Right and left ventricular arrhythmogenic

cardiomyopathy: two extremes of the clinical

expression of desmosomal disease

The Heart Hospital, UCLH Great Ormond Street Hospital

William J. McKenna, MD

Director, Institute of Cardiovascular Science

University College London

Exercise Test: 4.5min

11/2003 03/2005 05/2005 09/2005

ARVC Desmoplakin: normal echo/CMR

Arrhythmogenic Right Ventricular Cardiomyopathy

Autosomal Dominant ARVC Loci

ARVC1 14q23-24 Rampazzo, 1994

ARVC2 1q42-43 Rampazzo, 1995

ARVC3 14q12-22 Severini, 1996

ARVC4 2q32 Rampazzo, 1997

ARVC5 3p23 Ahmad, 1998

ARVC6 10q22.3 Melberg, 1999

ARVC7 10p12-14 Li, 2000

Naxos Disease - Hair

Naxos disease - keratoderma

Mutation in Plakoglobin cDNA(-catenin)

DESMOSOMEADHERENS JUNCTION

E-Cadherin Desmoglein-I

Plakoglobin-I

Desmoplakin

a-Catenin

b-Catenin

CytoSkeleton Cell-signalling

RV

LV

Carval-Huerta 1998, Norgett et al 2000

Recessive - 18 affected individuals (DCM)

Woolly hair, palmoplantar keratoderma

Carvajal SyndromeDesmoplakin mutation (7901/del G)

Mutation in Desmoplakin Domain

Binding to Plakoglobin Causes

Autosomal Dominant ARVC

Rampazzo et al 2002

Disease-Causing Mutations in

Desmosomal Proteins

Carvajal(Desmoplakin)

ARVC8 (Desmoplakin)

Plakophilin-2

Naxos(Plakoglobin)

• 82 ARVC pts

• 52% gene positive

• 14% >1 gene mutation

PKP2 = 80%

DSP = 2%

DSG2 = 16%

DSC2 = 0%

JUP = 2%

den Haan AD et al, Circ Cardiovasc Genet. 2009;2:428-435

Multiple gene mutations in ARVC

Seen in 7% probands

more severe form

early onset

more LV involvement

Bauce B et al. Heart Rhythm 2010;7:22–29

Multiple gene mutations in ARVC

PKP2 variant in 38 of 198 probands (19%)

A second variant was identified in 16 of the 38 (42%) and was associated with:

Early Onset

More severe form

Xu T et al. J Am Coll Cardiol 2010;55:587–97

49 probands SCD51 probands alive

Age at sudden cardiac death

100 Families with ARVC

Quarta, Circulation: in press

73%

27%

Gene mutation

No gene mutation

Genetics: living probands

Quarta, Circulation: in press

Desmosomal gene mutations in ARVC

27% 24%

36%13%

Desmoplakin

Plakophilin-2

Desmocollin-2

Desmoglein-2

Quarta, Circulation: in press

3%

41% 56% Gene mutation

No gene mutation

Not tested

85%

7%2% 2%4%

Single Mutation

Compound heterozygous

Double heterozygous

Three mutations in 3 genes

Four mutations in 2 genes

Genetics: families

Quarta, Circulation: in press

Disease penetrance in gene positive relatives

Definite 34%

Borderline 27%

No difference in frameshift (insertion or deletion) or a stop codon mutation vs missense or splice donor mutation (p=0.94)

Only 19% fulfilled 1994 ARVC criteria (p=0.03)

Quarta, Circulation: in press

Multiple desmosomal gene variants

More common in probands than in relatives 28.1% vs 9.7% (p=0.01)

In relatives, associated with 5 fold increase of risk of developing penetrant disease (OR=4.7, 95% CI 1.1-20.4, p=0.04)

