Aman S. Coonar

Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease)

BACKGROUNDnArrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant heart muscle disorder that causes arrhythmia, heart failure, and sudden death. Previously we mapped the genetic locus for the triad of autosomal recessive ARVC, palmoplantar keratoderma, and woolly hair (Naxos disease) to chromosome 17q21, in which the gene for plakoglobin is encoded. This protein is a key component of desmosomes and adherens junctions, and is important for the tight adhesion of many cell types, including those in the heart and skin.nnnMETHODSnWe studied 19 individuals with Naxos disease, as well as unaffected family members and unrelated individuals from the neighbouring Greek islands of Naxos and Milos. Gene sequence was determined by reverse transcriptase PCR from RNA isolated from the skin of an affected individual and mutations in other cases were confirmed by restriction-enzyme analysis.nnnFINDINGSnA homozygous 2 base pair deletion in the plakoglobin gene was identified only in the 19 affected individuals. This deletion caused a frameshift and premature termination of the protein, which was shown by western blot analysis. 29 clinically unaffected family members were heterozygous for the mutation; 20 unrelated individuals from Naxos and 43 autosomal dominant ARVC probands were homozygous for the normal allele.nnnINTERPRETATIONnThe finding of a deletion in plakoglobin in ARVC suggests that the proteins involved in cell-cell adhesion play an important part in maintaining myocyte integrity, and when junctions are disrupted, cell death, and fibrofatty replacement occur. Therefore, the discovery of a mutation in a protein with functions in maintaining cell junction integrity has important implications for other dominant forms of ARVC, related cardiomyopathies, and other cutaneous diseases.

Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease.

OBJECTIVESnThis study sought to determine whether early disease is identifiable in asymptomatic relatives of patients with dilated cardiomyopathy (DCM) by means of noninvasive cardiologic assessment.nnnBACKGROUNDnDCM is diagnosed on the basis of advanced heart failure, where cardiac dilation and impaired contractility are recognized in the absence of a recognized etiology (World Health Organization criteria). However, initial clinical presentation may be with severe complications: thromboembolism, arrhythmia or sudden death. DCM has recently been recognized to be familial, with autosomal dominant inheritance in many cases. Familial disease is present in 9% to 20% of patients with DCM, and the ability to identify early disease in such people may improve patient management and aid in the understanding of pathogenesis.nnnMETHODnWe prospectively assessed 408 asymptomatic relatives (mean [+/-SD] age 35 +/- 15 years, 193 men) of 110 consecutive patients with DCM by means of history and physical examination, two-dimensional echocardiography, 12-lead and signal-averaged electrocardiography and metabolic exercise testing. We hypothesized that signs of lesser cardiac dysfunction in such relatives might indicate early disease.nnnRESULTSnTwenty-nine percent of relatives had abnormal results on the echocardiogram. Twenty percent (n = 45) had left ventricular enlargement (LVE), defined as LV end-diastolic diameter (LVEDD) > or = 112% predicted; 6% (n = 13) had depressed fractional shortening (dFS), defined as FS < or = 25%; and 3% (n = 7) had frank DCM, defined as LV dilation, impaired contractile performance and LVEDD > or = 112% plus FS < or = 25%. Other abnormalities of cardiac function were identified in relatives with LVE or dFS: A greater number with LVE had an abnormal metabolic exercise test result than normal relatives (9% vs. 1%, p < 0.05). Relatives with LVE and abnormal maximal oxygen consumption (VO2max) (defined as VO2max < 80% predicted) had a lower absolute VO2max than normal relatives (30 +/- 8 vs. 43 +/- 9 ml/min per kg, p = 0.01). The QRS duration (at the 25-Hz filter) on the signal-averaged electrocardiogram was prolonged in relatives with LVE (103 +/- 13 ms) and dFS (102 +/- 12 ms) compared with that of normal relatives (97 +/- 12 ms, p < 0.05). Over a mean 39-month follow-up period, 12 relatives with LVE (27%) and none with dFS developed symptomatic DCM (p < 0.0001). One relative with LVE died suddenly, and another underwent heart transplantation.nnnCONCLUSIONSnNearly one-third of asymptomatic relatives (29%) have echocardiographic abnormalities, and 27% of such relatives progress to development of overt DCM. Early identification of such people would permit appropriate intervention that might influence the serious complications and mortality of this disease.

