Actin mutations in dilated cardiomyopathy, a heritable form of heart failure.

To test the hypothesis that actin dysfunction leads to heart failure, patients with hereditary idiopathic dilated cardiomyopathy (IDC) were examined for mutations in the cardiac actin gene (ACTC). Missense mutations in ACTC that cosegregate with IDC were identified in two unrelated families. Both mutations affect universally conserved amino acids in domains of actin that attach to Z bands and intercalated discs. Coupled with previous data showing that dystrophin mutations also cause dilated cardiomyopathy, these results raise the possibility that defective transmission of force in cardiac myocytes is a mechanism underlying heart failure.

Physical mapping of a translocation breakpoint in neurofibromatosis.

The gene for von Recklinghausen neurofibromatosis (NF1), one of the most common autosomal-dominant disorders of humans, was recently mapped to chromosome 17 by linkage analysis. The identification of two NF1 patients with balanced translocations that involved chromosome 17q11.2 suggests that the disease can arise by gross rearrangement of the NF1 locus, and that the NF1 gene might be identified by cloning the region around these translocation breakpoints. To further define the region of these translocations, a series of chromosome 17 Not I-linking clones has been mapped to proximal 17q and studied by pulsed-field gel electrophoresis. One clone, 17L1 (D17S133), clearly identifies the breakpoint in an NF1 patient with a t(1;17) translocation. A 2.3-megabase pulsed-field map of this region was constructed and indicates that the NF1 breakpoint is only 10 to 240 kilobases away from 17L1. This finding prepares the way for the cloning of NF1.

Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology.

We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.

Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1.

Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colorectal cancer and in a large number of sporadic tumors. To further characterize the type of alterations at these loci and their frequency of involvement in colon cancer, we studied DNA extracted from paraffin-embedded tissue from 508 patients using 11 microsatellites localized to chromosomes 5, 8, 15, 17, and 18. Overall, MSI at each locus varied in character and frequency and was observed with at least one marker in 191 cases (37.6%). Based on the number of markers displaying instability per tumor, three groups of patients were defined: those with <30% of the markers showing instability (MSI-L,, n = 109, 21.5%); those with > or = 30% (MSI-H, n = 82, 16.1%); and those showing no instability (MSS, n = 317, 62.4%). These groups were tested for correlations with a number of clinical and pathological parameters, including age, sex, stage, ploidy status, and site of tumor. Comparing across the three groups and verified by pair-wise comparisons, the MSI-H group was associated with tumor site (proximal colon, P = 0.001), sex (females, P = 0.005), stage (Dukes' B, P = 0.01), and ploidy status (diploid, P = 0.03). No significant differences were noted between the MSI-L and MSS group for any of the parameters tested. An additional 188 consecutive surgical colorectal cancer cases were examined for the presence of MSI and for the immunohistochemical expression of hMLH1 and hMSH2 proteins. Of this group, 129 (68.6%) were classified as MSS, 17 (9.0%) as MSI-L, and 42 (22.3%) as MSI-H. None of the MSS and none of the MSI-L tumors had altered expression of either hMLH1 or hMSH2. However, the majority of MSI-H (40 of 42, 95%) cases demonstrated absence of staining for these proteins. The most frequently altered protein was hMLH1, occurring in 95% of the tumors with altered expression. Cumulatively, these data suggest that the tumor phenotype MSI-H is distinct from tumor phenotypes MSI-L and MSS, with no apparent differences between MSI-L and MSS. Furthermore, altered hMLH1 protein expression appears to be responsible for the mutator phenotype in the vast majority of MSI-H tumors.

Spectrum of findings in a family with nonsyndromic autosomal dominant supravalvular aortic stenosis: a Doppler echocardiographic study.

Nonsyndromic familial supravalvular aortic stenosis is an autosomal dominant disorder. However, for many reported families, systematic study of all family members with echocardiographic or hemodynamic techniques has not been performed and degree of penetrance has not been assessed. The supravalvular stenosis in these family members usually is not associated with mental retardation or other characteristics of Williams syndrome. Although some believe that autosomal dominant supravalvular aortic stenosis is part of the spectrum of Williams syndrome, others believe that these are separate entities. Doppler echocardiograms were analyzed on 23 members of a 34 member family with several known to have supravalvular aortic stenosis; 20 studies were performed by the authors and 3 were done elsewhere and made available for review. No family member had mental retardation, characteristic facies or other findings of Williams syndrome. Three of the 34 had supravalvular aortic stenosis requiring surgery. Of 22 members examined echocardiographically who had not had prior surgical repair, 13 had supravalvular aortic stenosis. Echocardiographic findings ranged widely, from calcification of the ascending aorta in a 71 year old man with minimally increased flow velocity (1.7 m/s) to mild narrowing with mildly increased flow velocity in six members to significant narrowing with impressively increased flow velocity (2 to 4 m/s) in seven. In addition, four patients had mild narrowing of pulmonary artery branches and eight had peak pulmonary artery flow velocity above normal. This study demonstrates complete penetrance with extremely variable expression in this family with autosomal dominant supravalvular aortic stenosis and emphasizes the importance of using echocardiographic techniques in studying the family members who are suspected of having an inherited cardiovascular disease.

