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CARDIOMYOPATHIES: Genetic

Hypertrophic cardiomyopathy

• 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
    • α-Myosin heavy chain
    • β-Myosin heavy chain
    • α-Tropomyosin
    • Cardiac troponin I
    • Cardiac troponin T2
    • Cardiac myosin binding protein-C
    • Myosin light chain: MYL2; MYL3
    • α actin (Cardiac)
    • Myosin light chain kinase 2 (MYLK2)
    • MYH7
  • ATP generation systems
    • PRKAG2
    • Friedreichs
    • Mitochondrial
    • VLCAD
  • Other
    • Dystrophin complex: α-Dystrobrevin
    • Titin
• External link: Gene mutation data base

• CMH 1 : Cardiac β-myosin heavy chain (MYH7)
  l Chromosome 14q11.2-q13; Dominant
  • Genetics
    • Point mutations: > 70 described
  • Other MYH7 mutations cause
    • Hyaline body myopathy
    • Hypertrophic cardiomyopathy with cores
    • Hypertrophic cardiomyopathy, digenic
    • Distal myopathy (MPD1)
    • Dilated cardiomyopathy 1S (CMD 1S)
  • 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
  l Chromosome 1q32; Dominant
  
  
• CMH 3 : α-Tropomyosin (TPM1)
  l Chromosome 15q22; Dominant
  • TPM1 mutations also produce: CMD 1Y
  
  
• CMH 4 : Cardiac myosin binding protein-C (MYBPC3)
  l Chromosome 11p11.2; Dominant
  • Onset: Often later than other CMH syndromes
    • ~ 42% > 50 years
    • No deaths < 40 years
  • Causes of death: Sudden; Heart failure; Cerebrovascular
  • Incomplete penetrance
  • Homozygous splice site mutation
    • Severe neonatal hypertrophic cardiomyopathy
    • Epidemiology: Old Order Amish
  
  
• CMH 5: Hypertrophic cardiomyopathy, see CMH4
  
  
• CMH 6 : Hypertrophic cardiomyopathy with ventricular pre-excitation (WPW syndrome)
  l PRKAG2 ; Chromosome7q36; Dominant
  • Protein
    • γ2 subunit of AMP-activated protein kinase
    • Dominant isoform in regulatory γ subunit
    • AMPK protects cells from ATP depletion
      • Activates glycolysis & fatty acid uptake during hypoxic stres or metabolic demand
  • Clinical
    • Early onset
    • Sudden death
    • Prominent cardiac hypertrophy
  
  
• CMH 7
  l Troponin I, Cardiac; TNNI3; Chromosome 19p13.2-q13.2; Dominant
  • TNNI3 mutations also cause
    • Familial Restrictive cardiomyopathy (RCM1)
    • Dilated cardiomyopathy (CMD 2A)
  
  
• CMH 8 Mid left ventricular
  l Myosin light chain, alkali; Ventricular & Skeletal Slow (MYL3) ; Chromosome 3p; Dominant or Recessive
  
  
• CMH 9
  l Titin; Chromosome 2q24.3; ? Inheritance
  
  
• CMH 10 Mid-left Ventricular Chamber Type
  l Myosin light chain, Ventricular regulatory (MYL2) ; Chromosome 12q23-q24.3; Dominant
  
  
• CMH 11
  l α actin (Cardiac); Chromosome 15q14; Dominant
  • Mutation: Missense; Ala295Ser
  • Other mutations produce: Dilated cardiomyopathy (CMD 1R)
  
  
• CMH 12
  l Cysteine- and glycine-rich protein 3 (CSRP3) ; Chromosome 11p15.1; Dominant
  • Mutations: Missense; Cys58Gly, Leu44Pro, Ser54Arg & Glu55Gly
  • Other mutations produce: Dilated cardiomyopathy (CMD 1M)
  
  
• Cardiomyopathy: Familial hypertrophic
  l α-Myosin, heavy chain 6 (MYH6) ; Chromosome 14q12; Dominant
  • MYH6: Expression regulated by TBX5
  • Mutations also cause: Atrial septal defect
  
  
• Cardiomyopathy: Familial hypertrophic, midventricular, digenic
  l Myosin light chain kinase 2 (MYLK2) ; Chromosome 20q13.3
  l MYH7
  

