The combination of UCP3-55CT and PPARγ2Pro12Ala polymorphisms affects BMI and substrate oxidation in two diabetic populations.

BACKGROUND AND AIM: To evaluate the combined contribution of UCP3-55CT and PPARγ2 Pro12Ala polymorphisms as correlates of BMI, energy expenditure (REE) and substrate oxidation in people with type 2 diabetes. METHODS AND RESULTS: Two independent population with type 2 diabetes were studied: population A, n = 272; population B, n = 269. Based on both UCP3 and PPARγ2 genotypes three groups were created. Carriers of the PPARγ2 Pro12Ala in combination with the CC genotype of UCP3 (ProAla/CC, group 1); carriers of only one of these genotypes (either CC/ProPro or CT-TT/ProAla, group 2); people with neither variants (CT-TT/ProPro, group 3). In both populations BMI (kg/m(2)) was highest in group 1, intermediate in group 2 and lowest in group 3, independent of energy intake (i.e 35.3 ± 6.7 vs 33.4 ± 5.4 vs 31.8 ± 3, p < 0.02, population A; 32.4 ± 4.2 vs 31.7 ± 3.8 vs 30.1 ± 2.7; p < 0.03, population B). People with the ProAla/CC genotype (group 1) showed similar REE, but lower lipid oxidation (10.9 vs 13.9 g/kg fat free mass/day; p = 0.04) and higher carbohydrate oxidation (23.6 vs 15.6 g/kg fat free mass/day; p = 0.02) than carriers of other genotypes. CONCLUSIONS: The combination of UCP3-55 CC and PPARγ2 Pro12Ala genotypes is associated with significantly higher BMI than other PPARγ2-UCP3 genotype combinations, partly due to a reduced ability in lipids oxidation. The relative importance of these mechanism(s) may be different in non diabetic people.

The energy intake modulates the association of the -55CT polymorphism of UCP3 with body weight in type 2 diabetic patients.

BACKGROUND: Previous association studies of the -55CT polymorphism of the uncoupling protein 3 (UCP3) gene with body mass index (BMI) have provided inconsistent results. The study aim is twofold: (1) to evaluate the association of the -55CT polymorphism of UCP3 with BMI in two independent populations to verify the reproducibility of the finding; (2) to evaluate whether this association is modulated by energy intake. METHODS: Study participants are 736 males and females with type 2 diabetes belonging to independent populations (N=394 population 1; N=342 population 2). Anthropometry and laboratory parameters were measured; in population 2, energy intake and physical exercise were also assessed. RESULTS: The -55CT polymorphism was associated with a significantly lower BMI in population 1 (27.8±3.9 vs 28.9±4.6 kg m(-2); P<0.02), the finding was confirmed in population 2 (that is, 30.3±6.0 vs 32.1±5.9 kg m(-2); P<0.01) independent of gender, age, HbA1c, use of drugs and energy intake. To evaluate the role of diet in population 2, the study participants were stratified by genotype and tertiles of energy intake. In both genotype groups, BMI increased with increasing caloric intake with a significant trend (P<0.001), the BMI difference between the two genotype groups was large and statistically significant in the lower tertile (27.6 vs 31.2 kg m(-2); P<0.001), intermediate in the second tertile and negligible in the upper tertile (32.8 vs 32.9; kg m(-2); nonsignificant). The multivariate regression analysis confirmed a significant interaction between genotype and energy intake as correlates of BMI independent of age, gender, glucose control, physical activity and medications for diabetes (P=0.004). CONCLUSIONS: The study replicates in two independent populations the association between the -55CT polymorphism of UCP3 and a lower BMI. This association was modulated by energy intake, thus suggesting that the unmeasured effect of diet may partly account for inconsistencies of prior association studies.

DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients.

BACKGROUND: The most frequent mutation of Friedreich ataxia (FRDA) is the abnormal expansion of a GAA repeat located within the first intron of FXN gene. It is known that the length of GAA is directly correlated with disease severity. The effect of mutation is a severe reduction of mRNA. Recently, a link among aberrant CpG methylation, chromatin organisation and GAA repeat was proposed. METHODS: In this study, using pyrosequencing technology, we have performed a quantitative analysis of the methylation status of five CpG sites located within the region upstream of GAA repeat, in 67 FRDA patients. RESULTS: We confirm previous observation about differences in the methylation degree between FRDA individuals and controls. We showed a direct correlation between CpG methylation and triplet expansion size. Significant differences were found for each CpG tested (ANOVA p<0.001). These differences were largest for CpG1 and CpG2: 84.45% and 76.80%, respectively, in FRDA patients compared to 19.65% and 23.34% in the controls. Most importantly, we found a strong inverse correlation between CpG2 methylation degree and age of onset (Spearman's rho = -0.550, p<0.001). CONCLUSION: Because epigenetic changes may cause or contribute to gene silencing, our data may have relevance for the therapeutic approach to FRDA. Since the analysis can be performed in peripheral blood leucocytes (PBL), evaluation of the methylation status of specific CpG sites in FRDA patients could be a convenient biomarker.