Sodium-lithium countertransport and hypertension in Rochester, Minnesota.

The objectives of the present study were to determine whether increased sodium-lithium countertransport is associated with essential hypertension in the general Caucasian population and to determine whether this association is independent of the effects of gender, age, body size, and plasma lipids. We studied 543 men and 589 women from the population of Rochester, Minnesota. Mean sodium-lithium countertransport was higher in hypertensive than in normotensive subjects in men (370 +/- 147 [mean +/- SD] versus 315 +/- 110 mumol/l red blood cells [RBC]/hr, p less than 0.001) and in women (339 +/- 114 versus 269 +/- 92 mumol/l RBC/hr, p less than 0.001). Interindividual differences in plasma triglycerides, body mass index (wt/[ht]2), and plasma total cholesterol explained 13.0% of sodium-lithium countertransport variation in men (p less than 0.001) and 20.2% in women (p less than 0.001). Age did not predict additional sodium-lithium countertransport variation in either gender. Slopes of the regressions of sodium-lithium countertransport on plasma triglycerides, body mass index, and plasma total cholesterol did not differ between diagnostic groups in men (p = 0.31) or in women (p = 0.29). After adjustment to remove sodium-lithium countertransport variation attributable to these covariates, mean sodium-lithium countertransport remained significantly higher in hypertensive than in normotensive subjects in men (354 +/- 139 versus 319 +/- 104 mumol/l RBC/hr, p less than 0.01) and in women (311 +/- 103 versus 278 +/- 83 mumol/l RBC/hr, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of sodium-lithium countertransport and blood pressure in Caucasians five to eighty-nine years of age.

Case-control studies suggest that increased erythrocyte sodium-lithium countertransport may predict increased susceptibility to the development of essential hypertension. To characterize interindividual variation in sodium-lithium countertransport and its relation to blood pressure levels in the general population, we studied 1,475 Caucasians between 5 and 89 years of age (711 males and 764 females) ascertained through 266 households with children in the schools of Rochester, Minnesota. Individuals who were taking antihypertensive agents or combinations of estrogen and progesterone were not included in the sample. A third-order polynomial regression on age accounted for only a small fraction of variability in sodium-lithium countertransport (2.8% in males, p less than 0.001; 2.1% in females, p less than 0.01), whereas a fourth-order regression on age accounted for a large proportion of variability in systolic blood pressure (45.7% in males, p less than 0.001; 52.5% in females, p less than 0.001) and diastolic blood pressure (39.8% in males, p less than 0.001; 33.0% in females, p less than 0.001). Mean sodium-lithium countertransport was higher in males than females at all ages; but the rank order of male and female means for systolic and diastolic blood pressure was age dependent. Positively skewed distributions for age-, height-, and weight-adjusted sodium-lithium countertransport in male and female cohorts between 5-19.9, 20-49.9, and 50-89.9 years of age were explained significantly better by postulating a mixture of two partially overlapping sodium-lithium countertransport distributions rather than a single normal distribution (p less than 0.01). Among men in the 20-49.9-year-old cohort, adjusted sodium-lithium countertransport values in the upper distribution were associated with higher systolic and diastolic blood pressure (mean +/- SD) than values in the lower distribution (for systolic blood pressure: 115 +/- 11 vs. 111 +/- 11 mm Hg, p less than 0.07; for diastolic blood pressure: 71.2 +/- 8.0 vs. 68.4 +/- 8.6 mm Hg, p less than 0.08). Among females in the 50-89.9-year-old cohort, adjusted sodium-lithium countertransport values in the upper distribution were associated with significantly greater diastolic blood pressure than values in the lower distribution (77 +/- 10 vs. 70 +/- 9 mm Hg, p less than 0.03).(ABSTRACT TRUNCATED AT 400 WORDS)

A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma.

