Cardiomyopathies

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CARDIOMYOPATHIES: Genetic

Cardiac disease + Myopathy
Cardiomyopathy
Dilated
Dominant (CMD1)
Recessive (CMD2)
Hypertrophic
Right ventricular dilated (ARVD)
Left Ventricular Hypertrabeculation/Noncompaction
Ventricular fibrillation (Brugada)
Developmental
Atrial septal defect
Mitochondrial
Fatty acid metabolism disorders
Long Q-T syndromes
Other

Hypertrophic cardiomyopathy

General
Sarcomere proteins
Other cardiac proteins

General

Hypertrophic cardiomyopathy: Mechanisms
- ? Related to inefficiency of ATP utilization
- Reduced ATP: Interferes with Ca⁺⁺ reuptake
- Triggers Ca++ dependent hypertrophy & arrhythmias

Disorders produced by mutations in

Sarcomere contractile proteins
MYH7

α-Tropomyosin (TPM1)
Cardiac troponin I (TNNI3)
Cardiac troponin T2 (TNNT2)
Cardiac troponin C (TNNC1)
Cardiac myosin binding protein-C (MYBPC3)
Myosin light chain: MYL2; MYL3
α actin (Cardiac) (ACTC1)
Myosin light chain kinase 2 (MYLK2)

α-Myosin heavy chain
β-Myosin heavy chain

Z-disk proteins
CSRP3
Telethonin (TCAP)
LIM domain binding 3 (LDB3; ZASP)
α-actinin 2 (ACTN2)
Vinculin (VCL)
Myozenin 2 (MYOZ2; Calsarcin-1)
Ankyrin repeat domain 1 (ANKRD1)
Nexilin (NEXN)
Myopalladin (MYPN)
FHOD3

Calcium-induced calcium release
Phospholamban
Junctophilin-2 (JPH2)
Calreticulin 3 (CALR3)

ATP generation systems
PRKAG2
Friedreichs
Mitochondrial
VLCAD

Membrane & Basal lamina components
Dystrophin
Dystrophin complex: α-Dystrobrevin
Caveolin-3
Fukutin

Mitochondrial

Other
ADSSL1
ALPK3
BRAF
EPG5
FHL1
Filamin C
GYS1
KLHL24
LAMP2 (Danon)
MIPEP
Myosin 6 (MYO6)
QRSL1
Titin

Hypertrophic cardiomyopathy: Types

CMH 1
● Cardiac β-myosin heavy chain (MYH7) ; Chromosome 14q11.2; Dominant
- MYH7 Genetics
  - Mutation type: Point mutations; > 70 described
  - Mutation locations: Globular head + flexible neck
  - Allelic disorders
- Clinical
  - High QT variability: Especially with Arg403Gln mutation
  - Labile ventricular repolarization
  - Higher risk of sudden death from ventricular arrhythmias than other CMH
  - Degree of cardiac hypertrophy correlates with sudden death risk
CMH 2
● Cardiac troponin T2 (TNNT2) ; Chromosome 1q32.1; Dominant
CMH 3
● α-Tropomyosin (TPM1) ; Chromosome 15q22.2; Dominant
- Allelic disorders
  - CMH3
  - CMD 1Y
  - Left Ventricular Noncompaction 9 (LVNC9)
CMH 4
● Cardiac myosin binding protein-C (MYBPC3) ; Chromosome 11p11.2; Dominant
- Genetics
  - Allelic disorders
  - Incomplete penetrance
- MYBPC3 protein
- Clinical
  - Onset: Often later than other CMH syndromes
    - ~ 42% > 50 years
    - No deaths < 40 years
  - Causes of death: Sudden; Heart failure; Cerebrovascular
- Variants
  - Homozygous splice site mutation
    - Severe neonatal hypertrophic cardiomyopathy
    - Epidemiology: Old Order Amish
  - Left ventricular non-compaction
  - Cardiomyopathy with Myopathy ¹²
    - Mutation: Homozygous R943X
    - Onset: Infancy
    - Cardiomyopathy
    - Course: Fatal
    - Skeletal muscle
      - Many small fibers
      - Expresses cardiac specific MYBPC3
      - Disorganization of sarcomeres
      - Depletion of myosin thick filaments
CMH 5: Hypertrophic cardiomyopathy, see CMH4
CMH 6 : Hypertrophic cardiomyopathy with ventricular pre-excitation (WPW syndrome )
● PRKAG2 ; Chromosome7q36.1; Dominant
- Genetics
  - Allelic disorders
- PRKAG2 Protein
- Clinical
  - Early onset
  - Sudden death
  - Prominent cardiac hypertrophy
CMH 7
● Troponin I, Cardiac (TNNI3) ; Chromosome 19p13.42; Dominant
- Mutations: Missense
- TNNI3 mutations also cause
  - Familial Restrictive cardiomyopathy (RCM1)
  - Dilated cardiomyopathy (CMD 2A)
  - Dilated cardiomyopathy (CMD 1FF): Dominant
CMH 8 Mid left ventricular
● Myosin light chain, alkali; Ventricular & Skeletal Slow (MYL3) ; Chromosome 3p21.31; Dominant or Recessive
? CMH 9
● Titin (TTN) ; Chromosome 2q31.2; Familial or Sporadic
- CMH 9 mutations: May be polymorphisms
- See: Allelic disorders; Dilated Cardiomyopathy 1G (CMD 1G)
CMH 10 Mid-left Ventricular Chamber Type
● Myosin light chain, Ventricular regulatory (MYL2) ; Chromosome 12q24.11; Dominant
- Allelic with: Dilated cardiomyopathy with Hypotrophic type 1 muscle fibers, Recessive
CMH 11
● α actin (Cardiac; ACTC1) ; Chromosome 15q14; Dominant
- Mutation: Missense; Ala295Ser
- Other mutations produce
  - Dilated cardiomyopathy (CMD 1R)
  - Atrial septal defect 5
CMH 12
● Cysteine- and glycine-rich protein 3 (CSRP3) ; Chromosome 11p15.1; Dominant
- Mutations: Missense; Cys58Gly, Leu44Pro, Ser54Arg & Glu55Gly
- Other mutations produce: Dilated cardiomyopathy (CMD 1M)
CMH 13
● Troponin C, Slow (TNNC1) ; Chromosome 3p21.1; Dominant
- Mutations also produce: CMD 1Z
CMH 14
● α-Myosin, heavy chain 6 (MYH6) ; Chromosome 14q11.2; Dominant
- MYH6 protein
  - Location: Cardiac (Especially small animals (mouse)); Some jaw muscles
  - Expression regulated by TBX5
- MYH6 mutations also cause
  - Atrial septal defect
