Obesity is associated with type 2 diabetes mellitus, left ventricular diastolic dysfunction and heart failure but it is unclear to which extent it is related to left ventricular systolic dysfunction. ...The aim of the study was to explore the effects of overweight and obesity on left ventricular systolic function in patients with type 2 diabetes mellitus and a control group of non-diabetic persons.
We prospectively investigated 384 patients with type 2 diabetes mellitus, and 184 controls who participated in the CARDIPP and CAREFUL studies. The participants were grouped according to body mass index (normal weight < 25 kg/m
, overweight 25-29 kg/m
, and obesity ≥ 30 kg/m
). Echocardiography was performed at the beginning of the study and after 4-years in the patient group.
Univariable and multivariable regression analysis revealed that variations in left ventricular ejection fraction, global longitudinal strain, left ventricular mass and diastolic function expressed as E/é (the ratio between early diastolic mitral flow and annular motion velocities) all are related to body mass index. The mean and standard deviation of left ventricular ejection fraction and global longitudinal strain values were 57% (8%) vs. - 18.6% (2.3%) for normal weight patients, 53% (8%) vs. - 17.5% (2.3%) for overweight, and 49% (9%) vs. - 16.2% (3.0%) for obese (p < 0.05 vs. p < 0.05). Corresponding results in the control group were 58% (6%) vs. - 22.3% (3.0%), 55% (7%) vs. - 20.8% (3.1%) and 54% (8%) - 19.6% (4.0%) (p < 0.05 vs. p < 0.05). Patients who gained weight from baseline to follow-up changed left ventricular ejection fraction (median and interquartile range) by - 1.0 (9.0) % (n = 187) and patients who lost weight changed left ventricular ejection fraction by 1.0 (10.0) % (n = 179) (p < 0.05).
Overweight and obesity impair left ventricular ejection fraction and global longitudinal strain in both patients with type 2 diabetes mellitus and non-diabetic persons. Trial registration ClinicalTrials.gov identifier NCT 01049737.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is ...often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (
ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.
Factors for initiating hibernation are unknown, but the condition shares some metabolic similarities with consciousness/sleep, which has been associated with n-3 fatty acids in humans. We ...investigated plasma phospholipid fatty acid profiles during hibernation and summer in free-ranging brown bears (Ursus arctos) and in captive garden dormice (Eliomys quercinus) contrasting in their hibernation patterns. The dormice received three different dietary fatty acid concentrations of linoleic acid (LA) (19%, 36% and 53%), with correspondingly decreased alpha-linolenic acid (ALA) (32%, 17% and 1.4%). Saturated and monounsaturated fatty acids showed small differences between summer and hibernation in both species. The dormice diet influenced n-6 fatty acids and eicosapentaenoic acid (EPA) concentrations in plasma phospholipids. Consistent differences between summer and hibernation in bears and dormice were decreased ALA and EPA and marked increase of n-3 docosapentaenoic acid and a minor increase of docosahexaenoic acid in parallel with several hundred percent increase of the activity index of elongase ELOVL2 transforming C20-22 fatty acids. The highest LA supply was unexpectantly associated with the highest transformation of the n-3 fatty acids. Similar fatty acid patterns in two contrasting hibernating species indicates a link to the hibernation phenotype and requires further studies in relation to consciousness and metabolism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic ...disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine.
We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in-house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome.
We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neuromuscular disorders (NMDs) have a heterogeneous etiology. A genetic diagnosis is key to personalized healthcare and access to targeted treatment for the affected individuals.
In this study, 861 ...patients with NMDs were analyzed with genome sequencing and comprehensive variant calling including single nucleotide variants, small insertions/deletions (SNVs/INDELs), and structural variants (SVs) in a panel of 895 NMD genes, as well as short tandem repeat expansions (STRs) at 28 loci. In addition, for unsolved cases with an unspecific clinical presentation, the analysis of a panel with OMIM disease genes was added.
In the cohort, 27% (232/861) of the patients harbored pathogenic variants, of which STRs and SVs accounted for one-third of the patients (71/232). The variants were found in 107 different NMD genes. Furthermore, 18 pediatric patients harbored pathogenic variants in non-NMD genes.
Our results highlight that for children with unspecific hypotonia, a genome-wide analysis rather than a disease-based gene panel should be considered as a diagnostic approach. More importantly, our results clearly show that it is crucial to include STR- and SV-analyses in the diagnostics of patients with neuromuscular disorders.
Leber hereditary optic neuropathy (LHON) is a mitochondrial disease causing severe bilateral visual loss, typically in young adults. The disorder is commonly caused by one of three primary point ...mutations in mitochondrial DNA, but a number of other rare mutations causing or associated with the clinical syndrome of LHON have been reported. The mutations in LHON are almost exclusively located in genes encoding subunits of complex I in the mitochondrial respiratory chain. Here we report two patients, a mother and her son, with the typical LHON phenotype. Genetic investigations for the three common mutations were negative, instead we found a new and previously unreported mutation in mitochondrial DNA. This homoplasmic mutation, m.13345G>A, is located in the
gene, encoding a core subunit in complex I in the mitochondrial respiratory chain. Investigation of the patients mitochondrial respiratory chain in muscle found a mild defect in the combined activity of complex I+III. In the literature six other mutations in the
gene have been associated with LHON and by this report a new putative mutation in the
can be added.
Sweden has one neonatal screening laboratory, receiving 115 to 120 thousand samples per year. Among the one million babies screened by tandem mass spectrometry from November 2010 until July 2019, a ...total of 665 babies were recalled and 311 verified as having one of the diseases screened for with this methodology, giving a positive predictive value (PPV) of 47% and an incidence of 1:3200. The PPV was high (41%) already in the first year after start of screening, thanks to the availability of the collaborative project Region 4 Stork database. The PPV is presently 58%. This improvement was achieved by the implementation of second-tier analyses in the screening for methylmalonic aciduria, propionic aciduria, isovaleric aciduria, and homocystinuria, and the employment of various post analytical tools of the Region 4 Stork, and its successor the collaborative laboratory integrated reports.
Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial ...disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNA
Ala
and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNA
Leu
, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor–triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8
+
T cell metabolic remodeling and IFN-γ production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.
Objective
To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known.
Methods
Clinical, laboratory, and genetic data ...were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration.
Results
We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy.
Interpretation
Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor.
We present a biography of Gunnar Jungner, one of the authors of the Principles and Practice of Screening for Disease by JMG Wilson and G Jungner, published by the WHO in 1968. This publication ...contains ten criteria, which are still consulted, when a new disorder is evaluated for inclusion in a screening program. Gunnar Jungner was a Swedish MD, PhD, specialized in Clinical Chemistry, born in Sweden in 1914. In 1961 he built an automated instrument for the analysis of different components in plasma, with the aim to detect diseases in presumably healthy individuals, to enable start of treatment at an early disease stage. This first automated instrument for Clinical Chemistry in Sweden was used in a screening project, where 90 000 seemingly healthy individuals were included. The study was discussed extensively and he was invited to present the results at different international meetings, where he also met JMG Wilson. Gunnar Jungner developed the instrument further together with his brother Ingmar and the Swedish gas company AGA. The brothers also established an out-patient ward in Stockholm, where people could come for health screening.
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