The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with... more The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys-Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers-Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys-Dietz syndrome. We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys-Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular Ehlers-Danlos syndrome. Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular Ehlers-Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery.
The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according ... more The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.
Absolute (DeltaD) and relative (DeltaD/D) arterial diameter distension, parameters related to the... more Absolute (DeltaD) and relative (DeltaD/D) arterial diameter distension, parameters related to the elasticity of the vessel, can be measured in superficial arteries using ultrasound-based vessel "wall tracking" techniques. Currently available systems (e.g. the Wall Track System; WTS) measure the displacement of the media-adventitia transition (outer wall). We hypothesize that, given volume incompressibility of the vessel wall, DeltaD and DeltaD/D measured at the outer wall, significantly underestimate vessel distension at the lumen-intima interface (inner wall). We measured DeltaD and DeltaD/D at both the inner and outer wall of the common carotid artery in 39 subjects (aged 18-83 years) using a new prototype "wall tracking" system based on the Vivid-7 scanner (GE Vingmed Ultrasound, Horten, Norway). In addition, DeltaD and DeltaD/D were also measured using WTS. As anticipated, tracking the inner wall yielded lower diastolic diameters than when tracking the outer wall (Ddia = 5.70 +/- 0.80 and 6.91+/- 0.98 mm, respectively, P < 0.0001). DeltaD (0.54+/- 0.16 versus 0.49 +/- 0.16 mm; P < 0.0001) and DeltaD/D (0.096+/- 0.030 versus 0.071+/- 0.026, P < 0.0001) were indeed larger at the inner than at the outer wall. For WTS, Ddia, DeltaD and DeltaD/D were 7.04 +/- 1.02 mm, 0.45 +/- 0.14 mm and 0.066 +/- 0.022, respectively. On average, DeltaD and DeltaD/D are 10 and 25% higher on the inner than on the outer wall, respectively. Follow-up studies in larger cohort trials are mandatory to assess whether tracking the inner wall yields arterial function parameters with a higher cardiovascular prognostic potential.
Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan sy... more Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan syndrome (MFS). Although β-blockers remain the standard of preventive treatment, preliminary results from animal studies and a selected group of severely affected MFS children show significant benefit from treatment with losartan, an angiotensin II receptor blocker with TGF-β inhibiting potential. Large-scale human trials are now needed to confirm these results. This trial aims to evaluate the combined effect of both drugs. Methods: We are conducting a prospective randomized placebo controlled double blind phase III study aiming to include 174 MFS patients (age ≥ 10 years and z-score ≥ 2). Patients already taking β-blockers are randomized for weight-adjusted treatment with losartan versus placebo. The primary endpoint is decrease in aortic root growth rate. Secondary endpoints are aortic dissection/surgery, progression of aortic/mitral regurgitation, arterial stiffness, left ventricular systolic/diastolic function, quality of life and genetic modifiers. Echocardiography, vascular echo-Doppler and quality of life assessment will be performed at baseline and at 6-monthly follow-ups for 3 years. MRI evaluation will be performed at baseline and at the end of the trial. Conclusion: This trial will study new therapeutic strategies for the prevention of serious cardiovascular complications in MFS. The uniqueness in our trial is that the additive effect of losartan and β-blocker will be evaluated in a large spectrum of disease severity. A combination of ultrasound and MRI will allow detailed evaluation of anatomic and functional properties of the aorta and left ventricle.
