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Genetics of
Cardiovascular System
Genetic Diseases
• Single gene disorders
• Mendelian
• Nonmendelian
• Chromosomal disorders
• Multifactorial
Cardiovascular System Disorders
Associated with Single-gene Disorders
• Mendelian
• Autosomal Recessive- Inborn errors of metabolism
• Autosomal Dominant – Marfan’s Syndrome, Noonan
Syndrome, Long QT Syndrome, Dilated Cardiomyopathy
• X-linked- Duchenne/Becker Muscular Dystrophy, Fabry
Disease, Dilated Cardiomyopathy
• Non-Mendelian
• Triple nucleotide repeat disorders
• Mitochondrial
Autosomal recessive
• Male/Female equally
homozygous affected
• Parents are usually
heterozygous carriers
• Consanguinity
• Recurrence risk 1/4
Inborn Errors of Metabolism
See Medical Genetics Lecture in Committee V
Coming Soon…
Dilated Cardiomyopathy
• Dilated Cardiomyopathy (DCM) has a genetic basis in a
proportion (~25%) of cases with mutations found in
more than 10 genes encoding cytoskeleton proteins
leading to dilatation of the left ventricle
predominantly .
• Echocardiography usually shows a dilated poorly
contractile left ventricle, with accompanying
dilatation of the right ventricle in some cases.
Autosomal Dominant
• Male/Female equally
heterozygous affected
• Phenotype usually appears
in every generation
• Recurrence risk for any
child of affected parents is
Isolated cases are mostly
due to de-novo mutation
Marfan’s Syndrome
• Autosomal dominant inherited
connective tissue disorder
• Incidence 1/3000-5000
• Caused by mutations of
• FBN1 (fibrillin-1) gene – Microfibril
glycoprotein in elastic and non elastic
• TGFR B 1-2 (Transforming growth
factor beta 1-2) – works through
apoptosis cell cycle regulation and
prevents incorporation of fibrillin into
Marfan’s Syndrome /
Clinical Features
1. Musculoskeletal:
• Tall stature (dolichostenomelia)
• Long digits (arachnodactyly)
• Thumb sign (distal phalanx
protrudes beyond border of clenched
• Wrist sign (thumb and fifth digit
overlap when around the wrist)
Sternal deformity
Scoliosis > 20 degrees
Joint hypermobility
Arm span exceeding height (ratio
• Reduced elbow
Marfan’s Syndrome /
Clinical Features
2. Eye: superior lens dislocation
(ectopia lentis)
3. Pulmonary: Spontaneous
4. Neurologic: Dural ectasia
5. Cardiac:
• Mitral valve prolapse
• Aortic root dilation
Marfan’s Syndrome
Cardiovascular System
• Aortic root disease (MAJOR CRITERION)  aneurysms,
AR, dissection
In 50% children
In up to 80% of adults
May lead to neurovascular complications
AR murmur: decrescendo, diastolic
• Mitral valve prolapse (minor criterion)
• In 60-80% patients; most common valve disorder
• Worsens with time, complicated by rupture
• MVP murmur: ejection click, holosystolic
• Arrhythmias
• Clinical diagnosis: the Ghent criteria
• physical exam: 6 organ systems involved
• family history
• genetic testing
• If (+) family history, additionally you need:
• Involvement of 2 organ systems including 1 major criterion
• If (–) family history, additionally you need:
• Major criterion from 2 systems and involvement of a 3rd
• Marfan’s Syndrome is relatively common
• If you have a patient < 40 with evidence of aortic root
changes, think MFS
• No cure, only cardiovascular management
• Annual echo
• Beta blockers
• Counseling on physical activity
Noonan Syndrome
• Autosomal dominant dysmorphic
syndrome caused by
heterozygous mutation in the
nonreceptor type11) gene
• incidence of 1 in 1,000 to 2,500
live births
Noonan Syndrome /
Clinical Features
Dysmorphic features;
hypertelorism, a downward
eyeslant, and low-set
posteriorly rotated ears short
stature, a short neck with
webbing or redundancy of
skin, epicanthic folds,
• motor delay,
• bleeding diathesis.
