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R E Pyeritz

Publications and source records attributed to R E Pyeritz.

At least 19 recordsLinked to original sources
PubMed1992

Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains.

The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue with prominent involvement of the ocular, skeletal, and cardiovascular systems. The gene on chromosome 15 encoding fibrillin (FBN1), a 350-kDa glycoprotein component of the extracellular microfibril, is the site of defect in most, if not all cases. Complementary DNA sequence reveals a gene composed largely of epidermal growth factor-like repeats, each containing six predictably spaced cysteine residues. To date, two FBN1 gene missense mutations have been reported. Here we describe the identification of three new missense mutations in the FBN1 gene in patients with the Marfan syndrome. All of the 5 characterized missense mutations occur within the epidermal growth factor-like repeats of the FBN1 gene. In addition, 4 of 5 involve the substitution of cysteine residues and 3 of 5 substitute the third cysteine in the epidermal growth factor-like motif consensus sequence. These data suggest that defined residues within EGF-like domains of FBN1 have particular significance and, when altered, play a pivotal role in expression of the Marfan phenotype.

Amino Acid Sequence↗
PubMed1992

The organization and delivery of clinical genetics services.

Advances in genetics, including mapping the human genome, improved therapy for genetic disorders, recognition of the role of genetic factors in common diseases of adulthood, and new screening tests for carrier detection and presymptomatic diagnosis create an increased demand for and awareness of clinical genetic services. These services, focusing on diagnosis, management, and genetic counseling, had been supported by a variety of state, provincial, federal, and foundation grants. As clinical genetics has evolved from a service with roots in research provided solely at academic medical centers to one widely available in the community, the services in the United States are increasingly provided on a fee-for-service basis in various settings including private hospitals, state-supported outreach clinics, and free-standing genetics centers, whereas in Canada they are generally based in university hospital settings and are covered by universal health care. Given the limited numbers of clinical geneticists and genetic counselors now practicing, much of the application in this decade of new genetic technologies and knowledge will fall upon primary care physicians.

Genetic Counseling↗
PubMed1992

Marfan syndrome: defective synthesis, secretion, and extracellular matrix formation of fibrillin by cultured dermal fibroblasts.

We studied the synthesis, secretion, and aggregation into the extracellular matrix of fibrillin by dermal fibroblasts from 26 probands with the Marfan syndrome. Cells from seven probands synthesized approximately half the normal amount of fibrillin when compared with intrafamilial or unrelated controls. Cells from an additional seven probands synthesized a normal amount of fibrillin but secreted the protein less efficiently than control cells. Cells from a further eight probands synthesized and secreted normal amounts of fibrillin but the protein was poorly incorporated into extracellular matrix. Cells from the remaining four probands were indistinguishable from control cells in their synthesis and processing of fibrillin. Cells from 18 family members of 10 of the probands were also studied. Cells from affected individuals in the same family had the same biochemical defect and those from unaffected family members were indistinguishable from controls. These results indicate that mutations in the gene that encodes fibrillin are responsible for the Marfan syndrome in the majority of individuals (confirming recent immunohistochemical and genetic linkage studies) and that a variety of mutations can produce the phenotype associated with the syndrome.

Adolescent↗
PubMed1992

Marfan phenotype variability in a family segregating a missense mutation in the epidermal growth factor-like motif of the fibrillin gene.

To examine the associations among fibrillin gene mutations, protein function, and Marfan syndrome phenotype, we screened for alterations in the fibrillin coding sequence in patients with a range of manifestations and clinical severity. A cysteine to serine substitution at codon 1409 (C1409S) was identified in an epidermal growth factor (EGF)-like motif from one fibrillin allele which segregates with the disease phenotype through three generations of a family affected with the Marfan syndrome. This alteration was not observed in 60 probands from other families or in 88 unrelated normal individuals. The altered cysteine is completely conserved in all EGF-like motifs identified in fibrillin, and in all proteins that contain this motif. These observations strongly indicate that C1409S is the disease-producing mutation in this family. The phenotype of individuals carrying C1409S varied widely with respect to onset of disease, organ-system involvement, and clinical severity; certain affected adults were unaware of their status before being diagnosed through this investigation. We conclude that fibrillin gene defects cause familial Marfan syndrome, that mutations in the EGF-like motif of the fibrillin gene are not uniformly associated with severe disease, and that fibrillin genotype is not the sole determinant of Marfan phenotype.

Amino Acid Sequence↗
PubMed1992

The economics of clinical genetics services. IV. Financial impact of outpatient genetic services on an academic institution.

