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ABSTRACT: Oxidative stress plays an important role in the pathophysiology of neurodegenerative diseases, including X-linked adrenoleukodystrophy (X-ALD). In the present work, we evaluated lipid (malondialdehyde [MDA] content) and protein (sulfhydryl and carbonyl contents) oxidative damage parameters in plasma from X-ALD patients before and after bone marrow transplant (BMT), in order to verify if this treatment is capable to alter the oxidative parameters studied. We also evaluated the plasma concentration of hexacosanoic acid (C26:0) from X-ALD patients and correlated it with the oxidative damage parameters investigated. We observed that MDA content was significantly increased in plasma of X-ALD patients before BMT and after BMT when compared to controls, and that it was significantly reduced in plasma of X-ALD after BMT when compared to the before BMT group. These results indicate that lipid peroxidation is stimulated in X-ALD patients but there is a significant reduction of lipid peroxidation after BMT. Next, we observed a significant reduction of sulfhydryl content in plasma of X-ALD patients before BMT compared to controls indicating protein oxidative damage and that this measurement was increased in these patients after BMT as compared to before BMT. We found no significant differences in plasma carbonyl content in X-ALD patients before and after BMT as compared to controls. However, we observed a significant reduction in this parameter in X-ALD patients after BMT compared to before BMT. Finally, C26:0 plasma concentration was significantly reduced in X-ALD patients after BMT when compared to before BMT. We found no significant correlations between MDA and carbonyl values with C26:0 levels of the patients before BMT and after BMT, but a significant inverse correlation between sulfhydryl content and C26:0 levels was detected. In conclusion, the present study reinforces the hypothesis that lipid peroxidation and protein damage are induced in plasma of X-ALD patients and, in addition, demonstrates that BMT treatment is capable to reduce this pathogenic process. Taken together, the data obtained from plasma of X-ALD patients before and after BMT showing induction and protection, respectively, of oxidative stress, allowed to suggest that BMT, when well succeeded and under the recommendations, is effective to reduce C26:0 plasma levels and the increased lipid and protein oxidative damage in X-ALD.
Molecular Genetics and Metabolism 04/2012; 106(2):231-6. · 3.19 Impact Factor
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Conceição Bettencourt,
Mafalda Raposo,
Nadiya Kazachkova,
Cristina Santos,
Teresa Kay,
João Vasconcelos,
Patrícia Maciel,
Karina C Donis,
Maria Luiza Saraiva-Pereira, Laura B Jardim,
Jorge Sequeiros,
Jácome Bruges-Armas,
Manuela Lima
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ABSTRACT: Machado-Joseph disease (MJD) is a late-onset autosomal dominant neurodegenerative disorder, which is caused by a coding (CAG)(n) expansion in the ATXN3 gene (14q32.1). The number of CAG repeats in the expanded alleles accounts only for 50 to 75 % of onset variance, the remaining variation being dependent on other factors. Differential allelic expression of ATXN3 could contribute to the explanation of different ages at onset in patients displaying similar CAG repeat sizes. Variation in 5' regulatory regions of the ATXN3 gene may have the potential to influence expression levels and, ultimately, modulate the MJD phenotype. The main goal of this work was to analyze the extent of sequence variation upstream of the ATXN3 start codon. A fragment containing the core promoter and the 5' untranslated region (UTR) was sequenced and analyzed in 186 patients and 59 controls (490 chromosomes). In the core promoter, no polymorphisms were observed. In the 5' UTR, only one SNP (rs3814834) was found, but no improvements on the explanation of onset variance were observed, when adding its allelic state in a linear model. Accordingly, in silico analysis predicted that this SNP lays in a nonconserved position for CMYB binding. Therefore, no functional effect could be predicted for this variant.
The Cerebellum 03/2012; · 3.21 Impact Factor
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Conceição Bettencourt,
Mafalda Raposo,
Nadiya Kazachkova,
Teresa Cymbron,
Cristina Santos,
Teresa Kay,
João Vasconcelos,
Patrícia Maciel,
Karina C Donis,
Maria Luiza Saraiva-Pereira, Laura B Jardim,
Jorge Sequeiros,
Manuela Lima
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ABSTRACT: To investigate a modulating effect of the apolipoprotein E (APOE) polymorphism on age at onset of Machado-Joseph disease (MJD).
We collected blood samples from 192 patients with MJD and typed the APOE polymorphism. Patients The 192 patients with MJD included 59 from the Azores, 73 from mainland Portugal, and 60 from Brazil.