  - Dilated cardiomyopathy: CMD 1EE
  - Increased risk of: Sick sinus syndrome
CMH 15
● Metavinculin (Vinculin; VCL) ; Chromosome 10q22.2
- Genetics
  - Mutation: L277M
  - Allelic with: CMD 1W
- Metavinculin
  - Vinculin variant: Contains additional 68 amino acids
  - Expressed exclusively in cardiac & smooth muscle
  - May anchor actin filaments to intercalated discs in heart
  - Mutation: Reduced Vinculin/metavinculin staining in intercalated discs
CMH 16
● Myozenin 2 (MYOZ2; Calsarcin 1) ; Chromosome 4q26; Dominant
- Mutations: Ser48Pro; Ile246Met
- Myozenin 2 protein
  - Z-band: Co-localize with α-Actinin
  - Interacts with: Calcineurin
CMH 17
● Junctophilin-2 (JPH2) ; Chromosome 20q13.12; Dominant
- Epidemiology: Japanese patients
- Genetics
  - Mutations: Missense; Ser101Arg, Tyr141His, Ser165Phe; Gly505Ser
  - Allelic disorder: CMD2E
- JPH2 protein
  - Junctional membrane complex protein: Between plasma membrane (& endoplasmic/sarcoplasmic reticulum
  - Physically approximate for calcium-induced calcium release
    - L-type calcium channel: Plasmalemma
    - Ryanodine receptor: Sarcoplasmic reticulum
CMH 18
● Phospholamban (PLN) ; Chromosome 6q22.31; Dominant
- Genetics
  - Mutations: Promoter region;-42C-G transversion, -77A-G transition
  - Allelic with: CMD 1P
CMH 19
● Calreticulin 3 (CALR3) ; Chromosome 19p13.11; Dominant
- Epidemiology: Australian male
- Genetics
  - Mutation: Lys92Arg
- CALR3 protein
  - Ca⁺⁺-binding chaperone
  - Localized mainly in endoplasmic/sarcoplasmic reticulum
  - Colocalizes with: SPTLC2
  - Chaperone
CMH 20
● Nexilin (NEXN) ; Chromosome 1p31.1; Dominant
- Epidemiology: Chinese families
- Genetics
  - Mutations: Q131E; R279C
  - Allelic with: CMD 1CC
CMH 21
● Chromosome 7p12.1-q21; Dominant
- Epidemiology: 1 family
- Clinical
  - Onset age: 13 years to Adult
  - Cardiac failure
  - Sudden death
CMH 22
● Myopalladin gene (MYPN) ; Chromosome 10q21.3; Dominant
- Genetics
  - Mutation: Tyr20Cys
  - Allelic with: CMD 1KK; RCM4
CMH 23
● Actinin, α-2 (ACTN2) ; Chromosome 1q43; Dominant
- Genetics
  - Mutations: Ala119Thr, Thr495Met, Glu583Ala, Glu628Gly
  - Allelic disorders
    - Cardiomyopathy, dilated, 1AA ± LVNC
    - Multiple structured Core Disease
CMH 24
● LIM domain-binding 3 (LDB3; ZASP) ; Chromosome 10q23.2; Dominant
- Genetics
  - Mutation: Pro615Leu
  - Allelic disorders
CMH 25
● Titin-CAP (TCAP) ; Chromosome 17q12; Dominant
- Genetics
  - Mutations: Missense; Arg70Trp, Thr137Ile, Arg153His
  - Allelic with
    - LGMD 2G
    - ?? CMD 1N
CMH 26
● Filamin C (FILC) ; Chromosome 7q32.1; Dominant
- Genetics
  - Mutations
    - Missense
    - Cluster in ROD2 domain
  - Allelic disorders
    - Other cardiomyopathy: Cardiomyopathy, familial restrictive, 5
CMH 27 ¹⁸
● Alpha kinase 3 (ALPK3; MAK; MIDORI) ; Chromosome 15q25.3; Dominant
- Epidemiology: 3 families
- Genetics
  - Stop & Splice mutations
  - Allelic disorder: Dilated cardiomyopathy + Myopathy
- ALPK3 protein
  - Intercalated disk formation
  - Cardiac myofibrils organization
  - Regulation of transcription factors that control the differentiation & maturation of cardiomyocytes
- Clinical: Dilated cardiomyopathy + Myopathy
  - Epidemiology: 1 patient
  - Onset: Early childhood
  - Cardiomyopathy: Dilated
  - Skeletal muscle: Some patients
    - Scapular winging
    - Pectoralis major atrophy
    - No weakness
  - Course: Progressive
- Laboratory
  - Serum CK: 300
  - EMG: Myopathic in proximal muscles
  - Muscle biopsy
    - Vacuoles: Caveolin-3+
    - Desmin: aggregates
    - Internal nuclei
    - NADH: Internal clear regions
    - Ultrastructure: Membrane-bound vacuoles
    - May be Normal
CMH 28
● Formin homology-2 domain-containing protein 3 (FHOD3) ; Chromosome 18q12.2; Dominant
- Epidemiology: > 70 patients
- Genetics: Missense & Deletion mutations
- FHOD3 protein: Regulation of the actin cytoskeleton
- Clinical
  - Onset: Most > 30 years
  - Dyspnea
  - Septal hypertrophy, asymmetric
  - Atrial fibrillation
  - Nonsustained ventricular tachycardia
  - Sudden death
- Pathology
  - Hypertrabeculation of left ventricle with noncompaction
CMH29, with Polyglucosan Bodies
● Kelch-like (KLHL24) ; Chromosome 3q27.1; Recessive
- Epidemiology: 2 families
- Genetics
  - Mutations: Glu350X; Arg306His
  - Allelic disorder: Epidermolysis bullosa simplex 6, generalized + Scarring & hair loss (EBS6), Dominant
- Protein
  - Substrate-specific adaptors to cullin E3 ubiquitin ligases
  - Expression: Ubiquitous; High in cortex, skin
- Clinical
  - Onset age: 2nd to 3rd decade
  - Palpitations
  - Syncope
  - Dyspnea
  - Strength: Normal
  - Sudden death
- Laboratory
  - Cardiomyopathy, Hypertrophic
  - NCV: Normal
  - Pathology
    - Heart: Glycogen accumulation; Polyglucosan bodies
    - Skeletal muscle: Glycogen & Desmin accumulation
Cardiomyopathy: Familial hypertrophic, midventricular, digenic
● Myosin light chain kinase 2 (MYLK2) ; Chromosome 20q11.21
● MYH7