Quarta, Circulation: in press

Arrhythmogenic

LV cardiomyopathy

Desmoplakin: LV ARVC

2034insA mutation Norman et al, 2005

Case III.7 – True FISP ciné

Four-chamber view

Case III.7 – Late enhancement

ID Age LVED

% pred

LVED

mm

LVES

mm

FS

%

Abn CMR

gad

ECG VT/ VES/

24hrs

II.6 67 142% 64 48 25 ICD in situ T II, III, VF, V4-6 RBBB VT*

III.7 62 109% 50 28 44 positive T II, III, VF, V4-6 RBBB VT*

III.10 47 120% 53 34 36 ND N 1316 R&L VES

III.17 41 98% 42 26 38 ND T II, III, VF 7 L VES#

III.20 46 128% 64 45 29 ND T II, III, VF, V3-6 815 L VES

IV.2 36 118% 51 35 31 ICD in situ R V1-2, T V3 LBBB VT*

IV.3 39 113% 50 33 34 ND N 3661 R&L VES

IV.5 31 105% 48 32 33 positive N 1795 L VES

IV.8 36 125% 54 38 29 ND T II, III, VF, V4-6 5938 L VES

IV.9 28 127% 58 43 26 positive T V4-6 5612 L VES

IV.14 22 117% 54 36 33 positive T II, III, VF 47 L VES

Arrhythmogenic Cardiomyopathy

Clinical

GeneticHistological

ARVC ALVC

Molecular Diagnostics in Clinic?Genetic Disease

Diagnosed

Mutation analysis

Mutation identified No mutation identified

Molecular testing of Ist degree

relatives

Negative Positive Clinical follow-up

Research Lab

Discharge (50%)

Recommendations

• Genetic testing should be considered for patients

who fulfil diagnostic criteria for ACM where

cascade screening may facilitate identification of

at risk relatives

• When a proven or probable disease causing

mutation is identified in a proband who fulfils

diagnostic criteria for ACM testing should be

considered in all first degree relatives (parents,

siblings, offspring)

• Mutation analysis should not be performed in

probands with isolated non diagnostic features of

ACM

Medical/Nursing

Professor William McKenna

Professor John Deanfield

Dr Perry Elliott

Dr Michael Burch

Dr Maite Tomé-Esteban

Dr Pier Lambiase

Dr Antonis Pantazis

Mr Simon Waller

Sr Linda Moss

Mr Michael Baldini

Sr Sarah Mead-Regan

Sr Jo Mander

Registrars / Fellows

Dr Caroline Coats

Dr Costas O’Mahony

Dr Christopher Critoph

Dr Vimal Patel

Dr Eleanor Wicks

Dr Juan Pablo Kaski

Dr Giovanni Quarta

Dr Margherita Calcagnino

Dr Shereen Al-Shaikh

Dr Samer Arnous

Arrhythmia/EP

Dr Edward Rowland

Dr Martin Lowe

Dr Tony Chow

Dr Oliver Segal

Dr Laurence Nunn

Dr James McCready

Dr Akbar Ahmed

Dr Syed Ahsan

Sr Eileen Firman

Imaging

Dr James Moon

Dr Denis Pellerin

Dr Camelia Demetrescu

Dr Mariana Mirabel

Kalaiarasi Janagarajan

Dr Srijita Sen-Chowdhry

Dr Dan Sado

Exercise Physiology

Bryan Mist, PhD

Beverley Bates

Dr Graham Derrick

Inherited Cardiovascular Disease Unit, UCL

Cardiomyopathy Association

Robert Hall

Peter McBride

Cardiac Risk in the Young (CRY)

Alison Cox

Steven Cox

Administration/Databasing

Peter Woods

Shaughan Dickie

Marietta Meyer

Harriet St Pierre

Sarah Wilson

Genetics

Mike Hubank, PhD

Petros Syrris, PhD

Sharon Jenkins

Demetra Georghiou

Angeliki Asimaki, PhD

Pathology

Dr Michael Ashworth

Dr Siân Hughes