Objectives: To develop a quantitative event-free prediction model of late atrial arrhythmia after... more Objectives: To develop a quantitative event-free prediction model of late atrial arrhythmia after atrial septal defect (ASD) repair. Background: The clinical management of ASD is driven by risk factors that determine the occurrence of late atrial arrhythmia. Methods: Data from ASD type secundum patients, included in the Belgian Congenital Heart Disease Registry, were analyzed. Based on review of the literature, age at repair, gender, pulmonary hypertension, atrial arrhythmia before and within one month after repair were included in the model. Using Cox-regression analysis, a weighted risk score was derived, which was validated using the Brier score. Results: A total of 155 patients (117 women; median age at follow-up 53.9 years, range 18.0-78.8) having 349 follow-up years was included. Thirty-nine patients (25.2%) presented with late atrial arrhythmia. Multivariate analysis showed that a mPAP ≥ 25 mmHg (HR 4.39; 95%CI 2.17-9.09; P b 0.0001), the presence of atrial arrhythmia before (HR 3.52; 95%CI 1.75-7.14; P = 0.002) and ≤ 1 month after repair (HR 6.62; 95%CI 2.38-20.00; P b 0.0001) and gender (HR 2.18 95%CI 1.11-4.35) were associated with late atrial arrhythmia. A risk score (0 to 28 points) to predict atrial arrhythmia free survival was derived for follow-up times ranging from one to 5 years. Mean Brier score for the model was 0.10. Conclusions: We formulated a well validated risk model to predict arrhythmia-free survival in ASD patients undergoing ASD repair. Further research is needed whether this model can be used for individual clinical risk stratification and whether the model can be adapted for application in other congenital heart defects.
Background: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an... more Background: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGFβ) signaling (TGFβ receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK). Methods and result: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGFβ signaling pathway. Conclusions: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGFβ signaling.
Familial occurrence of sudden cardiac death (SCD) is related to a variety of clinical conditions,... more Familial occurrence of sudden cardiac death (SCD) is related to a variety of clinical conditions, which can be delineated in up to 40% of families through a combination of cardiovascular examination and genetic studies. Patients with Lamin A/C gene mutations are at increased risk for SCD, but "laminopathies" are not included into clinical algorithms of SCD.
Cardiovascular involvement in Marfan syndrome is mainly characterized by progressive dilatation o... more 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.
Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unk... more Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra-and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major-if not only-cause of classic EDS.
In order to estimate the contribution of mutations at the fibrillin-1 locus (FBN1) to classical M... more In order to estimate the contribution of mutations at the fibrillin-1 locus (FBN1) to classical Marfan syndrome (MFS) and to study possible phenotypic differences between patients with an FBN1 mutation vs. without, a comprehensive molecular study of the FBN1 gene in a cohort of 93 MFS patients fulfilling the clinical diagnosis of MFS according to the Ghent nosology was performed. The initial mutation screening by CSGE/SSCP allowed identification of an FBN1-mutation in 73 patients. Next, sequencing of all FBN1-exons was performed in 11 mutation-negative patients, while in nine others, DHPLC was used. This allowed identification of seven and five additional mutations, respectively. Southern blot analysis revealed an abnormal hybridization pattern in one more patient. A total of 23 out of the 85 mutations identified here are reported for the first time. Phenotypic comparison of MFS patients with cysteine-involving mutations vs. premature termination mutations revealed significant differences in ocular and skeletal involvement. The phenotype of the eight patients without proven FBN1 mutation did not differ from the others with respect to the presence of major cardiac, ocular, and skeletal manifestations or positive familial history. Most likely, a portion of FBN1-mutations remains undetected because of technical limitations. In conclusion, the involvement of the FBN1-gene could be demonstrated in at least 91% of all MFS patients (85/93), which strongly suggests that this gene is the predominant, if not the sole, locus for MFS.
Mutations in the COL1A1 and COL1A2 genes, encoding the proa1 and 2 chains of type I collagen, cau... more Mutations in the COL1A1 and COL1A2 genes, encoding the proa1 and 2 chains of type I collagen, cause osteogenesis imperfecta (OI) or Ehlers-Danlos syndrome (EDS) arthrochalasis type. Although the majority of missense mutations in the collagen type I triple helix affect glycine residues in the Gly-Xaa-Yaa repeat, few nonglycine substitutions have been reported. Two arginine-to-cysteine substitutions in the a1 I)-collagen chain are associated with classic EDS [R134C (p.R312C)] or autosomal dominant Caffey disease with mild EDS features [R836C (p.R1014C)]. Here we show a1(I) R-to-C substitutions in three unrelated patients who developed iliac or femoral dissection in early adulthood. In addition, manifestations of classic EDS in Patient 1 [c.934C4T; R134C (p.R312C); X-position] or osteopenia in Patients 2 [c.1720C4T; R396C (p.R574C); Y-position] and 3 [c.3277C4T; R915C (p.R1093C); Y-position] are seen.
