Prophylactic effect of angiotensin receptor blockers in children with genetic aortopathies: the early bird catches the worm.

AIMS: In genetic aortopathies (GA) particular attention is paid to aortic root dilatation which has an impact on morbidity and mortality. This study focuses on the effects of therapy with angiotensin-II-receptor-blockers (ARB) or beta-blockers (BB) on aortic root growth and the question which therapy should be initiated at which dosage and at what age. METHODS: Since 1998 we diagnosed 208 patients with GA (170 FBN-1). 81 patients between 5 months and 18 years receiving either ARB or BB therapy were included. We retrospectively analyzed the progression of the dilatation of Sinus Valsalva aortae (SV) using calculated z-scores before and after therapy initiation and compared BB and ARB treatment. RESULTS: Both ARB and BB (p < 0.05) therapy showed significant improvement in aortic root growth, while the effect is significantly more pronounced in ARB (p < 0.01) independent of age and genetic cause. A detailed comparison of the two drug groups showed a more sustained effect in limiting the progression of the dilatation of the aortic root in patients treated with ARB. Progression of dilatation of the SV was significantly lower in children treated with ARBs compared to BB (delta z-score, p < 0.05). In addition, ARBs were better tolerated and had a significantly lower discontinuation rate (3%) compared to BB (50%) (p < 0.01). Independently of age at initiation all children and adolescents were able to reach the target dose under ARB. CONCLUSION: We demonstrated a significant change in both treatment options, with the effect of ARB being more pronounced while being better tolerated throughout the treatment period.

[Vascular surgery in old people]. / Gefäßchirurgie bei alten Menschen.

The age pyramid in Germany is upside down. According to the Federal Statistical Office this development will continue in the coming years, which presents a challenge for surgeons to surgically treat increasingly more and increasingly older people. Particularly in vascular surgery, which is a surgery of old people, this fact represents a special challenge. The frailty of old people is, among other things, due to a series of comorbidities, which must be taken into consideration within the framework of surgical treatment. They can have an important influence on the perioperative planning, the operation, the postoperative treatment and the outcome of the patient. This treatment planning becomes more and more challenging, because due to the progress in endovascular surgery there will soon be no limits to what is feasible; however, the question arises whether the feasible is also reasonable? Within the scope of this article the authors try to give answers to the treatment of old patients in vascular surgery and to find strategies for planning and to establish an individualized optimal treatment.

[Medical care of adults with congenital heart diseases : Present and future]. / Medizinische Versorgung von Erwachsenen mit angeborenen Herzfehlern : Gegenwart und Zukunft.

Congenital heart diseases (CHD) are the most common types of congenital organ defects. Thanks to medical progress in congenital cardiology and heart surgery, most children with CHD reach adulthood. Despite primarily successful treatment residual and subsequent conditions as well as (non)cardiac comorbidities can influence the chronic course of the disease and lead to a higher morbidity and mortality. Adults with congenital heart disease (ACHD) in Germany are not tied to the healthcare structure despite the great need for aftercare. According to the results of the medical care of ACHD (MC-ACHD) study, ACHD centers and specialists in Germany are insufficiently perceived despite increased complication rates and the great need for specialist guidance. General practitioners and patients are not adequately informed about existing ACHD facilities. A better awareness of the ACHD problem should be created at the level of primary medical supply in order to optimize care and to reduce morbidity and mortality. Improved future-oriented patient care includes lifelong regular follow-up and the possibility of interdisciplinary, integrated medical care of CHD.

Does statin therapy impact the proximal aortopathy in aortic valve disease?

BACKGROUND: Studies have demonstrated that statin therapy decreases the growth rate of abdominal aneurysms. However, the effect of statin therapy on the proximal aortic disease has not been sufficiently elucidated. AIM: We aimed to analyse the association between statin treatment and the severity of proximal aortopathy in patients with aortic valve disease. DESIGN: Cross-sectional study. METHODS: We prospectively identified 458 patients who were referred for aortic valve surgery from 2008 to 2014. Pre-operative measurement of the proximal aorta was performed by TEE, CT or MRT scan. Data of dyslipidemia treatment was obtained by questionnaire. RESULTS: The mean ascending aortic diameter in the whole study population was comparable in patients with vs. without statin therapy (i.e. 42.7 mm vs. 43.6 mm, P = 0.46). Logistic regression analysis showed no significant association between statin therapy and proximal aortopathy ≥ 40 mm in the whole study group (OR = 0.69, P = 0.10). For the BAV sub-group, HDL (OR = 0.54, P = 0.038) and cholesterol levels (OR = 2.00, P = 0.038) were found significantly associated with the proximal aortic disease. In the BAV cohort, the statin users with target HDL levels presented a significantly smaller proximal aortic diameter (40.1 mm vs. 46 mm, P = 0.02). CONCLUSION: Pre-operative statin therapy demonstrated no significant association with the expression of proximal aortopathy. However, more than 40% of the statin users presented uncontrolled lipid levels at the time of the study. In the BAV sub-group, the statins users with target HDL levels showed a significantly smaller ascending aorta diameter. Target HDL and cholesterol levels were strongly associated with proximal aortic dilation in BAV patients.