Academic research center.
Cases with the ε2/ε3 genotype had an earlier onset compared with those with the ε3/ε3 or the ε3/ε4 genotype. In this series of patients, the presence of an APOE ε2 allele implies a decrease of nearly 5 years in the age at onset. When combining several other predictors in a general linear model, namely, the presence/absence of the APOE ε2 allele, with the size of the (CAG)(n) in expanded alleles, the model was significantly improved and the explanation of onset variance was raised from 59.8% to 66.5%. Furthermore, the presence of the ε2 allele was associated with an onset before age 39 years (odds ratio, 5.00; 95% CI, 1.18-21.14).
The polymorphism at the APOE gene plays a role as a genetic modifier of MJD phenotype.
Archives of neurology 12/2011; 68(12):1580-3. · 6.31 Impact Factor
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Giovana B Biancini,
Camila S Vanzin,
Daiane B Rodrigues,
Marion Deon,
Graziela S Ribas,
Alethéa G Barschak,
Vanusa Manfredini,
Cristina B O Netto, Laura B Jardim,
Roberto Giugliani,
Carmen R Vargas
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ABSTRACT: Fabry disease is an X-linked inborn error of glycosphingolipid catabolism due to deficient activity of α-galactosidase A that leads to accumulation of the enzyme substrates, mainly globotriaosylceramide (Gb3), in body fluids and lysosomes of many cell types. Some pathophysiology hypotheses are intimately linked to reactive species production and inflammation, but until this moment there is no in vivo study about it. Hence, the aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokines and Gb3 levels in Fabry patients under treatment with enzyme replacement therapy (ERT) and finally to establish a possible relation between them. We analyzed urine and blood samples of patients under ERT (n=14) and healthy age-matched controls (n=14). Patients presented decreased levels of antioxidant defenses, assessed by reduced glutathione (GSH), glutathione peroxidase (GPx) activity and increased superoxide dismutase/catalase (SOD/CAT) ratio in erythrocytes. Concerning to the damage to biomolecules (lipids and proteins), we found that plasma levels of malondialdehyde (MDA) and protein carbonyl groups and di-tyrosine (di-Tyr) in urine were increased in patients. The pro-inflammatory cytokines IL-6 and TNF-α were also increased in patients. Urinary Gb3 levels were positively correlated with the plasma levels of IL-6, carbonyl groups and MDA. IL-6 levels were directly correlated with di-Tyr and inversely correlated with GPx activity. This data suggest that pro-inflammatory and pro-oxidant states occur, are correlated and seem to be induced by Gb3 in Fabry patients.
Biochimica et Biophysica Acta 11/2011; 1822(2):226-32. · 4.66 Impact Factor
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Parkinsonism & Related Disorders 06/2011; 17(9):712-3. · 3.80 Impact Factor
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Osvaldo Artigalás,
Valeska Lizzi Lagranha,
Maria Luiza Saraiva-Pereira,
Maira Graeff Burin,
Charles Marques Lourenço,
Hélio van der Linden,
Mara Lúcia Ferreira Santos,
Sergio Rosemberg,
Carlos Eduardo Steiner,
Fernando Kok,
Carolina F Moura de Souza, Laura B Jardim,
Roberto Giugliani,
Ida Vanessa Schwartz
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ABSTRACT: Metachromatic leukodystrophy (MLD) is a lysosomal disorder caused by arylsulfatase A (ARSA) deficiency. It is classified into three forms according to the age of onset of symptoms (late infantile, juvenile, and adult). We carried out a cross-sectional and retrospective study, which aimed to determine the epidemiological, clinical, and biochemical profile of MLD patients from a national reference center for Inborn Errors of Metabolism in Brazil. Twenty-nine patients (male, 17) agreed to participate in the study (late infantile form: 22; juvenile form: 4; adult form: 1; asymptomatic: 2). Mean ages at onset of symptoms and at biochemical diagnosis were, respectively, 19 and 39 months for late infantile form and 84.7 and 161.2 months for juvenile form. The most frequently reported first clinical symptom/sign of the disease was gait disturbance and other motor abnormalities (72.7%) for late infantile form and behavioral and cognitive alterations (50%) for juvenile form. Leukocyte ARSA activity level did not present significant correlation with the age of onset of symptoms (r = -0.09, p = 0.67). Occipital white matter and basal nuclei abnormalities were not found in patients with the late infantile MLD. Our results suggest that there is a considerable delay between the age of onset of signs and symptoms and the diagnosis of MLD in Brazil. Correlation between ARSA activity and MLD clinical form was not found. Further studies on the epidemiology and natural history of this disease with larger samples are needed, especially now when specific treatments should be available in the near future.
