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Byline: G. Michele (1), G. Coppola (1), S. Cocozza (2), A. Filla (1) Keywords: hereditary ataxias; classification; pathogenesis Abstract: Abstract. Harding's classification takes credits for defining the homogeneous phenotypes that have been essential for the genetic linkage studies and it is still useful for didactic purposes. The advances in pathogenetic knowledge make it now possible to modify Harding's classification. Five main pathogenetic mechanisms may be distinguished: 1) mitochondrial 2) metabolic 3) defective DNA repair 4) abnormal protein folding and degradation 5) channelopathies. The present attempt to classify ataxia disorders according to their pathogenetic mechanism is a work in progress, since the pathogenesis of several disorders is still unknown. A pathogenetic classification may be useful in clinical practice and when new therapeutic strategies become available. Author Affiliation: (1) Dipartimento di Scienze Neurologiche, Universita degli Studi di Napoli Federico II, Via Pansini 5, 80131, Napoli, Italy (2) Molecular and Cellular Biology and Pathology and CEOS, CNR Federico II University, Naples, Italy Article History: Registration Date: 01/01/2004 Received Date: 19/03/2004 Accepted Date: 23/03/2004

Background and purpose: Changes of brain structure and function have been described in peripheral neuropathies. The aim of our study was to systematically investigate possible modifications of major large‐scale brain networks using resting‐state functional magnetic resonance imaging (RS‐fMRI) in Charcot–Marie–Tooth disease type 1A (CMT1A) patients. Methods: In this cross‐sectional study, 3‐T MRI brain scans were acquired of right‐handed genetically confirmed CMT1A patients and age‐ and sex‐comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing neurological impairment. RS‐fMRI data were analysed using a seed‐based approach, with 32 different seeds sampling the main hubs of default mode, sensorimotor, visual, salience (SN), dorsal attention, frontoparietal, language and cerebellar networks. Between‐group differences in terms of functional connectivity (FC) with the explored seeds were tested voxelwise, correcting for local grey matter density to account for possible structural abnormalities, whilst the relationship between FC modifications and neurological impairment was investigated using robust correlation analyses. Results: Eighteen CMT1A patients (34.0 ± 11.4 years; M/F 11/7) were enrolled, along with 20 healthy controls (30.1 ± 10.2 years; M/F 11/9). In the CMT group compared to controls, clusters of increased FC with the visual cortex (P = 0.001), SN (P < 6 × 10−4), dorsal attention network (P < 8 × 10−5) and language network (P < 7 × 10–4) were found, along with a single cluster of reduced FC with the visual cortex in the left lentiform nucleus (P = 10–6). A significant correlation emerged between neurophysiological impairment and increased FC with right temporal language areas (r = 0.655, P = 0.006), along with an association between walking ability and increased FC with the left supramarginal gyrus (SN) (r = 0.620, P = 0.006). Conclusions: Our data show evidence of diffuse functional reorganization involving multiple large‐scale networks in the CMT1A brain, independent of structural modifications and partially correlating with peripheral nerve damage and functional impairment. [ABSTRACT FROM AUTHOR]

Background and purpose: Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive‐affective syndrome (CCAS), named SCA48. Methods: Molecular screening was performed in a cohort of 235 unrelated patients with adult‐onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole‐exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico‐diagnostic findings were reviewed to define the phenotypic spectrum. Results: Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. Conclusions: Our results support SCA48 as a significant cause of adult‐onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1. [ABSTRACT FROM AUTHOR]