• ?CMH: Chromosome 16
• ?CMH: Chromosome 18
• Mitochondrial
  • tRNA glycine
  • tRNA leucine
    
• Hermansky-Pudlak syndromes
  l Chromosome 10q23.1-q23.3; Recessive
  • Lysosomal change
• Glycogen storage disease
  • Type 0
  • Type 2
• Mouse cardiomyopathy
  • Cardiac α-myosin heavy chain (MYH6)
    

• 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
• Also see dilated cardiomyopathy with myopathy

• Dilated cardiomyopathy (atrial) with atrioventricular block (CMD 1A; CDCD1)
  l Lamin A/C ; Chromosome 1q21.2; 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
    • 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)
  l 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)
  l LIM domain-binding 3 (LDB3; ZASP) ; Chromosome 10q21-q23; Dominant
  • Also mutated in: Myofibrillar myopathy
  • Clinical: Association with mitral valve prolapse
  
  
• Cardiomyopathy: Familial dilated 1D (CMD 1D)
  l Cardiac troponin T2 (TNNT2) ; Chromosome 1q32; Dominant
  • Pure DCM
  
  
• Dilated cardiomyopathy with conduction defect (CMD 1E; CDCD2)
  l Sodium channel, voltage-gated, Type V, Alpha subunit (SCN5A) ; Chromosome 3p21; Dominant
  • Sinus node dysfunction & stroke
  
  
• Dilated cardiomyopathy with conduction defect (CMD 1F; CDCD3)
  l Chromosome 6q23; Dominant
  • Other features: Limb-girdle muscular dystrophy 1E; Conduction disease
  
  
• Dilated cardiomyopathy 1G (CMD 1G)
  l Titin ; Chromosome 2q31
  • Dominant syndrome: Pure Dilated cardiomyopathy
    • 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)
  l Chromosome 2q14-q22; Dominant
  • Epidemiology: German family
  • Other features: Conduction disease
  
  
• Dilated cardiomyopathy 1I (CMD 1I)
  l Desmin ; Chromosome 2q35; Dominant
  
  
• Dilated cardiomyopathy with sensorineural hearing loss 1J (CMD 1J)
  l Eyes absent 4 (EYA4) ; Chromosome 6q23-q24; Dominant
  • Hearing loss: Onst late adolescence
  • Ventricular dysfunction: Progressive congestive heart failure after 4th decade
  
  
• Dilated cardiomyopathy 1K (CMD 1K)
  l Chromosome 6q12-q16; Dominant
  • Epidemiology: French family
  • Pure DCM
  
  
• Dilated cardiomyopathy 1L (CMD 1L)
  l δ-Sarcoglycan; Chromosome 5q33-q34; Recessive
  
  
• Dilated cardiomyopathy 1M (CMD 1M)
  l 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)
  l Telethonin ; Chromosome 17q12; Dominant
  • R87Q mutation
  • Also see: LGMD 2G
  
  
• Dilated cardiomyopathy 1O (CMD 1O): With ventricular tachycardia
  l ABCC9 (SUR2A) ; Chromosome 12p12.1; Dominant or Sporadic
  • Genetics
    • 2 patients
    • Mutations: Frameshift & Missense
  • ABCC9
    • ATP-sensitive potassium (K(ATP)) channel
    • Inhibition of channel opening when ATP concentration at cytoplasmic cell surface is increased
    • Sulfonylureas: Inhibit activity of K(ATP) channels
  • Clinical
    • Onset 5th to 6th decade
    • Severely dilated hearts
    • Compromised contractile function
    • Rhythm disturbances
  
  
• Dilated cardiomyopathy 1P (CMD 1P)
  l Phospholamban ; Chromosome 6q22.1; Dominant
  • Missense & inframe deletion mutations
  • 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)
  l Chromosome 7q22.3-q31.1; Dominant
  • Portugese family
  • Onset: 25 to 47 years
  • Cardiomyopathy, isolated: Dyspnea & Edema
  
  
• Cardiomyopathy: Idiopathic dilated (CMD 1R)
  l α actin (Cardiac) (ACTC); Chromosome 15q14; Dominant
  • Mutations: Missense; Arg312His, Glu361Gly
  • Other mutation produces hypertrophic cardiomyopathy
  
  
• Cardiomyopathy: Idiopathic dilated (CMD 1S)
  l β-myosin heavy chain (MYH7) ; Chromosome 14q12; Dominant
  
