We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor β receptor in ten families with a newly described human phenotype that includes widespread ...perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFβ signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFβ signaling. These data definitively implicate perturbation of TGFβ signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Aggressive arterial aneurysms, such as thoracic aortic aneurysms and aortic dissection, were found to be caused by mutations in the genes encoding the transforming growth factor β (TGF-β) receptor I ...or II, which are characteristic of the Loeys–Dietz syndrome. Screening for these mutations in persons at risk may allow preventive measures to be taken.
Aggressive arterial aneurysms were found to be caused by mutations in the genes encoding the transforming growth factor β receptor I or II. Screening for these mutations in persons at risk may allow preventive measures to be taken.
Mutations in the genes encoding transforming growth factor β (TGF-β) receptors 1 and 2 (
TGFBR1
and
TGFBR2,
respectively) have recently been found in association with a continuum of clinical features. On the mild end, the mutations have been found in association with a presentation similar to that of Marfan's syndrome or with familial thoracic aortic aneurysm and dissection,
1
,
2
and on the severe end, they are associated with a complex phenotype in which aortic dissection or rupture commonly occurs in childhood.
3
This complex phenotype is characterized by the triad of widely spaced eyes (hypertelorism); a bifid uvula, cleft palate, . . .
Osteogenesis Imperfecta (OI) is a heritable connective tissue disorder mainly caused by mutations in the genes COL1A1 and COL1A2 and is associated with hearing loss in approximately half of the ...cases. The hearing impairment usually starts between the second and fourth decade of life as a conductive hearing loss, frequently evolving to mixed hearing loss thereafter. A minority of patients develop pure sensorineural hearing loss. The interindividual variability in the audiological characteristics of the hearing loss is unexplained.
With the purpose of evaluating inter- and intrafamilial variability, hearing was thorougly examined in 184 OI patients (type I: 154; type III: 4; type IV: 26), aged 3-89 years, with a mutation in either COL1A1 or COL1A2 and originating from 89 different families. Due to the adult onset of hearing loss in OI, correlations between the presence and/or characteristics of the hearing loss and the underlying mutation were investigated in a subsample of 114 OI patients from 64 different families who were older than 40 years of age or had developed hearing loss before the age of 40.
Hearing loss was diagnosed in 48.4% of the total sample of OI ears with increasing prevalence in the older age groups. The predominant type was a mixed hearing loss (27.5%). A minority presented a pure conductive (8.4%) or pure sensorineural (12.5%) loss. In the subsample of 114 OI subjects, no association was found between the nature of the mutation in COL1A1 or COL1A2 genes and the occurrence, type or severity of hearing loss. Relatives originating from the same family differed in audiological features, which may partially be attributed to their dissimilar age.
Our study confirms that hearing loss in OI shows a strong intrafamilial variability. Additional modifications in other genes are assumed to be responsible for the expression of hearing loss in OI.
Summary Background Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. ...Our aim was to assess the ability of celiprolol, a β1 -adrenoceptor antagonist with a β2 -adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. Methods Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 ( COL3A1 ). Celiprolol was administered twice daily and uptitrated every 6 months by steps of 100 mg to a maximum of 400 mg per day. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov , number NCT00190411. Findings 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio HR 0·36; 95% CI 0·15–0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. Interpretation We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. Funding French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.
Thoracic aortic dilatation requires accurate and timely detection to prevent progression to thoracic aortic aneurysm and aortic dissection. The detection of thoracic aortic dilatation necessitates ...the availability of cut-off values for normal aortic diameters. Tools to evaluate aortic dimension above the root are scarce and inconsistent regarding age groups. The aim of this study was to provide reference values for aortic root and ascending aortic diameters on the basis of transthoracic echocardiographic measurements in a large cohort of children and adults. Diameters at the level of the sinuses of Valsalva (SoV) and ascending aorta (AA) were assessed with transthoracic echocardiography in 849 subjects (453 females, age range 1 to 85 years, mean 40.1 ± 21.3 years) and measured according to published guidelines. Linear regression analysis was applied to create nomograms, as well as equations for upper limits of normal and z-scores. SoV and AA diameters were strongly correlated with age, body surface area (BSA), and weight (r = 0.67 to 0.79, p <0.001 for all). Male subjects had significantly larger aortic dimensions at all levels in adulthood, even after BSA correction (p ≤0.004 for all age intervals). Gender-, age-, and BSA-specific upper limits of normal and z-score equations were developed from a multivariate regression model, which strongly predicts SoV and AA diameters (adjusted R2 for SoV = 0.84 and 0.67 and for AA = 0.82 and 0.74, for male and female subjects, respectively). In conclusion, this study provides widely applicable reference values for thoracic aortic dilatation screening purposes. Age, BSA, and gender must be taken into account when assessing an individual patient.
Rationale A number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients ...with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of β-blockade. Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial. Design A prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus β-blockers will be performed. A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes. The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will be made available online ( http://www.ctsu.ox.ac.uk/research/meta-trials ).