Background Spasticity in multiple sclerosis (MS) results from an imbalance of inputs from descending pathways to the spinal motor circuits, as well as from a damage of the corticospinal tract (CST). Objectives To assess CST impairment in MS patients with and without spasticity and to evaluate its evolution under Sativex® treatment. Methods Ten MS patients with spasticity ('cases') underwent clinical (EDSS, 9-hole Peg, Ashworth scale, Timed 25-Foot Walk, and NRS for spasticity), MRI (CST fractional anisotropy [FA]), and electrophysiological (central motor conduction time [CMCT] and H/M ratio) evaluations at baseline and after 12 months. We selected 20 MS patients without spasticity as control group at baseline. Results At baseline, cases showed a lower CST FA (0.492±0.045 vs 0.543±0.047; P=.01) and a higher CMCT ( P=.001) compared to the control group. No correlations were found between clinical, electrophysiological, and MRI features. After 12 months, cases showed a decrease in non-prevalent degree of impairment (PDI) side FA (0.502±0.023 vs 0.516±0.033; P=.01) without differences for electrophysiological features compared to baseline. Treatment with Sativex® resulted in a reduction of NRS for spasticity ( P=.01). Conclusions We confirm the presence of CST impairment in MS patients with spasticity. We did not identify structural/electrophysiological correlates that could explain Sativex® clinical effect. [ABSTRACT FROM AUTHOR]

Background and purpose Grey matter ( GM) and white matter ( WM) are both affected in multiple sclerosis ( MS). WM is predominantly involved in inflammatory demyelination of relapsing-remitting MS ( RRMS), whereas GM is predominantly involved in neurodegenerative processes of secondary progressive MS. Thus, we investigated the ratio between GM and WM volumes in predicting MS evolution. Methods The present 10-year retrospective cohort study included 149 patients with newly-diagnosed RRMS, undergoing magnetic resonance imaging for segmentation and brain volumetry. The ratio between GM and normal-appearing WM ( NAWM) volumes was calculated for each subject. Outcome measures of interest were Expanded Disability Status Scale ( EDSS) progression, reaching EDSS 4.0 and conversion to secondary progressive (SP) MS. Results During a period of 10.6 ± 2.4 years, a median 1.5 EDSS progression was observed (range 0-5.5), 54 subjects (36.2%) reached EDSS 4.0 and 30 subjects (20.1%) converted to SP. With ordinal logistic regression models, EDSS progression was associated with GM: NAWM ratio (coefficient, −2.918; 95% CI, −4.739-1.097). With Cox regression models, subjects with higher GM: NAWM ratio at diagnosis had a 90% lower rate of reaching EDSS 4.0 (hazard ratio, 0.111; 95% CI, 0.020-0.609) and of converting to secondary progressive MS (hazard ratio, 0.017; 95% CI, 0.001-0.203) compared with subjects with lower GM: NAWM ratio. Conclusions The GM: NAWM ratio is a predictor of disability progression and of SP conversion in subjects with newly diagnosed RRMS, suggesting that GM and NAWM are variably affected in relation to disease evolution from the early phases of MS. [ABSTRACT FROM AUTHOR]