  • See: Hypertrophic cardiomyopathy
  
  
• Cardiomyopathy: Idiopathic dilated (CMD 1T)
  l Thymopoetin (TMPO) ; Chromosome 12q22; Dominant
  
  • Mutation: Arg690Cys
  • Clinical: Severe cardiomyopathy
  
  
• Cardiomyopathy: Familial dilated (CMD 1U)
  l Presenilin-1 ; Chromosome 14q24.3; Dominant
  
  
• Cardiomyopathy: Familial dilated (CMD 1V)
  l Presenilin-2 ; Chromosome 1q31-q42; Dominant
  
  
• Cardiomyopathy: Idiopathic dilated (CMD 1W) ⁴
  l Metavinculin (Vinculin; VCN) ; Chromosome 10q22.1-q23
  • Mutations: Arg975Trp; 3-bp deletion (Leu954del)
  • 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
  l Fukutin ; Chromosome 9q31; Recessive
  • Epidemiology: 6 Japanese patients
  • Mutations: Heterozygous
    • One allele: 3kb insertion
    • Other allele: Missense; R179T, Q358P
  • Allelic with
    • Fukuyama congenital muscular dystrophy
    • LGMD 2M
  • 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)
  l Tropomyosin 1 (TPM1) ; Chromosome 15q22.1; Dominant
  • Mutations also produce: CMH 3
  
  
• Cardiomyopathy: Familial dilated (CMD 1Z)
  l Troponin C, Slow (TNNC1) ; Chromosome 3p21.3-p14.3; Dominant
  
  
• Cardiomyopathy: Familial dilated (CMD 1AA)
  l α-Actinin-2 (ACTN2) ; Chromosome 1q42-q43; Dominant
  • Epidemiology: Single patient
  • Mutation: Missense; Heterozygous; Gln9Arg
  • α-Actinin-2 protein
    • Muscle specific
    • Localized at Z-lines
  
  
• Cardiomyopathy: Familial dilated (CMD 2A)
  l TNNI3 ; Chromosome 19q13.4; Dominant
  • Mutation: A2V
  • Other TNNI3 mutations produce
    • Hypertrophic cardiomyopathy(CMH7)
    • Restrictive cardiomyopathy (RCM1)
  
  
• Cardiomyopathy: Familial dilated (CMD3A)
  l Chromosome Xq28; Recessive
  • Neonatal, lethal noncompaction of the left ventricular myocardium
  • Allelic with Barth syndrome
  
  
• Cardiomyopathy: Familial dilated (CMD3B)
  l Dystrophin; Chromosome Xp21.2; Recessive
  
  
• Right ventricular dilated (ARVD) cardiomyopathy
  • 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
  l ARVD1 : TGFB3 ; Chromosome 14q23-q24; Dominant
  l ARVD2 : Cardiac ryanodine receptor (RYR2) ; Chromosome 1q42; Dominant
  • RYR2 mutations also cause Ventricular tachycardia, stress-induced polymorphic
  l ARVD3 : Chromosome 14q12; Dominant
  l ARVD4 : Chromosome 2q32; Dominant
  l ARVD5 : TMEM43 ; Chromosome 3p23; Dominant⁸
  • Fully penetrant
  • Lethal: Shorter life expectancy in males than females
  l ARVD6 : Chromosome 10p12-p14; Dominant
  l ARVD7 : Chromosome 10q22; Dominant
  
  • Epidemiology: Swedish family
  • Onset: 3rd to 6th decades
  • Myofibrillar myopathy
  l ARVD8 : Desmoplakin ; Chromosome 6p24; Dominant
  • Missense mutation (S299R) in Desmoplakin domain binding to plakoglobin
  • Also see: Cardiomyopathy with wooly hair
  l ARVD9 : Plakophilin-2 (PKP2) ; Chromosome 12p11; Dominant
  
  • Genetics: Incomplete penetrance
  • PKP2 protein: Desmosomal
  l ARVD10 : Desmoglein-2 (DSG2) ; Chromosome 18q12.1-q12.2; Dominant or Recessive⁵
  • Mutations: Heterozygous missense or Compound heterozygous
  • DSG2 protein
    • Expressed in many tissues
    • Component of cardiac desmosome
  l ARVD11 : Desmocollin-2 (DSC2) ; Chromosome 18q12.1; Dominant
  l ARVD12 : Junction Plakoglobin (JUP) ; Chromosome 17q21
  • S39_K40insS mutation (Serine insertion): Dominant
  • Also see: Naxos disease (Recessive)
  
