Cases reported "Marfan Syndrome"

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1/15. FBN1 exon 2 splicing error in a patient with marfan syndrome.

    Mutations in FBN1 cause the autosomal dominant condition, marfan syndrome. A single-base mutation that results in a skipping of exon 2 of FBN1 was found in a Marfan patient. By sequencing this proband's entire FBN1 gene and comparing the mutated dna sequence with proband's unaffected family numbers, we confirmed this alteration was the causative mutation. The skipping of exon 2 creates a frameshift and premature termination codon, and forms a truncated fibrillin-1 composed only of 55 amino acids of N-terminus plus 45 nonsense amino acids. The mRNA transcription levels of the mutated FBN1 allele and the deposition of fibrillin-1 into extracellular matrix in fibroblast cells culture were assessed.
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2/15. marfan syndrome caused by a mutation in FBN1 that gives rise to cryptic splicing and a 33 nucleotide insertion in the coding sequence.

    We have studied a patient with marfan syndrome whose mutation was not detected by heteroduplex analysis. Primary cultured patient fibroblasts were metabolically labelled and found to secrete fibrillin-1 defectively when compared with an age-matched control. Sequencing of patient cDNA, isolated by reverse transcription-polymerase chain reaction of patient fibroblast rna, detected a 33-bp insertion. The reading frame of the mutant allele was maintained and predicted the insertion of 11 amino acids at the beginning of calcium-binding epidermal growth factor-like domain 29. Direct sequencing of genomic dna detected a heterozygous G 1-->A transversion in intron 46 of FBN1. The 11 amino acid insertion was the consequence of the usage of a cryptic splice site 33-bp downstream of the mutation. This is the first reported case of a splicing defect in FBN1 leading to the production of a full-length fibrillin-1 transcript containing a large amino acid insertion.
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3/15. Deficiencies of fibrillin and decorin in fibroblast cultures of a patient with neonatal marfan syndrome.

    Changes in the structure and metabolism of fibrillin, a microfibril associated protein, can result in classical marfan syndrome, and reduced expression of decorin, a small extracellular chondroitin sulphate/dermatan sulphate proteoglycan, has been observed in fibroblasts of a patient with neonatally lethal marfan syndrome. We have studied the synthesis of fibrillin and decorin in cultured fibroblasts of a further sporadic patient with neonatally lethal Marfan syndrome. Fibrillin immunoreactivity in the extracellular matrix of the patient's fibroblasts was markedly reduced, and the fibrillar pattern was absent, in spite of normal amounts of fibrillin mRNA. decorin mRNA, synthesis, and immunoreactivity in the matrix were also reduced. The results indicate involvement of both fibrillin and decorin in the pathogenesis of neonatal Marfan syndrome in this patient, but do not indicate which is the primary defect. We speculate, however, that a structural defect of fibrillin leads to diminished incorporation of the protein into the extracellular matrix, and that underexpression of decorin is secondary to the primary fibrillin defect. Combined deficiency of fibrillin and decorin may be the cause of the severe clinical phenotype.
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4/15. Infective endocarditis due to abiotrophia defectiva: a report of two cases.

    BACKGROUND AND AIM OF THE STUDY: endocarditis due to abiotrophia sp. is rare and often associated with negative blood cultures. The rates of treatment failure, infection relapse and mortality are higher than in endocarditis caused by other viridans streptococci. methods: A retrospective review of A. defectiva endocarditis in a patient with prosthetic aortic valve and in a patient with marfan syndrome was performed. RESULTS: A. defectiva, susceptible to penicillin (MIC 0.064 mg/l and 0.016 mg/l, respectively) was isolated from blood cultures of both patients. Treatment with penicillin and gentamicin was started in both patients. Since the first patient developed a macular rash and leukopenia, penicillin was substituted with ceftriaxone. Both patients responded well to antibiotic treatment, did not need prosthetic valve insertion or reinsertion, and were without any sequelae at one year follow up. CONCLUSION: Standard treatment of bacterial endocarditis with penicillin and gentamicin was effective in both patients. In contrast to previous reports, the present patients had a favorable outcome on completion of treatment and at one-year follow up.
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5/15. Unilateral microfibrillar abnormalities in a case of asymmetric marfan syndrome.

    The marfan syndrome is a dominantly inherited connective-tissue disorder characterized by ocular, cardiovascular, and musculoskeletal abnormalities. Although the underlying biochemical and molecular defect(s) of this pleiotropic disease is currently unknown, we have consistently observed apparent diminished content of elastin-associated microfibrillar fibers accumulating in skin, or produced by cultured fibroblasts, from patients with the marfan syndrome and have documented the cosegregation of these immunofluorescent abnormalities of microfibrillar fibers with the marfan syndrome phenotype in family studies. Recently, an unusual patient has been described with unilateral phenotypic features of the marfan syndrome, providing an unique opportunity to compare microfibrillar fibers and other connective-tissue components between the affected and nonaffected sides. In the present report, we demonstrate striking differences in apparent content of microfibrillar fibers, as determined by indirect immunofluorescence of skin and fibroblast cultures, that are revealed when multiple homologous samples derived from different sides of the patient's body are compared. In contrast, no differences in apparent content of type III collagen or in the biosynthesis and apparent structure of types I and III (pro)collagens were found. HLA types and chromosome heteromorphisms were identical in fibroblasts from both sides of the body, eliminating the formal possibility of chimerism and suggesting that a postzygotic mutation accounts for the asymmetric manifestation of the marfan syndrome in this patient. The observation of striking decreases in microfibrillar fibers on the affected side of the body provides further evidence that abnormalities of this component of the elastic fiber system may be central to the pathogenesis and possibly the etiology of the marfan syndrome.
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6/15. Deficient expression of the gene coding for decorin in a lethal form of marfan syndrome.