Background and Aims: Diabetic women have a more adverse plasma lipid profile than men. Sex differences in dietary habits may play a role, but are little investigated. The study evaluates the quality of diet, adherence to the nutritional recommendations of the Diabetes and Nutrition Study Group and their relation with plasma lipid in men and women with diabetes.Methods and Results: We studied 2573 people, aged 50-75, enrolled in the TOSCA.IT study (clinicaltrials.gov; NCT00700856). Plasma lipids were measured centrally. Diet was assessed with a semi-quantitative food frequency questionnaire. Women had a more adverse plasma lipid profile than men. Women consumed significantly more legumes, vegetables, fruits, eggs, milk, vegetable oils, and added sugar, whereas men consumed more starchy foods, soft drinks and alcoholic beverages. This stands for a higher proportion (%) of energy intake from saturated fat and added sugar (12.0 ± 2.4 vs 11.5 ± 2.5 and 3.4 ± 3.2 vs 2.3 ± 3.2, P < 0.04), and a higher intake of fiber (11.2 ± 2.8 vs 10.4 ± 2.6 g/1000 Kcal/day) in women. Adherence to the recommendations for saturated fat and fiber consumption was associated with significantly lower LDL-cholesterol regardless of sex. Adherence to the recommendations for added sugars was associated with significantly lower triglycerides and higher HDL-cholesterol in men and women.Conclusions: Men and women with diabetes show significant differences in adherence to nutritional recommendations, but sex differences in plasma lipid profile are unlikely to be explained by nutritional factors. Adherence to the nutritional recommendations is associated with a better plasma lipid profile regardless of sex, thus reinforcing the importance of substituting saturated for unsaturated fat sources, increasing fiber and reducing added sugar intake. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: We explore the relationship among BMI, habitual diet, and the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR)gamma2.Research Design and Methods: The Pro12Ala variant was characterized in 343 unrelated type 2 diabetic patients who were consecutively seen at the outpatient clinic of a health district of the province of Naples. Anthropometric and laboratory parameters were measured; habitual diet was assessed by a validated semiquantitative food frequency questionnaire.Results: The overall frequency of Ala12 was 12% (n = 42). BMI was significantly higher in Ala carriers than non-Ala carriers, whereas total daily energy intake or macronutrient composition of the diet were similar in the two groups. For further analysis, participants were stratified according to genotype and sex-specific quartiles of energy intake. BMI increased in both genotype groups with increasing energy intake (P < 0.03). BMI was similar in Ala carriers and non-Ala carriers (30.0 vs. 30.1 kg/m2, P > 0.10) in the lower quartile of energy intake but significantly higher in Ala carriers in the upper quartile (36.0 vs. 32.1 kg/m2, P < 0.001). Average daily energy intake and diet composition were comparable within each quartile for carriers or noncarriers of the Ala allele. Relative to the noncarriers, Ala carriers had a significantly lower energy intake per kilogram body weight, thus suggesting that the Ala allele is associated with a higher food efficiency. The confounding role of medications, glucose control, and physical exercise was ruled out.Conclusions: This study provides evidence of a differential susceptibility to fat accumulation, and, hence, weight gain, in response to habitual high energy intake for Ala carriers compared with Pro/Pro homozygotes. [ABSTRACT FROM AUTHOR]

The relationships between some genetic markers, as evaluated by DNA analysis, and ultrasound evidence of extracoronary athero-sclerosis, as detected by ultrasound methods, were evaluated in 39 myocardial infarction survivors of middle age and in 40 healthy controls of comparable age. Coronary heart disease (CHD) patients showed higher levels of triglycerides ( P = 0.01) and greater number of exsmokers ( P = 0.004). Carotid stenoses (> 15%) were detected in ten CHD patients and in two controls; iliac stenoses (> 15%) or abnormal ankle/arm ratio (< 0.97) were found in ten CHD patients and in one control; the scores of vascular disease severity in the myocardial infarction survivors were higher (Mann-Whitney test) than in controls ( P < 0.01). Molecular genetic analysis of Sstl restriction fragment length polymorphism (RFLP) of the apolipoprotein (apo) AI-CIII cluster and of the apo B gene demonstrated a higher frequency of the S2 allele ( SstI RFLP) in coronary patients than in controls ( P = 0.04) and no significant differences in the frequencies of XbaI RFLP of the apo B gene between patients and controls. The relative risk of myocardial infarction associated with an abnormal vascular score (> 8) or with the presence of the rare allele S2 ( SstI apo AI-CIII polymorphism) was estimated by odds ratios. The lower 95% limits of odds ratios were above 1 (indicating significant increase in the relative risk of myocardial infarction) both in the case of vascular score and that of SstI RFLP. These associations were independent of one another and of triglyceride levels. SstI RFLP association with CHD disappeared after adjustment for smoking habits. Ultrasound evidence of extracoronary atherosclerosis and SstI RFLP are markers of cardiovascular risk, which might be of help in identifying coronary-prone individuals, independently of the influence of life-style changes or ongoing treatments. [ABSTRACT FROM AUTHOR]

We used two recently described genetic markers in the region of the Friedreich's ataxia locus to study 33 affected pedigrees from central-southern regions of Italy. These markers are predicted, by physical mapping, to be localised more closely to the Friedreich's ataxia locus than other previously described markers. No recombination was found between these markers and the disease locus. Strong linkage disequilibrium is present between the compound haplotype and the disease locus. Since this population was also previously studied by using three other more distal genetic markers, a total of five markers has been used to identify the extended haplotype. Homozygosity in consanguineous pedigrees was also studied. Extended haplotype analysis and homozygosity studies suggest the presence of few common disease causing mutations in our population. [ABSTRACT FROM PUBLISHER]