I-SWOT as instrument to individually optimize therapy of thoracoabdominal aortic aneurysms: Effective, norm-compliant and meeting the needs.

BACKGROUND: Guidelines summarize medical evidence, they identify the most efficient therapy under study conditions and recommend this therapy for use. The physician now has the challenge to translate a therapy that is efficient under laboratory conditions to a patient who is an individual person. To accomplish this task the physician has to make sure that (I) the ideal typical therapy is applicable and effective in this individual patient taking the special features into consideration, that (II) therapy is compliant with the norm including guidelines, laws and ethical requirements (conformity) and that (III) the therapy meets the patient's needs. OBJECTIVE: How can physicians together with the patients translate the medical evidence into an individually optimized therapy? MATERIAL AND METHODS: At the German Aortic Center in Hamburg we use I­SWOT as an instrument to identify such individually optimized therapy. With I­SWOT, we present an instrument with which we have developed an (I) efficient, (II) conform and (III) needs-oriented therapeutic strategy for individual patients. RESULTS: I-SWOT cross-tabulates strengths (S) and weaknesses (W) related to therapy with opportunities (O) and threats (T) related to individual patients. This I­SWOT matrix identifies four fundamental types of strategy, which comprise "SO" maximizing strengths and opportunities, "WT" minimizing weaknesses and threats, "WO" minimizing weaknesses and maximizing opportunities and "ST" maximizing strengths and minimizing threats. We discuss the case of a patient with asymptomatic thoracoabdominal aneurysm to show how I­SWOT is used to identify an individually optimized therapy strategy.

Genetic diagnostics of inherited aortic diseases : Medical strategy analysis.

Genetic aortic syndromes (GAS) include Marfan, Loeys-Dietz, vascular Ehlers-Danlos, and Turner syndrome as well as congenital bicuspid aortic valve. The clinical management of these diseases has certain similarities and differences. We employed medical strategy analysis to test the utility of genetic diagnostics in the management of GAS. We chose the standpoint of the cardiologist for our analysis. In the first step, the medical goals in the management of GAS are specified. In the second step, the accuracy of genetic diagnostics for GAS is examined. Finally, conclusions can be drawn about the utility of genetic diagnostics in managing GAS. We found that genetic diagnostics is necessary to exclude GAS, to diagnose GAS, and to specify disease types. Second, combining phenotype with genotype information maximizes the predictability of the course of disease. Third, with genetic diagnostics it is possible to predict the birth of children with causative mutations for GAS and to initiate drug therapy to prevent the onset of aortic dilatation or to slow down its progression to aortic aneurysm. Finally, genetic diagnostics improves prognostic predictions and thereby contributes to a better timing of elective surgery and to a better choice of procedures. The findings of our medical strategy analysis indicate the high utility of genetic diagnostics for managing GAS.

[Vascular surgery in the elderly : What is possible? What is reasonable?] / Gefäßchirurgie bei alten Menschen : Was ist möglich? Was ist sinnvoll?

Nowadays vascular treatment of the elderly is a great challenge. Following the demographic change patients in the field of vascular surgery are becoming older and sicker. In addition to the actual main vascular pathology, the average patient arrives with a series of additional diagnoses that have an impact on the perioperative strategy, surgery and outcome of patients. This strategy becomes more and more challenging because on one hand there will be soon be no limits to treatment, which is attributable to the progress in endovascular surgery and on the other hand the question arises whether the feasible is reasonable? Within the scope of this article the problems of treatment of the elderly are presented and strategies and decisions for an individualized optimal therapy are proposed.