Those clinical genetic services that do not involve laboratory tests or procedures--i.e., the "cognitive" services such as diagnosis, management, and counseling--are labor-intensive, time-consuming, and not self-supporting. However, as a result of an evaluation at a genetics clinics, a patient will often receive other services at the same medical center. The full economic impact of the genetics clinic may be underappreciated. Therefore, at one medical center we examined (a) three settings that delivered genetics services and (b) two specialty clinics providing services to children with genetics conditions; and we calculated charges and payments for an unselected, consecutive group of outpatients. The results showed that cognitive genetics services accounted for a variable, but generally low, percentage of both the professional (generally physicians') and total charges accumulated by patients as a consequence of their visit to the genetics clinic. With laboratory and procedural charges included, patients seen in general genetics clinics (or their insurance plans) paid up to three times as much to the medical center and to its health professionals as to the genetics professional. These data confirm that clinical genetics services, while not generating enough income to cover their own costs, bring considerable revenue to the medical center. This fact alone should prove useful to the director of clinical genetics programs when they are negotiating finances with institutional administrators.

Fees and Charges↗
PubMed1991

Angular homeostasis. VIII. Pursuit of a slowly moving target in a plane: relevance to lateralization in cardiovascular ontogeny.

We explore the pursuit in a plane of a target moving at constant slow speed in a straight line. Two models of the pursuit are given. In the continuous case, the pursuer is moving at constant speed and is subject to proportionate angular homeostasis with correction constant b. In the discrete version movement occurs at a constant speed in a sequence of straight line segments of constant length (called the step size, s) the end of the segments being called the vertices. The pattern considered is not the absolute position of the pursuer, but its distance and orientation relative to the target. Both the transients and the asymptotic orbit are addressed. A key quantity is r, the speed of the target expressed as a fraction of that of the pursuer. If the speed of the pursuer is defined as unity, r is also the ratio of the speeds. There exists a critical speed fraction, R(b,s), a function of b and s, that defines what the term slow designates. R(b,s), which has to be found numerically, has the following property. For r less than R(b,s), the asymptotic path is a simple closed curve. In the discrete case the vertices converge to a simple closed curve. The larger r, the more the path (or in the discrete analogue its set of vertices) departs from a circle, and the more eccentric the target is with respect to it. Interest centers on two issues. First we address the transient patterns of the path, notably whether or not the sense of any particular path (clockwise or counterclockwise) is the same throughout, or changes at some stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Dextrocardia↗
PubMed1991

Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene.

Marfan syndrome is an inherited disorder of connective tissue manifested in the ocular, skeletal and cardiovascular systems. It is inherited as an autosomal dominant with high penetrance, but has great clinical variability. Linkage studies have mapped the Marfan locus to chromosome 15q15-21.3. There have been no reports of genetic heterogeneity in the syndrome. Following the identification of fibrillin (a glycoprotein component of the extracellular microfibril), immunohistopathological quantification of the protein in skin and fibroblast culture, and examination of fibrillin synthesis, extracellular transport, and incorporation into the extracellular matrix (D. M. Milewicz, R.E.P., E. S. Crawford and P. H. Byers, manuscript in preparation) have demonstrated abnormalities of fibrillin metabolism in most patients. A portion of the complementary DNA encoding fibrillin has been cloned and mapped by in situ hybridization to chromosome 15. Here we report that the fibrillin gene is linked to the Marfan phenotype (theta = 0.00; logarithm of the odds (lod) = 3.9) and describe a de novo missense mutation in the fibrillin gene in two patients with sporadic disease. We thus implicate fibrillin as the protein defective in patients with the Marfan syndrome.

Adult↗
PubMed1991

Composite graft repair of Marfan aneurysm of the ascending aorta: results in 100 patients.

One hundred consecutive patients with the Marfan syndrome underwent composite graft repair of an ascending aortic aneurysm between September 1976 and June 1989. Twenty-two patients had ascending aortic dissection at the time of composite graft repair; 18 patients also had a mitral valve procedure. There were no hospital deaths among 92 patients undergoing elective repair. One of 8 patients undergoing emergency repair of a ruptured aneurysm died in the operating room. The overall hospital mortality rate was 1%. There have been ten late deaths among the 99 hospital survivors (10.1%). Five deaths occurred among the first 11 patients in this series and five occurred among the last 88 patients (5.7%). Three late deaths resulted from composite graft endocarditis; 3 other patients with endocarditis are alive after aortic root replacement with cryopreserved homografts. Late coronary dehiscence caused death in 1 patient and was successfully repaired in a second. Actuarial survival for the 100 patients was 92.6% at 5 years and 75.8% at 10 years. Currently, composite graft repair of Marfan aneurysms of the ascending aorta can be performed with low hospital and late mortality. Marfan aneurysms with a diameter of 6 cm or greater should be repaired with the Bentall composite graft procedure, even if the patient is asymptomatic.