Purpose: The prevalence of most minor cardiovascular manifestations in Marfan syndrome (MFS) is u... more Purpose: The prevalence of most minor cardiovascular manifestations in Marfan syndrome (MFS) is unknown. We assessed the prevalence of minor cardiovascular manifestations in MFS to evaluate their usefulness in a diagnostic setting. Methods: Seventy-seven patients with MFS (aged 4 months to 55 years) underwent echocardiography to assess the presence of mitral valve prolapse and the diameter of the main pulmonary artery. A subset of 29 adult patients with MFS also underwent magnetic resonance imaging evaluation of the diameters of the thoracoabdominal aorta. Results: Mitral valve prolapse was encountered in 66% of patients with MFS, with an equal distribution of classic and nonclassic mitral valve prolapse. The main pulmonary artery diameter was significantly larger in patients with MFS at all ages when compared with controls. In the adult group (Ն14 years), we were able to provide a cutoff value of 23 mm to define pulmonary artery dilatation. The descending aorta was enlarged, but with substantial overlap with controls, thus precluding the use of a cutoff value. Conclusions: Mitral valve prolapse and main pulmonary artery dilatation are common findings in MFS patients at all ages and are easy to assess with echocardiography. Cutoff values to define dilatation of the descending aorta are hard to define, making them of limited value in the diagnostic evaluation. We recommend echocardiographic evaluation of mitral valve proplase and main pulmonary artery diameter in patients referred for cardiovascular diagnostic assessment for MFS. Genet Med 2006:8(7):401-408.
The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with... more The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys-Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers-Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys-Dietz syndrome. We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys-Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular Ehlers-Danlos syndrome. Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular Ehlers-Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery.
The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according ... more The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.
Absolute (DeltaD) and relative (DeltaD/D) arterial diameter distension, parameters related to the... more Absolute (DeltaD) and relative (DeltaD/D) arterial diameter distension, parameters related to the elasticity of the vessel, can be measured in superficial arteries using ultrasound-based vessel "wall tracking" techniques. Currently available systems (e.g. the Wall Track System; WTS) measure the displacement of the media-adventitia transition (outer wall). We hypothesize that, given volume incompressibility of the vessel wall, DeltaD and DeltaD/D measured at the outer wall, significantly underestimate vessel distension at the lumen-intima interface (inner wall). We measured DeltaD and DeltaD/D at both the inner and outer wall of the common carotid artery in 39 subjects (aged 18-83 years) using a new prototype "wall tracking" system based on the Vivid-7 scanner (GE Vingmed Ultrasound, Horten, Norway). In addition, DeltaD and DeltaD/D were also measured using WTS. As anticipated, tracking the inner wall yielded lower diastolic diameters than when tracking the outer wall (Ddia = 5.70 +/- 0.80 and 6.91+/- 0.98 mm, respectively, P < 0.0001). DeltaD (0.54+/- 0.16 versus 0.49 +/- 0.16 mm; P < 0.0001) and DeltaD/D (0.096+/- 0.030 versus 0.071+/- 0.026, P < 0.0001) were indeed larger at the inner than at the outer wall. For WTS, Ddia, DeltaD and DeltaD/D were 7.04 +/- 1.02 mm, 0.45 +/- 0.14 mm and 0.066 +/- 0.022, respectively. On average, DeltaD and DeltaD/D are 10 and 25% higher on the inner than on the outer wall, respectively. Follow-up studies in larger cohort trials are mandatory to assess whether tracking the inner wall yields arterial function parameters with a higher cardiovascular prognostic potential.
Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan sy... more Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan syndrome (MFS). Although β-blockers remain the standard of preventive treatment, preliminary results from animal studies and a selected group of severely affected MFS children show significant benefit from treatment with losartan, an angiotensin II receptor blocker with TGF-β inhibiting potential. Large-scale human trials are now needed to confirm these results. This trial aims to evaluate the combined effect of both drugs. Methods: We are conducting a prospective randomized placebo controlled double blind phase III study aiming to include 174 MFS patients (age ≥ 10 years and z-score ≥ 2). Patients already taking β-blockers are randomized for weight-adjusted treatment with losartan versus placebo. The primary endpoint is decrease in aortic root growth rate. Secondary endpoints are aortic dissection/surgery, progression of aortic/mitral regurgitation, arterial stiffness, left ventricular systolic/diastolic function, quality of life and genetic modifiers. Echocardiography, vascular echo-Doppler and quality of life assessment will be performed at baseline and at 6-monthly follow-ups for 3 years. MRI evaluation will be performed at baseline and at the end of the trial. Conclusion: This trial will study new therapeutic strategies for the prevention of serious cardiovascular complications in MFS. The uniqueness in our trial is that the additive effect of losartan and β-blocker will be evaluated in a large spectrum of disease severity. A combination of ultrasound and MRI will allow detailed evaluation of anatomic and functional properties of the aorta and left ventricle.
Objectives: To develop a quantitative event-free prediction model of late atrial arrhythmia after... more Objectives: To develop a quantitative event-free prediction model of late atrial arrhythmia after atrial septal defect (ASD) repair. Background: The clinical management of ASD is driven by risk factors that determine the occurrence of late atrial arrhythmia. Methods: Data from ASD type secundum patients, included in the Belgian Congenital Heart Disease Registry, were analyzed. Based on review of the literature, age at repair, gender, pulmonary hypertension, atrial arrhythmia before and within one month after repair were included in the model. Using Cox-regression analysis, a weighted risk score was derived, which was validated using the Brier score. Results: A total of 155 patients (117 women; median age at follow-up 53.9 years, range 18.0-78.8) having 349 follow-up years was included. Thirty-nine patients (25.2%) presented with late atrial arrhythmia. Multivariate analysis showed that a mPAP ≥ 25 mmHg (HR 4.39; 95%CI 2.17-9.09; P b 0.0001), the presence of atrial arrhythmia before (HR 3.52; 95%CI 1.75-7.14; P = 0.002) and ≤ 1 month after repair (HR 6.62; 95%CI 2.38-20.00; P b 0.0001) and gender (HR 2.18 95%CI 1.11-4.35) were associated with late atrial arrhythmia. A risk score (0 to 28 points) to predict atrial arrhythmia free survival was derived for follow-up times ranging from one to 5 years. Mean Brier score for the model was 0.10. Conclusions: We formulated a well validated risk model to predict arrhythmia-free survival in ASD patients undergoing ASD repair. Further research is needed whether this model can be used for individual clinical risk stratification and whether the model can be adapted for application in other congenital heart defects.
Background: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an... more Background: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGFβ) signaling (TGFβ receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK). Methods and result: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGFβ signaling pathway. Conclusions: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGFβ signaling.
Familial occurrence of sudden cardiac death (SCD) is related to a variety of clinical conditions,... more Familial occurrence of sudden cardiac death (SCD) is related to a variety of clinical conditions, which can be delineated in up to 40% of families through a combination of cardiovascular examination and genetic studies. Patients with Lamin A/C gene mutations are at increased risk for SCD, but "laminopathies" are not included into clinical algorithms of SCD.
Cardiovascular involvement in Marfan syndrome is mainly characterized by progressive dilatation o... more 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.
Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unk... more Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra-and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major-if not only-cause of classic EDS.
