Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy

BACKGROUND: Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown. METHODS: DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed. RESULTS: Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly. CONCLUSIONS: The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy.     

Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy

Five disease genes encoding sarcomeric proteins and associated with familial and classical forms of hypertrophic cardiomyopathy have been determined since 1989. In 1996 two other genes encoding ventricular regulatory and essential myosin light chains were shown to be associated with a particular phenotype of the disease characterized by mid left ventricular obstruction. The aim of the present study was to search for mutations in the ventricular regulatory myosin light chain gene (MYL2), located on chromosome 12q23q24.3, in a panel of 42 probands presenting a classical phenotype of familial hypertrophic cardiomyopathy. Single-strand conformation polymorphism analysis was used to search for mutations in the coding segments of the MYL2 gene, and the abnormal products were sequenced. Two novel missense mutations, Phe18Leu in exon 2 and Arg58Gln in exon 4 were identified in three unrelated families. None of the affected patients had hypertrophy localized only at the level of the papillary muscle with mid left ventricular obstruction. By analysis of genetic recombinations, one of these mutations identified in a large family allowed us to refine the localization of the MYL2 gene on the genetic map, in an interval of 6 cM containing six informative microsatellite markers. In conclusion, we show that mutations in the MYL2 gene may be involved in familial and classical forms of hypertrophic cardiomyopathy, and we provide new tools for the genetic analysis of patients with familial hypertrophic cardiomyopathy.     

Codon 102 of the cardiac troponin T gene is a putative hot spot for mutations in familial hypertrophic cardiomyopathy

BACKGROUND: Familial hypertrophic cardiomyopathy is a phenotypically and genetically heterogeneous disease. In some families, the disease is linked to the CMH2 locus on chromosome 1q3, in which the cardiac troponin T gene (TNNT2) has been identified as the disease gene. The mutations found in this gene appear to be associated with incomplete penetrance and poor prognosis. Because mutational hot spots offer unique possibilities for analysis of genotype-phenotype correlations, new missense mutations that could define such hot spots in TNNT2 were looked for in unrelated French families with familial hypertrophic cardiomyopathy. METHODS AND RESULTS: Family members were genotyped with microsatellite markers to detect linkage to the four known disease loci. In family 715, analyses showed linkage to CMH2 only. To accurately position potential mutations on TNNT2, its partial genomic organization was established. Screening for mutations was performed by single-strand conformation polymorphism analysis and sequencing. A new missense mutation, Arg102Leu, was identified in affected members of family 715 because of a G-->T transversion located in the 10th exon of the gene. Penetrance of this new mutation is complete; echocardiographic data show a wide range of hypertrophy; and there was no sudden cardiac death in this family. CONCLUSIONS: The codon 102 of the TNNT2 gene is a putative mutational hot spot in familial hypertrophic cardiomyopathy and is associated with phenotypic variability. Analysis of more pedigrees carrying mutations in this codon is necessary to better characterize the clinical and prognostic implications of TNNT2 mutations.     

Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene

OBJECTIVES: We studied the clinical and genetic features of familial hypertrophic cardiomyopathy (FHC) caused by an Asp175Asn mutation in the alpha-tropomyosin gene in affected subjects from three unrelated families. BACKGROUND: Correlation of genotype and phenotype has provided important information in FHC caused by beta-cardiac myosin and cardiac troponin T mutations. Comparable analyses of hypertrophic cardiomyopathy caused by alpha-tropomyosin mutations have been hampered by the rarity of these genetic defects. METHODS: The haplotypes of three kindreds with FHC due to an alpha-tropomyosin gene mutation, Asp175Asn, were analyzed. The cardiac histopathologic findings of this mutation are reported. Distribution of left ventricular hypertrophy in affected members was assessed by two-dimensional echocardiography, and patient survival rates were compared. RESULTS: Genetic studies defined unique haplotypes in the three families, demonstrating that independent mutations caused the disease in each. The Asp175Asn mutation caused cardiac histopathologic findings of myocyte hypertrophy, disarray and replacement fibrosis. The severity and distribution of left ventricular hypertrophy varied considerably in affected members from the three families (mean maximal wall thickness +/- SD: 24 +/- 4.5 mm in anterior septum of Family DT; 15 +/- 2.7 mm in anterior septum and free wall of Family DB; 18 +/- 2.1 mm in posterior septum of Family MI), but survival was comparable and favorable. CONCLUSIONS: Nucleotide residue 579 in the alpha-tropomyosin gene may have increased susceptibility to mutation. On cardiac histopathologic study, defects in this sarcomere thin filament component are indistinguishable from other genetic etiologies of hypertrophic cardiomyopathy. The Asp175Asn mutation can elicit different morphologic responses, suggesting that the hypertrophic phenotype is modulated not by genetic etiologic factors alone. In contrast, prognosis reflected genotype; near normal life expectancy is found in hypertrophic cardiomyopathy caused by the alpha-tropomyosin mutation Asp175Asn.     

