Alterations In Carriers Research Articles

Pervasive alterations of intra-axonal volume and network organization in young children with a 16p11.2 deletion

Reciprocal Copy Number Variants (CNVs) at the 16p11.2 locus confer high risk for autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs). Morphometric MRI studies have revealed large and pervasive volumetric alterations in carriers of a 16p11.2 deletion. However, the specific neuroanatomical mechanisms underlying such alterations, as well as their developmental trajectory, are still poorly understood. Here we explored differences in microstructural brain connectivity between 24 children carrying a 16p11.2 deletion and 66 typically developing (TD) children between 2 and 8 years of age. We found a large pervasive increase of intra-axonal volume widespread over a high number of white matter tracts. Such microstructural alterations in 16p11.2 deletion children were already present at an early age, and led to significant changes in the global efficiency and integration of brain networks mainly associated to language, motricity and socio-emotional behavior, although the widespread pattern made it unlikely to represent direct functional correlates. Our results shed light on the neuroanatomical basis of the previously reported increase of white matter volume, and align well with analogous evidence of altered axonal diameter and synaptic function in 16p11.2 mice models. We provide evidence of a prevalent mechanistic deviation from typical maturation of brain structural connectivity associated with a specific biological risk to develop ASD. Future work is warranted to determine how this deviation contributes to the emergence of symptoms observed in young children diagnosed with ASD and other NDDs.

Genetic testing and management of prostate cancer patients with pathogenic germline variants

SummaryProstate cancer (PCa) is an androgen-receptor signaling-dependent disease with a subset of patients harboring pathogenic germline variants (PGVs) in genes essential for DNA repair. In the last decade, several guidelines and recommendations have been developed to define which PCa patients should receive genetic testing to identify individuals at higher risk due to inherited alterations and to facilitate personalized treatment strategies. Notably, the presence of specific germline alterations in carriers undergoing PCa screening has implications for screening strategies, and PGV carriers with advanced disease are eligible to receive targeted therapies such as poly-ADP-ribose polymerase inhibitors (PARPi) or immune checkpoint inhibitors (CKI) depending on the alterations encountered. Although less information is available on carriers with localized disease, several trials are addressing this specific patient population and will help to collect data and improve clinical management of PCa patients with PGVs.

Subcortical Brain Alterations in Carriers of Genomic Copy Number Variants.

Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs), including autism (ASD) and schizophrenia. Little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, the authors investigated gross volume, vertex-level thickness, and surface maps of subcortical structures in 11 CNVs and six NPDs. Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (CNVs at 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2; age range, 6-80 years; 340 males) and 782 control subjects (age range, 6-80 years; 387 males) as well as ENIGMA summary statistics for ASD, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, bipolar disorder, and major depression. All CNVs showed alterations in at least one subcortical measure. Each structure was affected by at least two CNVs, and the hippocampus and amygdala were affected by five. Shape analyses detected subregional alterations that were averaged out in volume analyses. A common latent dimension was identified, characterized by opposing effects on the hippocampus/amygdala and putamen/pallidum, across CNVs and across NPDs. Effect sizes of CNVs on subcortical volume, thickness, and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and schizophrenia. The findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions, as well distinct effects, with some CNVs clustering with adult-onset conditions and others with ASD. These findings provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD and why a single CNV increases the risk for a diverse set of NPDs.