In order to estimate the contribution of mutations at the fibrillin-1 locus (FBN1) to classical M... more In order to estimate the contribution of mutations at the fibrillin-1 locus (FBN1) to classical Marfan syndrome (MFS) and to study possible phenotypic differences between patients with an FBN1 mutation vs. without, a comprehensive molecular study of the FBN1 gene in a cohort of 93 MFS patients fulfilling the clinical diagnosis of MFS according to the Ghent nosology was performed. The initial mutation screening by CSGE/SSCP allowed identification of an FBN1-mutation in 73 patients. Next, sequencing of all FBN1-exons was performed in 11 mutation-negative patients, while in nine others, DHPLC was used. This allowed identification of seven and five additional mutations, respectively. Southern blot analysis revealed an abnormal hybridization pattern in one more patient. A total of 23 out of the 85 mutations identified here are reported for the first time. Phenotypic comparison of MFS patients with cysteine-involving mutations vs. premature termination mutations revealed significant differences in ocular and skeletal involvement. The phenotype of the eight patients without proven FBN1 mutation did not differ from the others with respect to the presence of major cardiac, ocular, and skeletal manifestations or positive familial history. Most likely, a portion of FBN1-mutations remains undetected because of technical limitations. In conclusion, the involvement of the FBN1-gene could be demonstrated in at least 91% of all MFS patients (85/93), which strongly suggests that this gene is the predominant, if not the sole, locus for MFS.
Mutations in the COL1A1 and COL1A2 genes, encoding the proa1 and 2 chains of type I collagen, cau... more Mutations in the COL1A1 and COL1A2 genes, encoding the proa1 and 2 chains of type I collagen, cause osteogenesis imperfecta (OI) or Ehlers-Danlos syndrome (EDS) arthrochalasis type. Although the majority of missense mutations in the collagen type I triple helix affect glycine residues in the Gly-Xaa-Yaa repeat, few nonglycine substitutions have been reported. Two arginine-to-cysteine substitutions in the a1 I)-collagen chain are associated with classic EDS [R134C (p.R312C)] or autosomal dominant Caffey disease with mild EDS features [R836C (p.R1014C)]. Here we show a1(I) R-to-C substitutions in three unrelated patients who developed iliac or femoral dissection in early adulthood. In addition, manifestations of classic EDS in Patient 1 [c.934C4T; R134C (p.R312C); X-position] or osteopenia in Patients 2 [c.1720C4T; R396C (p.R574C); Y-position] and 3 [c.3277C4T; R915C (p.R1093C); Y-position] are seen.
Purpose: The prevalence of most minor cardiovascular manifestations in Marfan syndrome (MFS) is u... more Purpose: The prevalence of most minor cardiovascular manifestations in Marfan syndrome (MFS) is unknown. We assessed the prevalence of minor cardiovascular manifestations in MFS to evaluate their usefulness in a diagnostic setting. Methods: Seventy-seven patients with MFS (aged 4 months to 55 years) underwent echocardiography to assess the presence of mitral valve prolapse and the diameter of the main pulmonary artery. A subset of 29 adult patients with MFS also underwent magnetic resonance imaging evaluation of the diameters of the thoracoabdominal aorta. Results: Mitral valve prolapse was encountered in 66% of patients with MFS, with an equal distribution of classic and nonclassic mitral valve prolapse. The main pulmonary artery diameter was significantly larger in patients with MFS at all ages when compared with controls. In the adult group (Ն14 years), we were able to provide a cutoff value of 23 mm to define pulmonary artery dilatation. The descending aorta was enlarged, but with substantial overlap with controls, thus precluding the use of a cutoff value. Conclusions: Mitral valve prolapse and main pulmonary artery dilatation are common findings in MFS patients at all ages and are easy to assess with echocardiography. Cutoff values to define dilatation of the descending aorta are hard to define, making them of limited value in the diagnostic evaluation. We recommend echocardiographic evaluation of mitral valve proplase and main pulmonary artery diameter in patients referred for cardiovascular diagnostic assessment for MFS. Genet Med 2006:8(7):401-408.
Uploads
Papers by Julie Backer