The aim of the study was to assess different outcome measures in a cohort of ambulant boys with Duchenne muscular dystrophy (DMD) over 12 months in order to establish the spectrum of possible changes ...in relation to age and steroid treatment.
The study is a longitudinal multicentric cohort study. A total of 106 ambulant patients with DMD were assessed using the 6-minute walk test (6MWT) and North Star Ambulatory Assessment (NSAA) at baseline and 12 months. Clinical data including age and steroid treatment were collected.
During the 12 months of the study, we observed a mean decline of 25.8 meters in the 6MWT with a SD of 74.3 meters. On NSAA, the mean decline was 2.2 points with a SD of 3.7. Not all the boys with DMD in our cohort showed a decline over the 12 months, with young boys showing some improvement in their 6MWT and NSAA scores up to the age of 7. NSAA and the 6MWT had the highest correlation (r = 0.52, p < 0.001).
This study provides longitudinal data of NSAA and 6MWT over a 12-month period. These data can be useful when designing a clinical trial.
Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to ...influence MS risk.
Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®).
Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13.
These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients.
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•The 233 genetic loci associated with MS explain less than 40% of disease heritability, leaving a role to epigenetics in disease risk•We compared whole-genome methylation profiles in whole blood of affected and unaffected relatives of 8 multiplex MS families•We used MeDIP-seq and technical and biological replication in 2 additional families using a custom panel•Due to the heterogeneity of results in families, we adopted a method which leveraged consistency of signal across families•Filtering criteria lead to 2 hypo- and 2 hyper-methylated DMRs which relate to NTM, BAI3, PIK3R1 and CAPN13 genes•Replication of these signals is needed in additional cohort of MS patients
Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of ...genetic and environmental factors, and it can cluster in families.
to evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families.
We performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection.
We identified 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p = 5 × 10−4 and 3 × 10−4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families.
Despite limitations, this is one of the first studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our findings and to evaluate the role of identified genes in MS pathogenesis.
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•We evaluated at gene-level the aggregate contribution of damaging low-frequency and rare variants to multiple sclerosis risk in multiplex families adopting a literature-driven and data-driven candidate gene selection;•Twelve genes were identified to be enriched in damaging low-frequency and rare variants in multiple sclerosis affected subjects compared to unaffected individuals.•In UBR2 gene, one of the top associated genes, the signal was mostly driven by rs62414610-A, a missense damaging variant which was in 22% MS patients across 25% of families.
In small studies, a thrifty human phenotype, defined by a greater 24-hour energy expenditure (EE) decrease with fasting, is associated with less weight loss during caloric restriction. In rodents, ...models of diet-induced obesity often have a phenotype including a reduced EE and decreased core body temperature. We assessed whether a thrifty human phenotype associates with differences in core body temperature or body composition.
Data for this cross-sectional analysis were obtained from 77 individuals participating in one of two normal physiology studies while housed on our clinical research unit. Twenty-four-hour EE using a whole-room indirect calorimeter and 24-h core body temperature were measured during 24 h each of fasting and 200% overfeeding with a diet consisting of 50% carbohydrates, 20% protein and 30% fat. Body composition was measured by dual X-ray absorptiometry. To account for the effects of body size on EE, changes in EE were expressed as a percentage change from 24-hour EE (%EE) during energy balance.
A greater %EE decrease with fasting correlated with a smaller %EE increase with overfeeding (r=0.27, P=0.02). The %EE decrease with fasting was associated with both fat mass and abdominal fat mass, even after accounting for covariates (β=-0.16 (95% CI: -0.26, -0.06) %EE per kg fat mass, P=0.003; β=-0.0004 (-0.0007, -0.00004) %EE kg(-1) abdominal fat mass, P=0.03). In men, a greater %EE decrease in response to fasting was associated with a lower 24- h core body temperature, even after adjusting for covariates (β=1.43 (0.72, 2.15) %EE per 0.1 °C, P=0.0003).
Thrifty individuals, as defined by a larger EE decrease with fasting, were more likely to have greater overall and abdominal adiposity as well as lower core body temperature consistent with a more efficient metabolism.
Summary
A new sequence‐tagged site (STS) was identified within intron 26 of the bovine USP9Y gene, showing an 81‐base pair insertion (g.76439_76440ins81 in sequence with GenBank accession FJ195366) ...able to distinguish Y2 and Y3 Bos Y haplogroups from Y1. Moreover, four Y3‐specific sequence variants allow a distinction from haplogroup Y2. The typing of a Bison bison Y chromosome indicates that the ancestral allele for the USP9Y 81‐bp insertion is the short Y1 version. The results from typing the new STS in 1230 cattle Y chromosomes are fully consistent with their classification through standard methods. Thanks to the newly identified STS, it is now possible to assign cattle Y chromosomes to the currently known haplogroups using a single marker.
Abstract Six minute walk test (6MWT), timed items and North Star Ambulatory Assessment (NSAA) are increasingly used as possible outcome measures in clinical trials in Duchenne Muscular Dystrophy ...(DMD). Longitudinal data have previously been reported following changes in their scores over a 12 month period. The aim of the study was to assess 6MWT and NSAA in a cohort of 119 ambulant DMD boys over 24 months in order to establish the spectrum of possible changes over a longer period of time. The study is a longitudinal multicentric cohort study. 119 ambulant DMD patients were assessed using 6MWT, NSAA at baseline 12 and 24 months. Clinical data including age and steroid treatment were collected. During the 24 months of the study, we observed a progressive decline in both measures that was more obvious in the second year. Not all the DMD boys in our cohort showed a decline as young boys showed some improvement in their 6MWT and NSAA scores up to the age of 7. Fifteen patients (12.6%) lost the ability to walk independently: 2/15 by the end of the first year and the other 13 in the second year. Another 22 patients (21.1%) were still able to walk independently but were unable to get up from supine (8/22 at baseline, 4 at 12 months, 10 at 24 months). Four children also lost the ability to perform the 6MWT (2 at 12 months and the other 2 at 24 months). This study provides longitudinal data of NSAA and 6MWT over a 24 month period. These data can be useful when designing a clinical trial.
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