  
• Naxos disease ¹
  l Plakoglobin (JUP) ; Chromosome 17q21; 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
      • Endomyocardial fibrous & fatty replacement
      • Right ventricle: Fibrofatty replacement
      • Left ventricle: Fibrosis
  
  
• Dilated cardiomyopathy with woolly hair and keratoderma
  l Desmoplakin ; Chromosome 6p24; Recessive
  • Desmoplakin protein: Intermediate filament associated protein
  • Also see: ARVD
  
  
• Dilated cardiomyopathy ± Isolated non-compaction of left ventricular myocardium (LVNC)
  l ZASP
  • ZASP mutations in linker region between the PDZ & LIM domains
  • Allelic with
    • Markesbery distal myopathy
    • ZASP myofibrillar myopathy
  
  
• Dilated cardiomyopathy + Sensorineural hearing loss
  l EYA4; Chromosome 6q23-q24
  • EYA4: Transcriptional coactivator
  
  
• Cardiomyopathies: Genes producing dilated or hypertrophic
  • Cardiac troponin T2 ; CMH2
    l Chromosome 1q32; Dominant
  • Cardiac β-myosin heavy chain (MYH7) ; CMH1
    l Chromosome 14q11.2-q13; Dominant
  • α actin (Cardiac)
    l Chromosome 15q14; Dominant
  • α-Tropomyosin (TPM1) ; CMH3 ; CMD 1Y
    l Chromosome 15q22; Dominant
  
  
• Cardiomyopathies: Dystrophy-related genes
  • Dilated cardiomyopathy: Dystrophin-related (CMD 3B)
    l Chromosome Xq21; 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)
    l Desmin ; Chromosome 2q35; Dominant
  • Dilated cardiomyopathy 1L (CMD1L)
    l δ-Sarcoglycan; Chromosome 5q33-q34; Recessive
  • Dilated cardiomyopathy (atrial) with atrioventricular block (CMD1A; CDCD1)
    l Lamin A/C ; Chromosome 1q21.2; Dominant
  • Cardiomyopathy: Familial dilated (CMD3A)
    l Chromosome Xq28; Recessive
    • Allelic with Barth syndrome
  
  
• Other
  • Amyloidosis (TTR; III)
  • Mitochondrial disorders
  • Mouse model: Mitochondrial superoxide dismutase (SOD2) deletion

Other Cardiomyopathies

• Fabry's
• Glycogenosis
  • Pompe (GSD II)
    l acid α-1-4-glucosidase; Chromosome 17q23; Autosomal Recessive
  • Forbes (GSD III)
  • Anderson (GSD IV)
  • Phosphorylase kinase
• Glycoproteinosis
  • Fucosidosis, type I
    l α-Fucosidase; Chromosome 1p34; Autosomal Recessive
    
  • Mannosidosis
    l α-Mannosidase; Chromosome 19q13.1-q13.3; Autosomal Recessive
• Mucolipidosis II (I-cell disease)
  l Chromosome 4p21-p23; Autosomal Recessive
  • Valvular heart disease
• Mitochondrial
• Mucopolysaccharidoses
  • Hurler (MPS1)
    l α-L-iduronidase; Chromosome 4p16.3; Autosomal Recessive
  • Hunter (MPS2)
    l Iduronidase sulfate; Chromosome Xq28; Autosomal Recessive

• Noncompaction of left ventricular myocardium ± congenital heart defects (LVNC)
  
  • LVNC1
    l α-Dystrobrevin ; Chromosome 18q12.1-q12.2; Dominant
    • 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
    l TAZ ; Chromosome Xq28; Recessive
    • Onset: Childhood
  • Left ventricular non-compaction 2 (LVNC2)
    l Chromosome 11p15; Dominant
    • Onset: Adult
  • Dilated cardiomyopathy ± Isolated non-compaction of left ventricular myocardium
    l ZASP
  • Other associations of noncompaction of left ventricule
    • Skeletal muscle biopsy: Mitochondrial changes common
    • Myotonic dystrophy, Type 1
    • Becker MD
  