    The markedly decreased level of the messenger rna of decorin, an abundant dermatan/chondroitin sulfate proteoglycan was found in the skin fibroblast culture of a lethally sick Marfan infant. Also, the amount of decorin polypeptide in the culture medium of the fibroblasts of this infant was markedly decreased. When the effect of interleukin-1 beta on the transcription of decorin was tested in these fibroblasts, the response was deficient as compared to control fibroblasts whereas transcription of type I and III collagen genes and versican was stimulated normally. The decreased decorin mRNA level, unresponsive to interleukin-1 beta in this lethally sick Marfan patient, stresses the significance of this proteoglycan in the formation of normal connective tissue. Furthermore, the low expression of this gene could be responsible for the connective tissue findings in this patient, representing a rare type of marfan syndrome. The identical finding in three other, unrelated Marfan individuals suggests a more general significance of deficient decorin expression in this disease.
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7/15. marfan syndrome: abnormal alpha 2 chain in type I collagen.

    cells in culture from a woman with a variety of the marfan syndrome produce two species of the alpha 2 chains of type I collagen. One alpha 2 chain appears normal; the abnormal chain has a higher apparent molecular weight than normal and migrates more slowly during electrophoresis in sodium dodecyl sulfate/polyacrylamide gels. A similar change in electrophoretic behavior is seen in the prepro alpha 2 chain and the pN alpha 2 chain (which contains the amino-terminal extension). Asymmetric cleavage of the pepsin-treated procollagens with a fibroblast collagenase locates the abnormal segment amino terminal to the cleavage site, and analysis of cyanogen bromide peptides of collagenase cleavage peptides and of whole collagens indicates that the abnormal segment is in either the alpha 2CB3 peptide or the short segment of alpha 2CB5 amino terminal to the collagenase site of the altered alpha 2 chain. The higher apparent molecular weight is consistent with the insertion of a small peptide fragment of approximately 20 amino acids. This alteration in chain size has marked effects on crosslinking because collagen from the patient's skin was 5-10 times more extractable in nondenaturing solvents than that from control skins. Although the abnormal chain was not found in several other individuals with the marfan syndrome, these findings suggest that the phenotype may be the expression of a variety of primary structure alterations in the chains of type I collagen that interfere with normal crosslink formation.
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8/15. A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection.

    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.
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9/15. A compound-heterozygous Marfan patient: two defective fibrillin alleles result in a lethal phenotype.

    We describe here the identification of defined mutations in both alleles of the fibrillin gene (FBN1) in a compound-heterozygote marfan syndrome (MFS) child who had a very severe form of MFS resulting in death from cardiac failure at the age of 4 mo. The nonconsanguineous parents were both affected with MFS. The father's heterozygous point mutation has earlier been reported to result in W217G substitution, the mother was here shown to carry a heterozygous point mutation resulting in G2627R substitution, and the child had inherited both these mutations. The mutant FBN1 alleles were demonstrated to be transcribed with equal efficiency compared with the normal alleles, but metabolic labeling of fibroblast cultures from the child and both parents showed reduced biosynthesis and secretion of profibrillin. Also, the respective amounts of fibrillin in cell-culture media and extracellular-matrix extracts were markedly diminished, particularly in the cell cultures from father and child. In addition, immunofluorescence analysis of the cell cultures of all three family members revealed a drastically reduced amount of microfibrils, and virtually no visible fibrils could be seen in the case of the compound-heterozygote child. These findings demonstrate incomplete dominance of fibrillin mutations and underline the fatal consequences of the complete absence of normal fibrillin molecules in the microfibrils.
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10/15. Decreased extracellular deposition of fibrillin and decorin in neonatal marfan syndrome fibroblasts.

    Abnormalities of the microfibrillar protein fibrillin (Fib) have been reported in marfan syndrome (MFS). The so-called neonatal marfan syndrome (nMFS) is a lethal phenotype displaying features that are not seen in classical MFS. We have therefore studied the biosynthesis and extracellular deposition of Fib and decorin in fibroblasts from a patient with nMFS and controls. Immunofluorescence of the patient's cell cultures showed an almost complete absence of Fib and a marked reduction of decorin in the extracellular matrix (ECM). The nMFS skin revealed Fib on subbasal microfibrillar bundles in the papillary dermis, and Fib associated with elastic fibers in the reticular dermis; the bundles and fibers were fragmented and thinner than normal. pulse-chase labeling of cells with [35S]Met/Cys revealed moderately reduced secretion, but a diminished deposition of Fib in the ECM; this was more apparent at a longer chase time. Fib mRNA and synthesis appeared to be normal, whereas both decorin mRNA and biosynthesis were reduced. We therefore assume a structural Fib defect in this patient causing reduced deposition into and/or enhanced removal from the ECM, whereas the reduced decorin biosynthesis may be a secondary regulatory phenomenon. The clinical relevance of this remains unclear. Our findings imply that Fib defects may be responsible for the severe, complex phenotype of nMFS.
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