Adolescent↗
PubMed1991

The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3.

The Marfan syndrome is a common autosomal dominant disorder of connective tissue. Despite many years of intensive investigation, the primary genetic defect has not yet been identified. Reverse genetic methods, targeted at mapping this disease gene, have resulted in an initial report of linkage of the genetic locus for the Marfan phenotype in Finnish families to two polymorphic markers on chromosome 15. We have investigated four large multiplex American families with classic Marfan syndrome using standard genetic linkage methods. Our data confirm the assignment of the Marfan syndrome gene to chromosome 15, but establish a more centromeric location (defined by markers D15S25 and D15S1) as the most probable site for the genetic defect (lod score = 12.1, theta = 0.00). These data should facilitate identification and characterization of the Marfan syndrome gene and, in selected families, have immediate application to diagnosis of equivocal cases or prenatal counseling.

Chromosome Mapping↗
PubMed1991

Analysis of the chondroitin sulfate proteoglycan core protein (CSPGCP) gene in achondroplasia and pseudoachondroplasia.

Achondroplasia and pseudoachondroplasia are autosomal dominant skeletal dysplasias resulting in short-limbed dwarfism. Histologic and ultrastructural studies of the cartilage in pseudoachondroplasia and in homozygous achondroplasia have suggested a structural abnormality in chondroitin sulfate proteoglycan (CSPG), a major structural protein in the extra-cellular matrix. The gene encoding CSPG core protein (CSPGCP) is thus a logical "candidate gene" for analysis in these conditions. cDNA probes encoding CSPGCP were used to identify restriction fragment length polymorphisms (RFLPs) in DNA from a panel of control individuals. No gross alterations at the CSPGCP locus were noted in DNA from 37 individuals with achondroplasia and 5 individuals with pseudoachondroplasia. In addition, allelic frequencies of the RFLPs were not significantly different among controls and patients with either condition. In one three-generation family with achondroplasia, close linkage of the CSPGCP locus and the skeletal dysplasia was excluded using a Bgl II polymorphism. Similarly, in a three-generation family with pseudoachondroplasia, the CSPGCP gene was not tightly linked to the disease phenotype. These results indicate that mutations at the chondroitin sulfate proteoglycan core protein locus do not cause achondroplasia or pseudoachondroplasia in these families.

Achondroplasia↗
PubMed1991

Marfan syndrome: no evidence for heterogeneity in different populations, and more precise mapping of the gene.

Marfan syndrome is a dominantly inherited connective tissue disorder with manifestations in the cardiovascular, ocular, and skeletal systems. The diagnosis is hampered by both high variability in the phenotypic expression and late manifestation of symptoms. The cause of Marfan syndrome remains unknown, but our group has recently reported the genetic linkage of Marfan syndrome to a polymorphic marker on chromosome 15. To analyze the possible heterogeneity behind Marfan syndrome, we have performed linkage analyses for four chromosome 15 markers in 17 families from five different populations: Scottish, English, Swiss, American, and Finnish. By combining the linkage data of all the studied families into a LINKMAP analysis we obtained a maximal LOD score of 11.2, which maps the Marfan syndrome locus between D15S25 and D15S45 on the long arm of chromosome 15. The data reveal no evidence for genetic heterogeneity behind Marfan syndrome and provide us with a more precise location of both the Marfan syndrome locus and flanking markers. This information will provide the basis for the DNA diagnostics of Marfan syndrome in the future.

Chromosome Mapping↗
PubMed1991

Clinical management of the cardiovascular complications of the Marfan syndrome.

The Marfan syndrome is an autosomal dominant disorder of connective tissue with manifestations throughout the body. Diagnosis is based on the cardinal effects on the skeletal, ocular, and cardiovascular systems. Long limbs and digits, thoracic cage deformity, dislocation of the ocular lens, mitral valve prolapse, and dilatation of the aortic root are typical signs. Before recent advances in management, valvular regurgitation and aortic dissection accounted for over 90 percent of deaths, often in the third through fifth decades of life. Echocardiography, introduced nearly 2 decades ago, and the recent enhancements of cardiovascular Doppler techniques have greatly improved the ability of identifying patients with Marfan syndrome and following their clinical courses. Cardiovascular surgery has progressed over the same period to provide Marfan patients relatively safe approaches to repair of the life-threatening complications, and surgery should be offered prophylactically. The ability to intervene effectively in the Marfan syndrome requires a clear understanding of its natural history throughout life. This review discusses the clinical course and current management of the cardiovascular complications of the Marfan syndrome in children, young adults, and women considering pregnancy. These approaches have relevance to valvular and aortic problems found in the general population.

Aortic Aneurysm↗