Familial DilatedCardiomyopathy Georgios K Efthimiadis, MD

Familial DilatedCardiomyopathy Georgios K Efthimiadis, MD

Dilated Cardiomyopathy Dilated LV/RV, reduced EF, in the absence of CAD valvulopathy pericardial disease Prevalence:40/100.000 persons Natural history: heart failure heart transplantation high rate of SCD high mortality rate: 30% (5 years after initial diagnosis)

Dilated Cardiomyopathy: Aethiology Viral Immune 50% Alcoholic/Toxic Idiopathic: 50% Familial/genetic:..%

Familial Dilated Cardiomyopathy:Criteria 1. Presence of 2 affected individuals in a single family 2. Presence of a first-degree relative with well documented unexplained sudden death at <35 years of age

Petretta M, et al. prevalence rate of FDC in 22 studies. Am J Cardiol. 2011;108:1171-6.

Familial Dilated Cardiomyopathy (FDC) Patterns of inheritance 1. autosomal dominant 2. autosomal recessive 3. X-linked 4. matrilineal (mitochondrial DC)

Evaluation for Familial DCM Careful 3-4 generation family history Clinical screening of first-degree family members

Clinical Evaluation in Asymptomatic First-Degree Relatives History (HF symptoms, arrhythmias, presyncope, syncope) Physical examination (cardiac and skeletal muscle systems) Electrocardiogram Echocardiogram CK-MM Negative: rescreened at 3-5-year intervals Abnormal clinical screening test: repeat at 1 year

Mahon NG et al. Echocardiographic evaluation in asymptomatic relatives of patients with dilated cardiomyopathy reveals preclinical disease. Ann Intern Med. 2005;143:108-15 767 PATIENTS EVALUATED 592 (77.2%):healthy 35 (4.6%):DCM 119 (15.5%): LV enlargement without systolic dysfunction 21 (2.7%):depressed FS without LV dilatation FOLLOW-UP[(median of 57 months (range,1 to 133 months)] progression to DCM 13 (10%) with LV enlargement or depressed FS 3 (1.3%) healthy relatives LV enlargement or depressed FS independently predicted progression to DCM (hazard ratio, 10.0 [CI, 2.8 to 35.5]; P < 0.001)

Fatkin D. Evaluation of Left Ventricular Enlargement as a Marker of Early Disease in Familial Dilated CardiomyopathyCirculation: Cardiovascular Genetics. 2011; 4: 342-348 457 relatives in 128 DCM families 110 individuals (24%) with LVE 13%: DCM over 10-152 months (median 52)

The phenotype can be characterized isolated cardiac dysfunction (isolated DCM) conduction defects (AV block or sinus node dysfunction) skeletal muscular disorders

Genetic causes and phenotypes of DCM Sarcomere ß-Myosin heavy chain (MYH7) Troponin T (TNNT2) Troponin I (TNNI3) Troponin C (TNNC1) Cardiac -actin (ACTC) Tropomyosin (TPM1) Myosin-binding protein C (MYBPC3) force generation

FDC due to sarcomere protein genes mutations Frequency: 10% Gene Mutation Clinical presentation B-MHC Ser532Pro CHF in children or Phe764Leu young adults C-TnT Arg141Trp no myopathy Kamisago M et al N Engl Med2000;343:1688-96 Li D,et al. Circulation 2001;104:2188-2193

Β-myosin heavy chain gene mutations DCM HCM

Genetic causes and phenotypes of DCM Sarcomere and Z-disc associated proteins Titin (TTN) Titin-cap/telethonin (TEL) Muscle LIM protein (CRP3) Metavinculin (VCL) Cypher/ZASP (LDB3)

Subjects with TTN Truncating Variants, According to Cohort. Herman DS et al. N Engl J Med 2012;366:619-628

Kaplan Meier Estimates of Age at Diagnosis and Clinical Progression in Subjects with Dilated Cardiomyopathy Caused by TTN Mutations. Herman DS et al. N Engl J Med 2012;366:619-628

Genetic causes and phenotypes of DCM Cytoskeleton Dystrophin (DMD) Sarcoglycan(SGCD) Intermediate filaments Desmin (DES) Lamin A/C (LMNA)

X-linked Dilated Cardiomyopathy (XLDC) Dystrophin gene:locus xp21.2 Mid rod mutations -NH2 or - COOH terminus Becker XLDC(1-3) : frequency(4) :6.5% or Duchenne MALE FEMALE Dystrophy <20 years 5 th decade cardiac death mild symptoms or transplantation slowly progressive 1-2 years after diagnosis no clinical myopathy 1.Ortiz-Lopez R,et al.circulation1997;95:2434-40 2.Milasin j etal.hum Mol Genet 1995;5:73-9 3.Melis MA et al.neuromuscul Disord 1998;8:244 4.Arbustini et al.jacc 2000;35:1760-8

FDC due to Dystrophin Gene Mutations male patients increased CK X-linked inheritance high risk of end-stage HF lower risk of life-threatening arrhythmias.

Desmin Mutations Intermediate thin filament Stabilization of sarcomere Clinically: A-V block with or no Restrictive Cardiomyopathy

Nuclear Envelope Protein Genes Mutations causing FDC Role of nuclear envelope proteins: structural integrity of nuclear envelope, mechanical support for the nucleus. Identified genes mutations causing FDC Lamin A/C Emerin

Lamin A/C Gene Mutations (Laminopathies) Lamin A/C: major constituents of inner nuclear membrane Lamin gene: 12 exons, mutations have been identified in 10 exons

Age-Related Penetrance of Phenotypes in Patients With LMNA Gene Mutations Pasotti, M. et al. J Am Coll Cardiol 2008;52:1250-1260 Copyright 2008 American College of Cardiology Foundation. Restrictions may apply.

Dilated Cardiomyopathy with Conduction System Disease Missense mutations in the rod domain of Lamin A/C gene Clinical presentation 3th decade, no or mild clinical myopathy Asymptomatic ECG abnormalities (100%) CHF(33%), SCD (30%) Permanent pacing(>50%,a-v block) Fatkin D et al.n Engl J Med 1999;341:1715-24 Account for 33% of DCMs with AVB Arbustini E et al. JACC2002;39:981-90

Laminopathies:Natural History Incidence:8% Event free survival rate:30%vs75% at the age of 45 years compared to other forms of DC Taylor MR et al. JACC 2003;41:771-80

Genetic causes and phenotypes of DCM Channel and channelassociated proteins Cardiac sodium channel (SCN5A) ATP-sensitive potassium channel (SUR2A/ABCC9) Phospholamban (PLN)

Genetic causes and phenotypes of DCM Mitochondria Tafazzin (G4.5)

Mitochondrial DNA Mutations causing FDC Mutations in the genes coding for respiratory chain reaction proteins: energy production

Future Considerations Identification of healthy carriers Prevention of cardiac dysfunction and sudden death Gene therapy