Sensor-based gait analysis in the premotor stage of LRRK2 G2019S-associated Parkinson's disease

IntroductionThere is a need for biomarkers to monitor the earliest phases of Parkinson's disease (PD), especially in premotor stages. Here, we studied whether there are early gait alterations in carriers of the G2019S mutation of LRRK2 that can be detected by means of an inertial sensor system. MethodsTwenty-one idiopathic PD patients, 20 LRRK2-G2019S PD, 27 asymptomatic carriers of LRRK2-G2019S mutation (AsG2019S) and 36 controls walked equipped with 16 lightweight inertial sensors in three different experiments: i/normal gait, ii/fast gait and iii/dual-task gait. In the AsG2019S group, DaT-SPECT (123I-ioflupane) with semi-quantitative analysis was carried out. Motor and cognitive performance were evaluated using MDS-UPDRS-III and MoCA scales. We employed neural network techniques to classify individuals based on their walking patterns. ResultsPD patients and controls showed differences in speed, stride length and arm swing amplitude, variability and asymmetry in all three tasks (p < 0.01). In the AsG2019S group, the only differences were detected during fast walking, with greater step time on the non-dominant side (p < 0.05), lower step/stride time variability (p < 0.01) and lower step time asymmetry (p < 0.01). DaT uptake showed a significant correlation with step time during fast walking on the non-dominant side (r = −0.52; p < 0.01). The neural network was able to differentiate between AsG2019S and healthy controls with an accuracy rate of 82.5%. ConclusionOur sensor-based analysis did not detect substantial and robust changes in the gait of LRRK2-G2019S asymptomatic mutation carriers. Nonetheless, step or stride time during fast walking, supported by the observed correlation with striatal DaT binding deserves consideration as a potential biomarker in future studies.

Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms

Individuals with autosomal dominant mutations for Alzheimer disease are valuable in determining biomarkers present prior to the onset of cognitive decline, improving the ability to diagnose Alzheimer disease as early as possible. Optical coherence tomography (OCT) has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease. To evaluate whether OCT can detect early retinal alterations in carriers of the presenilin 1 (PSEN1 [OMIM 104311]) E280A mutation who are cognitively unimpaired. A cross-sectional imaging study conducted from July 13, 2015, to September 16, 2020, included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired and 10 healthy noncarrier family members, all leveraged from a homogenous Colombian kindred. Statistical analysis was conducted from September 9, 2017, to September 16, 2020. Mixed-effects multiple linear regression was performed to compare the thickness values of the whole retina and individual retinal layers on OCT scans between mutation carriers and noncarriers. Simple linear-effects and mixed-effects multiple linear regression models were used to assess whether age was an effect modifier for PSEN1 mutation of amyloid β levels and retinal thickness, respectively. Fundus photographs were used to compare the number of arterial and venous branch points, arterial and venous tortuosity, and fractal dimension. This study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (7 women [70%]; mean [SD] age, 36.3 [8.1] years) and 10 healthy noncarrier family members (7 women [70%]; mean [SD] age, 36.4 [8.2] years). Compared with noncarrier controls, PSEN1 mutation carriers who were cognitively unimpaired had a generalized decrease in thickness of the whole retina as well as individual layers detected on OCT scans, with the inner nuclear layer (outer superior quadrant, β = -3.06; P = .007; outer inferior quadrant, β = -2.60; P = .02), outer plexiform layer (outer superior quadrant, β = -3.44; P = .03), and outer nuclear layer (central quadrant, β = -8.61; P = .03; inner nasal quadrant, β = -8.39; P = .04; inner temporal quadrant, β = -9.39; P = .02) showing the greatest amount of statistically significant thinning. Age was a significant effect modifier for the association between PSEN1 mutation and amyloid β levels in cortical regions (β = 0.03; P = .001) but not for the association between PSEN1 mutation and retinal thickness. No statistical difference was detected in any of the vascular parameters studied. These findings suggest that OCT can detect functional and morphologic changes in the retina of carriers of familial Alzheimer disease who are cognitively unimpaired several years before clinical onset, suggesting that OCT findings and retinal vascular parameters may be biomarkers prior to the onset of cognitive decline.

GBA Variants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes.

Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Plasma Metabolomics Reveal Alterations of Sphingo- and Glycerophospholipid Levels in Non-Diabetic Carriers of the Transcription Factor 7-Like 2 Polymorphism rs7903146

Aims/HypothesisPolymorphisms in the transcription factor 7-like 2 (TCF7L2) gene have been shown to display a powerful association with type 2 diabetes. The aim of the present study was to evaluate metabolic alterations in carriers of a common TCF7L2 risk variant.MethodsSeventeen non-diabetic subjects carrying the T risk allele at the rs7903146 TCF7L2 locus and 24 subjects carrying no risk allele were submitted to intravenous glucose tolerance test and euglycemic-hyperinsulinemic clamp. Plasma samples were analysed for concentrations of 163 metabolites through targeted mass spectrometry.ResultsTCF7L2 risk allele carriers had a reduced first-phase insulin response and normal insulin sensitivity. Under fasting conditions, carriers of TCF7L2 rs7903146 exhibited a non-significant increase of plasma sphingomyelins (SMs), phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) species. A significant genotype effect was detected in response to challenge tests in 6 SMs (C16:0, C16:1, C18:0, C18:1, C24:0, C24:1), 5 hydroxy-SMs (C14:1, C16:1, C22:1, C22:2, C24:1), 4 lysoPCs (C14:0, C16:0, C16:1, C17:0), 3 diacyl-PCs (C28:1, C36:6, C40:4) and 4 long-chain acyl-alkyl-PCs (C40:2, C40:5, C44:5, C44:6).DiscussionPlasma metabolomic profiling identified alterations of phospholipid metabolism in response to challenge tests in subjects with TCF7L2 rs7903146 genotype. This may reflect a genotype-mediated link to early metabolic abnormalities prior to the development of disturbed glucose tolerance.

INTIMA-MEDIA THICKNESS OF THE COMMON CAROTID ARTERY AND LDL-R DEFECT IN ASYMPTOMATIC SEVERE HYPERCHOLESTEROLEMIA

The data on the examination of early vascular alterations in carriers of molecular defects of the LDL-R in comparison to non-carriers with severe hypercholesterolemia are controversial. Aim: To examine the difference between patients with severe hypercholesterolemia, who are carriers and non-carriers of LDL-R defective gene, with respect to their structural (intima-media thickness of carotid artery) characteristics of arterial wall. A total of 60 hypercholesterolemic patients were enrolled. Biochemistry parameters were examined by routine methods. Determination of intima-media thickness of common carotid artery was performed with Hewlett Packard Sonos 5 500, using automated computer software MedicaSoft. IMT.lab. Results: There was no significant difference between the groups with respect to total cholesterol, LDL, HDL, triglycerides. We were founded a significantly higher carotid IMT in the carriers versus non-carriers. This significant difference was confirmed after adjustment for age and gender. Conclusion: Our data demonstrate that carriers of the LDL-R defective gene have a higher carotid IMT than non-carriers, whereas no difference between the groups was found with respect to the level of lipid parameters.

Increased Intima-Media Thickness in Carriers of the LDL-Receptor Defective Gene versus Noncarriers with Newly Detected Asymptomatic Severe Hypercholesterolemia

