Biomedical subjects
Publications and source records attributed to C Gasner.
This study reviewed the utility of echocardiography in following patients with the Marfan syndrome for whom cardiovascular complications, especially aortic root dilatation, dissection and rupture, are the major causes of morbidity and mortality. We conclude that echocardiography can be used to follow asymptomatic patients with the Marfan syndrome.
Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder of connective tissue and is characterized by multiple congenital contractures, arachnodactyly, and external ear malformations. Recent investigations indicate that mutations in the fibrillin-2 gene (FBN2) cause CCA. Here, we report a G-->C transversion at nucleotide 3340 (G3340C) of FBN2 in a family with phenotypic characteristics of CCA. The G3340C mutation predicts the substitution of histidine for aspartic acid at amino acid residue 1114 (Asp1114His) and also alters the 5' donor splice site consensus sequence of exon 25. Reverse transcription/polymerase chain reaction and DNA sequence analyses demonstrate that this missense mutation also causes low level in-frame mis-splicing of exon 25 (del exon 25). Consequently, this single point mutation produces a heterogeneous population of mutant fibrillin-2 molecules in a single individual. Despite the complex manifestation of the mutation, it is associated with a relatively mild phenotype. Analysis of FBN2 allele expression in cultured dermal fibroblasts derived from the proband has shown that the mutant allele is preferentially expressed, contributing about 84% of the total transcript. This indicates that an overabundance of mutant transcript does not necessarily correlate with a more severe CCA phenotype.
Marfan syndrome (MFS), a multisystem autosomal-dominant disorder, is characterized by mutations of the fibrillin-1 (FBN1) gene and by abnormal patterns of synthesis, secretion, and matrix deposition of the fibrillin protein. To determine the sensitivity and specificity of fibrillin protein abnormalities in the diagnosis of MFS, we studied dermal fibroblasts from 57 patients with classical MFS, 15 with equivocal MFS, 8 with single-organ manifestations, and 16 with other connective tissue disorders including homocystinuria and Ehlers-Danlos syndrome. Abnormal fibrillin metabolism was identified in 70 samples that were classified into four different groups based on quantitation of fibrillin synthesis and matrix deposition. Significant correlations were found for phenotypic features including arachnodactyly, striae distensae, cardiovascular manifestations, and fibrillin groups II and IV, which included 70% of the MFS patients. In addition, these two groups were associated with shortened "event-free" survival and more severe cardiovascular complications than groups I and III. The latter included most of the equivocal MFS/single manifestation patients with fibrillin abnormalities. Our results indicate that fibrillin defects at the protein level per se are not specific for MFS, but that the drastically reduced fibrillin deposition, caused by a dominant-negative effect of abnormal fibrillin molecules in individuals defined as groups II and IV, is of prognostic and possibly diagnostic significance.
Osteopenia at the hip and low total body calcium content have been reported in women with Marfan syndrome. Using dual X-ray absorptiometry (DXA), we evaluated the lumbar spine L2-L4 and proximal femur bone mineral density (BMD,/cm2) in 32 women and 16 children with Marfan syndrome. The women were 38 +/- 10 (SD) years old (23-58 years); their mean height was 178.7 +/- 8 cm. The children (9 boys and girls were 9.9-17.5 years old. Children were tall for their ages but of normal weight. All subjects were moderately active, without previous nontraumatic fracture. In the women, BMD was reduced at L2-L4, femoral neck (fnk), trochanter (tr), and intertrochanter (intr) (p < 0.0001-0.006), compared with age-predicted values. Z scores for L2-L4 and for the fnk, tr, and intr, were -0.59 +/- 1.06,-1.25 +/- 0.99,-1.03 +/- 0.91, respectively. The average hip axis length (HAL) of 11.5 +/- 0.093 cm was at the 80th percentile for women. No significant change was observed in 1 year follow-up BMD measurements in 13 women (fnk = -0.23 +/- 2.3%/year; L2-L4 = -0.43 +/- 1.57%/year). In Marfan children, BMD correlated with age, height, and pubertal development. Femoral neck BMG was reduced (Z = -0.74 +/- 1.22,p < 0.05) with a nonsignificant trend toward decreased BMD at L2-L4 (Z = 33 +/- 1.48). Resorption markers in Marfan women were normal and did not correlate with bone status. We conclude that women with Marfan syndrome have both axial and peripheral osteopenia as well as an increased HAL. This combination of findings likely increases substantially their long-term risk for hip fracture. Presence of osteopenia in Marfan children indicates that the skeletal deficits of Marfan syndrome may reflect inadequate bone acquisition.