Journal of Inherited Metabolic Disease 07/2010; · 3.58 Impact Factor
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ABSTRACT: Spinocerebellar ataxia type 6 (SCA6) is a common cause of dominantly inherited ataxia due to an expansion of the CAG repeat in the CACNA1A gene. Affected individuals from the same population share a common haplotype, raising the possibility that most SCA6 cases have descended from a small number of common founders across the globe. To test this hypothesis, we carried out haplotype analysis on SCA6 families from Europe, South America and the Far East, including an established de novo SCA6 expansion. A core CACNA1A disease haplotype was found in affected individuals across the globe. This was also present in the unaffected father of the de novo case, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies within a CpG island, which could act as a cis-acting element predisposing to repeat expansion as for other CAG/CTG repeat diseases. Polymorphic variation in this region may explain the high-risk haplotype found in SCA6 families.
European Journal of HumanGenetics 08/2008; 16(7):841-7. · 4.40 Impact Factor
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ABSTRACT: In repeat expansion disorders, the size of pathological alleles is the most relevant factor accounting for the disease severity and age-at-onset, emphasizing the clinical significance of their underlying intergenerational instability. In one of these diseases, Machado-Joseph disease (MJD), the sex of transmitting progenitor and the C(987)GG/G(987)GG polymorphism are the best studied factors acting on intergenerational instability of expanded alleles. Here, we assessed the influence of other cis and inter-allelic acting factors, at the ATXN3 locus, through the analysis of MJD lineages, flanking STR-based haplotypes, the initial repeat size and parental age. A total of 100 transmissions of the expanded MJD allele were analyzed according to the sex of the transmitting parent. We have shown that independent origin mutations (identified by intragenic SNP-based haplotypes) behave differently, as the status of instability (contraction, no change or further expansion) is concerned. Indeed, 72% of expansions were associated to the worldwide spread TTACAC lineage, whereas the GTGGCA displayed 75% of all contractions observed. The analysis of flanking recombinant haplotypes did not suggest any further distant cis elements acting up- or downstream the ATXN3 locus. Considering the increased amplitude of expansions seen in older transmitting fathers, a repair-based mechanism may be suggested for the meiotic instability at this locus; furthermore, the lack of correlation between the initial repeat size and degree of instability did not support a replication-based mechanism. In summary, our findings point to different mechanisms of instability underlying male and female meioses, as well as contraction and expansion processes in MJD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2008; 147B(4):439-46. · 3.70 Impact Factor
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Parkinsonism & Related Disorders 04/2008; 15(1):76-8. · 3.80 Impact Factor
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Marion Deon,
Angela Sitta,
Alethea G Barschak,
Daniela M Coelho,
Thatiana Terroso,
Graziela O Schmitt,
Hector Y C Wanderley, Laura B Jardim,
Roberto Giugliani,
Moacir Wajner,
Carmen R Vargas
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ABSTRACT: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disease biochemically characterized by the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic (C26:0) and tetracosanoic acids (C24:0) in different tissues and in biological fluids and clinically characterized by central and peripheral demyelination and adrenal insufficiency. A considerable number of heterozygotes (HTZ) for X-ALD develop neurological symptoms like spinal cord involvement resembling milder forms of adrenomyeloneuropathy. However, the mechanisms of brain damage in hemizygotes and heterozygotes X-ALD individuals are poorly understood. Considering that oxidative stress was involved in various neurodegenerative disorders and that in a previous study we showed evidence that oxidative stress is probably involved in the pathophysiology of X-ALD symptomatic patients, in the present study we evaluated various oxidative stress parameters, namely thiobarbituric acid-reactive substances (TBA-RS), total antioxidant status (TAS) and total antioxidant reactivity (TAR) in plasma of HTZ individuals for X-ALD. It was observed that female carriers present a significant increase of TBA-RS measurement, indicating a stimulation of lipid peroxidation, as well as a decrease of TAR, reflecting a deficient capacity to rapidly handle an increase of reactive species. These results indicate that oxidative stress is involved in the pathophysiology of heterozygotes for X-ALD.
