A combined voxel-based morphometry and (1)H-MRS study in patients with Friedreich's ataxia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Friedreich's ataxia (FA) is the most frequent autosomal recessive ataxia and essentially considered a disease of the dorsal root ganglia and spinal cord. It is caused by homozygous GAA expansions in the Frataxin gene in most cases. Although only a few studies have addressed cerebral involvement in FA, cognitive symptoms have lately been emphasized. To evaluate brain damage in vivo, we employed whole-brain VBM and analysis of pre-defined regions of interest (ROIs) over the cerebellum to compare 24 patients with 24 age-and-sex-matched normal controls. (1)H-MRS of deep cerebral white matter (WM) was subsequently performed. Mean age of patients was 28 years (range 14-45), mean duration of disease was 14 years (range 5-28) and 11 were men. Mean length of shorter (GAA1) and longer (GAA2) alleles were 735 and 863, respectively. VBM analysis identified WM atrophy in the posterior cyngulate gyrus, paracentral lobule and middle frontal gyrus. ROIs over the infero-medial cerebellar hemispheres and dorsal brainstem presented gray matter atrophy, which correlated with duration of disease (r = -0.4). NAA/Cr ratios were smaller among patients (P = 0.006), but not Cho/Cr (P = 0.08). Our results provide evidence of axonal damage in the cerebellum, brainstem and subcortical WM in FA. This suggests that neuronal dysfunction is more widespread than previously thought in FA.256711141120Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [04/13725-4

Polymorphisms in methylenetetrahydrofolate reductase gene (MTHFR) and the age of onset of sporadic colorectal adenocarcinoma

Background and aims Evidence is accumulating for a role of folate in the aetiology of colorectal cancer (CRC). The methylenetetrahydrofolate reductase (MTHFR) gene, involved in folate metabolism, is polymorphic in humans. Since it is unknown whether the MTHFR C677T and A1298C polymorphisms alter the risk for CRC, this was the aim of our study. Materials and methods Genomic DNA from 102 sporadic colorectal adenocarcinoma (SCA) patients and 300 controls was analyzed by polymerase chain reaction followed by restriction digestion for the polymorphisms analyses. Results/findings The frequencies of MTHFR C677T and A1298C genotypes were similar in patients and controls. Similar overall risks for disease were seen in individuals with the distinct MTHFR genotypes. However, an excess of the MTHFR 677TT and 677CT genotypes was seen in patients under 50 years, compared with patients at an older age (19.2 vs 13.1% and 61.6 vs 39.5%, respectively; P=0.04). The differences were more prominent when the frequency of the 677TT plus 677CT genotype was seen in both group of patients (80.8 vs 52.6%, respectively; P=0.01), and in younger patients compared to controls (80.8 vs 52.3%, P < 0.01). Individuals with the combined genotype had 3.82-fold (95% confidence interval, 1.41-10.42) increased risk of developing SCA under 50 years, compared with those harboring the wild-type genotype. Interpretation/conclusion These results suggest a role for the MTHFR 677TT plus 677CT genotype in increasing SCA diagnosed at a low age in southeastern Brazil, but additional studies with larger sample sizes should be carried out to clarify this issue.22775776

Measurements of CFTR-Mediated Cl- Secretion in Human Rectal Biopsies Constitute a Robust Biomarker for Cystic Fibrosis Diagnosis and Prognosis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: Cystic Fibrosis (CF) is caused by similar to 1,900 mutations in the CF transmembrane conductance regulator (CFTR) gene encoding for a cAMP-regulated chloride (Cl-) channel expressed in several epithelia. Clinical features are dominated by respiratory symptoms, but there is variable organ involvement thus causing diagnostic dilemmas, especially for non-classic cases. Methodology/Principal Findings: To further establish measurement of CFTR function as a sensitive and robust biomarker for diagnosis and prognosis of CF, we herein assessed cholinergic and cAMP-CFTR-mediated Cl- secretion in 524 freshly excised rectal biopsies from 118 individuals, including patients with confirmed CF clinical diagnosis (n = 51), individuals with clinical CF suspicion (n = 49) and age-matched non-CF controls (n = 18). Conclusive measurements were obtained for 96% of cases. Patients with "Classic CF'', presenting earlier onset of symptoms, pancreatic insufficiency, severe lung disease and low Shwachman-Kulczycki scores were found to lack CFTR-mediated Cl- secretion (= 30-35% and data evidenced good correlations with various clinical parameters. Finally, comparison of these values with those in "CF suspicion'' individuals allowed to confirm CF in 16/49 individuals (33%) and exclude it in 28/49 (57%). Statistical discriminant analyses showed that colonic measurements of CFTR-mediated Cl- secretion are the best discriminator among Classic/Non-Classic CF and non-CF groups. Conclusions/Significance: Determination of CFTR-mediated Cl- secretion in rectal biopsies is demonstrated here to be a sensitive, reproducible and robust predictive biomarker for the diagnosis and prognosis of CF. The method also has very high potential for (pre-) clinical trials of CFTR-modulator therapies.710TargetScreen2 [EU/FP6/LSH/2005/037365, PIC/IC/83103/2007]FCT (Portugal) [PEstOE/BIA/UI4046/2011, PEstOE/MAT/UI0006/2011, SFRH/BD/35936/2007, SFRH/BD/69180/2010]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Mukoviszidose e.V. (Germany) [S02/10][PTDC/MAT/118335/2010]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)TargetScreen2 [EU/FP6/LSH/2005/037365, PIC/IC/83103/2007]FCT (Portugal) [PEstOE/BIA/UI4046/2011, PEstOE/MAT/UI0006/2011, SFRH/BD/35936/2007, SFRH/BD/69180/2010]CNPq [40.8924/2006/3]Mukoviszidose e.V. (Germany) [S02/10][PTDC/MAT/118335/2010

The <it>ACE</it> gene D/I polymorphism as a modulator of severity of cystic fibrosis

<p>Abstract</p> <p>Background</p> <p>Cystic Fibrosis (CF) is a monogenic disease with complex expression because of the action of genetic and environmental factors. We investigated whether the <it>ACE</it> gene D/I polymorphism is associated with severity of CF.</p> <p>Methods</p> <p>A cross-sectional study was performed, from 2009 to 2011, at University of Campinas – UNICAMP. We analyzed 180 patients for the most frequent mutations in the <it>CFTR</it> gene, presence of the <it>ACE</it> gene D/I polymorphism and clinical characteristics of CF.</p> <p>Results</p> <p>There was an association of the D/D genotype with early initiation of clinical manifestations (OR: 1.519, CI: 1.074 to 2.146), bacterium <it>Burkholderia cepacia</it> colonization (OR: 3.309, CI: 1.476 to 6.256) and Bhalla score (BS) (p = 0.015). The association was observed in subgroups of patients which were defined by their <it>CFTR</it> mutation genotype (all patients; subgroup I: no mutation detected; subgroup II: one <it>CFTR</it> allele identified to mutation class I, II or III; subgroup III: both <it>CFTR</it> alleles identified to mutation class I, II and/or III).</p> <p>Conclusion</p> <p>An association between the D allele in the <it>ACE</it> gene and the severity of CF was found in our study.</p