblasts. Our findings add to the array of mutations in TTC19, corroborate the notion of genotype/phenotype variability in mitochondrial encephalomyopathies even within a single family, and indicate that psychiatric manifestations are a further presentation of low CIII.

Satisfaction With Life Among Adolescents From Portuguese Immigrant Families in Switzerland

The aims of this study were to determine the level of satisfaction with life among adolescents from Portuguese immigrant families in Switzerland and the factors related thereto. The sample consisted of 93 participants (mean age = 16.1 years; SD = 1.4). The mean duration of sojourn in Switzerland was 7.2 years. A control group of 187 Portuguese youth was also included in the study. There were no significant differences in level of life satisfaction between Portuguese adolescents living in Portugal and those living in Switzerland. Whereas demographic factors accounted for only 8% of the variance explained, demographic and psychosocial factors accounted for 31% of the variance explained. Psychological symptoms were the most important predictor of life satisfaction. Behavioral problems, gender, and mastery were also found to be significant predictors of life satisfaction.

Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype

AbstractHuntington disease (HD) is an autosomal dominant neurodegenerative disorder characterised by chorea, cognitive impairment, dementia and personality changes, caused by the expansion of a CAG repeat in the HD gene. Often, patients with a similar clinical presentation do not carry expansions of the CAG repeat in this gene [Huntington disease-like (HDL) patients]. We report the genetic analysis of 107 Portuguese patients with an HDL phenotype. The HDL genes PRNP and JPH3, encoding the prion protein and junctophilin-3, respectively, were screened for repeat expansions in these patients. Given the partial clinical overlap of SCA17, DRPLA and neuroferritinopathy with HD, their causative genes (TBP, ATN1, and FTL, respectively) were also analysed. Finally, repeat expansions in two candidate genes, CREBBP and POU3F2, which encode the nuclear transcriptional coactivator CREB-binding protein and the CNS-specific transcription factor N-Oct-3, respectively, were also studied. Expansions of the repetitive tracts of the PRNP, JPH3, TBP, ATN1, CREBBP and POU3F2 genes were excluded in all patients, as were sequence alterations in the FTL gene. Since none of the genes already included in the differential diagnosis of HD was responsible for the disease in our sample, the genetic heterogeneity of the HDL phenotype is still open for investigation.