Comparison of Cine-MRI and Transthoracic Echocardiography for the Assessment of Aortic Root Diameters in Patients with Suspected Marfan Syndrome.

PURPOSE: Patients with Marfan syndrome require repeated imaging for monitoring of aortic root aneurysms. Therefore, we evaluated the agreement and reproducibility of cine-MRI and echocardiography measurements of the sinuses of Valsalva in patients with suspected Marfan syndrome. MATERIALS AND METHODS: 51 consecutive patients with suspected Marfan syndrome were prospectively examined using cine-MRI and echocardiography. Two readers independently measured aortic root diameters at the level of the sinuses of Valsalva in both cine-MRI and echocardiography. Statistics included intraclass correlation coefficient, Pearson correlation coefficient, Bland-Altman analysis, and two-sided t-test. RESULTS: In 38 of the 51 individuals (74.5 %), the diagnosis of Marfan syndrome was established according to the criteria of the Ghent-2 nosology. Cine-MRI measurements of the sinuses of Valsalva revealed a strong correlation with echocardiography (r = 0.929), but a statistically significant bias of -1.0  mm (p < 0.001). The mean absolute diameter for sinuses of Valsalva obtained by cine-MRI was 32.3  ±  5.8 mm as compared to 33.4  ±  5.4 mm obtained by echocardiography. Interobserver agreement of measurements of the sinuses of Valsalva was higher for cine-MRI than for echocardiography (p = 0.029). CONCLUSION: Despite small, but statistically significant differences in terms of agreement and reproducibility, cine-MRI and echocardiographic measurements of aortic root diameters provide comparable results without a significant clinical difference. Therefore both techniques may be used for monitoring of the aortic root in patients with Marfan syndrome.

Chronic type B aortic dissection: indications and strategies for treatment.

Chronic type B aortic dissection is a distinctive condition that needs individual treatment strategies and different considerations than in therapy of acute or subacute type B aortic dissection. The most common indication for treatment of this complex disease is aneurysmal dilatation of the dissected aortic segment. While open repair of the enlarged dissected aorta remains the best option for good-risk patients and patients with connective tissue disorders in high-volume centers with respective expertise, endovascular management of chronic type B aortic dissection with postdissection aneurysms has significantly gained ground in the past years. But the concept of TEVAR with implantation of a tubular stent-graft into the thoracic aorta to seal the proximal entry tear and reroute the blood flow into the true lumen alone, is not associated with satisfactory results. This is mainly due to the sparse remodeling capacity of the aortic tissue compared to earlier stages of the disease as the aortic wall and the dissection membrane are thickened and more rigid. On the other hand, it is restricted by the most limiting factor for endovascular success in chronic type B aortic dissection: persistent false lumen perfusion. This problem also affects patients with residual dissection after surgical repair of a DeBakey type I aortic dissection or dissection after ascending aortic repair for other pathologies. Hence, it is evident that strategies to achieve endovascular false lumen occlusion are of increasing importance and novel techniques have been introduced to solve the problem of persisting false lumen flow. Thus, the evolution of a large variety of techniques to address the false lumen perfusion issue indicates that complicated chronic type B dissection involves a high diversity in clinical presentation and morphology. A large armamentarium of catheter skills as well as critical individualized treatment strategies are required to address the heterogenous morphological disease pattern for each individual patient. The rapid development in endovascular techniques gives new directions for treatment indications and strategies in chronic aortic dissection and enables new insights into this old disease.

[Genetics and prevention of genetic aortic syndromes (GAS) and of the Marfan syndrome]. / Genetik und Prävention am Beispiel genetischer Aortensyndrome (GAS) und des Marfan-Syndroms.

BACKGROUND: Genetic aortic syndromes are autosomal-dominantly heritable aneurysms of the thoracic aorta, which carry a high risk of aortic rupture or acute thoracic aortic dissection at young age. OBJECTIVES: We introduce the reader to the principles of genetic diagnostics and the medical and surgical prevention of thoracic aortic dissection in patients with genetic aortic syndromes. METHODS: A cardiologist, a health economist, a patient representative, a heart surgeon, and a molecular geneticist teamed up to elucidate their perspective on major aspects of genetics and prevention of genetic aortic syndromes. RESULTS: Genetic aortic syndromes reflect a broad spectrum of diverse disease entities comprising the Marfan syndrome, the Loeys-Dietz syndrome or the vascular Ehlers-Danlos syndrome. The diagnosis of each respective disease entity requires combined assessment of phenotype and genotype information. A medical prevention of aortic complications such as dissection is mandatory although a curative therapy currently appears unlikely in humans. The single most important measure against acute aortic dissection is the preventive replacement of the aortic root, where valve preserving techniques appear preferable. Comprehensive prophylaxis including molecular diagnostics seem reasonable also from an economic point of view. DISCUSSION: Optimal prevention requires individualization of concepts, which entail a detailed diagnostic characterization of each specific genetic aortic syndrome including characterization of the genotype.