Fibulin-4 is a member of the fibulin family, a group of extracellular matrix proteins prominently expressed in medial layers of large veins and arteries. Involvement of the FBLN4 gene in ...cardiovascular pathology was shown in a murine model and in three patients affected with cutis laxa in association with systemic involvement. To elucidate the contribution of
FBLN4
in human disease, we investigated two cohorts of patients. Direct sequencing of 17 patients with cutis laxa revealed no
FBLN4
mutations. In a second group of 22 patients presenting with arterial tortuosity, stenosis and aneurysms,
FBLN4
mutations were identified in three patients, two homozygous missense mutations (
p.Glu126Lys
and
p.Ala397Thr
) and compound heterozygosity for missense mutation
p.Glu126Val
and frameshift mutation
c.577delC
. Immunoblotting analysis showed a decreased amount of fibulin-4 protein in the fibroblast culture media of two patients, a finding sustained by diminished fibulin-4 in the extracellular matrix of the aortic wall on immunohistochemistry. pSmad2 and CTGF immunostaining of aortic and lung tissue revealed an increase in transforming growth factor (TGF)
β
signaling. This was confirmed by pSmad2 immunoblotting of fibroblast cultures. In conclusion, patients with recessive
FBLN4
mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis. This confirms the important role of fibulin-4 in vascular elastic fiber assembly. Furthermore, we provide the first evidence for the involvement of altered TGF
β
signaling in the pathogenesis of
FBLN4
mutations in humans.
Cardiovascular involvement in Marfan syndrome is mainly characterized by progressive dilatation of the proximal aorta. Whether left ventricular dysfunction is present in these patients is not clear ...at present.
Assess left ventricular function in patients with Marfan syndrome, free of significant valvular heart disease, using a combination of MRI and Tissue Doppler imaging (TDI).
A total of 26 Marfan patients (mean age
=
32.0
±
10.9, 12 men) without significant valvular heart disease, and 26 age- and sex-matched controls were studied. Left ventricular volumes and ejection fraction were measured with magnetic resonance imaging. Systolic and diastolic function parameters were assessed using conventional echocardiography and TDI. When compared to controls, Marfan patients showed impairment of left ventricular contractile function as expressed by a reduced ejection fraction (53.5
±
9.0% vs. 59.6
±
6.7%,
p
=
0.009), an increased end-systolic volume (36.0
±
9.5 vs. 29.5
±
6.7 ml/m
2,
p
=
0.007), and reduced peak systolic velocities at the basal septal and lateral myocardial wall (5.2
±
1.4 vs. 6.4
±
1.3 cm/s,
p
=
0.003 and 6.0
±
2.2 vs. 7.5
±
2.3 cm/s,
p
=
0.03, respectively). Diastolic function was impaired with an increased deceleration time of the
E wave (171
±
41 ms vs. 141
±
36 ms,
p
=
0.006). Peak early diastolic velocity at the mitral valve annulus was significantly lower (9.6
±
2.4 cm/s vs. 11.9
±
3.3 cm/s,
p
=
0.006).
These data provide evidence for mild, but significant impairment of left ventricular systolic and diastolic function in Marfan patients, not related to valvular heart disease.
Elastin gene mutations have been associated with a variety of phenotypes. Autosomal dominant cutis laxa (ADCL) is a rare disorder that presents with lax skin, typical facial characteristics, inguinal ...hernias, aortic root dilatation and pulmonary emphysema. In most patients, frameshift mutations are found in the 3' region of the elastin gene (exons 30-34) which result in a C-terminally extended protein, though exceptions have been reported.
We clinically and molecularly characterized the thus far largest cohort of ADCL patients, consisting of 19 patients from six families and one sporadic patient.
Molecular analysis showed C-terminal frameshift mutations in exon 30, 32, and 34 of the elastin gene and identified a mutational hotspot in exon 32 (c.2262delA). This cohort confirms the previously reported clinical constellation of skin laxity (100%), inguinal hernias (51%), aortic root dilatation (55%) and emphysema (37%).
ADCL is a clinically and molecularly homogeneous disorder, but intra- and interfamilial variability in the severity of organ involvement needs to be taken into account. Regular cardiovascular and pulmonary evaluations are imperative in the clinical follow-up of these patients.
Abstract Objectives Many non-musculoskeletal complaints in EDS-HT may be related to dysautonomia. This study therefore aims to investigate whether dysautonomia is present and to explore the ...underlying mechanisms. Methods A total of 39 females with EDS-HT and 35 age-matched controls underwent autonomic function testing. Resting autonomic tone was assessed using heart rate variability (frequency domain) and baroreflex sensitivity analysis (cross correlation). Autonomic reactivity was assessed using the Autonomic Reflex Screen test battery. Factors suspected to contribute to dysautonomia, e.g., neuropathy, medication use, decreased physical activity, depression, pain-induced sympathetic arousal, and connective tissue laxity, were quantified using validated questionnaires, the Beighton score, and measurement of skin extensibility. Results The EDS-HT group showed autonomic deregulation with increased sympathetic activity at rest and reduced sympathetic reactivity to stimuli. Increased resting activity was indicated by a higher LF/HF ratio compared to controls (1.7 ± 1.23 vs 0.9 ± 0.75, p = 0.002); decreased reactivity by a greater BP fall during valsalva (−19 ± 12 vs −8 ± 10, p < 0.001), and a smaller initial diastolic BP increase during tilt (7% vs 14%, p = 0.032). Orthostatic intolerance was significantly more prevalent in EDS-HT than controls (74% vs 34%) and was most frequently expressed as postural orthostatic tachycardia. Lowered QSART responses suggest that sympathetic neurogenic dysfunction is common in patients ( p < 0.013), which may explain the dysautonomia in EDS-HT. Further, connective tissue laxity and vasoactive medication use were identified as important factors in aggravating dysautonomia ( p < 0.035). Conclusion Dysautonomia consisting of cardiovascular and sudomotor dysfunction is present in EDS-HT. Neuropathy, connective tissue laxity, and vasoactive medication probably play a role in its development.
PDF