Ascending aortic disease, ranging from mild aortic root enlargement to aneurysm and/or dissection, has been identified in 10 individuals of a kindred, none of whom had classical Marfan syndrome (MFS). Single-strand conformation analysis of the entire fibrillin-1 (FBN1) cDNA of an affected family member revealed a G-to-A transition at nucleotide 3379, predicting a Gly1127Ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. This mutation was present in 9 of 10 affected family members and in 1 young unaffected member but was not found in other unaffected members, in 168 chromosomes from normal controls, and in 188 chromosomes from other individuals with MFS or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a significant role in modulating the phenotype in this family. Pulse-chase studies revealed normal fibrillin synthesis but reduced fibrillin deposition into the extracellular matrix in cultured fibroblasts from a Gly1127Ser carrier. We postulate that the Gly1127Ser FBN1 mutation is responsible for reduced matrix deposition. We suggest that mutations such as this one may disrupt EGF-like domain folding less drastically than do substitutions of cysteine or of other amino acids important for calcium-binding that cause classical MFS. The Gly1127Ser mutation, therefore, produces a mild form of autosomal dominantly inherited weakness of elastic tissue, which predisposes to ascending aortic aneurysm and dissection later in life.
PURPOSE: With effective surgical correction of vascular abnormalities, skeletal health is an important issue for patients with Marfan syndrome. Osteopenia has been radiographically described, yet no systematic evaluation of bone status has been published. The purpose of this study was to determine the bone mineral density (BMD, g/cm2) in women with Marfan syndrome. PATIENTS AND METHODS: Seventeen women, 37.2 +/- 7.3 years old, with Marfan syndrome were studied. Dual energy x-ray absorptiometry (DXA) was used to measure BMD at the lumbar spine (L2-L4), proximal femur, and total body in all subjects. Scoliosis scores were assigned from 0 (no curvature) to 3 (severe curvature). RESULTS: Highly significant deficits in BMD were observed at the proximal femur (p = 0.0001) as well as of the whole body (p < 0.05). Femoral neck BMD Z-score (mean +/- SD) = -1.36 +/- 0.94, trochanter Z = -1.07 +/- 0.80, and intertrochanter Z = -1.44 +/- 0.71; whole-body BMD Z-score = -0.30 +/- 0.16. BMD at L2-L4, however, did not differ from age-predicted values, Z = -0.48 +/- 1.16. There was no significant association between BMD and scoliosis, nor between BMD and fracture history. To correct for bone size, the bone mineral apparent density (BMAD, g/cm3) was calculated. The femoral neck BMAD values (mean +/- SD) were significantly lower than predicted (0.125 +/- 0.02 versus 0.147 +/- 0.001 g/cm3, p < 0.001). All subjects had normal menarche, and 15 reported regular menses. There was no history of nontraumatic fracture. CONCLUSIONS: Women with Marfan syndrome have bone deficits at the proximal femur as well as of the whole body. This deficit is not related to scoliosis and persists when corrected for bone size. Women with Marfan syndrome may be at increased risk for proximal femoral fracture.
Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder characterized by cardiovascular, ocular and skeletal manifestations. Previously, mutations in the fibrillin-1 gene on chromosome 15 (FBN1) have been reported to cause MFS. We have now screened 44 probands with MFS or related phenotypes for alterations in the entire fibrillin coding sequence (9.3 kb) by single strand conformation analysis. We report four unique mutations in the fibrillin gene of unrelated MFS patients. One is a 17 bp deletion and three are missense mutations, two of which involve 8-cysteine motifs. Another missense mutation was found in two unrelated individuals with annuloaortic ectasia but was also present in unaffected relatives and controls from various ethnic backgrounds. By using allele-specific oligonucleotide hybridization, we screened 65 unrelated MFS patients, 29 patients with related phenotypes and 84 control individuals for these mutations as well as for a previously reported mutation and two polymorphisms. Our results suggest that most MFS families carry unique mutations and that the fibrillin genotype is not the sole determinant of the connective tissue phenotype.