[Transcardiac Access Routes for Endovascular Treatment of Ascending Aortic Pathologies]. / Transkardiale Zugangswege zur endovaskulären Versorgung der Aorta ascendens.

Gold standard for treatment of pathologies of the ascending aorta is still open surgery with extracorporal circulation in moderate to deep hypothermia. These procedures are associated with high morbidity and mortality, especially if performed in older patients or after previous cardiac surgery. Thoracic endovascular aortic repair (TEVAR) has become the preferred treatment option for thoracic aortic pathologies of the descending aorta even in high-risk patients with severe comorbidities resulting in reduced morbidity and mortality compared to open repair. Despite the continuous development of endograft technology an adequate arterial access still poses a relevant limitation of this treatment option accentuated in the proximal segments of the aorta. The transfemoral access may be limited due to severe kinking or arteriosclerotic plaque stenosis of femoral or iliac vessels. Furthermore, the long distance between femoral access vessels and the aortic lesion impairs device torsibility and exact deployment of the stent graft. To provide a practical alternative endovascular access to the ascending aorta, antegrade transcardiac access routes including transapical or transseptal techniques have recently gained increasing interest.

Pediatric patients with Marfan syndrome: frequency of dural ectasia and its correlation with common cardiovascular manifestations.

PURPOSE: Marfan syndrome (MFS) is a genetic disorder of the connective tissue. Aortic root dilation is a main criterion of the Ghent Nosology. Dural ectasia and the presence of mitral valve prolapse (MVP) contribute to its systemic score. The purpose of this study was to investigate the frequency of dural ectasia and its correlation with cardiovascular manifestations in a pediatric study population. PATIENTS AND METHODS: 119 pediatric patients with confirmed or suspected MFS were examined in the local Marfan Clinic. 31 children with MFS who underwent magnetic resonance imaging (MRI) were included. Each patient was evaluated according to the Ghent nosology. Echocardiography was used to measure the aortic root diameter and assess the presence of MVP and mitral regurgitation. Z-scores were calculated for the evaluation of the aortic root diameters. MRI was performed to determine the dural sac ratio (DSR). RESULTS: The prevalence of dural ectasia was 90.3 %, of aortic root dilation 32.2 %, of MVP 64.5 % and of mitral regurgitation 51.6 %. DSR at L5 correlated with the intraindividual z-scores (slope, 3.62 ±â€Š1.5 [0.56; 6.68]; r = 0.17; p = 0.02; F = 5.84). Z-scores ≥ 2 were accompanied by dural ectasia in 100 %, MVP in 95 % and mitral regurgitation in 100 % of cases. MVP was accompanied by mitral regurgitation in 70 % of cases. CONCLUSION: As the examined cardiac manifestations show a coincidence with dural ectasia in 95 - 100 % of cases, MRI for diagnostic dural sac imaging should be reserved for MFS suspicions with the absence of those manifestations in order to establish the diagnosis according to the Ghent criteria. Thus, the present study supports the recent downgrading of dural ectasia to a contributor to the systemic score.

Comprehensive analysis of dural ectasia in 150 patients with a causative FBN1 mutation.

The purpose of this study was to perform a comprehensive study of dural ectasia (DE) related to FBN1 mutations. We performed a database analysis of two German metropolitan regions of 150 patients (68 men, 82 women; mean age 35 ± 16 years). All patients had a FBN1 mutation and underwent dural magnetic resonance imaging. Age was <16 years in 20, 16-25 in 27, 26-35 in 67, and >35 in 36 patients. Prevalence of dural ectasia was 89% with criteria of Oosterhof and Habermann, 83% with Fattori, 78% with Lundby, and 59% with Ahn. DE was less frequent in patients <16 years with Ahn and Fattori. DE related to skeletal manifestations with all criteria, to aortic Z-scores and mitral valve prolapse with criteria of Habermann and Lundby, and to age with criteria of Fattori. The Fattori-grade of DE increased with age, aortic Z-scores, and skeletal score points. There was no consistent relationship of DE with any type of FBN1 mutation. DE is frequent in patients with FBN1 mutations irrespective of age and its severity increases during life. Criteria of Oosterhof and Habermann yielded most consistent diagnostic results. DE relates to skeletal involvement, aortic Z-scores, and mitral valve prolapse.

