Maureen Boxer

Life expectancy in the Marfan syndrome

Data reported in 1972 indicated that lifespan in patients with the Marfan syndrome is markedly shortened, and that most deaths are cardiovascular. This study was performed to determine whether survival in the Marfan syndrome has changed since 1972, and to discern whether treatment (medical or surgical) has altered prognosis. Survival curves were generated on 417 patients from 4 referral centers, with a definite diagnosis of the Marfan syndrome. Birth date, age at death, cardiovascular surgery, or treatment with beta blockers, or any combination of these, were included in the analysis. Forty-seven of 417 patients died. Mean age at death (41 +/- 18 years) was significantly increased compared with age in 1972 (32 +/- 16 years, p = 0.0023). Median (50%) cumulative probability of survival in 1993 was 72 years compared with 48 years in 1972. Of 112 surgically treated patients, 10-year probability of survival was 70%. Patients undergoing surgery after 1980 enjoyed significantly increased survival than patients who had undergone operation before 1980 (p = 0.008). In conclusion, life expectancy for patients with the Marfan syndrome has increased > 25% since 1972. Reasons for this dramatic increase may include (1) an overall improvement in population life expectancy, (2) benefits arising from cardiovascular surgery, and (3) greater proportion of milder cases due to increased frequency of diagnosis. Medical therapy (including beta blockers) was also associated with an increase in probable survival.

Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias.

Congenital familial non-haemolytic hyperbilirubinaemias are potentially lethal syndromes caused by genetic lesions that reduce or abolish hepatic bilirubin UDP-glucuronosyltransferase activity. Here we describe genetic defects that occur in the UGT1 gene complex that cause three non-haemolytic unconjugated hyperbilirubinaemia syndromes. The most severe syndrome, termed Crigler-Najjar syndrome type I, is mainly associated with mutations in exons 2 to 5 that affect all UGT1 enzymes and many of the mutations result in termination codons and frameshifts. Crigler-Najjar type II syndrome which is treatable with phenobarbital therapy is associated with less dramatic missense mutations or heterozygous expression of mutant and normal alleles. Gilberts syndrome, the most prevalent (2-19% in population studies) and mildest of the three syndromes is principally caused by a TA insertion at the TATA promoter region upstream of the UGT1A1 exon. Current methods used for the diagnosis and treatment of these diseases are discussed.

Family history of severe cardiovascular disease in Marfan syndrome is associated with increased aortic diameter and decreased survival

OBJECTIVES We attempted to determine whether a family history of severe cardiovascular disease in patients with the Marfan syndrome is associated with increased aortic dilation or decreased survival, or both. BACKGROUND The prognostic importance of a family history of severe cardiovascular disease in patients with the Marfan syndrome has been incompletely examined. We hypothesized that such a family history would correlate with increased aortic dilation and would be associated with decreased survival. METHODS One hundred eight affected patients and 48 unaffected family members from 33 multigenerational families with the Marfan syndrome underwent echocardiographic measurement of the aortic root, arch and mid-abdominal aorta. Date of birth and age at death ascertained from family pedigrees were used to perform life table analysis and estimate survival. RESULTS Aortic root and arch diameters were significantly greater in patients with a family history of severe cardiovascular disease than in patients without such a family history. Of subjects in the highest quartile for aortic size, > 80% had such a family history in contrast to < 10% of those in the lowest quartile (chi-square 57.37, p < 0.00001). Mean age at death and cumulative probability of survival were significantly lower in patients with such a family history. CONCLUSIONS Among patients with the Marfan syndrome, aortic dilation is greater and life expectancy shorter in those with a family history of severe cardiovascular manifestations. These data suggest that such a family history is an important risk factor for cardiovascular events in patients with the Marfan syndrome.

Ascertainment and severity of Marfan syndrome in a Scottish population.

This study in north east Scotland has shown that Marfan syndrome has a minimal birth incidence of 1:9802 live births, a minimal prevalence of 1:14217, and that 8/30 (26.7%) of cases in our series are new mutations. The calculated mutation rate is 15 +/- 6.7 x 10(-6) and there is evidence of reduced reproductive fitness.

Life expectancy in British Marfan syndrome populations

A total of 206 patients with Marfan syndrome were ascertained throughout genetic clinics in Wales and Scotland during the period 1970–1990. There were 45 deaths representing 22% of the cohort. Mean age at death was 45.3 ± 16.5 years. 50% median cumulative survival in the total cohort (n = 206) was 53 years for males and 72 years for females. Multivariate analysis confirmed severity as the best independent indicator of survival. These findings and survival curves will assist in the counselling of British families and individuals with Marfan syndrome.

Marfan Database (second edition): software and database for the analysis of mutations in the human FBN1 gene.

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS. These mutations are private, essentially missense, generally non-recurrent and widely distributed throughout the gene. To date no clear genotype/phenotype relationship has been observed excepted for the localization of neonatal mutations in a cluster between exons 24 and 32. The second version of the computerized Marfan database contains 89 entries. The software has been modified to accomodate new functions and routines.