The data on the examination of early vascular alterations in carriers of molecular defects of the low-density lipoprotein-receptor (LDL-R) in comparison to noncarriers with severe hypercholesterolemia are controversial. To examine the difference between patients with severe hypercholesterolemia, who are carriers and noncarriers of LDL-R defective gene, with respect to their functional (flow-mediated vasodilation) and structural (intima-media thickness of carotid artery) characteristics of arterial wall. A total of 250 hypercholesterolemic patients were enrolled. Biochemistry parameters were examined by routine methods. The molecular biological analysis included-R3500Q-mutation in the Apolipoprotein-B (Apo-B) gene, LDL-R gene mutation and polymorphism (and the promoter region), as large rearrangements. Determination of flow-mediated vasodilation and intima-media thickness of common carotid artery was performed with Hewlett Packard Sonos 5500, using automated computer software MedicaSoft. IMT.lab. There was no significant difference between the groups with respect to total cholesterol, LDL, HDL, Apo-B, Apolipoprotein A(1) (Apo-A(1) ), asymmetric dimethylarginine (ADMA), homocysteine, and cellular adhesion molecules. The Apo-B/Apo A(1) index differed significantly (t = 11.23, P < 0.001) between the two groups and this difference was found even after adjustment for age and gender. There was no significant difference with respect to the endothelial dependent and independent vasodilatation between the examined groups (P > 0.05). We were founded a significantly higher carotid IMT in the carriers versus noncarriers. This significant difference was confirmed after adjustment for age and gender. Statistically significant correlations we were founded between IMT mean and age (log) (r(xy) = 0.45; P < 0.01), cholesterol × years score (log) (r(xy) = 0.53; P < 0.01), Apo-B/A(1) (log) (r(xy) = 0.66; P < 0.001) in the group of the carriers. Backward selection process selected Apo-B/A(1) as the most important statistically significant factor related to IMT mean of common carotid artery (F = 105.22; P = 0.001; R(2) = 0.72). Our data demonstrate that carriers of the LDL-R defective gene have a higher carotid IMT and Apo B/Apo A(1) index than noncarriers, whereas no difference between the groups was found with respect to the level of lipid parameters, ADMA, total homocysteine, cell adhesion molecules and %FMD. Apo-B/A(1) is a predictor of IMT mean in the group of the carriers of the LDL-receptor gene.

No early signs of atherosclerotic alterations in carriers of inherited thrombophilia

Background Congenital thrombophilia is a risk factor for venous thromboembolism (VTE). Whether it is associated with increased risk of arterial disease is today a matter of debate. We aimed to look for early signs of atherosclerotic alterations in carriers of inherited thrombophilic alterations (ITA). Methods Between January 2006 and September 2008 ultrasonography assessment of the carotid arteries with measurement of intima-media thickness (IMT), and determination of the ankle/brachial pressure index (ABI), was performed in: a) 161 carriers of ITA (deficiency of antithrombin, protein C or S, factor V Leiden or prothrombin G20210A mutations), 84 of whom with previous VTE, and b) 180 subjects without ITA, matched for age, sex and previous VTE. All subjects were < 66 year old. Results Carotid plaques were found in 8 subjects [3 (1.9%) with ITA]. Increased IMT values (> 1 mm) were detected in 6 subjects with and 1 without thrombophilia (p = 0.055). The prevalence of IMT values > 90 th percentile was not different in subjects with/without thrombophilia (15.2% vs 11.6%, p = 0.416). At multivariate analysis only age was significantly associated with increased odds ratios for IMT values > 90 th percentile. No subjects had abnormal (< 0.9) ABI values. Conclusions The present study, the first to investigate the presence of atherosclerotic markers in relatively young subjects with inherited thrombophilia, did not find a particular prevalence of signs of early atherosclerotic markers in these subjects.

Optical coherence tomography and electro-oculogram abnormalities in X-linked retinitis pigmentosa

To determine the correlations between morphological optical coherence tomography (OCT) and electrophysiological electro-oculogram (EOG) alterations in families with X-linked retinitis pigmentosa (XLRP). Observational case series. About 32 eyes of 16 members of four different families: Seven obligate carriers, four affected male homozygotes and five unaffected females underwent ophthalmologic completed exams including EOG and OCT. All the subjects were previously tested with genetic analysis. The results were statistically analysed. The abnormalities in OCT were detected in all carriers and affected males consisting of macular edema and increased RPE reflectivity compared to no alterations in unaffected females. The EOG was flat in all affected males; distinctly abnormal in eight eyes of obligate carriers; normal in two eyes of obligate carriers and in all unaffected females. In two obligate carriers, the EOG was not performed due to a nuclear cataract. The correlations between OCT and EOG alterations were statistically significant. The OCT and EOG were demonstrated to be useful methods to identify the minimal alterations in carriers of X-linked retinitis pigmentosa.