Other hypertrophic cardiomyopathies

?CMH: Chromosome 16
?CMH: Chromosome 18
Mitochondrial
- tRNA glycine
- tRNA leucine
- COX15: Hypertrophic cardiomyopathy with Leigh syndrome
- ANT1: Hypertrophic cardiomyopathy + Mild myopathy; Recessive
- NDUFAF1: Cardiomyopathy, Hypertrophic + Encephalopathy; Recessive
Hermansky-Pudlak syndromes
● HPS1 ; Chromosome 10q24.2; Recessive
- Lysosomal change
Glycogen storage disease
- Type 0
- Type 2
Mouse cardiomyopathy
- Cardiac α-myosin heavy chain (MYH6)

Dilated Cardiomyopathy

General Features

Etiology: Most 2° ischemia; 25% genetic
Mechanisms underlying inherited dilated cardiomyopathies: General
- Impairment of cardiac muscle force production or transmission
- Disturbance of myocellular Ca⁺⁺ metabolism
Most common mutations: Titin
Also see: Dilated cardiomyopathy with myopathy

Cardiomyopathy, Dilated & Other: Specific Hereditary Types

Dominant
Recessive
X-linked
Arhythmogenic

Cardiomyopathy, Dilated, Dominant (CMD1)

Dilated cardiomyopathy (atrial) with atrioventricular block (CMD 1A; CDCD1)
● Lamin A/C ; Chromosome 1q22; Dominant
- Mutation locations
  - Usually in Lamin A/C rod domain; Arg644Cys in C-terminus of Lamin A
  - Cardiomyopathy may occur with mutations only affecting Lamin A (R644C) or Lamin C (R571S)
  - N195K mutation: Severe phenotype
  - R225X: Cardiac conduction disease without dilated cardiomyopathy
- Clinical: No myopathic features or contractures
- Laboratory: Serum CK normal or high; Muscle biopsy not myopathic
- Allelic with
  - Cardiomyopathy, dilated, with hypergonadotropic hypogonadism (Malouf; Najjar)
  - Emery-Dreifuss Muscular Dystrophy 2 (EMD2): Mutations in Head or tail domain
  - Familial partial lipodystrophy
  - LGMD 1B
  - AR-CMT2A
  - Mandibuloacral dysplasia
Familial dilated cardiomyopathy 1B (CMD 1B)
● Chromosome 9q13-q22; Dominant
- Epidemiology: Single family
- Maps to same region as
  - Friedreich's ataxia, tropomodulin & c-AMP dependent protein kinase
- Pure DCM: Heart failure & ventricular arhythmia
- Age-related penetrance; onset in 2nd or 3rd decade
Cardiomyopathy: Familial dilated 1C (CMD 1C)
● LIM domain-binding 3 (LDB3; ZASP) ; Chromosome 10q23.2; Dominant
- Allelic disorders
- Clinical association: Mitral valve prolapse
Cardiomyopathy: Familial dilated 1D (CMD 1D)
● Cardiac troponin T2 (TNNT2) ; Chromosome 1q32.1; Dominant
- Pure DCM
- Mutations also produce: Restrictive cardiomyopathy 3 (RCM3) (Infantile)
Dilated cardiomyopathy with conduction defect (CMD 1E; CDCD2)
● Sodium channel, voltage-gated, Type V, Alpha subunit (SCN5A) ; Chromosome 3p22.2; Dominant
- SCN5A: Allelic disorders
- Clinical
  - Onset ages: Prenatal to 62 years
  - Palpitations
  - Dyspnea
  - Syncope
  - Sudden death
- EKG:
  - Multifocal ectopic Purkinje-related premature contractions
  - Narrow sinus & junctional QRS complexes: Compete with RBBB or LBBB pattern complexes
Dilated cardiomyopathy 1G (CMD 1G)
● Titin (TTN) ; Chromosome 2q31.2
- Epidemiology
  - Most common cause of Familial DCM
  - Familial dilated cardiomyopathy: 25%
  - Sporadic dilated cardiomyopathy: 18%
- Genetics
  - Mutations
    - Type: Truncating
    - Locations: Common in titin A-band
  - Allelic disorders
    - Also see: CMH9
- Clinical
  - Dominant syndrome: Dilated cardiomyopathy, Pure
    - Titin Mutations: Insertion; Missense
    - No skeletal myopathy or Conduction defects
  - Recessive syndrome: Congenital myopathy + Fatal dilated cardiomyopathy
    - Titin mutations: Homozygous deletions
    - Muscle: Disruption of sarcomeric M-line protein complex
Dilated cardiomyopathy 1H (CMD 1H)
● Chromosome 2q14-q22; Dominant
- Epidemiology: German family
- Other features: Conduction disease
Dilated cardiomyopathy 1I (CMD 1I; CMD 1F; CDCD3)
● Desmin ; Chromosome 2q35; Dominant
- Epidemiology: 2% of pure dilated cardiomyopathies
- Desmin: Disorders (Myofibrillar myopathies)
- Cardiac
  - Conduction disease
  - Dilation
  - Course: High mortality
- Associated myopathies
  - Limb-girdle muscular dystrophy 1E
  - Myofibrillar myopathy I
Dilated cardiomyopathy with sensorineural hearing loss 1J (CMD 1J)
● Eyes absent 4 (EYA4) ; Chromosome 6q23.2; Dominant
- Hearing loss: Onst late adolescence
- Ventricular dysfunction: Progressive congestive heart failure after 4th decade
Dilated cardiomyopathy 1K (CMD 1K)
● Chromosome 6q12-q16; Dominant
- Epidemiology: French family
- Pure DCM
Dilated cardiomyopathy 1L (CMD 1L)
● δ-Sarcoglycan ; Chromosome 5q33.3; Recessive
- Mutation: Ser151Ala
- Allelic with: LGMD 2F
Dilated cardiomyopathy 1M (CMD 1M)
● Cysteine- and glycine-rich protein 3 (CSRP3; MLP) ; Chromosome 11p15.1; Dominant
- Mutation: Trp4Arg
- Chamber dilation; Thin ventricular walls; Decreased contractility; Impaired relaxation
- Other mutations produce: Hypertrophic cardiomyopathy (CMH 12)
Dilated cardiomyopathy 1N (CMD 1N)
● Telethonin (TCAP) ; Chromosome 17q12; Dominant
- R87Q mutation: ? Polymorphism
- Allelic disorders
  - Hypertrophic cardiomyopathy: CMH25
  - LGMD 2G
Dilated cardiomyopathy 1O (CMD 1O): With ventricular tachycardia
● Sulfonylurea receptor 2 (SUR2, ABCC9) ; Chromosome 12p12.1; Dominant or Sporadic
- Genetics
  - 2 patients
  - Mutations: Frameshift & Missense
  - Allelic disorders
    - Atrial fibrillation, familial, 12
    - Cantu syndrome (Hypertrichotic osteochondrodysplasia; Hypertrichosis, Macrosomia, Osteochondrodysplasia, Cardiomegaly)
    - CMD1O
    - Intellectual Disability - Myopathy
    - Mouse Myopathy
  - ABC disorders
- ABCC9
  - Regulatory subumit of ATP-sensitive potassium (K_ATP) channel (Kir 6.1 or 6.2)
  - Inhibition of channel opening when ATP concentration at cytoplasmic cell surface is increased
  - Sulfonylureas: Inhibit activity of K_ATP channels
  - Channel activation
    - Cardiac muscle: Action potential shortening
    - Skeletal muscle: Action potential decreased amplitude; Membrane potential hyperpolarization
- Clinical
  - Onset age: 5th to 6th decade
  - Cardiac
    - Dilation: Severe
    - Contractile function: Disordered
    - Rhythm disturbances
- ABCC9 variant: Intellectual Disability - Myopathy ¹⁵
  - Epidemiology: 15 patients
  - Genetics
    - Inheritance: Recessive
    - Mutation: Homozygous; Loss of function; Splice site, Truncation
  - ABCC9 protein: K_ATP channel
  - Clinical
    - Onset: Childhood
    - Hypotonia
    - CNS
      - Developmental delay, Global
      - Intellectual disability
      - Anxiety disorder
      - Spasticity
      - Seizures: Some patients
    - Face: Dysmorphism
      - Orbital ridges: Prominent
      - Hypotelorism
      - Upper lip: Thin
      - Midface: Flat
      - Microcephaly
    - Myopathy
      - Weakness: Proximal; Legs > Arms
      - Fatigability
    - Skeletal: Lordosis & Scoliosis
    - Skin: Marmoration
    - Cardiomyopathy: Older patients
    - Hearing loss: 50%
    - Food allergies
  - Laboratory
    - Brain MRI
      - Cerebral white matter hyperintensities
      - Periventricular leukomalacia
      - Corpus callosum hypoplasia
      - Calcifications
    - Cardiac: Systolic dysfunction
    - RNS, EMG & NCV: Normal
- ABCC9 variant: Mouse Myopathy ⁴
  - Genetics: Recessive inheritance
  - Myopathy + Reduced exercise capacity
  - Coronary vasospasm
  - Loss of K_ATP channels
Dilated cardiomyopathy 1P (CMD 1P)
● Phospholamban ; Chromosome 6q22.31; Dominant
- Genetics
  - Mutations: Missense & Inframe deletion
  - Allelic with: CMH 18
- Phospholamban protein
  - Modulates sarcoplasmic reticulum calcium-ATPase activity
  - Regulator of cardiac diastolic function
  - Substrate for cAMP-dependent protein kinase in cardiac muscle
  - Inhibits cardiac muscle sarcoplasmic reticulum Ca⁺⁺-ATPase (SERCA2a) in unphosphorylated state
  - Leads to enhanced muscle relaxation rates
  - Also expressed in slow-twitch skeletal muscle & some smooth muscle cells
  - Mutated protein action: Blocks PLN^wt phosphorylation
- Cardiomyopathy ± Ventricular arrhythmia
  - Progression: Over 5 to 10 years
  - Death: Mean 25 years
Dilated cardiomyopathy 1Q (CMD 1Q)
● Chromosome 7q22.3-q31.1; Dominant
- Portugese family
- Onset: 25 to 47 years
- Cardiomyopathy, isolated: Dyspnea & Edema
Cardiomyopathy: Idiopathic dilated (CMD 1R)
● α actin (Cardiac) (ACTC1) ; Chromosome 15q14; Dominant