Abstract Background The analysis of complex diseases is an important problem in human genetics. Because multifactoriality is expected to play a pivotal role, many studies are currently focused on collecting information on the genetic and environmental factors that potentially influence these diseases. However, there is still a lack of efficient and thoroughly tested statistical models that can be used to identify implicated features and their interactions. Simulations using large biologically realistic data sets with known gene-gene and gene-environment interactions that influence the risk of a complex disease are a convenient and useful way to assess the performance of statistical methods. Results The Gene-Environment iNteraction Simulator 2 (GENS2) simulates interactions among two genetic and one environmental factor and also allows for epistatic interactions. GENS2 is based on data with realistic patterns of linkage disequilibrium, and imposes no limitations either on the number of individuals to be simulated or on number of non-predisposing genetic/environmental factors to be considered. The GENS2 tool is able to simulate gene-environment and gene-gene interactions. To make the Simulator more intuitive, the input parameters are expressed as standard epidemiological quantities. GENS2 is written in Python language and takes advantage of operators and modules provided by the simuPOP simulation environment. It can be used through a graphical or a command-line interface and is freely available from http://sourceforge.net/projects/gensim. The software is released under the GNU General Public License version 3.0. Conclusions Data produced by GENS2 can be used as a benchmark for evaluating statistical tools designed for the identification of gene-gene and gene-environment interactions.

Abstract Background Many natural phenomena are directly or indirectly related to latitude. Living at different latitudes, indeed, has its consequences with being exposed to different climates, diets, light/dark cycles, etc. In humans, one of the best known examples of genetic traits following a latitudinal gradient is skin pigmentation. Nevertheless, also several diseases show latitudinal clinals such as hypertension, cancer, dismetabolic conditions, schizophrenia, Parkinson's disease and many more. Results We investigated, for the first time on a wide genomic scale, the latitude-driven adaptation phenomena. In particular, we selected a set of genes showing signs of latitude-dependent population differentiation. The biological characterization of these genes showed enrichment for neural-related processes. In light of this, we investigated whether genes associated to neuropsychiatric diseases were enriched by Latitude-Related Genes (LRGs). We found a strong enrichment of LRGs in the set of genes associated to schizophrenia. In an attempt to try to explain this possible link between latitude and schizophrenia, we investigated their associations with vitamin D. We found in a set of vitamin D related genes a significant enrichment of both LRGs and of genes involved in schizophrenia. Conclusions Our results suggest a latitude-driven adaptation for both schizophrenia and vitamin D related genes. In addition we confirm, at a molecular level, the link between schizophrenia and vitamin D. Finally, we discuss a model in which schizophrenia is, at least partly, a maladaptive by-product of latitude dependent adaptive changes in vitamin D metabolism.

Abstract Background This study evaluated the relationship between the G(-866)A polymorphism of the uncoupling protein 2 (UCP2) gene and high-sensitivity C reactive protein (hs-CRP) plasma levels in diabetic patients. Methods We studied 383 unrelated people with type 2 diabetes aged 40-70 years. Anthropometry, fasting lipids, glucose, HbA1c, and hs-CRP were measured. Participants were genotyped for the G (-866)A polymorphism of the uncoupling protein 2 gene. Results Hs-CRP (mg/L) increased progressively across the three genotype groups AA, AG, or GG, being respectively 3.0 ± 3.2, 3.6 ± 5.0, and 4.8 ± 5.3 (p for trend = 0.03). Since hs-CRP values were not significantly different between AA and AG genotype, these two groups were pooled for further analyses. Compared to participants with the AA/AG genotypes, homozygotes for the G allele (GG genotype) had significantly higher hs-CRP levels (4.8 ± 5.3 vs 3.5 ± 4.7 mg/L, p = 0.01) and a larger proportion (53.9% vs 46.1%, p = 0.013) of elevated hs-CRP (> 2 mg/L). This was not explained by major confounders such as age, gender, BMI, waist circumference, HbA1c, smoking, or medications use which were comparable in the two genotype groups. Conclusions The study shows for the first time, in type 2 diabetic patients, a significant association of hs-CRP levels with the G(-866)A polymorphism of UCP2 beyond the effect of major confounders.

