Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for similar to 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for similar to 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)

IRON COMPLEXES AS CATALYSTS IN ALDOL ADDITIONS

(Dicarbonyl)(\u3b75-cyclopentadienyl) iron halides function as catalysts for the aldol addition of enolsilanes to aldehydes

Effect of hydrothermally processed cereals on the performance of weaned piglets

Antisecretory factor (AF) is an endogenous protein that has shown to be a potent inhibitor of intestinal fluid secretion and inflammation. AF content in sows' milk is important for protection against neonatal diarrhoea in suckling piglets. Feeding specific hydrothermally processed cereals (HPC) has proven to increase the plasma level of AF and to be helpful in counteracting diarrhoea in domestic animals. The aim of the study was to investigate the effects of an AF-inducing diet on piglets' growth performance and intestinal mucosa. 144 weaned piglets with a body weight (BW) of 6.35 +/- 0.52 kg were randomized for sex and weight and allotted to 3 groups fed ad libitum: (C) control diet; (T1) control diet with 3% supplemental HPC; (T2) control diet with 6% supplemental HPC. On days 0, 14, and 42, animals were weighted, feed consumption and feed:gain ratio (FCR) were determined. Blood samples were collected (n = 6 animals per treatment group) to determine the effect of HPC on the intestinal enterocytes. None of the piglet showed diarrhoea during the study. Piglets fed the diet supplemented with 6% of HPC had higher (P<0.05) final BW compared to piglets fed the control diet. ADG was higher for the piglets fed the diet supplemented with 6% HPC 14 days after weaning (P<0.05) and during the whole experimental period (P<0.05). Animals fed 6% HPC grew more than piglets receiving 3% HPC supplemented diet during 14-42 days. Piglets fed 12 had a lower FCR (P=0.05) than piglets fed C. No difference was detected on feed intake and blood parameters. Intestinal health status and assessed monitoring the plasma level of I-FABP were low for all animals and did not significantly differ between treatment groups. The results of this experiment support the use of HPC as a natural alternative to AGP

Efficient total syntheses of (1R, 2R, 3R, 9R, 9aR)-1,2,3,9-tetrahydroxyquinolizidine and its enantiomer

Concise syntheses of two enantiomeric tetrahydroxyquinolizidines, 10 and ent-10, have been achieved from D-arabinose and L-arabinose, respectively. Highly diastereoselective homologation of imine 5 (or ent-5) using 2-(trimethylsiloxy)furan provided the nine-carbon butenolide 6 (or ent-6) which was elaborated into the quinolizidine 10 (or ent-10) via a clean sequence involving, as key operations, DBU-promoted γ-lactone to δ-lactam ring expansion (e.g. 7 to 8) and cyclodehydration of a fully-deprotected hydroxypiperidine employing Ph3P, CCl4, Et3N (e.g. 9 to 10). The procedure comprises five steps from 5 or ent-5 and provides the title quinolizidine 10 or its enantiomer ent-10 in 36-37% overall yields. © 1993