- Mutations: Missense; Arg312His, Glu361Gly
- Other mutations produce
Cardiomyopathy: Idiopathic dilated (CMD 1S)
● β-myosin heavy chain (MYH7) ; Chromosome 14q11.2; Dominant
- Mutations
  - α-Helicoidal rod domain
  - Exons 25 to 39
- Also: Left ventricular non-compaction 5 (LVNCS5)
- See: Hypertrophic cardiomyopathy (CMH1)
Cardiomyopathy: Idiopathic dilated (CMD 1T)
● Thymopoetin (TMPO) ; Chromosome 12q23.1; Dominant
- Mutation: Arg690Cys
- Protein location: Nuclear
- Clinical: Severe cardiomyopathy
Cardiomyopathy: Familial dilated (CMD 1U)
● Presenilin-1 (PSEN1) ; Chromosome 14q24.2; Dominant
- Genetics
  - Mutation: Asp333Gly
  - Allelic disorders
    - Alzheimer disease 3 ± Spastic paraparesis
    - Acne inversa
    - Pick disease
    - Frontotemporal dementia
- Clinical: Syncope
Cardiomyopathy: Familial dilated (CMD 1V)
● Presenilin-2 ; Chromosome 1q42.13; Dominant
- Genetics
  - Mutation: Ser130Leu
  - Partial penetrance
  - Allelic with: Alzheimer disease 4
- Clinical
  - Syncope
  - Milder disease than CMD 1U
Cardiomyopathy: Idiopathic dilated (CMD 1W) ⁴
● Metavinculin (Vinculin; VCL) ; Chromosome 10q22.2
- Genetics
  - Mutations: Arg975Trp; 3-bp deletion (Leu954del)
  - Allelic with: CMH 15
- Metavinculin
  - Vinculin variant: Contains additional 68 amino acids
  - Expressed exclusively in cardiac & smooth muscle
  - May anchor actin filaments to intercalated discs in heart
Cardiomyopathy: Familial dilated (CMD 1X) ⁶
● Fukutin ; Chromosome 9q31.2; Recessive
- Epidemiology: 6 Japanese patients
- Mutations: Heterozygous
  - One allele: 3kb insertion
  - Other allele: Missense; R179T, Q358P
- Allelic disorders
- Clinical
  - Onset age: 11 to 46 years
  - Muscle hypertrophy: Calf
  - Weakness
    - Minimal until adulthood
    - Proximal
- Laboratory
  - Serum CK: 400 to 4,000
  - Skeletal muscle
    - Minimal dystrophic features
      - Varied fiber size
      - Internal nuclei
      - Regenerating muscle fibers
    - Altered glycosylation of α-dystroglycan
    - Reduced laminin binding ability
  - Cardiac muscle: Altered glycosylation of α-dystroglycan
Cardiomyopathy: Familial dilated (CMD 1Y)
● Tropomyosin 1 (TPM1) ; Chromosome 15q22.2; Dominant
- Allelic disorders
- Clinical: Adult onset
Cardiomyopathy: Familial dilated (CMD 1Z)
● Troponin C, Slow (TNNC1) ; Chromosome 3p21.1; Dominant
- Mutations also produce: CMH 13
Cardiomyopathy: Familial dilated (CMD 1AA)
● α-Actinin-2 (ACTN2) ; Chromosome 1q43; Dominant
- Epidemiology: Single patient
- Genetics
  - Mutation: Missense; Heterozygous; Gln9Arg
  - Allelic disorders
    - Hypertrophic cardiomyopathy 23
    - Multiple structured Core Disease
- α-Actinin-2 protein
  - Muscle specific
  - Localized at Z-lines
Cardiomyopathy: Familial dilated (CMD 1BB)
● Desmoglein-2 (DSG2) ; Chromosome 18q12.1; Dominant
- Allelic with: ARVD10
Cardiomyopathy: Familial dilated (CMD 1CC)
● Nexilin (NEXN) ; Chromosome 1p31.1; Dominant
- Genetics
  - Mutations: P611Y; G650del; Y652C
  - Allelic with: CMH20 (Q131E; R279C)
- NEXN protein
  - Z-disk
  - F-actin binding
  - Forms complex with α-actin, β-actin & α-actinin
  - Stabilizes & Protects Z-discs from mechanical forces
  - Mutations: Dominant negative; Destabilize Z-disk
Cardiomyopathy: Familial dilated (CMD 1DD)
● RNA-binding motif protein 20 (RBM20) ; Chromosome 10q25.2; Dominant
- Epidemiology: 8 families
- Mutations
  - Missense
  - Location: RS domain in exon 9
  - Arg634Gln, Arg636Ser, Arg636His, Ser637Gly, Pro638Leu, Met950Lys
- RBM20 protein: Contains RNA binding domain
- Clinical
  - Onset age: Mean 30 years
  - End-stage: Heart failure; Ventricular tachycardia
  - High mortality: Sudden death
CMD 1EE: Familial dilated
● α-Myosin, heavy chain 6 (MYH6) ; Chromosome 14q11.2; Dominant
- MYH6: Expression regulated by TBX5
- Mutations also cause
  - Atrial septal defect
  - Hypertrophic cardiomyopathy: CMH 14
CMD 1FF: Familial dilated
● TNNI3 ; Chromosome 19q13.42; Dominant
- Mutations: Lys36Gln; Asn185Lys
- Other TNNI3 mutations produce
  - Hypertrophic cardiomyopathy(CMH7)
  - Restrictive cardiomyopathy (RCM1)
  - Dilated cardiomyopathy, Recessive (DCM 2A)
CMD 1GG: Cardiomyopathy, Familial dilated
● SDHA ; Chromosome 5p15.33; Recessive
- Epidemiology: Bedouin family
- Genetics
  - Mutation: G555E
  - Inheritance: Recessive
    - Same mutation in severe & mild Leigh syndromes
    - Patient reported with mutation non-penetrance
- Clinical
  - Onset age: Neonatal; Prenatal to 8 months
  - Onset age: < 1 year
  - Neuromuscular exam: Normal
  - Cardiomyopathy
    - Dilated
    - Severe
    - Noncompaction of left ventricle
    - Complex II activity: Reduced in heart; Normal in skeletal muscle
- Mitochondrial function
  - Complex II activity reduced: Muscle 50%; Cardiac 18% of normal
CMD 1HH: Cardiomyopathy, Familial dilated
● BAG3 ; Chromosome 10q26.11; Dominant
- Genetics
  - Mutations: A218W, L462P, R71W, R90X, H109R, R123X, A262T, R218GfsX89, R477H
  - Allelic with: Myofibrillar myopathy
  - Non-penetrance: ~ 25%
- Clinical
  - Onset age: 21 to 64 years
  - Severity: Varied
  - Heart transplant: 55%
CMD 1II: Cardiomyopathy, Familial dilated
● αB-crystallin (CRYAB) ; Chromosome 11q23.1; Dominant
- Genetics
  - Mutations: Missense; Heterozygous; G154S, R157H
  - Allelic disorders
CMD 1JJ: Cardiomyopathy, Familial dilated
● Laminin α-4 (LAMA4) ; Chromosome 6q21; Dominant
- Genetics
  - Mutations: Heterozygous; Arg1073X, Pro943Leu
- LAMA4 protein: Mutations produce defects in cardiomyocytes & endothelial cells
- Onset ages: 29 to 68 years
CMD 1KK: Cardiomyopathy, Familial dilated
● Myopalladin gene (MYPN) ; Chromosome 10q21.3; Dominant
- Genetics
  - Mutations: Heterozygous; Pro961Leu; Arg1088His, Pro1112Leu
  - Allelic disorders
    - CMH22
    - RCM4
    - CMD 1KK
    - Sudden arrhythmic death syndrome
    - Sudden unexpected death in infancy with incomplete penetrance
    - Nemaline rod myopathy
    - Cap myopathy
- Myopalladin protein
CMD 1LL: Cardiomyopathy, Familial dilated
● PR domain-containing protein 16 (PRDM16) ; Chromosome 1p36.32; Dominant
- Epidemiology: 4 patients
- Genetics
  - Mutations: Missense
  - Allelic with: Left ventricular noncompaction-8 (LVNC8)
- PRDM16 protein
  - Subcellular: Nuclei
  - Cardiac: Cardiomyocytes & Interstitial cells
- Clinical
  - Onset age: 11 to 33 years
CMD 1MM: Cardiomyopathy, Familial dilated
● Myosin-binding protein C, Cardiac (MYBPC3) ; Chromosome 11p11.2; Dominant
- Genetics
  - Mutations: Missense; Cys1264Phe, Gly490Arg
  - Allelic disorders
- MYBPC3 protein
- Clinical
  - Onset age: Adult; Up to 70 years
  - Pathology: Left ventricular noncompaction (LVNC10)
  - May be end stage of CMH4
CMD 1NN: Cardiomyopathy, Familial dilated
● V-RAF-1 murine leukemia viral oncogene homolog 1 (RAF1) ; Chromosome 3p25.2; Dominant
- Epidemiology: 3 families
- Genetics
  - Mutations: Missense
  - Allelic with
    - LEOPARD syndrome 2
    - Noonan syndrome 5
- RAF1 protein
  - Activated by
    - Basic fibroblast growth factor (FGFB)
    - Vascular endothelial growth factor (VEGF)
- Clinical
  - Onset age: 3 to 45 years
  - Mitral regurgitation
CMD 1OO: Cardiomyopathy, Familial Dilated
● Vascular endothelial zinc finger 1 (VEZF1) ; Chromosome 17q22; Dominant
- Epidemiology: 1 Chinese family
- Genetics
  - Mutation: K164X
- VEZF1 protein
  - Location: Nucleus
  - Function: DNA-binding transcription factor activity, RNA polymerase II-specific
  - Binds to: Interleukin-3 (IL3)
  - Angiogenesis
- Clinical
  - Onset age: 5th to 7th decades
  - Heart failure: Progressive
- Laboratory
  - Atrial-Septal defect: Some patients
CMD: Cardiomyopathy, Familial Dilated
● SYNE-1 (Nesprin-1) ; Chromosome 6q25.1-q25.2; Dominant
- Epidemiology: Several families
- Genetics
  - Mutations: Missense; R374H
  - Allelic with: Emery-Dreifuss MD 4
- Clinical
  - Onset age: Adult or Child
  - Neuromuscular exam: Normal
CMD: Cardiomyopathy, Familial dilated
● Filamin C (FLNC) ; Chromosome 7q32.1; Dominant
- Genetics: Premature stop codons common
- Clinical: Malignant
  - Ventricular arrhythmias
  - Myocardial fibrosis
  - Sudden cardiac death
- Pathology
  - Left heart dominant
  - Left ventricle: Ring-like scar pattern
  - EKG: Inferolateral negative T waves