Journal of the Neurological Sciences 04/2008; 266(1-2):79-83. · 2.35 Impact Factor
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Marion Deon,
Mariana Pires Garcia,
Angela Sitta,
Alethéa G Barschak,
Daniella M Coelho,
Graziela O Schimit,
Maiara Pigatto, Laura B Jardim,
Moacir Wajner,
Roberto Giugliani,
Carmen R Vargas
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ABSTRACT: X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal metabolism, biochemically characterized by deficient beta-oxidation of saturated very long chain fatty acids (VLCFA). The consequent accumulation of these fatty acids in different tissues and in biological fluids is associated with a progressive central and peripheral demyelination, as well as with adrenocortical insufficiency and hypogonadism. Seven variants of this disease have been described, cerebral childhood being the most frequent. The recommended therapy consists of the use of the glyceroltrioleate/glyceroltrierucate mixture known as Lorenzo's Oil (LO), combined with a VLCFA-poor diet, but only in asymptomatic patients will this treatment prevent the progression of the symptomatology. In the present study we evaluated the biochemical course of patients with cerebral childhood (CCER) and asymptomatic clinical forms of X-ALD treated with LO associated with a VLCFA-restricted diet. We observed that hexacosanoic acid plasma concentrations and hexacosanoic/docosanoic ratio were significantly reduced in CCER patients during treatment when compared with diagnosis. Hexacosanoic acid plasma level was significantly reduced when compared with that at diagnosis and achieved the normal levels only in asymptomatic patients under LO treatment. In asymptomatic patients the magnitude of hexacosanoic acid decrease was higher than that of the CCER patients. These results show the good biochemical response of LO treatment in asymptomatic X-ALD patients. It is possible to suppose that this could be correlated with the prevention of the appearance of neurological signals in this group of patients treated with LO.
Metabolic Brain Disease 04/2008; 23(1):43-9. · 2.20 Impact Factor
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ABSTRACT: Patients affected by X-linked adrenoleukodystrophy (X-ALD) present a progressive brain and peripheral demyelination and adrenal cortex insufficiency, associated with accumulation of the very long chain fatty acids (VLCFA) hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in different tissues and biological fluids. X-ALD is characterized by heterogeneous clinical phenotypes. Seven clinical variants have been described for this genetic disorder, being the childhood cerebral form (CCER), adrenomyeloneuropathy (AMN) and asymptomatic the most common clinical forms. In a previous work, we showed evidence that oxidative stress is involved in the pathophysiology of X-ALD symptomatic patients. In the present study, we compared oxidative stress parameters, namely thiobarbituric acid reactive substances (TBA-RS) and total antioxidant status (TAS), in plasma from patients with CCER, AMN and in asymptomatic X-ALD patients. It was observed that symptomatic and asymptomatic X-ALD patients presented a significant increase of plasma TBA-RS measurement, indicating a stimulation of lipid peroxidation. Furthermore, lipid peroxidation was higher in AMN, as compared to CCER and asymptomatic patients. We also observed that the total antioxidant defenses (TAS) were decreased in symptomatic but not in asymptomatic X-ALD patients. Therefore, it may be presumed that asymptomatic patients seem to be protected against oxidative stress because of their normal antioxidant defenses and that other factors besides oxidative damage may be responsible for the severity of the symptoms in X-ALD and need to be investigated.
International Journal of Developmental Neuroscience 12/2007; 25(7):441-4. · 2.42 Impact Factor
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Sandra Martins,
Francesc Calafell,
Claudia Gaspar,
Virginia C N Wong,
Isabel Silveira,
Garth A Nicholson,
Ewout R Brunt,
Lisbeth Tranebjaerg,
Giovanni Stevanin,
Mingli Hsieh, [......],
Mitsunori Watanabe, Laura B Jardim,
Paola Giunti,
Olaf Riess,
Laura P W Ranum,
Alexis Brice,
Guy A Rouleau,
Paula Coutinho,
António Amorim,
Jorge Sequeiros
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ABSTRACT: Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution.
To trace back in history the main mutational events in Machado-Joseph disease, we aimed to assess ancestral haplotypes and population backgrounds, to date the mutations, and to trace the routes and time of introduction of the founder haplotypes in different populations. Design, Setting, and
We studied 264 families with Machado-Joseph disease from 20 different populations. Six intragenic single-nucleotide polymorphisms were used to determine ancestral mutational events; 4 flanking short tandem repeats were used to construct extended haplotypes and measure accumulation of genetic diversity over time within each lineage.