We describe a family in which cutaneous malignant melanoma or cerebral astrocytoma, or both, developed in eight members over three generations. Other malignancies also occurred with a lesser frequency. In two patients with both malignant melanoma and astrocytoma, the brain tumor followed the diagnosis of melanoma by a period of 2 and 10 years and was the primary cause of morbidity and mortality. The findings in this family may represent a newly described genetic disorder.

Heritable connective tissue disorders in cervical artery dissections: a prospective study.

We prospectively evaluated 15 consecutive patients with spontaneous cervical artery dissections. Three patients (20%) had a heritable connective tissue disorder, each with a unique phenotype. None of these patients met the criteria of any of the named syndromes, and collagen and fibrillin analyses were normal. Heritable connective tissue disorders are common among patients with spontaneous cervical artery dissections, but, despite intensive investigations, the type of disorder usually cannot be identified. The underlying arteriopathy in cervical artery dissections is likely to be heterogeneous.

Umbilical morphology: normal values for neonatal periumbilical skin length.

Malformations of the umbilicus are a feature of many dysmorphic syndromes including Rieger syndrome, Robinow syndrome, and Aarskog syndrome. The characteristic umbilical malformation in Rieger syndrome consists of redundant periumbilical skin which extends along the cord for an excessive distance. Although the measurement of umbilical skin length plays an important role in the neonatal diagnosis of Rieger syndrome, normal values for this measurement in healthy neonates have not been established. Umbilical skin length was measured in 104 healthy neonates. The length to which the umbilical skin extended along the cranial aspect of cord (mean 11.53 mm, SD 3.58) was significantly longer than the umbilical skin length along the caudal aspect (mean 8.71 mm, SD 2.89) (P less than .05). Multiple regression analysis revealed a significant association between age and umbilical skin length. Birth weight, length, and gestational age were not significantly associated with umbilical skin length when adjusted for the other three variables. No significant differences in umbilical skin length were observed between male and female groups. The above normal values should aid in the neonatal diagnosis of Rieger syndrome, and furthermore it is recommended that cranial umbilical skin length measurement be included in the examination of the dysmorphic child.

Velo-cardio-facial syndrome associated with ventricular septal defect, pulmonary atresia, and hypoplastic pulmonary arteries.

We report on 15 patients with velo-cardiofacial syndrome who had a severe form of tetralogy of Fallot (pulmonary atresia, ventricular septal defect, and hypoplastic pulmonary arteries). Noncardiac anomalies in these patients included typical facial and ear anomalies in 15, nasal speech in 13, palate anomalies in 10, and developmental delay in 10. Seven patients had significant bronchospasm, which has not been reported in association with the velo-cardio-facial syndrome. All 15 patients had severe abnormalities of the arborization of the pulmonary arterial tree, which also has not been reported in velo-cardio-facial syndrome. All patients underwent staging operations to prepare the true pulmonary vascular tree for complete repair of the defect (five underwent complete repair and three survived). Of the remaining 10 patients, 6 are awaiting further operation, 3 are not candidates for complete repair, and 1 has died.

Occurrence of congenital heart defects in siblings of patients with univentricular heart and tricuspid atresia.

Because of the rarity of univentricular heart and tricuspid atresia, no study of a large number of patients has been made to determine the empiric occurrence risks of a congenital heart defect in their siblings. A retrospective chart review was performed of 223 patients with univentricular heart and 113 with classic tricuspid atresia evaluated from 1982 to 1987. Thirty-four patients with univentricular heart and 17 with tricuspid atresia had no siblings and were excluded. Eleven of the total 388 siblings (2.8%) of the 189 patients with univentricular heart had a congenital heart defect. Of the siblings born after the index case of univentricular heart, 7 of 169 (4.1%) had a congenital heart defect. Two of the 210 siblings (1.0%) of the 96 patients with tricuspid atresia had a congenital heart defect. The patients with univentricular heart were subdivided into 4 groups: (1) double-inlet left ventricle; (2) complex univentricular heart with single or common inlet, or with a ventricle of common or right ventricular morphology; (3) complex univentricular heart with asplenia; and (4) complex univentricular heart with polysplenia. One of the 202 siblings (0.5%) of the 102 patients with double-inlet left ventricle had a congenital heart defect, compared with 7 of the 140 siblings (5.0%) of the 69 patients with complex univentricular heart, 1 of the 29 siblings (3.4%) of the 14 patients with complex univentricular heart and asplenia, and 2 of the 7 siblings (28.6%) of the 4 patients with complex univentricular heart and polysplenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute workshop.