Cardiomyopathy, Dilated, Recessive (CMD2)

Cardiomyopathy: Familial dilated (CMD 2A)
● TNNI3 ; Chromosome 19q13.42; Recessive
- Mutation: A2V
- Other TNNI3 mutations produce
  - Hypertrophic cardiomyopathy(CMH7)
  - Restrictive cardiomyopathy (RCM1)
  - CMD 1FF
Cardiomyopathy: Familial dilated (CMD 2B)
● GATA zinc finger domain-containing protein 1(GATAD1) ; Chromosome 7q21.2; Recessive
- Epidemiology: Norwegian family
- Mutation: Ser102Pro
- GATAD1 protein
  - Heart: Nucleus & Cytoplasm; Homogeneous striated staining pattern
- Onset age: 6th decade
Cardiomyopathy: Familial dilated 2C (CMD 2C)
● Phosphopantothenoylcysteine synthetase (PPCS) ; Chromosome 1p34.2; Recessive
- Epidemiology: Arab-Muslim & German families; 5 patients
- Mutation: Missense
- PPCS protein: Biosynthesis of coenzyme A (CoA) from pantothenic acid (vitamin B5)
- Clinical: Varied severity
  - Onset: Neonatal to 3 years
  - Heart: Dilated left ventricle
  - Course: Progressive; Early death in many
Cardiomyopathy: Familial dilated 2D (CMD 2D)
● Ribosomal Protein L3-like (RPL3L) ; Chromosome 16p13.3; Recessive
- Epidemiology: 7 patients; 4 families
- Genetics
  - Mutations: Missense
- RPL3L protein
  - Expression: Highest in Muscle & Heart
  - Ribosomal protein subunit
- Clinical
  - Onset: Neonatal
  - Heart: Dilated atria & ventricles; Valvular insufficiency
  - Course: Progressive; Early death without transplant in many
- Cardiac pathology
  - Muscle fibers: Hypertrophy
  - Interstitial fibrosis: Diffuse
  - Myocyte degeneration
Cardiomyopathy: Familial dilated 2E (CMD 2E)
● Junctophilin 2 (JPH2) ; Chromosome 20q13.12 Recessive
- Allelic disorder: CMH17
Cardiomyopathy: Familial dilated 2F (CMD 2F)
● BAG cochaparone 5 (BAG5) ; Chromosome 14q32.33 Recessive
- Also see: BAG3 MFM6
Cardiomyopathy: Familial dilated 2G (CMD 2G)
● Leiomodin 2 (LMOD2) ; Chromosome 7q31.32 Recessive
- Also see: LMOD3 Rod myopathy
Cardiomyopathy: Familial dilated 2H (CMD 2H)
● Guided entry of tail-anchored proteins factor 3, ATPase (GET3) ; Chromosome 19p13.13; Recessive
- GET3 protein: Catalytic component of multisubunit oxyanion pump
Cardiomyopathy: Familial dilated 2I (CMD 2I)
● Cyclase-associated actin cytoskeleton regulatory protein 2 (CAP2) ; Chromosome 6p22.3; Recessive
Cardiomyopathy: Familial dilated 2J (CMD 2J)
● FLII Actin Remodeling protein (FLII) ; Chromosome 17p11.2; Recessive
Cardiomyopathy: Familial dilated 2K (CMD 2K)
● Myocardial zonula adherens protein (MYZAP) ; Chromosome 15q21.3; Recessive
Cardiomyopathy: Familial dilated: POMT1
CMD: Other
- Cardiomyopathy, Familial dilated (CDG Type 1t (CDG1T))
  ● PGM1 ; 1p31.3; Recessive
- Cardiomyopathy: Familial dilated with type 1 muscle fiber hypotrophy
  ● Myosin, light chain 2, regulatory, Cardiac, Slow (MYL2) ; Chromosome 12q24.11; Recessive
- Cardiomyopathy, Familial dilated (CDG Type 1m (CDG1M))
  ● Dolichol kinase (DOLK) ; Chromosome 9q34.11; Recessive
  - Epidemiology: 7 families
  - Genetics
    - Mutations: Often missense
  - DOLK protein
    - Location: Endoplasmic reticulum membrane
    - Dolichol pathway: Protein glycosylation
    - Catalyzes: CTP + di-trans,poly-cis-Dolichol → CDP + Dolichyl phosphate
  - Clinical
    - Onset: Neonatal
    - Skin: Thin; Hyperkeratosis; Hair loss
    - Seizures
    - Hypotonia
    - Quadriplegia
    - Cardiomyopathy: Dilated
    - Death: < 1 year
  - Laboratory
    - Transferrin: Loss of oligosaccharide structures
- Cardiac conduction disease with or without dilated cardiomyopathy (CCDD)
  ● TNNI3K ; Chromosome 1p31.1; Dominant

Cardiomyopathy, Dilated, X-linked (CMD3)

Cardiomyopathy: Familial dilated (CMD3A)
● TAZ ; Chromosome Xq28; Recessive
- Neonatal, lethal noncompaction of the left ventricular myocardium
- Allelic with Barth syndrome
Cardiomyopathy: Familial dilated (CMD3B)
● Dystrophin ; Chromosome Xp21.2-p21.1; Recessive

Cardiomyopathy: Arrhythmogenic Right Ventricular Dysplasia (ARVD)
- General
  - Clinical
    - Many arrhythmias well tolerated
    - Common causes of juvenile syncope & sudden death
  - EKG
    - Left branch block
    - T-wave inversion in the right precordial leads
    - Late potentials in signal averaging EKG
  - Cardiac pathology: Right ventricle
    - Preferentially involves right ventricular free wall
    - Fibro-fatty replacement
    - Myocardial degeneration
    - Myocyte hypertrophy
    - Mitochondrial abnormalities
- Syndromes
  - ARVD1 : TGFB3 ; Chromosome 14q24.3; Dominant
  - ARVD2 : Cardiac ryanodine receptor (RYR2) ; Chromosome 1q43; Dominant
    - RYR2 mutations also cause: Ventricular tachycardia, catecholaminergic polymorphic, 1 (CPVT 1)
  - ARVD3 : Chromosome 14q12; Dominant
  - ARVD4 : Chromosome 2q32.1-q32.3; Dominant
  - ARVD5 : TMEM43 ; Chromosome 3p25.1; Dominant ⁸
    - Fully penetrant
    - Lethal: Shorter life expectancy in males than females
    - Allelic with: Emery-Dreifuss MD 7
  - ARVD6 : Chromosome 10p14-p12; Dominant
  - ARVD7 : Desmin (DES) ; Chromosome 2q35; Dominant
    - Epidemiology: Swedish family
    - Genetics: Previously localized to 10q22.3
    - Onset: 3rd to 6th decades
    - Myofibrillar myopathy
  - ARVD8 : Desmoplakin (DSP) ; Chromosome 6p24.3; Dominant
    - Genetics
      - Missense mutation (S299R) in Desmoplakin domain binding to plakoglobin
    - Desmoplakin protein: Intermediate filament associated protein
    - Variant syndromes
      - Dilated cardiomyopathy with woolly hair & keratoderma (DCWHK)
        
        Inheritance: Recessive
      - Dilated cardiomyopathy with woolly hair, keratoderma & tooth agenesis (DCWHKTA)
        
        Inheritance: Recessive
      - Epidermolysis bullosa, lethal acantholytic
      - Keratosis palmoplantaris striata II
      - Skin fragility-woolly hair syndrome
  - ARVD9 : Plakophilin-2 (PKP2) ; Chromosome 12p11.21; Dominant
    - Genetics: Incomplete penetrance
    - PKP2 protein: Desmosomal
  - ARVD10 : Desmoglein-2 (DSG2) ; Chromosome 18q12.1; Dominant or Recessive⁵
    - Genetics
      - Mutations: Heterozygous missense or Compound heterozygous
      - Allelic with: CMD1BB
    - DSG2 protein
      - Expressed in many tissues
      - Component of cardiac desmosome
  - ARVD11 : Desmocollin-2 (DSC2) ; Chromosome 18q12.1; Dominant
  - ARVD12 : Junction Plakoglobin (JUP) ; Chromosome 17q21.1; Dominant
    - Mutation: S39_K40insS (Serine insertion)
    - Also see: Naxos disease (Recessive)
  - ARVD13 : Catenin α-3 (CTNNA3) ; Chromosome 10q21.3; Dominant
    - Mutations: Val94Asp; Inframe deletion
  - ARVD14 : Cadherin 2 (CDH2) ; Chromosome 18q12.1; Dominant
    - Mutations: Gln229Pro, Asp407Asn; Inframe Missense
Naxos disease ¹
● Plakoglobin (JUP) ; Chromosome 17q21.2; Recessive
- Mutations: 2 bp deletion at C-terminus (2157TG)
- Plakoglobin protein
  - Role in cell-cell adhesion
  - Present in adhering junctions, desmosomes & intermediate junctions
- Clinical
  - Palmoplantar keratoderma
  - Curly (Wooly) hair
  - Cardiac: ARVD
    - Cardiomyopathy: Dilated; Right ventricular
    - Arrhythmias & Sudden death
    - Pathology
Dilated cardiomyopathy ± Isolated non-compaction of left ventricular myocardium (LVNC)
● ZASP ; Chromosome 10q23.2
- ZASP mutations in linker region between the PDZ & LIM domains
- Allelic disorders
Cardiomyopathies: Genes producing dilated or hypertrophic
- Cardiac troponin T2 ; CMH2
  ● Chromosome 1q32.1; Dominant
- Cardiac β-myosin heavy chain (MYH7) ; CMH1
  ● Chromosome 14q11.2; Dominant
- α actin (Cardiac)
  ● Chromosome 15q14; Dominant
- α-Tropomyosin (TPM1) ; CMH3 ; CMD 1Y
  ● Chromosome 15q22.2; Dominant
Cardiomyopathies: Dystrophy-related genes
- Dilated cardiomyopathy: Dystrophin-related (CMD 3B)
  ● Chromosome Xp21.2-p21.1; Recessive
  - Due to deletion in promoter & 1st exon
  - Onset
    - Males: 15 to 21 yrs
    - Females: 40's
  - Dystrophin: Low cardiac; Normal skeletal muscle
- Dilated cardiomyopathy 1I (CMD1I)
  ● Desmin ; Chromosome 2q35; Dominant
- Dilated cardiomyopathy 1L (CMD1L)
  ● δ-Sarcoglycan ; Chromosome 5q33.3; Recessive
- Dilated cardiomyopathy (atrial) with atrioventricular block (CMD1A; CDCD1)
  ● Lamin A/C ; Chromosome 1q22; Dominant
- Cardiomyopathy: Familial dilated (CMD3A)
  ● TAZ ; Chromosome Xq28; Recessive
  - Allelic with Barth syndrome
Other
- Amyloidosis (TTR; III)
- Mitochondrial disorders
- Mouse model: Mitochondrial superoxide dismutase (SOD2) deletion