The worldwide-spread lineage, TTACAC, had its highest diversity in the Japanese population, where we identified the ancestral short tandem repeat-based haplotype. Accumulated variability suggested a postneolithic mutation, about 5774 +/- 1116 years old, with more recent introductions in North America, Germany, France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA lineage, only 7 families (of 71 families) did not have Portuguese ancestry, although gene diversity was again smaller in Portuguese families (0.44) than in non-Portuguese families (0.93).
The worldwide-spread mutation may have first occurred in Asia and later been diffused throughout Europe, with a founder effect accounting for its high prevalence in Portugal; the other Machado-Joseph disease lineage is more recent, about 1416 +/- 434 years old, and its dispersion may be explained mainly by recent Portuguese emigration.
Archives of Neurology 11/2007; 64(10):1502-8. · 7.58 Impact Factor
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Laura B Jardim,
Flávio Aesse,
Leonardo M Vedolin,
Cláudio Pitta-Pinheiro,
João Marconato,
Maira G Burin,
Cláudia Cecchin,
Cristina B O Netto,
Ursula S Matte,
Fernanda Pereira,
Luciane Kalakun,
Roberto Giugliani
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ABSTRACT: To report the clinical and neuroimaging, central nervous system (CNS) findings of patients with Fabry disease (FD) during 24 months of enzyme replacement therapy (ERT) with agalsidase-alpha.
Eight patients were included. Six completed 24 months of ERT. Clinical and magnetic resonance imaging (MRI) data were obtained at 0, 12 and 24 months of ERT. White matter lesions (WML) were evaluated as well as their relation to age, symptoms and neurological examination (CNS score).
MRI was stable in 3 patients. WML and CNS score worsened in one patient, fluctuated in another, and improved in the sixth patient. In the whole series, there were 15 WML at baseline, and 19 at the 24th month. In two years, 4 lesions disappeared, whereas 8 appeared.
A widespread pattern of silent WML in FD was seen. In two years, some WML appeared, and some disappeared. If these phenomena were related to the natural history, remains to be demonstrated.
Arquivos de Neuro-Psiquiatria 10/2006; 64(3B):711-7. · 0.72 Impact Factor
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ABSTRACT: NSE and S100B are considered as neuronal and glial peripheral markers of central nervous system pathologies, respectively. We evaluated the potential use of S100B and NSE serum concentrations as peripheral markers of symptomatic patients with Machado Joseph disease (MJD).
We measured S100B and NSE peripheral concentrations of 22 MJD patients and compared with healthy subjects concentrations. The correlations of both markers with CAG repeat size, age of onset, disease duration, and the scores of the Extended Disability Status Scale of Kurtzke, Unified Parkinson's Disease Rating Scale, and the Montgomery-Asberg depression rating scale were also assessed.
S100B serum concentrations between control and MJD subjects were not statistically different, whereas NSE serum concentrations were higher in MJD patients than in control subjects (p=0.00001). S100B presented a moderate correlation with disease duration and depression score, whereas NSE presented a moderate correlation with depression score and a good negative correlation with EDSS score.
Symptomatic MJD patients present increased concentrations of NSE and normal concentrations of S100B in blood.
Clinica Chimica Acta 02/2005; 351(1-2):143-8. · 2.54 Impact Factor
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ABSTRACT: Machado-Joseph disease (MJD), an autosomal dominant spinocerebellar degeneration caused by an expanded CAG repeat on chromosome 14q32.1, is a disorder with wide range of neurological findings and brain regions involved. Studies evaluating neurophysiological parameters related to sensory gating in MJD are lacking.
This study intends to investigate P50 suppression, an auditory mid-latency evoked potential in a test-conditioning paradigm, considered as an index of sensory gating function. Twelve patients with MJD, 24 normal subjects and 12 schizophrenic patients were evaluated.
MJD subjects had higher P50 ratios as compared to normal subjects (76.2 vs. 42.1%, P = 0.001), but similar to the group of schizophrenic patients. The difference from controls was due to greater test amplitudes (3.4 vs. 2.0 microV, P = 0.002), rather than to conditioning amplitudes. Latencies were higher for the MJD subjects than for controls (60.4 vs. 56.1 ms, P = 0.016).
MJD may present sensory gating dysfunction. However, the pattern of this dysfunction seems to slightly differ from that classically found in schizophrenia, were both test and conditioning amplitudes seem to be implicated.
These results point out the P50 paradigm as a potential tool for further neurophysiological surveying in MJD.
Clinical Neurophysiology 11/2004; 115(10):2231-5. · 3.41 Impact Factor