Abstract Background Complex diseases are multifactorial traits caused by both genetic and environmental factors. They represent the major part of human diseases and include those with largest prevalence and mortality (cancer, heart disease, obesity, etc.). Despite a large amount of information that has been collected about both genetic and environmental risk factors, there are few examples of studies on their interactions in epidemiological literature. One reason can be the incomplete knowledge of the power of statistical methods designed to search for risk factors and their interactions in these data sets. An improvement in this direction would lead to a better understanding and description of gene-environment interactions. To this aim, a possible strategy is to challenge the different statistical methods against data sets where the underlying phenomenon is completely known and fully controllable, for example simulated ones. Results We present a mathematical approach that models gene-environment interactions. By this method it is possible to generate simulated populations having gene-environment interactions of any form, involving any number of genetic and environmental factors and also allowing non-linear interactions as epistasis. In particular, we implemented a simple version of this model in a Gene-Environment iNteraction Simulator (GENS), a tool designed to simulate case-control data sets where a one gene-one environment interaction influences the disease risk. The main aim has been to allow the input of population characteristics by using standard epidemiological measures and to implement constraints to make the simulator behaviour biologically meaningful. Conclusions By the multi-logistic model implemented in GENS it is possible to simulate case-control samples of complex disease where gene-environment interactions influence the disease risk. The user has full control of the main characteristics of the simulated population and a Monte Carlo process allows random variability. A knowledge-based approach reduces the complexity of the mathematical model by using reasonable biological constraints and makes the simulation more understandable in biological terms. Simulated data sets can be used for the assessment of novel statistical methods or for the evaluation of the statistical power when designing a study.

Abstract Background It is widely accepted that Type 2 Diabetes Mellitus (T2DM) and other complex diseases are the product of complex interplay between genetic susceptibility and environmental causes. To cope with such a complexity, all the statistical and conceptual strategies available should be used. The working hypothesis of this study was that two well-known T2DM risk factors could have diverse effect in individuals carrying different genotypes. In particular, our effort was to investigate if a well-defined group of genes, involved in peripheral energy expenditure, could modify the impact of two environmental factors like age and obesity on the risk to develop diabetes. To achieve this aim we exploited a multianalytical approach also using dimensionality reduction strategy and conservative significance correction strategies. Methods We collected clinical data and characterised five genetic variants and 2 environmental factors of 342 ambulatory T2DM patients and 305 unrelated non-diabetic controls. To take in account the role of one of the major co-morbidity conditions we stratified the whole sample according to the presence of obesity, over and above the 30 Kg/m2 BMI threshold. Results By monofactorial analyses the ADRB2-27 Glu27 homozygotes had a lower frequency of diabetes when compared with Gln27 carriers (Odds Ratio (OR) 0.56, 95% Confidence Interval (CI) 0.36 – 0.91). This difference was even more marked in the obese subsample. Multifactor Dimensionality Reduction method in the non-obese subsample showed an interaction among age, ADRB2-16 and UCP3 polymorphisms. In individuals that were UCP3 T-carriers and ADRB2-16 Arg-carriers the OR increased from 1 in the youngest to 10.84 (95% CI 4.54–25.85) in the oldest. On the contrary, in the ADRB2-16 GlyGly and UCP3 CC double homozygote subjects, the OR for the disease was 1.10 (95% CI 0.53–2.27) in the youngest and 1.61 (95% CI 0.55–4.71) in the oldest. Conclusion Although our results should be confirmed by further studies, our data suggests that, when properly evaluated, it is possible to identify genetic factors that could influence the effect of common risk factors.