Idiopathic dilated cardiomyopathy (IDC) is the primary indication for cardiac transplantation, with associated costs of approximately $177 million per year. Recognizing the economic implications of IDC, the increasing incidence, and the limited information on pathogenesis and prognosis, the National Heart, Lung, and Blood Institute convened a workshop on the Prevalence and Etiology of Idiopathic Dilated Cardiomyopathy on June 13 to 14, 1991. The difficulties of studying the disease were reviewed, including its relatively low prevalence, its potentially pluricausal nature, and the fact that it is often a diagnosis of exclusion. Still, it presents significant challenges to the cardiovascular scientific community, since the mechanism of myocardial damage and related etiologic and prognostic factors are virtually unknown. The development of more reliable measures of immune-mediated damage and noninvasive measures of impaired cardiac function present new research opportunities in this disorder. Standardized diagnostic criteria for use in observational and interventional trials were developed, and priorities for future research were proposed. Population-based registries and nested case-control studies, where feasible, are appropriate study designs for tracking incidence and prevalence, and for identifying risk factors, respectively. Interventional studies should focus on secondary prevention, through modifying immune-mediated damage in clinically evident dilated cardiomyopathy, and through prevention of sudden death in patients with the disorder. Primary prevention trials must await the identification of modifiable risk factors and of appropriate and effective interventions.

Fragile sites on human chromosomes: description and clinical significance.

The fragile sites of human chromosomes are specific sites that are characterized by a tendency to show gaps, multiradial figures, acentric fragments, and deleted chromosomes on microscopy. These characteristics seem to reflect an inherent fragility at the site, although the underlying biochemical cause of fragile sites is unknown. Investigators have proposed several categories of fragile sites: "rare" or "heritable," "common," and "constitutive." Although the clinical significance of most fragile sites is unknown, fragile site Xq27.3 is associated with one form of X-linked mental retardation. In this article, the three types of chromosome fragile sites are described, and their possible relevance to chromosomal breakage that results in birth defects or cancer is discussed.

Childhood-onset schizophrenia associated with parkinsonism in a patient with a microdeletion of chromosome 22.

The deletion of a gene or genes on chromosome 22q11 is responsible for the velocardiofacial syndrome (VCFS), which is associated with cardiac anomalies, short stature, palate abnormalities, learning disabilities, and developmental delay. Herein we describe a 30-year-old man with VCFS in whom a chronic psychotic disorder originated during childhood. A 10% rate of psychotic disorders has been reported in association with this genetic syndrome. In our patient, the clinical manifestation was complicated by extrapyramidal symptoms that predated the onset of psychotic symptoms. To our knowledge, extrapyramidal symptoms have not previously been reported in a patient with VCFS. The diagnosis of VCFS was confirmed with the fluorescence in situ hybridization probe for VCFS. The role of the atypical antipsychotic drug clozapine is discussed with respect to treating this patient who has severe psychotic symptoms coexisting with extrapyramidal symptoms and seizures. In light of the observation that patients with VCFS have an unexpectedly high rate of psychotic disorders, issues concerning the genetics of schizophrenia are intriguing.

von Hippel-Lindau disease.

An autosomal dominant tumor predisposition syndrome, von Hippel-Lindau disease (VHL) is characterized by the presence of benign and malignant tumors. Hallmark lesions include retinal angiomas, hemangioblastomas of the cerebellum and spinal cord, and renal cell carcinomas. Affected persons may also have angiomatous or cystic lesions of the kidneys, pancreas, and epididymis, as well as adrenal pheochromocytomas. In this article, we discuss the clinical features and diagnostic criteria for this clinically underdiagnosed condition. An update on recent findings regarding the molecular genetics of VHL is provided, including a discussion of the evolving understanding of genotype-phenotype correlations. Understanding the molecular and functional aspects of this condition will lead to the development of strategies for the management and treatment of inherited and sporadic VHL-associated tumors.

Tracking and prediction of blood pressure in children.