Familial hypertrophic cardiomyopathy: from mutations to functional defects

Hypertrophic cardiomyopathy is characterized by left and/or right ventricular hypertrophy, which is usually asymmetric and involves the interventricular septum. Typical morphological changes include myocyte hypertrophy and disarray surrounding the areas of increased loose connective tissue. Arrhythmias and premature sudden deaths are common. Hypertrophic cardiomyopathy is familial in the majority of cases and is transmitted as an autosomal-dominant trait. The results of molecular genetics studies have shown that familial hypertrophic cardiomyopathy is a disease of the sarcomere involving mutations in 7 different genes encoding proteins of the myofibrillar apparatus: ss-myosin heavy chain, ventricular myosin essential light chain, ventricular myosin regulatory light chain, cardiac troponin T, cardiac troponin I, alpha-tropomyosin, and cardiac myosin binding protein C. In addition to this locus heterogeneity, there is a wide allelic heterogeneity, since numerous mutations have been found in all these genes. The recent development of animal models and of in vitro analyses have allowed a better understanding of the pathophysiological mechanisms associated with familial hypertrophic cardiomyopathy. One can thus tentatively draw the following cascade of events: The mutation leads to a poison polypeptide that would be incorporated into the sarcomere. This would alter the sarcomeric function that would result (1) in an altered cardiac function and then (2) in the alteration of the sarcomeric and myocyte structure. Some mutations induce functional impairment and support the pathogenesis hypothesis of a "hypocontractile" state followed by compensatory hypertrophy. Other mutations induce cardiac hyperfunction and determine a "hypercontractile" state that would directly induce cardiac hypertrophy. The development of other animal models and of other mechanistic studies linking the genetic mutation to functional defects are now key issues in understanding how alterations in the basic contractile unit of the cardiomyocyte alter the phenotype and the function of the heart.     

A novel mitochondrial DNA point mutation associated with mitochondrial encephalocardiomyopathy

A novel mitochondrial DNA (mtDNA) mutation at position nt 4320 in the tRNA(Ile) gene was associated with severe encephalopathy in a 7-month-old infant, who died of intractable hypertrophic cardiomyopathy. The mutation was present in heteroplasmic fashion (88%) in muscle and fulfills accepted criteria for pathogenicity. This is the fourth pathogenic mutation identified in this gene, which appears to be a "hotspot" for deleterious mutations affecting the heart. This report adds to the evidence of genetic heterogeneity in hypertrophic cardiomyopathies.     

Early expression of a malignant phenotype of familial hypertrophic cardiomyopathy associated with a Gly716Arg myosin heavy chain mutation in a Korean family

The clinical course and prognosis of familial hypertrophic cardiomyopathy (HCM) are different according to the type of mutation in the genes for sarcomere proteins. It has been disputed that a mutation, which occurs at a functionally important region in the sarcomere proteins, may increase the penetrance and expressivity of the disease. We searched for a causative mutation in an HCM family, which is characterized by early expression of clinical phenotype, high incidence of sudden death at young ages, and progressive heart failure in adults. Among the 32 family members in 4 generations, 13 were affected; 4 died suddenly before age 16, 2 children have already had full expression of the cardiac hypertrophy, and other adults have either progressive heart failure or poor left ventricular systolic functions. PCR-SSCP (polymerase chain reaction-single strand confirmation polymorphism) analysis of genomic DNAs isolated from peripheral blood leukocytes of the family members identified a Gly716Arg mutation in the cardiac beta-myosin heavy chain gene, which was cosegregated with the clinical phenotype. The mutation is localized near a functionally important site of the myosin heavy chain, the 2 active thiols, which contribute to the adenosine triphosphatase activity of myosin S1. This family provides further evidence that the mutation, which occurs at a functionally important site of the myosin heavy chain, is associated with the high penetrance and early expression of HCM.     