Dural ectasia in Loeys-Dietz syndrome: comprehensive study of 30 patients with a TGFBR1 or TGFBR2 mutation.

The purpose of this study was to assess the frequency, severity, and clinical associations of dural ectasia (DE) in Loeys-Dietz syndrome (LDS). Database analysis of three German metropolitan regions identified 30 patients with LDS and TGFBR1 mutation in 6 and a TGFBR2 mutation in 24 individuals (17 men; mean age: 31 ± 19 years), as well as 60 age and sex-matched control patients with Marfan syndrome carrying a FBN1 mutation. DE was present in 22 patients with LDS (73%), and it related to skeletal score points (p = 0.008), non-skeletal score points (p < 0.001), and to the presence of ≥7 systemic score points (p = 0.010). Similarly, the severity of DE was related to body height (p = 0.010) and non-skeletal score points (p = 0.004). Frequency (p = 0.131) and severity of DE (p = 0.567) was similar in LDS and Marfan syndrome. DE is a manifestation of LDS that occurs with similar frequency and severity as in Marfan syndrome. Severity of DE may serve as a marker of the overall connective tissue disease severity. LDS may be considered in patients with DE.

A simple clinical model to estimate the probability of Marfan syndrome.

BACKGROUND: Marfan syndrome is a heritable connective tissue disease. Definitive diagnosis is complex, and requires sequencing of a large gene, FBN1. AIM: We aimed to develop a simple model to estimate the pre-test probability of Marfan syndrome. DESIGN: Prospective cross-sectional study. METHODS: We applied diagnostic standards for definitive diagnosis or exclusion of Marfan syndrome in 329 consecutive persons. In 208 persons with random assignment to our derivation group, we performed multivariate logistic regression to assess 14 clinical variables for inclusion in a prediction model with derivation of score points from the estimated coefficients. We created cut-offs to classify low, moderate and high probability of Marfan syndrome. For validation, we applied the model to the remaining 121 persons. RESULTS: We identified seven variables for inclusion in the final model, where we assigned four score points to ectopia lentis, two points to a family history of Marfan syndrome, and one point to previous thoracic aortic surgery, to pectus excavatum, to a wrist and thumb sign, to previous pneumothorax, and to skin striae. In the derivation group 12, 42 and 92% of persons with low (≤1 point), moderate (>1-3.5 points) or high pre-test probability (>3.5 points) had Marfan syndrome, compared to 12, 57 and 91%, respectively, in the validation group. Positive likelihood ratios were 13.96 and 8.54 in the high probability group of the derivation and validation group, respectively. CONCLUSION: A simple prediction model provides evidence for Marfan syndrome. This model can be used to identify patients who require definitive diagnostic work-up.

Analysis of phenotype and genotype information for the diagnosis of Marfan syndrome.

Marfan syndrome is considered a clinical diagnosis. Three diagnostic classifications comprising first, Marfan genotype with a causative FBN1 gene mutation; second, Marfan phenotype with clinical criteria of the original Ghent nosology (Ghent-1); and third, phenotype with clinical criteria of its current revision (Ghent-2) in 300 consecutive persons referred for confirmation or exclusion of Marfan syndrome (150 men, 150 women aged 35 ± 13 years) were used. Sequencing of TGBR1/2 genes was performed in 128 persons without FBN1 mutation. Marfan genotype was present in 140, Ghent-1 phenotype in 139, and Ghent-2 phenotype in 124 of 300 study patients. Marfan syndrome was confirmed in 94 and excluded in 129 persons consistently by all classifications, but classifications were discordant in 77 persons. With combined genotype and phenotype information confirmation of Marfan syndrome was finally achieved in 126 persons by Ghent-1 and in 125 persons by Ghent-2 among 140 persons with Marfan genotype, and exclusion was accomplished in 139 persons by Ghent-1 and in 141 persons by Ghent-2 among 160 persons without Marfan genotype. In total, genotype information changed final diagnoses in 22 persons with Ghent-1, and in 32 persons with Ghent-2. It is concluded that genotype information is essential for diagnosis or exclusion of Marfan syndrome.