External link: E-medicine

Other Cardiomyopathies

Brugada syndrome: Ventricular fibrillation

Brugada syndrome 1
● SCN 5A; ; Chromosome 3p22.2; Dominant
Brugada syndrome-2
● GPD1L ; Chromosome 3p22.3; Dominant
Brugada syndrome-3
● CACNA1C ; Chromosome 12p13.33; Dominant
- Shortened QT interval
Brugada syndrome-4
● CACNB2 ; Chromosome 10p12.33-p12.31; Dominant
- Shortened QT interval
Brugada syndrome-5
● SCN1B ; Chromosome 19q13.12; Dominant
Brugada syndrome-6
● KCNE3 ; Chromosome 11q13.4; Dominant
Brugada syndrome-7
● SCN3B ; Chromosome 11q24.1; Dominant
Brugada syndrome-8
● HCN4 ; Chromosome 15q24.1; Dominant
Brugada syndrome-9
● KCND3 ; Chromosome 1p13.2; Dominant

Metabolic

Fabry's
Glycogenosis
- Pompe (GSD II)
  ● acid α-1-4-glucosidase; Chromosome 17q25.3; Autosomal Recessive
- Forbes (GSD III)
- Anderson (GSD IV)
- Phosphorylase kinase
Glycoproteinosis
- Fucosidosis, type I
  ● α-Fucosidase (FUCA1) ; Chromosome 1p36.11; Autosomal Recessive
- Mannosidosis
  ● α-Mannosidase (MAN2B1) ; Chromosome 19q13.2; Autosomal Recessive
Mucolipidosis II (I-cell disease)
● Chromosome 4p21-p23; Autosomal Recessive
- Valvular heart disease
Mitochondrial
Mucopolysaccharidoses
- Hurler (MPS1)
  ● α-L-iduronidase; Chromosome 4p16.3; Autosomal Recessive
- Hunter (MPS2)
  ● Iduronidase sulfate; Chromosome Xq28; Autosomal Recessive

Developmental

Noncompaction of left ventricular myocardium ± congenital heart defects (LVNC) ⁹
- Definition
  - Cardiac abnormality of left ventricular apex, lateral wall & rarely, the septum
  - Characterized by meshwork of interwoven myocardial strings lined with endocardium
  - Constitutes a spongy myocardial layer clearly distinct from underlying compacted myocardium
  - Nosology: Left ventricular hypertrabeculation (LVHT)
- Mitochondrial disorders
  - mtDNA mutations
    - mtRNA Leu (A3243G)
    - MTATP8 (A8381G)
    - ND1 +
      - mtRNA gene mutations ¹⁰
      - Cytochrome b (MTCYB) mutations ¹¹
    - LHON
  - MIPEP
  - Skeletal muscle biopsy: Mitochondrial changes common
- LVNC1
  ● α-Dystrobrevin (DTNA) ; Chromosome 18q12.1; Dominant
  - Mutations: P121L, P121K
  - α-Dystrobrevin: Cytoplasmic subunit of Dystrophin-associated protein complex (DPC)
  - Left ventricular noncompaction (LVNC)
    - Hypertrophic left ventricule: Deep trabeculations; Poor systolic function
    - Due to arrest of myocardial morphogenesis
  - Onset: Congenital
- Barth syndrome variant
  ● TAZ ; Chromosome Xq28; Recessive
  - Onset: Childhood
- Left ventricular non-compaction 2 (LVNC2)
  ● Chromosome 11p15; Dominant
  - Onset: Adult
- Dilated cardiomyopathy ± Isolated non-compaction of left ventricular myocardium
  ● ZASP (LDB3) ; Chromosome 10q23.2
- Hypertrophic cardiomyopathy
  - MYH7: Several mutations
  - ACTC1: E101K
  - MYBPC3: 4 mutations
- Noncompaction of left ventricle: Other associations
  - Myotonic dystrophy
    - Type 1: 140 to 800 CTG repeats
    - Type 2
  - Becker MD: Exon 45�48 deletion
  - SCN5A: Sick-sinus, long-QT syndrome; R219H, E1784K
  - PTPN11 (SHP2) : Noonan syndrome ; Leopard syndrome
  - LMNA
  - TPM1
  - TNNT2
  - Fibrillin-2: Beals-Hecht Syndrome
  - Methymalonic aciduria & homocystinuria (MMACHC) : Cobalamin-C Deficiency
  - Desmin
  - LMX1B : Nail-patella syndrome
  - HCCS : Microphthalmia with linear skin defects syndrome (MLS; MIDAS)
  - MIB1 : LVNC7
  - NR0B1 : Adrenal hypoplasia, congenital
  - Filamin A (FLNA) : Melnick Needles syndrome
  - Chromosomal disorders
    - 1p36 deletion, Mosaic trisomy 22, Distal4q trisomy/Distal 1q monosomy, 1q43 deletion, Trisomy 13, Distal 5q deletion/li>
    - Cornelia de Lange syndrome, DiGeorge syndrome, Ohtahara Syndrome, Turner syndrome
  - Other linkages: X (Roifman syndrome); 6p24.3; Pierre Robin syndrome
  - Other possible associations
    - AMPD1
    - PMP22
Atrial septal defect
- Atrial septal defect 1 (ASD1)
  ● Chromosome 5p; Dominant
- Atrial septal defect 2 (ASD2)
  ● GATA-Binding protein 4 (GATA4) ; Chromosome 8p23.1; Dominant
  - Congenital heart disease, but no conduction defects or noncardiac abnormalities
- Atrial septal defect 3 (ASD3)
  ● Myosin heavy chain 6 (MYH6) ; Chromosome 14q11.2; Dominant
  - MYH6: Expression regulated by TBX5
  - No other cardiac abnormalities
  - Mutations also cause: Hypertrophic cardiomyopathy
- Atrial septal defect 4 (ASD4)
  ● T-Box 20 (TBX20) ; Chromosome 7p14.2; Dominant
  - Congenital heart disease, but no conduction defects or noncardiac abnormalities
- Atrial septal defect 5 (ASD5)
  ● ACTC1 ; Chromosome 15q14; Dominant
  - No other cardiac abnormalities
- Atrial septal defect 6 (ASD6)
  ● Tolloid-like 1 (TLL1) ; Chromosome 4q32.3; Dominant
  - Associated with: Aneurysm of interatrial septum; Cardiac arrhythmias
- ASD with A-V conduction defects
  ● Cardiac specific homeobox (CSX; NKX2-5) ; Chromosome 5q35.1; Dominant
- Atrial septal defect
  ● Chromosome 6p21.3; Dominant
- Holt-Oram
  ● T-Box 5 (TBX5) ; Dominant; Chromosome 12q24.21
Visceroatrial heterotaxia
● Connexin 43 Gap junction protein (GJA1) ; Recessive; Chromosome 6q22.31

Other cardiomyopathies

Long QT syndromes
Amyloid
Emery-Dreifuss
- Female carriers with atrial cardiomyopathy but no weakness
- Skeletal muscle may show myopathic changes
Selenium deficiency
Congestive cardiomyopathies with conduction defects (CMD)
Toxic
- Herceptin (trastuzumab): ErbB2 blockade; Dilated cardiomyopathy

Fatty Acid Oxidation: Errors ¹⁶

Fatty Acid Oxidation Disorders
Acyl-CoA dehydrogenase deficiencies
Acyl-CoA dehydrogenase, short-chain (ACADS): SCAD
Acyl-CoA dehydrogenase, medium-chain (ACADM): MCAD
Acyl-CoA dehydrogenase, long-chain (ACADL): LCAD
Acyl-CoA dehydrogenase, very long-chain (ACADVL): VLCAD
Acetyl-CoA acetyltransferase 1 (ACAT1)
2-Enoyl-CoA hydratase deficiency
ECHS1
See Trifunctional protein
L-3-Hydroxyacyl-CoA dehydrogenase deficiencies
L-3-Hydroxyacyl-CoA dehydrogenase, short chain (SCHAD)
Trifunctional protein: Long-chain FA (LCHAD)
Alpha subunit (HADHA)
Beta subunit (HADHB)
3-Ketoacyl-CoA thiolase deficiency
3-Ketoacyl-CoA thiolase, Medium chain (MCKAT)
Trifunctional protein
α-Methylacyl-CoA racemase (AMACR) deficiency
Carnitine-acylcarnitine translocase deficiency (CACT): 3p21
2,4-Dienoyl-CoA reductase deficiency (DECR1): 8q21
Electron transfer flavoprotein (ETF) deficiency: 15q23
Ichthyosiform erythroderma (NCIE2): CGI58 gene; 3p21
TANGO2: 22q11
Trifunctional protein deficiencies: Subunits A & B
Tyrosinemia

Also see
1° Disorders of Carnitine metabolism
Cystinosis
Fatty acid & Carnitine transport pathways
Fatty acid oxidation pathways
Laboratory: Acylcarnitine
Lipids & Lipid disorders
Mitochondria: Biochemical abnormalities
Peroxisomal disorders
Valine

