I112M SOD1 mutation causes ALS with rapid progression and reduced penetrance in four Mediterranean families.

We evaluated a possible genotype-phenotype correlation and looked for a founder effect in four Mediterranean families carrying the I112M SOD1 mutation. The structural characteristics of the mutated protein were also analysed. Clinical data of FALS subjects from four families were evaluated. Mutational analysis of the SOD1 gene was carried out by direct sequencing. A haplotype study was carried out using 11 polymorphic markers flanking the SOD1 gene. Structural analysis was performed by means of homology modelling and molecular graphics methods. The clinical pattern of 17 FALS patients was characterized by prevalent spinal onset, mean age at onset of 47.1 years and mean duration of 20.7 months. Several obligate carriers were observed. These findings indicate that the I112M mutation is consistently associated with a uniform, fast-progressing phenotype with reduced penetrance of the disease. The haplotype analysis did not show a common haplotype among the Spanish families and the Italian family; however, a possible common founder could be hypothesized for Spanish families. From a structural viewpoint, mutation at codon 112 seems to confer a severe phenotype, probably related to altered protein functionality.

Personality and the effects of acute alcohol intake. A contingent negative variation study in healthy subjects.

This study investigates the relationship between blood alcohol concentrations (BACs) and contingent negative variation (CNV). Fourteen healthy subjects were divided on the basis of their personality profiles--the Minnesota Multiphasic Personality Inventory (Hs+Hy+D/3)--into a high score (HS) and low score (LS) subgroup. The CNV was recorded using a choice-reaction time (RT) task. CNV recording was performed in two conditions: inter-stimulus intervals (ISIs) of 1500 ms and 2500 ms at three different BACs (0.3, 0.5 and 0.8 g/L) after acute alcohol administration. At the high BAC (0.8 g/L), both subgroups showed a reduced CNV amplitude area and a longer RT (p<.05) in both ISI conditions. No effects either on the CNV or on the RT were observed at the low BAC (0.3 g/L). At the intermediate BAC (0.5 g/L), the HS subgroup displayed an increased CNV amplitude (p<.05), not accompanied by a significantly longer RT (short ISI condition), and a reduced late CNV (p<.05) with a longer RT (p<.05) (long ISI condition). In the LS group, only a longer RT was observed in the long ISI condition. CNV modifications point to an individual, apparently personality-related, threshold of sensitivity to different alcohol levels.

Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI.

The aim of our work was to evaluate the early presence of white matter changes on magnetic resonance imaging (MRI) in young asymptomatic children of patients with full-blown cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in whom DNA analysis revealed a Notch3 Cys146Tyr missense mutation on chromosome 19. Brain MRI was performed in all subjects using axial and coronal spin-echo proton density and T2-weighted images, axial fluid-attenuated inversion recovery (FLAIR) and sagittal and axial T1-weighted images. In asymptomatic subjects with Notch3 gene mutation, MRI showed small T2 hyperintense foci in periventricular and subcortical white matter. Routine use of MRI in the initial phases of a CADASIL diagnostic work up and the subsequent recognition of early abnormal findings in asymptomatic subjects may lead to prompt diagnosis of the disease in these patients. Moreover, these findings suggest that genetic screening is warranted in the presence of a suspect clinical history with specific MRI abnormalities.