Dural ectasia in individuals with Marfan-like features but exclusion of mutations in the genes FBN1, TGFBR1 and TGFBR2.

Mutations in the genes FBN1, TGFBR1, and TGFBR2 can result in heritable connective tissue disorders comprising the Marfan syndrome and the Loeys-Dietz syndrome. Dural ectasia is a characteristic manifestation of both syndromes. However, dural ectasia has not yet been investigated in connective tissue disorders that are unrelated to mutations in the FBN1, TGFBR1 or TGFBR2 genes. Here, we assessed dural ectasia in 33 individuals both with typical manifestations of heritable connective tissue disease and in whom mutations in all three genes had been excluded. We identified 19 individuals with dural ectasia (58%), who exhibited major skeletal manifestations of the Marfan syndrome more frequently than the remaining 14 persons without dural ectasia (p = 0.06). Moreover, only persons with dural ectasia fulfilled clinical criteria of the Marfan syndrome (p = 0.01). Conversely, aortic aneurysm (12 patients; p = 0.8), aortic dissection (five patients; p = 0.1), spontaneous dissection of the carotid arteries (five patients; p = 1), and mitral valve prolapse (13 patients; p = 0.4) were similarly frequent irrespective of dural ectasia. We conclude that dural ectasia is a marker for connective tissue disease which coincides with skeletal rather than with cardiovascular manifestations, and which may involve currently uncharacterized pathogenetic mechanisms and syndromes.

Aortic aneurysms after correction of aortic coarctation: a systematic review.

Despite advanced techniques for surgical or percutaneous therapy coarctation of the aorta continues to carry a high risk of aneurysmal formation. Mortality of these aneurysms ranges between <1 and >90%, reflecting remarkable differences in surgical strategies and the follow-up management of coarctation. We review the frequency, anatomical types, risk factors and mechanisms of aortic aneurysm forming late after surgical or percutaneous therapy of aortic coarctation. We emphasize that aneurysms do not form exclusively at the site of previous intervention, but also at remote locations such as the ascending aorta. Moreover, aneurysm formation may only in part be attributed to a specific technique of coarctation therapy, and we emphasize the role of a bicuspid aortic valve and inherent weakness of the aortic wall as significant risk factors for aneurysm after aortic coarctation. We report the presenting symptoms, follow-up protocols, and imaging criteria for local and proximal aneurysms. Finally, we discuss criteria for prophylactic intervention at the site of such aneurysms, and present therapeutic options for different types of aneurysms. With this systematic review, we wish to provide data for establishing more uniform strategies for preventing, diagnosing and treating aneurysms associated with aortic coarctation.

Marfan syndrome and the evolving spectrum of heritable thoracic aortic disease: do we need genetics for clinical decisions?

Marfan syndrome (MFS) is a disorder of the connective tissue that is inherited in an autosomal dominant fashion and that is classically caused by mutations in the gene coding for fibrillin-1, FBN1. The high mortality of untreated MFS results almost exclusively from aortic complications such as aortic dissection and rupture. However, more than half of patients with Marfan-like features do not have MFS, but have other diseases including inherited aortic aneurysms and dissections (TAAD). We elucidate the increasing spectrum of syndromes associated with Marfan-like features and discuss the clinical implications of these diseases. We performed a systematic review to tabulate all known inherited diseases and syndromes carrying a risk for thoracic aortic disease. We discuss evidence that different syndromes with different causative genes and mutations have different prognoses and profiles of cardiovascular manifestations. We conclude that future decisions for optimized management of patients with inherited TAAD require a comprehensive clinical and genetic work-up.

Predicting severity of haemophilia A and B splicing mutations by information analysis.

Bleeding symptoms and clotting activity vary among mutations that alter mRNA splicing of either the factor VIII or factor IX genes. We analyzed splicing mutations in both genes for changes in individual information (R(i), in bits) involving both donor or acceptor sites. Mutations with low or negative R(i) values (<2.4 bits) or significant changes in R(i) (DeltaR(i) > or = 7 bits) exhibited either reduced protein activity, increased clotting time and bleeding frequency and were predictive of severe disease. Thus, information analysis of splicing mutations may be useful in predicting phenotypes in hemophilia.