Mitochondrial Fatty Acid Oxidation: 3 processes
Carnitine uptake (Transport): Through plasma membrane
Carnitine shuttle: Acyl-CoAs into mitochondria
Fatty acid β-oxidation

Disorders of Fatty Acid metabolism: General features

Fatty Acid metabolism
- Location: Present in mitochondria
- Components
  - Fatty acid synthesis
  - Fatty acid & Carnitine transport
  - Fatty acid β-oxidation: 2 Systems
    - Inner mitochondrial membrane
      - Oxidation of Long chain fatty acids (LCFA)
    - Soluble enzymes in mitochondrial matrix
      - β-oxidation: Medium- & Short-chain Acyl-CoAs
  - Transport of electrons to respiratory chain
    - From Acyl-CoA dehydrogenases via
      - Electron transfer flavoprotein (ETF)
      - ETF:Coenzyme-Q oxidoreductase (ETF:QO)
    - From L-3-Hydroxyacyl-CoA dehydrogenases: From NADH to Complex I
- Function: Mitochondrial oxidative metabolism of lipids
  - Major source for energy production: Increased with stress or fasting
  - Tissues: Highest in heart, liver & skeletal muscle
  - Skeletal muscle
    - Rest: Long chain fatty acids (LCFA) are major energy substrate
    - Early exercise: Energy derived mainly from blood glucose & muscle glycogen
    - Prolonged exercise: Shift to 70% fatty acid utilization over few hours
  - Heart: Substantially dependent on LCFA
Categories of β-oxidation Disorders
Clinical syndromes
- General associated features
  - Hypoketotic hypoglycemia
  - Encephalopathy
  - Cardiomyopathy
  - Myopathy
  - Precipitation by: Infections; Fasting
  - Laboratory: Hypoglycemia; High CK, Liver enzymes, Lactate, Ammonia
- Fasting Hypoketotic Hypoglycemia
  - Carnitine deficiency, 1°
  - Carnitine/acylcarnitine translocase (CACT; SLC25A20)
  - Carnitine palmitoyltransferase deficiency: I , II
  - Acyl-CoA dehydrogenase deficiencies: MCAD, SCAD, VLCAD
  - Trifunctional protein (LCHAD)
  - ACAD9
- Nonfasting Hypoglycemia (Hyperinsulinism)
  - Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency (HADH)
- Ketoacidosis
  - Acetyl-CoA acetyltransferase 1 (ACAT1)
- Rhabdomyolysis, Weakness or Myalgia
  - CPT II
  - Acyl-CoA dehydrogenase deficiencies: VLCAD
  - ACAD9
  - Trifunctional protein (LCHAD): HADHA; HADHB
- Cardiomyopathy
  - Carnitine deficiency, 1°
  - Carnitine/acylcarnitine translocase (CACT; SLC25A20)
  - CPT II
  - VLCAD
  - ACAD9
  - Trifunctional protein (HADHB)
  - 2,4-Dienoyl-CoA reductase deficiency
- Encephalopathy
  - ECHS1
- Polyneuropathy
  - Trifunctional protein
- Hemolysis, Liver & Low platelets, Maternal (HELLP)
  - Trifunctional protein
Management & Treatment
- Avoid fasting
- Aggressive treatment during illness
- Supplementation: Carnitine or Nutritional support
- Specific syndromes
  - MCADD: Avoid medium-chain triglyceride (MCT) oil
  - LCFAODs: Fat-restricted diet, Higher protein intake & MCT supplementation; No carnitine
  - Carnitine transporter defects: Carnitine supplementation

FAOD: Laboratory

Fatty Acid Oxidation Disorders: Acylcarnitine
Disorder	Gene	Acyl-Carnitine: Elevations
CPT-IA	CPT1A	C0, C0/(C16 + C18)
CACT	SLC25A20	C16, C16:1, C18, C18:1
CPT-II	CPT2	C16, C16:1, C18, C18:1
CDSP	SLC22A5	C0
VLCAD	ACADVL	C12:1, C14:2, C14:1, C14, C16:1, C16
LCHAD	HADHA	C16:1-OH, C16-OH, C18:1-OH, C18-OH
TFP	HADHA HADHB	C16:1-OH, C16-OH, C18:1-OH, C18-OH
MCAD	ACADM	C8, C10, C10:1
SCAD	ACADS	C4
MAD	ETFA ETFB ETFDH	C4, C5, C6, C8, C10:1, C12, C14, C14:1, C16, C16:1, C18, C18:1, C16-OH, C16:1-OH, C18-OH, C18:1-OH

Fatty acid metabolism: Specific Disorders

Medium chain acyl-CoA dehydrogenase deficiency (MCAD)
● Acyl-CoA dehydrogenase, medium-chain (ACADM) ; Chromosome 1p31.1; Recessive
- Genetics
  - Common Northern European mutation: K304E
- ACADM protein
  - Function: Catalyzes initial reaction in β-oxidation of fatty acids
- Clinical
  - Onset age: 3 months and 5.1 years; Some Teens & Adults
  - Precipitating factors: Alcohol; Starvation; ? Breast feeding
  - Hepatic
    - Hypoketotic hypoglycemia
    - Metabolic encephalopathy
  - Habitus: Overweight
  - CNS: Episodic encephalopathy
  - Muscle
    - Fatigue (35%)
    - Muscle pain (31%)
    - Exercise tolerance: Reduced
    - Proximal weakness: Transient reported
  - Cardiac: Few features
  - Course
    - High mortality
    - Sudden infant death: Some patients
- Laboratory
  - Organic acids: Abnormal
  - Acylcarnitine profile: High medium chain (C8, C10, C12)
Medium chain 3-ketoacyl-CoA thiolase deficiency
● Recessive
- Epidemiology: Single Japanese patient
- Clinical
  - Muscle: Rhabdomyolysis
  - Hepatic
    - Hyopketotic hypoglycemia
    - ± Metabolic encephalopathy
- Laboratory
  - Organic acids: Abnormal
  - Enzyme deficiency: 60%
Long chain acyl-CoA dehydrogenase (LCAD) deficiency
● Long-chain acyl-CoA dehydrogenase (ACADL) ; Chromosome 2q34; Recessive
- Genetics
  - Mutation: Missense; Gln303Lys
- LCAD protein
  - Location: Mitochondrial matirx
  - Action: Catalyzes 1st step in mitochondrial β-oxidation of fatty acids
- Clinical
  - Onset: Early childhood
  - Episodes: Associated with fasting
    - Hypoglycemia, Hypoketotic
    - Cardiac arrest
  - Clinical findings
    - Hepatomegaly
    - Cardiomegaly
    - Hypotonia
- Laboratory
  - Plasma carnitine: Low
  - Urine
    - Dicarboxylic aciduria
    - β-hydroxybutyrate levels: Low
- Mouse mutants
  - Sensitivity to cold: Rapidly lose body temperature
Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency
● Very long-chain acyl-CoA dehydrogenase (ACADVL) ; Chromosome 17p13.1; Recessive
- Epidemiology: > 100 patients
- Genetics
  - Mutations: Missense, Splice & Stop
- Protein
  - Structure: Dimer of 70 kD subunits
  - Mitochondrial: Bound to inner membrane
  - Relative selectivity for palmitoyl-CoA vs LCAD
  - Active toward CoA esters of longer chain substrates: Arachidoyl-CoA; Behenoyl-CoA; Lignoceroyl-CoA
  - Initial step of mitochondrial β-oxidation system
  - Tissue distribution: Abundant in heart, skeletal muscle & liver
- Infantile type
  - Hypoketotic hypoglycemia
  - Hepatic dysfunction: Hepatomegaly
  - Cardiomyopathy: Hypertrophic
  - Prognosis: High mortality
  - CNS: Encephalopathy; Hypotonia
  - Lab: Low free plasma carnitine
- Hepatic type
  - Hypoketotic hypoglycemia
  - Low mortality
- Childhood & Adult type (Myopathic) ^3, ¹⁷
  - Epidemiology: 15 patients with adult onset
  - Genetics
    - Inheritance: Recessive
    - Mutations
      Missense
      Lysine238 deletion (Homozygous); Met300Ile; Ala304Val; Gly401Asp + Arg410His;
      Ala416Thr (Temperature sensitive) + Arg450His
      Other: Splice; Stop
  - Clinical
    - Onset age: Childhood or Adult; Mean 3rd decade
    - Myalgic episodes
      - Exercise & Fasting induced
      - Relatively easily triggered
    - Muscle pain
      - Relatively severe: More than CPT2 deficiency
    - Rhabdomyolysis
      - Precipitant: Exercise
    - Weakness (10%)
      - Proximal & Trunk ± Distal
      - Symmetric
    - Systemic features: Variably present
      - Hypoglycemia
      - Hepatomegaly
      - Cardiomyopathy
  - Lab
    - Fasting ketogenesis: Low
    - Diagnostic testing
      - Organic acids
        