Cardiac defects
• Hypertrophic obstructive
• Atrial septal defects
• Ventricular septal defects
• Pulmonic stenosis
X-linked recessive
• Heterozygous females
are carriers,
heterozygous males
are affected
• Isolated cases are
mostly due to de-novo
• Recurrence risk for
any sons of carrier
mother is ½
Duchenne/Becker Muscular
• X-linked recessive progressive muscular dystrophy
caused by mutation on dystrophin gene.
• DMD lethal form
• BMD mild form
• Dystrophin gene encodes an important protein of
dystroglycan complex of the muscle membrane.
• Progressive muscle weakness
• Symptoms usually appear at age 3-4 for DMD, for
BMD later
• Cardiomyopathy is common
• About 5 to 10% of female carriers of this X-linked
disorder show muscle weakness,and may develop
dilated cardiomyopathy !!!
Fabry Disease
• An X-linked inborn error of glycosphingolipid catabolism
caused by mutations in the gene encoding alpha-galactosidase
• deficient or absent activity of the lysosomal enzyme alphagalactosidase A.
• This defect leads to accumulation of glycosphingolipids in
the plasma and cellular lysosomes of vessels, nerves, tissues,
and organs throughout the body .
• The disorder is a systemic disease, manifest as progressive
renal failure, cardiac disease (left ventricule hypertrophy),
cerebrovascular disease, small-fiber peripheral neuropathy,
and skin lesions.
Cardiovascular System Disorders
Associated with Chromosomal
Caused by structural or numerical changes of chromosomes
Chromosome mutations; Structural
Deletions, duplcations, insertions, translocations
Genome mutations; Numerical
Aneuploidies: triploidy (3n) tetraploidy (4n)
Monosomy (2n-1), trisomy (2n+1), tetrasomy(2n+2)
Down Syndrome
• 47,XX,+21 or 47,XY,+21
• Most common chromosomal disorder
(1/700) and the common cause of
mental retardation
Typical facial feature (flat face, down
slanting palpebral fissures, broad nasal
root, micrognatia,etc.)
Congenital Heart Diseases (CHD)
present in 40-50%
• Endocardial cushion defect – most
• Atrial septal defect with cleft mitral
• Pulmonary Hypertention !!!
Turner Syndrome
• 1/2500 females lacks an X
• Short stature and
amenorrhea is evaluated
• 20-50% cardiovascular
• Aortic coarctation – most
• Bicuspid aortic valve
• Dilated aortic root
Microdeletion syndromes
 Williams syndrome –
 Elfin facies
 Friendly behavior
 MR
 Supravalvular
Aortic Stenosis
 Pulmonary stenosis
Microdeletion syndromes
• DiGeorge syndrome – 22q11
• conotruncal anomalies
• tertrology of fallot (TOF) !!!
• hypoplasia or agenesis of the thymus and
parathyroid gland resulting in frequent infections
and hypocalcemia,
Isolated congenital heart diseases
Teratogenic effects
Isolated Congenital Heart
Prevalence:0.5-0.8% of live births
Recurrence risk of isolated
Etiology: Unknown,multifactorial
inheritance,genetic factors
with one affected child 2-5%
two affected children 10-15%
3% have a single gene defect,13%
have associated chromosomal
2-4% are associated with
environmental or maternal
conditions & teratogenic
Teratogenic Efects
• Alcohol- 50% CHD: VSD, ASD
• Most common teratogen to which fetal embryo and
fetus are exposed-first trimester (Fetal Alcohol
• Warfarin- 10% CHD: PDA, PS, intracranial
• Rubella- 50% of fetuses become infected with
rubella virus when mother is infected during first
trimester. PDA and ASD, PS
Hereditary disorders of
lymphatic and venous system
• Milroy Disease (hereditary
lymphedema I )
• FLT4 gene mutation, Autosomal
• Hennekam Lymphangietasia (AR)
• Klippel-Trenaunay-Weber Syndrome