Ataxia with oculomotor apraxia type 1 in Southern Italy: late onset and variable phenotype.

Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive disorder characterized by early-onset cerebellar ataxia, oculomotor apraxia, and peripheral neuropathy. The causative gene (APTX) has been recently identified in Portuguese and Japanese kindreds. Three patients with AOA1 were identified in an APTX mutation screening on 28 Southern Italian patients with progressive ataxia and peripheral neuropathy. A novel homozygous missense mutation (H201Q) was found in one patient and a Japanese missense mutation (P206L) in two. AOA1 clinical heterogeneity and onset later than previously described are shown.

Real time PCR quantification of frataxin mRNA in the peripheral blood leucocytes of Friedreich ataxia patients and carriers.

The most common causative mutation of Friedreich ataxia (FRDA) is the unstable hyperexpansion of an intronic GAA triplet repeat that impairs frataxin transcription. Using real time quantitative PCR, we showed that FRDA patients had residual levels of frataxin mRNA ranging between 13% and 30% and that FRDA carriers had about 40% of that of controls. Asymptomatic carriers also showed reduced frataxin mRNA levels. We found an inverse correlation between the number of GAA repeats and frataxin mRNA levels. Real-time quantitative PCR may represent an alternative assay for FRDA molecular diagnosis.

A novel mutation in SACS gene in a family from southern Italy.

A form of autosomal recessive spastic ataxia (ARSACS) has been described in the Charlevoix and Saguenay regions of Quebec. So far a frameshift and a nonsense mutation have been identified in the SACS gene. The authors report a new mutation (1859insC), leading to a frameshift with a premature termination of the gene product sacsin, in two sisters from consanguineous parents. The phenotype is similar to previously described patients with ARSACS.

[Infrequent deletion in 67 codon in HIV reverse transcriptase in antiretroviral treatment failure]. / Deleción infrecuente en el codón 67 del gen de la transcriptasa reversa de HIV en falla al tratamiento antirretroviral.

We present a clinical case of antiretroviral treatment failure with appearance of mutations demonstrated by genotyping. We also show the evolution of the pattern of mutations that confers resistance to protease and reverse transcriptase inhibitors along with changes in the scheme of drugs indicated to the patient. A deletion was found in codon 67 of the TR gen, along with a novel resistance model to AZT pointing out the benefits of the detection of antiviral resistance by sequencing (genotyping).

Friedreich's ataxia: clinical and molecular study of 25 Brazilian cases.

INTRODUCTION: Friedreich's ataxia is a neurodegenerative disorder whose clinical diagnostic criteria for typical cases basically include: a) early age of onset (< 20 or 25 years), b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes. METHODS: We studied the frequency and the size of expanded GAA and their influence on neurologic findings, age at onset, and disease progression in 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia - 19 typical and 6 atypical - using a long-range PCR test. RESULTS: Abnormalities in cerebellar signs, in electrocardiography, and pes cavus occurred more frequently in typical cases; however, plantar response and speech were more frequently normal in this group when the both typical and atypical cases were compared. Homozygous GAA expansion repeats were detected in 17 cases (68%) - all typical cases. In 8 patients (32%) (6 atypical and 2 typical), no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, foot deformity, cardiac abnormalities, and some neurologic findings occurred more frequently; however, abnormalities in cranial nerves and in tomographic findings were detected less frequently than in patients without GAA expansions. DISCUSSION: Molecular analysis was imperative for the diagnosis of Friedreich's ataxia, not only for typical cases but also for atypical ones. There was no genotype-phenotype correlation. Diagnosis based only on clinical findings is limited; however, it aids in better screening for suspected cases that should be tested. Evaluation for vitamin E deficiency is recommended, especially in cases without GAA expansion.

Deleción infrecuente en el codón 67 del gen de la transcriptasa reversa de HIV en falla al tratamiento antirretroviral. / [Infrequent deletion in 67 codon in HIV reverse transcriptase in antiretroviral treatment failure]

We present a clinical case of antiretroviral treatment failure with appearance of mutations demonstrated by genotyping. We also show the evolution of the pattern of mutations that confers resistance to protease and reverse transcriptase inhibitors along with changes in the scheme of drugs indicated to the patient. A deletion was found in codon 67 of the TR gen, along with a novel resistance model to AZT pointing out the benefits of the detection of antiviral resistance by sequencing (genotyping).

Accuracy of clinical diagnostic criteria for Friedreich's ataxia.