Structure of the human UGT2B4 gene encoding a bile acid UDP-glucuronosyltransferase

Glucuronidation, a major phase II conjugation reaction in the mammalian detoxification system, is catalyzed by the UDPglucuronosyltransferases (UGTs; Burchell and Coughtrie 1989). This family of isoenzymes (50-60 kDa) is localized mainly in hepatic endoplasmic reticulum and nuclear envelope and has discrete but overlapping substrate specificities that permit the conversion of a large range of toxic endogenous and xenobiotic compounds to more water-soluble forms for subsequent excretion (Tephly and Burchell 1990). UGT expression is differentially regulated by chemicals, hormonal inducers and during development, which results in different tissue-specific profiles of activity (Burchell and Conghtrie 1989). A reduction or absence of UGT activity has been observed in the inherited hyperbilimbinemias, Gilberts and Crigler-Najjar syndromes, and has been implicated in adverse drug reactions (Burchell and Coughtrie 1989). Several mammalian UGT cDNAs have been cloned, and two subfamilies (UGT1 & UGT2) have been identified from their amino acid sequence identities (Burchell et al. 1991). The human UGT1 isoenzymes, catalyzing the glucuronidation of phenols and bilirubin, are thought to be generated by the differential splicing of a single mRNA transcript encoded by the UGT1 gene complex (Ritter et al. 1992b). The UGT2 subfamily has been further subdivided into the UGT2A (olfactory-specific isoforms) and the UGT2B (steroid/bile acid-sl~ecific isoforms of the liver). To date, no human UGT2A cDNAs have been isolated, but 10 distinct UGT2B cDNAs laave been isolated in different laboratories (see Harding et al. 1988; Jin et al. 1993; Ritter et al. 1992a). It is not clear whether the human UGT2B cDNAs, encoding isoenzymes that specifically catalyze the glucuronidation of steroids and bile acids, are derived from a gene complex (as in the case of the UGT1 isoforms) or from independent genes. Primers specific for four of the human UGT2B cDNAs (UGT2B4, UGT2B8, UGT2B9, UGT2B 15) were used in conjunction with the polymerase chain reaction (PCR), a panel of human/ rodent somatic cell hybrid DNAs, yeast artificial chromosome (YAC) technology, and fluorescent in situ hybridization (FISH) to localize the human UGT2B gene(s) to Chr 4q13 (Monaghan 1994; Monaghan et al. 1994). The use of UGT2B4, UGT2B9, and UGT2B15-specific primers for the amplification of UGT2Bcontaining yeast artificial chromosome (YAC) DNAs revealed that the gene(s) are localized within a 195 kb region of the genome (Monaghan et al. 1994). Sequence differences that occur along the entire length of the human UGT2B cDNAs (unlike UGT1 cDNAs) strongly suggest that the UGT2B isoenzymes are encoded by independent genes rather than a gene complex. The existence of independent UGT2B genes in the rat has been demonstrated (Haque et al. 1991). Aligning the genomic sequences of two rat genes revealed that the positional location of introns has been conserved. Data presented here will show that the human UGT2B4

Chromosomal assignment of human phenol and bilirubin UDP‐glucuronosyltransferase genes (UGT1A‐subfamily)

DNA probes were prepared from the 5′ ‐terminal portion of four cDNA clones encoding human phenol and bilirubin UDP‐glucuronosyltransferases (UGTs). An additional sequence common to all four clones was isolated from the 3′ ‐terminal portion of one of the clones (UGT1A1).

A novel de novo mutation in exon 14 of the fibrillin-1 gene associated with delayed secretion of fibrillin in a patient with a mild Marfan phenotype.

Abstract The Marfan syndrome, an autosomal dominant heritable disorder of connective tissue, is caused by mutations in the gene for fibrillin-1, FBN1. A novel FBN1 mutation was identified using temperature-gradient gel electrophoresis of a reverse-transcribed polymerase chain reaction product spanning exons 14 to 16. The mutation, G1760A, is predicted to result in the amino acid substitution C587Y and thus to disrupt one of the disulfide bonds of the calcium-binding epidermal growth factor-like module encoded by exon 14. C587Y was found to be a de novo mutation in a relatively mildly affected 15-year-old girl whose clinical phenotype was characterized mainly by ectopia lentis and thoracic scoliosis. Metabolic labeling of cultured dermal fibroblasts from the affected patient demonstrated delayed secretion of fibrillin with normal synthesis and no decrease in incorporation into the extracellular matrix compartment. Fibrillin immunostaining of confluent dermal fibroblast cultures revealed no visible difference between the patient’s cells and control cells. Characterization of many different FBN1 mutations from different regions of the gene may provide a better understanding of clinical and biochemical genotype-phenotype relationships.

A linkage map of 10 loci flanking the Marfan syndrome locus on 15q: results of an International Consortium study.

Members of an International Consortium for Linkage Analysis of the Marfan Syndrome (MFS1) have pooled data for joint analysis in an attempt to determine the precise location of the MFS1 gene and the order of 10 DNA markers on 15q. Five laboratories performed a total of 2111 genotypes in 22 families consisting of 225 affected and 248 normal subjects. For each marker a mean of 98 meioses was informative. D15S48 and D15S1 were identified as the closest linked markers with 99% upper confidence intervals of 12% and 13% respectively. We have used the CRI-MAP program to construct the most likely order as: D15S24-D15S25-D15S1-MFS1-D15S48-D15S49+ ++-(D15S45/S51)-(D15S29/S38). Placement of D15S2 in relation to -D15S1-D15S48- cannot be determined with certainty. The genetic map of these markers extends 53.6 cM in males and 65.0 cM in females with a sex averaged map of 60.7 cM. The sex difference was statistically significant (p = 0.005). Linkage heterogeneity between 22 MFS1 families was documented (p = 0.009) necessitating the exclusion of one family from the analysis. However, comparison of the remaining 21 families for two point and multipoint lod scores showed no evidence for linkage heterogeneity of the MFS1 locus.