Three periods of one and a half decade of ischemic stroke susceptibility gene research: lessons we have learned

Candidate gene association studies, linkage studies and genome-wide association studies have highlighted the role of genetic factors in the development of ischemic stroke. This research started over a decade ago, and can be separated into three major periods of research. In the first wave classic susceptibility markers associated with other diseases (such as the Leiden mutation in Factor V and mutations in the prothrombin and 5,10-methylenetetrahydrofolate reductase (MTHFR) genes) were tested for their role in stroke. These first studies used just a couple of hundred samples or even less. The second and still ongoing period bridges the two other periods of research and has led to a rapid increase in the spectrum of functional variants of genes or genomic regions, discovered primarily in relation to other diseases, tested on larger stroke samples of clinically better stratified patients. Large numbers of these alleles were originally discovered by array-based genome-wide association studies. The third period of research involves the direct array screening of large samples; this approach represents significant progress for research in the field. Research into susceptibility genes for stroke has taught us that careful stratification of patients is critical, that susceptibility alleles are often shared between diseases, and that not all susceptibility factors that associate with clinical traits that are themselves risk factors for stroke (such as increase of triglycerides) necessarily represent susceptibility for stroke. Research so far has been mainly focused on large- and small-vessel associated stroke, and knowledge on other types of stroke, which represent much smaller population samples, is still very scarce. Although some susceptibility allele tests are on the palette of some direct-to-consumer companies, the clinical utility and clinical validity of these test results still do not support their use in clinical practice

Cytotoxic T lymphocyte-Associated Antigen +49G Variant Confers Risk for Anti-CCP- and Rheumatoid Factor-Positive Type of Rheumatoid Arthritis Only in Combination with CT60∗G Allele

Controversial observations have been published on the association of the cytotoxic T lymphocyte associated antigen gene's variants with rheumatoid arthritis (RA). After genotyping 428 patients and 230 matched controls, the prevalence of the CT60∗G allele was more frequent in RF- and/or anti-CCP-seropositive RApatients, compared to the healthy controls (P < .001). Regression analysis revealed that the CT60∗G allele is a possible predisposing factor for RA in these subgroups. No accumulation of the +49∗G allele was found among patients, and this variant was not found to correlate with RA. Assaying the possible genotype variations, the +49∗G-CT60∗G allelic combination was accumulated in seropositive RA-subtypes, and was associated with the risk of RA (OR = 1.73, P = .001 for the whole RA-population). Although the +49∗G allele did not mean a predisposition to RA alone, in combination with CT60∗G it, also conferred risk, suggesting that the +49A/G variant is associated with the risk of RA only in certain haplotypes

Differences in Circulating Carnitine Status of Preterm Infants Fed Fortified Human Milk or Preterm Infant Formula

Objective:The aim of the study was to compare plasma carnitine profiles in fortified human milk (HM)-fed preterm infants or formula-fed preterm infants.Methods:Plasma acylcarnitine concentrations were determined in 20 formula-fed and 18 HM-fed preterm infants (birth weights between 1000 and 2200 g) by isotope dilution ESI MS/MS technique on study days 0, 14, and 28.Results:Concentrations of free carnitine (FC) and different acylcarnitines did not change during the 4 weeks of the study in infants fed HM. In contrast, in infants fed formula FC increased markedly (day 0: 29.989 16.646] mol/L, median interquartile range], day 14: 43.972 8.455], P<0.05) along with increases of short-chain esters (C2 day 0: 5.300 3.272], day 14: 6.773 2.127], P<0.05; C3 day 0: 0.070 0.059], day 14: 0.110 0.069], P<0.05). In contrast, some medium-chain (C8:1, C12) and long-chain esters (C14, C16) decreased significantly in infant formula by day 14, whereas FC and C2 and C3 esters increased further by day 28 (FC: 47.672 14.753], C2: 7.430 4.688], C3: 0.107 0.047]).Conclusions:The altered carnitine ester profile likely reflects active involvement of the carnitine molecule in the buffering, metabolism, and elimination of nonphysiological acyl moieties

Reconstructing Roma History from Genome-Wide Data

The Roma people, living throughout Europe and West Asia, are a diverse population linked by the Romani language and culture. Previous linguistic and genetic studies have suggested that the Roma migrated into Europe from South Asia about 1,000–1,500 years ago. Genetic inferences about Roma history have mostly focused on the Y chromosome and mitochondrial DNA. To explore what additional information can be learned from genome-wide data, we analyzed data from six Roma groups that we genotyped at hundreds of thousands of single nucleotide polymorphisms (SNPs). We estimate that the Roma harbor about 80% West Eurasian ancestry–derived from a combination of European and South Asian sources–and that the date of admixture of South Asian and European ancestry was about 850 years before present. We provide evidence for Eastern Europe being a major source of European ancestry, and North-west India being a major source of the South Asian ancestry in the Roma. By computing allele sharing as a measure of linkage disequilibrium, we estimate that the migration of Roma out of the Indian subcontinent was accompanied by a severe founder event, which appears to have been followed by a major demographic expansion after the arrival in Europe.Országos Tudományos Kutatási Alapprogramok (OTKA K 103983)Országos Tudományos Kutatási Alapprogramok (OTKA 73430)National Science Foundation (U.S.) (HOMINID grant 1032255)National Institutes of Health (U.S.) (grant GM100233

Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.Acknowledgements: This work was supported by the Horizon 2020 research and innovation programme (grant 779257 Solve-RD to MS and RS), the National Ataxia Foundation (grant to CW and MS), the Wilhelm Vaillant Stiftung (grant to CW), the EU Joint Programme—Neurodegenerative Disease Research (JPND) through participating national funding agencies, and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643417. BM was supported in part from the grant NKFIH 119540. HJ was funded by the Medical Faculty of the University of Heidelberg. CB was funded by the University of Basel (PhD Program in Health Sciences). The funding sources had no role in the study design, data collection, data analysis, data interpretation or writing of the manuscript

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

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European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death.

Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation

Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype

BACKGROUND: Kleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features - brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. Some additional symptoms are observed in different percentage of the patients. Epilepsy is common symptom as well. The underlying cause of the syndrome is a submicroscopic deletion in the chromosomal region 9q34.3 or disruption of the euchromatin histone methyl transferase 1. CASE PRESENTATION: We describe two Hungarian Kleefstra syndrome patients, one with the classic phenotype of the syndrome, the diagnosis was confirmed by subtelomeric FISH. Meanwhile in our second patient beside the classic phenotype a new symptom - abnormal antiepileptic drug metabolic response - could be observed. Subtelomere FISH confirmed the 9q34.3 terminal deletion. Because of the abnormal drug metabolism in our second patient, we performed array CGH analysis as well searching for other rearrangements. Array CGH analysis indicated a large - 1.211 Mb -, deletion only in the 9q subtelomeric region with breakpoints ch9:139,641,471-140,852,911. CONCLUSIONS: This is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism. KEYWORDS: 9q subtelomeric deletion syndrome; Drug metabolism; Epilepsy; Kleefstra syndrom