        Normal with random testing or during myalgic episode
        
        Hypoketotic dicarboxylic aciduria after 36 hour fast
        
        NOTE: Monitor for hypoglycemia during fast
      - Acylcarnitine analysis: Elevated C_14:1 acylcarnitine
    - Free plasma carnitine: Normal
    - Intramuscular pH regulation: Abnormal at rest & during mild exercise
    - Serum CK
      - Recurent elevations with moderate exercise: Up to 90,000
      - Normal or Mildly high between attacks
    - EMG: Myopathic
    - Muscle MRI involvement
      - Asymmetric
      - Thigh; Adductors; Vastus
      - Leg: Medial gastrocnemius
    - Muscle biopsy
      - Histology: Normal between attacks
      - Lipid storage (30%)
        
        Type 1 muscle fibers
        
        Small droplets
      - COX- fibers: Some patients
      - VLCAD immunostain: Reduced VLCAD protein in muscle fibers in many patients
    - VLCAD protein in fibroblasts
      - Abundance reduced by 50%
      - Enzyme activity present but reduced to ~ 10% of control
  - Possible treatments
    - Daily: L-Carnitine 2 g, Coenzyme Q10 300 mg, Riboflavin 300 mg
    - Bezafibrate: Increases fatty acid oxidation
    - Avoid: Fasting; Myocardial irritation; Dehydration; High fat diet; Volatile anesthetics
Long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD; Trifunctional protein)
- Genetic disorders
  - HADHA: Alpha subunit
  - HADHB: Beta subunit
- Clinical
  - Muscle
    - Rhabdomyolysis
    - Myopathy
  - Hepatic
    - Hypoketotic hypoglycemia
    - Metabolic encephalopathy
  - Retinitis pigmentosa
  - Polyneuropathy: Axon loss
  - Cardiomyopathy
- Laboratory: Organic acids abnormal
Carnitine-acylcarnitine translocase deficiency
● Carnitine-acylcarnitine translocase (SLC25A20) ; Chromosome 3p21.31; Recessive
- Clinical
  - Muscle: Myopathy
  - Cardiomyopathy
  - Hepatic
    - Hypoketotic hypoglycemia
    - Metabolic encephalopathy
- Laboratory
  - ± Abnormal organic acids
Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency
● HADH (SCHAD; HADHSC) ; Chromosome 4q25; Recessive
- Allelic with
  - Hyperinsulinemic hypoglycemia, familial, 4
- Enzyme
  - Catalyzes reversible dehydrogenation of 3-hydroxyacyl-CoAs to corresponding 3-ketoacyl-CoAs
  - Concomitant reduction of NAD to NADH
  - Exerts highest activity toward 3-hydroxybutyryl-CoA
  - No clear correlation between HADH residual activity and clinical phenotype
- Clinical
  - Muscle: Rhabdomyolysis
    - Juvenile onset
    - Recurrent
  - Hepatic
    - Hypoketotic hypoglycemia: Triggered by infections
    - Metabolic encephalopathy
- Laboratory
  - Abnormal organic acids
  - Muscle specific defect in HADH
Triglyceride storage disease with impaired long-chain fatty acid oxidation (CDS)
● CGI58 gene (ABHD5) ; Chromosome 3p21.33; Recessive
- Nosology
  - Neutral lipid storage disease with ichthyosis (NLSDI)
  - NCIE2
  - Chanarin-Dorfman disease
  - Ichthyosiform erythroderma
- Genetics
  - Mutations: Stop; Splice; Missense
- CGI58 protein
  - Widely expressed: Skin, lymphocytes, liver, skeletal muscle, & brain
  - α/β hydrolase fold
  - Similar to esterase/lipase/thioesterase subfamily
  - Located on surface of cytoplasmic lipid droplets
  - Also see
    - Triglyceride disorders
    - Lipid disorders
- Clinical
  - Onset
    - Age: Birth
    - Collodion babies
  - Ichthyosiform erythroderma: Fine white scales; Erythematous background; All over body
  - Hepatomegaly
  - Muscle weakness (60%)
    - Proximal
    - Slowly progressive
    - Mild
  - Other organ systems: Variable
    - Ears
      - External: Thick; Small; Malformed
      - Deafness
    - CNS: Mental retardation
    - Eyes
      - Movement: Strabismus; Nystagmus
      - Ectropion
      - Cataract
- Laboratory
  - Serum CK: Mildly elevated (2x to 3x)
  - Liver function tests: Mildly elevated (2x to 3x)
  - Muscle MRI: Normal or Mildly abnormal
  - Muscle pathology
    - Triglyceride storage
    - Lipid droplets in types 1 & 2 muscle fibers
  - Granulocytes ± Skin: Lipid droplets (Jordan�s anomaly)

Neutral Lipid Storage Disease with Myopathy (NLSDM; TGCV)

⁷
● Patatin-like phospholipase domain-containing 2 (PNPLA2; ATGL)

; Chromosome 11p15.5; Recessive

Epidemiology: 56 patients
Genetics
- Mutations: Missense & Truncation
PNPLA2 (Adipose triglyceride lipase) protein: Lipase
- Lipid droplet metabolism
- Activated by CGI-58
- Rate limiting enzyme for hydrolysis of cytoplasmic triglycerides

Clinical

Onset
- Age: Childhood or Adult (3rd decade)
- Psychomotor retardation
- Weakness
Myopathy
- Delayed walking (66%)
- Weakness
  - Most severe: Proximal arms
  - Scapular winging: Some patients
  - Other: Proximal legs & Distal
  - Asymmetric: R > L
  - Difficulty walking
  - Face: Normal
Heart (54%)
- More involvement at later disease stages: ≥ 40 years
- Cardiomyopathy (33%)
- Abnormal EKG (100%)
- Heart failure
- Arrhythmias
GI
- Liver: Hepatomegaly (22%)
- Pancreatitis (17%)
CNS: Mental retardation (Mild) (66%)
Hearing loss: Sensorineural (17%)
? Treatment
- ? β-adrenergic agents
- Bezafibrate ¹³
  - May improve fatty acid oxidation & mitochondrial function
  - No function benefit over 6 months

From: F Fatehi

Jordans' Anomaly
Lipid Droplets in Leukocytes

Laboratory
- Serum CK: High
- Serum transaminases: High
- Leukocytes: Triglyceride-containing cytoplasmic droplets (Jordans' anomaly) (100%)
- Diabetes (30%)
- Hypertriglyceridemia (36%)
- EMG: Myotonia in some patients
- Muscle pathology
  - Lipid storage
    - Type 1 & 2 fibers, or More in Type 1
    - May be predominantly subsarcolemmal
  - Autophagic vacuoles, Rimmed
  - Oxidative enzyme activity: Normal
- Muscle MRI
  - Pattern of involvement within muscle: Patchy
  - Legs (Posterior) > Arms
  - Involved muscles: Gluteus minimus, Lumbar paraspinal; Semimembranosus, Soleus & Gastrocnemius medialis; Infraspinatus
  - Spared muscles: Gracilis, Sartorius, Subscapularis, Pectoralis, Triceps brachii, Sternocleidomastoid
Heterozygotes may have
- Exercise intolerance
- Myalgias
Also see
- Triglyceride disorders
- Lipid disorders

Fatty Acid Synthesis: Disorder

Childhood-Onset Dystonia & Optic Atrophy (DYTOABG)

¹⁴
● Mitochondrial Trans-2-Enoyl-CoA Reductase (MECR)

; Chromosome 1p35.3; Recessive

Nosology: Mitochondrial Enoyl CoA reductase Protein-associated Neurodegeneration (MEPAN)
Epidemiology: 8 families
Genetics
- Mutations: Nonsense, Missense & Splice-site
- Allelic disorder: OPA16 ¹⁹
  - Epidemiology: 2 patients
  - Visual loss: Sudden or Progressive
MECR protein
- Function: Mitochondrial fatty acid synthesis (mtFAS)
- mtFAS
  - Involved in synthesis of: Lipoic acid (LA)
  - Lipoic acid: Essential for activity of
    - Pyruvate dehydrogenase (PDH)
    - α-ketoglutarate dehydrogenase (KGD)
    - Branched chain keto-acid dehydrogenase
    - 2-Oxoadipate dehydrogenase
    - Glycine cleavage system
  - FAS pathway
    - Acetyl group: Elongated
    - Growing acyl chains: Bound to an acyl carrier protein (ACP)
- Other
  - Lipoic acid disorders
  - OPA15: MCAT
Clinical
- Onset age: 15 months to 7 years
- Movement disorders
  - Dystonia
  - Other (Some patients): Facial dystonia, myoclonus, chorea, dyskinesias
- Optic atrophy
  - Onset age: Childhood; After dystonia
  - Visual acutiy: Reduced
- Intellect: Preserved or Reduced
- Spasticity (Some patients)
  - Legs
  - Tendon reflexes increased
  - Gait disorder
- Bulbar: Dysarthria; Dysphagia
- Course: Progressive motor disorders
Laboratory
- Brain MRI: Pallidum T2 hyperintense
- MR spectroscopy: Lactate peak

Return to Cardiac disease & Myopathy

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