A novel Phe75fsdelT mutation in the hepatocyte nuclear factor-4alpha gene in a Danish pedigree with maturity-onset diabetes of the young

Mutations in 5 different genes [the hepatocyte nuclear factor (HNF)-4alpha), glucokinase, HNF-1alpha, insulin promoter factor-1, and HNF-1beta genes] have been shown to cause maturity onset diabetes of the young (MODY). About 50% of all known MODY in Danish Caucasian MODY probands can be explained by mutations in the HNF-1alpha gene (MODY3). To estimate the prevalence of MODY caused by mutations in the HNF-4alpha gene (MODY1), we screened 10 non-MODY3 probands for mutations in the minimal promoter and the 12 exons of the HNF-4alpha gene. One of the probands had a novel frameshift mutation (Phe75fsdelT) in exon 2 of the HNF-4alpha gene, resulting in a premature termination of translation after 117 amino acids of the messenger RNA encoded by that allele. The mutation cosegregated with diabetes in the pedigree and was not detected in 84 unrelated Danish Caucasian healthy glucose-tolerant control subjects or in 84 type 2 diabetic patients. At the time of examination, 4 of 6 mutation carriers were treated with insulin and 2 with oral hypoglycemic medication. Two mutation carriers had late-diabetic complications. Even though the HNF-4alpha protein is known to be important in the regulation of genes involved in lipid metabolism, carriers of the mutation did not differ from age and sex-matched control subjects, in regard to levels of fasting serum total cholesterol, serum high-density lipoprotein-cholesterol, and serum triglyceride. In conclusion, by screening 10 non-MODY3 probands for mutations in the HNF-4alpha gene, we identified 1 diabetes-associated frameshift mutation (Phe75fsdelT), suggesting that defects in HNF-4alpha are a rare cause of MODY in Denmark.     

Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene

BACKGROUND: Little information is available on phenotype-genotype correlations in familial hypertrophic cardiomyopathy that are related to the cardiac myosin binding protein C (MYBPC3) gene. The aim of this study was to perform this type of analysis. METHODS AND RESULTS: We studied 76 genetically affected subjects from nine families with seven recently identified mutations (SASint20, SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon 25, and a duplication/deletion in exon 33) in the MYBPC3 gene. Detailed clinical, ECG, and echocardiographic parameters were analyzed. An intergene analysis was performed by comparing the MYBPC3 group to seven mutations in the beta-myosin heavy-chain gene (beta-MHC) group (n=52). There was no significant phenotypic difference among the different mutations in the MYBPC3 gene. However, in the MYBPC3 group compared with the beta-MHC group, (1) prognosis was significantly better (P<0.0001), and no deaths occurred before the age of 40 years; (2) the age at onset of symptoms was delayed (41+/-19 versus 35+/-17 years, P<0.002); and (3) before 30 years of age, the phenotype was particularly mild because penetrance was low (41% versus 62%), maximal wall thicknesses lower (12+/-4 versus 16+/-7 mm, P<0.03), and abnormal T waves less frequent (9% versus 45%, P<0.02). CONCLUSIONS: These results are consistent with specific clinical features related to the MYBPC3 gene: onset of the disease appears delayed and the prognosis is better than that associated with the beta-MHC gene. These findings could be particularly important for the purpose of clinical management and genetic counseling in familial hypertrophic cardiomyopathy.     

Absence of linkage disequilibrium at amyloid precursor protein gene locus in Japanese familial Alzheimer's disease with 717Val-->Ile mutation

To date, eleven independent early onset familial Alzheimer's disease (EOFAD) pedigrees with the 717Val-->Ile mutation of amyloid precursor protein (APP) gene have been identified. Interestingly, five pedigrees have been of Japanese origin. The apparent ethnic prediction of this mutation raises the possibility that there is a founder effect in Japan. If the hypothesis holds true, we can expect the presence of linkage disequilibrium at the APP locus. We did not, however, observe any significant linkage disequilibrium at any locus of APP or the adjacent GT12 locus in the five Japanese EOFAD probands with the 717Val-->Ile mutation. The result indicates that a founder effect would probably not be present in Japanese EOFAD pedigrees with the 717Val-->Ile mutation.     

Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young, is an autosomal dominant disease characterized by ventricular hypertrophy accompanied by myofibrillar disarrays. Linkage studies and candidate-gene approaches have demonstrated that about half of the patients have mutations in one of six disease genes: cardiac beta-myosin heavy chain (c beta MHC), cardiac troponin T (cTnT), alpha-tropomyosin (alpha TM), cardiac myosin binding protein C (cMBPC), ventricular myosin essential light chain (vMLC1) and ventricular myosin regulatory light chain (vMLC2) genes. Other disease genes remain unknown. Because all the known disease genes encode major contractile elements in cardiac muscle, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene.     

Molecular interactions in cell adhesion complexes

The mechanism(s) by which mutations in sarcomeric proteins cause hypertrophic cardiomyopathy (HCM) remains unknown. A leading hypothesis proposes that mutant sarcomeric proteins impair cardiac myocyte contractility, providing an impetus for compensatory hypertrophy. To test this hypothesis, we determined the impact of expression of a mutant (Arg92Gln) human cardiac troponin T (cTnT), known to cause HCM in humans, on adult cardiac myocyte contractility. A full-length human cTnT cDNA was cloned, and the Arg92Gln mutation was induced. Recombinant adenoviruses Ad5/CMV/cTnT-N and Ad5/CMV/cTnT-Arg92Gln were generated through homologous recombination. Adult feline cardiac myocytes were infected with recombinant adenoviruses or a control viral vector (Ad5 delta E1) at a multiplicity of infection of 100. Expression levels of the full-length normal and mutant cTnT proteins were equal on Western blots. Expression of the exogenous cTnT proteins in cardiac myocytes was also shown by immunocytochemistry and immunofluorescence, and their incorporation into myofibrils was confirmed by Western blotting on myofibrillar extracts. Electron microscopy showed intact sarcomere structure in rod-shaped cardiac myocytes in all groups. Cell fractional shortening and the peak velocity of shortening were not significantly different among the groups 24 hours after transduction. However, 48 hours after transduction, both fractional shortening and the peak velocity of shortening were significantly reduced (24% [P < .001] and 26% [P < .001], respectively) in cardiac myocytes in the Ad5/CMV/cTnT-Arg92Gln compared with the Ad5/CMV/cTnT-N groups. The magnitude of the reductions was greater at 72 hours after transduction (45% and 39%, respectively; P < .001). Our results indicated that expression of the mutant (Arg92Gln) cTnT, known to cause HCM in humans, impaired intact adult cardiac myocyte contractility. Our data also show that both normal and mutant cTnT were incorporated into myofibrils. These results provide a potential mechanism by which mutations in sarcomeric proteins cause HCM.     

Hypertensive cardiac hypertrophy--is genetic variance the missing link?

1. Hypertensive cardiac hypertrophy is a major independent predictor of adverse cardiovascular events. In man the cardiac response to increased afterload is very variable, even when ambulatory blood pressure monitoring is used. Analysis of breeding experiments using normotensive and hypertensive rat strains, human twin studies and other data indicate that genetic factors play a significant role in regulating cardiac mass; in other words, a large component of total variability is accounted for by genetic variance. 2. The observation that some patients with only mild-to-moderate hypertension exhibit gross left ventricular hypertrophy (LVH) similar to the inherited hypertrophic cardiomyopathies such as familial hypertrophic cardiomyopathy (FHC) and Friedreich's ataxia (FA) has prompted us to investigate the hypothesis that genetic factors associated with excessive myocardial hypertrophy, viz. mutations in FHC and FA genes alter the hypertrophic response of the heart to pressure overload. Here we review briefly three lines of study: (i) association analysis to test whether the allele frequencies differ in hypertensive patients with or without left ventricular hypertrophy; (ii) characterization of the cardiac manifestations of FA to understand the mechanism by which the heart is affected in a disease associated with pathology in a subgroup of neurons, and (iii) creation of transgenic models to facilitate the investigation of the interaction between hypertrophic stimuli and underlying genetic predisposition. 3. Information on the nature of the cardiac-mass-modifying genes involved may be useful not only for selecting high risk patients in strategies aimed at preventing the development of LVH, but also in opening new avenues of research on the reprogramming of cardiac myocytes to encourage them to hypertrophy in situations where cardiac muscle has been damaged or is hypoplastic.     

Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. Evidence for a dominant negative action

Mutations in the beta-myosin heavy chain gene are believed to cause hypertrophic cardiomyopathy (HCM) by acting as dominant negative alleles. In contrast, a truncated cardiac troponin T (TnT) that causes HCM implies that altered stoichiometry of contractile proteins may also cause cardiac hypertrophy. Wild-type and HCM-mutant (truncated) TnT were studied in a novel quail myotube expression system. Unexpectedly, antibody staining demonstrated incorporation of both forms of human cardiac TnT into the sarcomeres of quail myotubes. Functional studies of wild type and mutant transfected myotubes of normal appearance revealed that calcium-activated force of contraction was normal upon incorporation of wild type TnT, but greatly diminished for the mutant TnT. These findings indicate that HCM-causing mutations in TnT and beta-myosin heavy chain share abnormalities in common, acting as dominant negative alleles that impair contractile performance. This diminished force output is the likely stimulus for hypertrophy in the human heart.     

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a heterogeneous, progressive disease with a variable age of debut. Hypertrophic cardiomyopathy is characterized by myocardial hypertrophy with a bizarre fibre disarray. Angina pectoris, dyspnoea and syncope are the most frequent symptoms. Hypertrophic cardiomyopathy is an important cause of sudden death, especially in children and young adults. The aetiology is genetic in more than 60% of the cases, with an autosomal dominant mode of inheritance. More than 50 different mutations involving six genes have so far been associated with the development of hypertrophic cardiomyopathy. These mutations are located to genes coding for several of the proteins in the cardiac sarcomere. The protein changes seem to compromise contractility as well as sarcomere assembly, thereby secondarily causing compensatory hypertrophy. The management of hypertrophic cardiomyopathy has been markedly improved within the last few years. This emphasizes the importance of determining prognostic markers in each patient. A specific genetic diagnosis may prove to be of major importance.     

Progress of the molecular genetic analysis for Alzheimer's disease

The pathogenesis of Alzheimer's disease (AD) remains unclear. We ascertained 57 Japanese families with early onset familial Alzheimer's disease (EOFAD; mean onset age < 65 years). Screening the known beta/A4 amyloid precursor protein (APP) mutations in familial AD by a simplified PCR product detection system disclosed only one EOFAD with the APP717Val-Ile mutation (AD1 locus). Four of 6 families showing a positive linkage to AD3 locus had four different mutations on the presenilin 1 gene. These mutations were Val 96 Phe, Ile223Thr, His163Arg and splicing mutation with an AG-AA substitution at the acceptor site of intron 9. The allele frequency of APOE-e4 of late-onset and early-onset AD was significantly higher than that of age-matched controls (p < 0.0001). These results suggest that APOE-e4 (AD2 locus) is a susceptibility gene for AD in the Japanese population, regardless of the age at onset. It is probable that the risk for AD in most subjects is likely to arise from the cumulative effects of environmental factors along with various genetic factors. Advances in molecular biology and molecular genetics have enabled us to more easily understand these genetic factors.     

Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene (G8363A)

A novel G8363A mutation in the mtDNA tRNA(Lys) gene was associated, in two unrelated families, with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The G8363A mutation was very abundant (>95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% +/- 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome (c) oxidase-negative fibers than in cytochrome (c) oxidase-positive fibers. The mutation was not found in >200 individuals, including normal controls and patients with other mitochondrial encephalomyopathies, thus fulfilling accepted criteria for pathogenicity.     

Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disease characterized by neoplasia of the parathyroid glands, the endocrine pancreas, and the anterior pituitary gland. In addition, families with isolated endocrine neoplasia, notably familial isolated hyperparathyroidism (FIHP) and familial acromegaly, have also been reported. However, whether these families constitute MEN 1 variants or separate entities remains speculative as the genetic bases for these diseases are unclear. The gene for MEN 1 has recently been cloned and characterized. Using single strand conformation analysis (SSCA) and sequencing, we performed mutation analysis in: a) a total of 55 MEN 1 families from 7 countries, b) 13 isolated MEN 1 cases without family history of the disease, c) 8 acromegaly families, and d) 4 FIHP families. Mutations were identified in 27 MEN 1 families and 9 isolated cases. The 22 different mutations spread across most of the 9 translated exons and included frameshift (11), nonsense (6), splice (2), missense mutations (2), and in-frame deletions (1). Among the 19 Finnish MEN 1 probands, a 1466del12 mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was found in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common "warm" spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case one mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved and that additional such families need to be analyzed.     

Relation between smoking in reproductive-age women and disorders in reproduction]

BACKGROUND: Genotype-phenotype correlation studies consistently have shown that mutations are prognosticators in patients with hypertrophic cardiomyopathy (HCM). While Arginine (Arg)719Tryptophan (Trp) mutation in the beta-myosin heavy chain (MyHC) gene is associated with a high incidence of sudden cardiac death (SCD), the Valine (Val)606Methionine (Met) mutation in the same gene is associated with a near normal life expectancy. It is unknown whether the prognostic significance of mutations is reflective or independent of their hypertrophic expressivity. We determined the indices of left ventricular hypertrophy (LVH) in patients with beta-MyHC mutations associated with high, moderate, and low incidence of SCD. METHODS: Mutations were identified by chemical cleavage (Val606Met and Glu930Lys) or polymerase chain reaction (PCR) and MspI restriction mapping (Arg719Gln). Left ventricular mass was determined using 2-D echocardiograms, and was indexed (LVMI) for body surface area. The extent of LVH was determined using a semiquantitative point score method that takes into account the extent of involvement of the septum, apex, and lateral wall of the left ventricle. RESULTS: The Arg719Trp, Glu930Lys, and Val606Met mutations were associated with high (14/29, 48%), moderate (3/16, 19%), and low (1/11, 9%) risk of premature death, respectively. Concordant with the incidence of premature death, the LVMI was the greatest (148.0 +/- 37 g/m2) in patients with the Arg719Trp mutation, the smallest (111.7 +/- 19 g/m2) in patients with the Val606Met mutation, and in between (127.1 +/- 15 g/m2) in patients with the Glu930Lys mutation (p = 0.023). Similarly, the LVH score was also greater in patients with the Arg719Trp mutation than in those with the Val606Met mutation (5.92 +/- 2.3 vs 3.2 +/- 1.5, respectively, p = 0.015). A trend toward a greater septal thickness was also present in patients with the Arg719Trp compared to the Val606Met mutations (20.7 +/- 6.8 mm vs 16.2 +/- 2.6 mm, p = 0.077). CONCLUSION: Hypertrophic cardiomyopathy patients with the malignant Arg719Trp mutation have more extensive hypertrophy than those with the benign Leu606Val mutation. This findings suggests that the prognostic significance of beta-MyHC mutations is reflective of their hypertrophic expressivity.     

Nonmetastatic accumulations in bone radionuclide scans in a patient with breast neoplasm

Left ventricular dilation and systolic dysfunction develop in 14-16% of patients with hypertrophic cardiomyopathy. Such findings may easily be misdiagnosed as dilated cardiomyopathy. It is unknown whether left ventricular dilatation and systolic dysfunction in patients with hypertrophic cardiomyopathy are reversible. A 35-year-old man had been a heavy drinker for 13 years and was abstinent for 1 year. Five years previously he suffered cardiac arrest and, based on echocardiographic, radionuclide, and cardiac catheterization findings, the diagnosis of alcohol-induced dilated cardiomyopathy was established. At presentation the heart was of normal size, with concentric left ventricular hypertrophy and only slightly reduced systolic function. Hypertrophic cardiomyopathy was diagnosed since no other cause for left ventricular hypertrophy could be detected. In hypertrophic cardiomyopathy, alcohol may induce reversible systolic dysfunction and left ventricular dilatation.