Gene for Arrhythmogenic Right Ventricular Cardiomyopathy With Diffuse Nonepidermolytic Palmoplantar Keratoderma and Woolly Hair (Naxos Disease) Maps to 17q21

BACKGROUNDnArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease of unknown etiology that causes arrhythmias, heart failure, and sudden death. Diagnosis can be difficult, and this hampers investigation of its molecular basis. Forms of ARVC in which gene penetrance and disease expression are greater should facilitate genetic study. We undertook a clinical and genetic investigation of Naxos disease, originally described by Protonotarios in 1986. This disease constitutes the triad of ARVC, diffuse nonepidermolytic palmoplantar keratoderma, and woolly hair.nnnMETHODS AND RESULTSnWe evaluated the population of Naxos, Greece, to identify probands, which was followed by family screening. Twenty-one affected persons from 9 families of 150 persons were identified. Linkage analysis was performed with microsatellite markers. The disease locus mapped to 17q21. A peak 2-point LOD score of 3.62 at theta=0.0 was found with a marker within intron 4 of the keratin 9 gene, a member of the type I (acidic) keratin family. A preserved homozygous disease haplotype was identified. Haplotype analysis delimited the disease interval.nnnCONCLUSIONSnHair and skin abnormalities were found to be reliable markers of subsequent heart disease. This suggests the presence of a single mutant gene with novel cardiac, skin, and hair function or two or more tightly linked disease genes. Recessive inheritance of Naxos disease and a founder effect were demonstrated. Identification of a fully informative genetic marker linked to the disease and uncommon in the background population may be of use as a test to identify disease gene carriers.

Molecular genetics of familial cardiomyopathies.

Publisher Summary This chapter reviews the molecular genetics of familial cardiomyopathies. The major cardiomyopathies are hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), and restrictive cardiomyopathy. The chapter focuses on these four disease entities. HCM is defined as a “heart muscle disease of unknown cause” that is characterized by disproportionate hypertrophy of the left ventricle and occasionally also of the right ventricle which typically involves the septum more than the free wall but occasionally is concentric. Dilated cardiomyopathy, which is clinically recognized by uni- or biventricular dilatation, is accompanied by impairment of contractile function, and is associated with rhythm disturbances, thromboembolism, and sudden death. ARVC is characterized by fibro-fatty replacement of the myocardium with a marked predilection for the right ventricle. Initially the disease tends to be patchy, but more diffuse right ventricular involvement, with or without left ventricular abnormalities, may occur later. Clinical features include palpitation, syncope, sudden death, and systolic heart failure. Restrictive cardiomyopathy is probably has the greatest degree of controversy regarding diagnosis and it truly represents a distinct myocardial disorder. It is probable that the majority of cases are the consequence of a nonmyocardial pathological process and thus it is not a primary myocardial disease.

Homozygosity at chromosome 8qter in individuals affected by mal de Meleda (Meleda disease) originating from the island of Meleda.

Backgroundu2003The inherited palmoplantar keratodermas (PPKs) are a clinically heterogeneous group of disorders characterized by thickening of the skin of the palms and the soles. These diseases also exhibit genetic heterogeneity and many autosomal dominant and recessive forms have been described. Mal de Meleda (Meleda disease, MD) is an autosomal recessive form of PPK first described on the Dalmatian island of Meleda. A gene for MD has recently been assigned to the most telomeric portion of chromosome 8q using two large Algerian families.

1050-1 Computer Assisted Instruction in Cardiology

Computer Assisted Instruction (CAI) is a novel method of medical education. The teaching of cardiology may benefit from the use of text, sound, images, animation, video as well as hypertext in the true hypermedia environment provided by CAI. Our pilot has been developed for use by undergraduate and postgraduate students. The knowledge base and analytical skills are given in the introduction to each section, following which a range of clinical scenarios, laboratory values, ECG, X-Ray, echocardiographic, CT and MRI cases are presented for interpretation. Progress is assessed by multiple choice questions, case and data interpretations, and the ability to employ established management algorithms. A sophisticated series of ‘ What If ’ ® challenges are built in, allowing the student to alter the complicating factors and degree of patient compromise. By use of multiple cross-references, students may determine their unique path through the material. The software includes a feature, Talkback ’ ® enabling students to comment anonymously on the tutorial. Sy mapping the students path, and including their comments at each stage, focussed supplementary tutorials can be provided. The pilot is undergoing evaluation. Early data is positive for face validity, and compares favourably against conventional methods of teaching such as lectures. On completion the project will undergo a full evaluation process at St Georges Hospital Medical School, and elsewhere in the UK. The CAl runs on a standard PC 486 as well as the Macintosh.

The Genetics of Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a heterogeneous condition, and probably encompasses a number of different disease entities which manifest similarly in their later stages as heart failure, but which are aetiologically distinct. The recent recognition of familial disease with mendelian inheritance implies the significant role of single genes in disease pathology, and thus provides an avenue to identify the molecular abnormality. Such molecular differences may in the future allow genetic classification of these disorders.