A significant but weak correlation between an initial and a subsequent blood pressure measurement in the same patient has been found in several previous longitudinal studies of blood pressure in children. In the current study, single determinations of blood pressure, weight, and height were recorded in 142 children at 5.9 to 9.5 years of age and again 9 years later. Both examinations were performed in a schoolroom. Body size at the first examination was associated with body size 9 years later. A significant correlation was noted between initial and subsequent raw systolic blood pressures (r = 0.36 in boys and in girls; P less than 0.01). Correlations of systolic blood pressure based on percentiles for age and for height and weight were smaller but also statistically significant. Correlations involving diastolic blood pressure, with use of raw blood pressure measurements, were significant only for boys (r = 0.24, P less than 0.05). Correlations were not improved when indices of body size were used. Single blood pressure measurements obtained under the usual conditions in a schoolroom had only slightly weaker correlations with subsequent blood pressure determinations than those obtained in studies in which considerable care was taken to achieve more "basal" measurements. This degree of blood pressure correlation is insufficient to allow accurate prediction of subsequent blood pressure levels on the basis of a single casual blood pressure measurement in an individual child. This result was indicated by a wide 95% confidence interval for the predicted subsequent systolic blood pressure, even when sex, initial diastolic blood pressure, weight, and change in weight were considered.

DNA fluorescent probes for diagnosis of velocardiofacial and related syndromes.

OBJECTIVE: To study the usefulness of fluorescent in situ hybridization (FISH) with the DNA probe D22S75 for detecting microdeletions in chromosome 22q11.2 in metaphases from patients with features of "CATCH 22" (cardiac anomalies, abnormal facies, thymic hypoplasia or aplasia, cleft palate, and hypocalcemia). METHODS: High-resolution chromosome analysis and FISH were performed on metaphases from 10 control subjects, 42 patients with features of CATCH 22, and 6 parents of children with CATCH 22. Patients were screened for conotruncal heart defect, palatal abnormality, and facial features. We correlated the phenotype, karyotype, and deletion of a D22S75 locus. RESULTS: Specimens from nine patients with one or more features of CATCH 22 had a single hybridization signal for D22S75, indicating a deletion of chromosome 22q11.2. Four patients had all the major features of the syndrome and a chromosomal deletion. Thirteen patients had two CATCH 22 features, five of whom had a deletion. None of the 25 patients with a single CATCH 22 feature had a deletion. One patient with a deletion detected by FISH also had a deletion noted on high-resolution banding. All six parents who had blood samples studied by FISH had normal hybridization patterns. CONCLUSION: FISH is a useful adjunct to chromosome analysis for assessing patients with features of CATCH 22. Detecting a chromosomal deletion by FISH provides a definitive diagnosis and helps to ensure appropriate medical management and genetic counseling.

Levels of lipids, lipoproteins, and apolipoproteins in a defined population.

As part of a large cross-sectional investigation--the Rochester Family Heart Study--plasma levels of lipids, lipoproteins, and apolipoproteins were measured in a sample from the general population of male and female subjects who ranged in age from 5 to 90 years. Polyclonal radioimmunoassays developed at the Mayo Clinic were used for measurement of apolipoproteins A-I, A-II, C-II, C-III, and E, whereas a monoclonal enzyme-linked immunosorbent assay was used for apolipoprotein B. On the basis of 984 subjects who reported that they were fasting, were not pregnant, had never smoked, and were taking no medications thought to influence lipid levels, we determined age- and gender-specific percentiles for plasma levels of cholesterol, triglycerides, high-density lipoprotein cholesterol, and six apolipoproteins. These percentiles will facilitate identification of persons who are in the highest and lowest percentiles for their age and gender. The levels of the apolipoproteins varied for both age and gender. This is the first study to provide a reference sample for plasma levels of these apolipoproteins for male and female subjects 5 to 90 years of age selected from the general population.

Carrier identification of cystic fibrosis by recombinant DNA techniques.

As a result of recent advances in molecular genetics, carrier testing for cystic fibrosis (CF) is now available as a clinical assay in a limited number of laboratories. Because neither the gene nor the mutation for this disorder has yet been defined, the analysis relies on an indirect approach that uses DNA sequence polymorphisms and linkage analysis. With use of this general approach, several family members, in addition to those persons seeking carrier information, must be tested. Currently, more than 97% of families are "fully informative" when these markers are used in a linkage analysis; thus, the carrier status of most persons who have a relative with CF can be determined. Recently, strong linkage disequilibrium has been shown between two polymorphic loci (defined by the DNA probes KM.19 and XV-2c) and the CF locus. Because of this important finding, haplotype testing can be used in many clinical settings, such as for families in which a DNA sample is not available from the affected person or for those families in which one spouse has no family history of CF and the other is either affected or is at a high risk of carrying the CF mutation. Overall, the application of recombinant DNA techniques has greatly enhanced the ability to determine, with a high level of accuracy, the carrier status of those persons at risk for inheriting the CF mutation.