The accuracy of the diagnostic criteria for Friedreich's ataxia proposed by Harding and by the Quebec Cooperative Study on Friedreich's Ataxia was studied in 142 patients with progressive unremitting ataxia of autosomal recessive inheritance or sporadic occurrence. Eighty-eight patients received the molecular diagnosis of Friedreich's ataxia. Traditional diagnostic criteria are characterized by high specificity, but they yield a high number of false-negative diagnoses. We suggest three levels of diagnostic certainty: (1) possible Friedreich's ataxia, defined as sporadic or recessive progressive ataxia with (a) lower limb areflexia and dysarthria, Babinski sign, or electrocardiographic repolarization abnormalities, or (b) with lower limb retained reflexes and electrocardiographic repolarization abnormalities (95% sensitivity and 88% positive predictive value); (2) probable Friedreich's ataxia as defined by Harding's criteria (63% sensitivity and 96% positive predictive value) or by Quebec Cooperative Study on Friedreich's Ataxia criteria (63% sensitivity and 98% positive predictive value); (3) definite diagnosis, molecularly confirmed.

Regression of AIDS-related Kaposi's sarcoma following combined antiretroviral treatment

The aim of the study was to assess regression of Kaposi's sarcoma (KS) in AIDS patients in Argentina. Eighteen male AIDS patients with human immunodeficiency virus (HIV)-associated Kaposi's sarcoma at different clinical stages received KS specific treatment and/or anti-retroviral therapy. Triple anti-retroviral therapy was given to most of the patients with the exception of four who received zidovudine (ZDV) in combination with another nucleoside analogue but no protease inhibitors. Plasma viral load and CD4+ T lymphocyte number were measured in two blood samples (before and after treatment). Complete remission was found in all patients (five) at KS stage I, three out of eight patients at stage II but in none at stages III and IV. Two out of three patients at KS stage IV did not respond to treatments at all. Three patients at KS stages I and II showed complete remission of sarcoma with only anti-retroviral therapy suggesting that anti-retroviral therapy and non-KS specific chemotherapy can successfully control KS.

Regression of AIDS-related Kaposis sarcoma following combined antiretroviral treatment

The aim of the study was to assess regression of Kaposis sarcoma (KS) in AIDS patients in Argentina. Eighteen male AIDS patients with human immunodeficiency virus (HIV)-associated Kaposis sarcoma at different clinical stages received KS specific treatment and/or anti-retroviral therapy. Triple anti-retroviral therapy was given to most of the patients with the exception of four who received zidovudine (ZDV) in combination with another nucleoside analogue but no protease inhibitors. Plasma viral load and CD4+ T lymphocyte number were measured in two blood samples (before and after treatment). Complete remission was found in all patients (five) at KS stage I, three out of eight patients at stage II but in none at stages III and IV. Two out of three patients at KS stage IV did not respond to treatments at all. Three patients at KS stages I and II showed complete remission of sarcoma with only anti-retroviral therapy suggesting that anti-retroviral therapy and non-KS specific chemotherapy can successfully control KS.(AU)

Atypical Friedreich ataxia phenotype associated with a novel missense mutation in the X25 gene.

We describe two sisters with early onset gait ataxia, rapid disease progression, absent or very mild dysarthria and upper limb dysmetria, retained knee jerks in one, slight to moderate peripheral nerve involvement, and diabetes. Molecular analysis showed that they are compound heterozygotes for GAA expansion and a novel exon 5a missense mutation (R165P). This mutation appears to be associated with an atypical but not milder Friedreich ataxia phenotype.

Regression of AIDS-related Kaposi's sarcoma following combined antiretroviral treatment.

The aim of the study was to assess regression of Kaposi's sarcoma (KS) in AIDS patients in Argentina. Eighteen male AIDS patients with human immunodeficiency virus (HIV)-associated Kaposi's sarcoma at different clinical stages received KS specific treatment and/or anti-retroviral therapy. Triple anti-retroviral therapy was given to most of the patients with the exception of four who received zidovudine (ZDV) in combination with another nucleoside analogue but no protease inhibitors. Plasma viral load and CD4+ T lymphocyte number were measured in two blood samples (before and after treatment). Complete remission was found in all patients (five) at KS stage I, three out of eight patients at stage II but in none at stages III and IV. Two out of three patients at KS stage IV did not respond to treatments at all. Three patients at KS stages I and II showed complete remission of sarcoma with only anti-retroviral therapy suggesting that anti-retroviral therapy and non-KS specific chemotherapy can successfully control KS.

Regression of AIDS-related Kaposis sarcoma following combined antiretroviral treatment.

The aim of the study was to assess regression of Kaposis sarcoma (KS) in AIDS patients in Argentina. Eighteen male AIDS patients with human immunodeficiency virus (HIV)-associated Kaposis sarcoma at different clinical stages received KS specific treatment and/or anti-retroviral therapy. Triple anti-retroviral therapy was given to most of the patients with the exception of four who received zidovudine (ZDV) in combination with another nucleoside analogue but no protease inhibitors. Plasma viral load and CD4+ T lymphocyte number were measured in two blood samples (before and after treatment). Complete remission was found in all patients (five) at KS stage I, three out of eight patients at stage II but in none at stages III and IV. Two out of three patients at KS stage IV did not respond to treatments at all. Three patients at KS stages I and II showed complete remission of sarcoma with only anti-retroviral therapy suggesting that anti-retroviral therapy and non-KS specific chemotherapy can successfully control KS.