Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

Heterogeneous pattern of chromosomal breakpoints involving the MYC locus in multiple myeloma

Chromosomal rearrangements of the MYC locus, which often involve the IG loci, are recurrent events in multiple myeloma (MM) and plasma cell leukemia (PCL). We used dual-color fluorescence in situ hybridization (FISH) to characterize the breakpoint locations of chromosomal translocations/rearrangements involving the MYC locus at 8q24 found in a panel of 14 MM cell lines and 70 primary tumors (66 MM and 4 PCL). MYC locus alterations were observed in 21 cases: MYCIIG (mainly IGH@) fusions in II cell lines and three patients (2 MM and 1 PCL), and extra signals and/or abnormal MYC localizations in seven patients (5 MM and 2 PCL). Fourteen of these cases were investigated by FISH analyses by use of a panel of BAC clones covering about 6 Mb encompassing the MYC locus. The breakpoints were localized in a region 100-250 kb centromeric to MYC in four cases, a region 500-800 kb telomeric to the gene in four cases, and regions 652 Mb centromeric or telomeric to MYC in five cases. Two different breakpoints were detected in the KMS-18 cell line, whereas the insertion of a MYC allele was found in a complex t(16;22) chromosomal translocation in the RPM18226 cell line. Our data document a relatively high dispersion of 8q24 breakpoints in MM

Determinação da energia metabolizável de alimentos para codornas japonesas em postura Metabolizable energy of different feedstuffs tested in female Japanese quails

Foram determinados os valores de energia metabolizável aparente (EMA), de energia metabolizável aparente corrigida por retenção de nitrogênio (EMAn) e do coeficiente de metabolização aparente da energia bruta (CMAEB%) do milho, sorgo, farelo de soja, farelo de glúten de milho e óleo de soja refinado. Foram utilizadas 240 codornas japonesas (Coturnix japonica), fêmeas com idade inicial de 60 dias, em delineamento experimental inteiramente ao caso, com seis tratamentos, cinco repetições e oito codornas por unidade experimental. Os tratamentos consistiram de cinco rações experimentais e uma ração referência. Cada ração experimental foi constituída, na base da matéria natural, por 70% da ração referência e 30% do ingrediente a ser testado, com exceção da ração para determinação da EMAn do óleo de soja, com 10% de inclusão e 90% da ração referência. O experimento foi realizado em gaiolas distribuídas em baterias metálicas. Os valores de EMA, EMAn (em kcal/kg de matéria natural) e do CMAEB (%) do milho moído, sorgo, farelo de soja, farelo de glúten de milho e óleo de soja refinado foram, respectivamente: 3.572 e 3.612kcal/kg e 92,6%; 3.108 e 3.149kcal/kg e 80,9%; 2.633 e 2.676kcal/kg e 65,3%; 4.043 e 4.096kcal/kg e 75,0%; 9.335 e 9.379kcal/kg e 98,8%. Os valores de EMA descritos para outras espécies de aves são discrepantes dos obtidos no presente estudo, não sendo recomendado seu uso em formulação de rações para codornas japonesas em postura.<br>The values of the apparent metabolizable energy (AME), the apparent metabolizable energy corrected for nitrogen retention (AMEn), and the apparent metabolization coefficient of crude energy (AMCCE) were determined in corn, sorghum, soybean meal, corn gluten meal, and refined soybean oil. Two-hundred and forty six-day-old female Japanese quails (Coturnix japonica) were used in a completely randomized design, with five replicates and eight quails per experimental unit. The treatments consisted of six experimental diets and one reference diet. Each experimental diet was constituted, as fed basis, for 70% of the reference ration and 30% of food that would be tested, except the ration that contained refined soybean oil that was tested, as fed basis, with 10% of addition and 90% of the reference ration. The biological assay was carried out in wired floor cages distributed in iron batteries. The respective values of AME, AMEn (kcal/kg of natural matter basis), and AMCCE (%) of ground corn, sorghum, soybean meal, corn gluten meal, and refined soybean oil were respectively: 3,572, 3,612kcal/kg, and 92.6%; 3,108, 3,149kcal/kg, and 80.9%; 2,633, 2,676kcal/kg, and 65.3%; 4,043, 4,096kcal/kg, and 75.0%; and 9,335, 9,379kcal/kg, and 98.8%. The values of AME described for other birds species were different from those obtained in this study and are not recommended to be used in ration composition for Japanese quails