  
• Holt-Oram
  l T-Box 5 (TBX5) ; Dominant; Chromosome 12q24.1
  • T-Box 5: Transcription factor
  • Clinical
    • Thumb anomaly
    • Atrial septal defect
• Atrial septal defect with A-V conduction defects
  l Cardiac specific homeobox (CSX; NKX2-5) ; Dominant; Chromosome 5q34
• Atrial septal defect
  l Myosin heavy chain 6 (MYH6) ; Dominant; Chromosome 14q12
  • MYH6: Expression regulated by TBX5
  • Mutations also cause: Hypertrophic cardiomyopathy
• Atrial septal defect
  l GATA4 ; Chromosome 8p23.1-p22; Dominant
• Atrial septal defect
  l Chromosome 6p21.3; Dominant
• Visceroatrial heterotaxia
  l Connexin 43 Gap junction protein; Recessive; Chromosome 6q21-q23.2

• 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

Errors of Fatty acid oxidation

Fatty Acid Oxidation Disorders Acyl-CoA dehydrogenase deficiencies     Acyl-CoA dehydrogenase, short-chain (SCAD)     Acyl-CoA dehydrogenase, medium-chain (MCAD)     Acyl-CoA dehydrogenase, long-chain (LCAD)     Acyl-CoA dehydrogenase, very long-chain (VLCAD) 2-Enoyl-CoA hydratase deficiency: 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: 3p21 2,4-Dienoyl-CoA reductase deficiency: 8q21 Electron transfer flavoprotein (ETF) deficiency: 15q23 Ichthyosiform erythroderma (NCIE2): CGI58 gene; 3p21 Trifunctional protein deficiencies: Subunits A & B Tyrosinemia Also see   1° Disorders of Carnitine metabolism   Fatty acid & Carnitine transport pathways   Fatty acid oxidation pathways   Lipid disorders   Mitochondria: Biochemical abnormalities   Peroxisomal disorders

• Fatty Acid metabolism
  • Location: Present in mitochondria
  • Components
    • 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 of 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
  • 1° Disorders of carnitine metabolism
  • 2° Disorders of carnitine metabolism
  • Mitochondrial disorders

• Medium chain acyl-CoA dehydrogenase deficiency
  l Acyl-CoA dehydrogenase, medium-chain (ACADM) ; Chromosome 1p31; Recessive
  • Function: Catalyze initial reaction in β-oxidation of fatty acids
  • Hepatic
    • Hypoketotic hypoglycemia
    • Metabolic encephalopathy
  • Muscle & Cardiac features: Few
  • Laboratory: Abnormal organic acids
  
  
• Medium chain 3-ketoacyl-CoA thiolase deficiency
  l Recessive
  • Single patient: 60% enzyme deficiency
  • Muscle: Rhabdomyolysis
  • Hepatic
    • Hyopketotic hypoglycemia
    • ± Metabolic encephalopathy
  • Laboratory: Abnormal organic acids
  
  
• Long chain acyl-CoA dehydrogenase (LCAD) deficiency
  l Long-chain acyl-CoA dehydrogenase (ACADL) ; Chromosome 2q34-q35; Recessive
  • Genetics
    • Mutation: Missense; Gln303Lys
  • LCAD protein
    • Location: Mitochondrial matirx
    • Action: Catalyzes 1st step in mitochondrial β-oxidation of fatty acids
  • 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
  l Very long-chain acyl-CoA dehydrogenase (ACADVL) ; Chromosome 17p11.2-p11.1; Recessive
  • 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
    • Mutations
          Lysine238 deletion (Homozygous); Gly401Asp + Arg410His;
          Ala416Thr (Temperature sensitive) + Arg450His
    • Onset: Childhood or Adult
    • Clinical
      • Myalgic episodes
        • Exercise & Fasting induced
        • Relatively easily triggered
      • Muscle pain: Relatively severe (More than CPT2 deficiency)
      • Rhabdomyolysis
    • Systemic features (hypoglycemia, hepatomegaly, cardiomyopathy) may be absent
    • 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
      • Abnormal intramuscular pH regulation at rest & during mild exercise
      • Serum CK
        • Recurent elevations with moderate exercise: Up to 15,000
        • Normal between attacks
      • Muscle biopsy
        • Histology: Normal between attacks
        • 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 treatment
      • Bezafibrate: Increases fatty acid oxidation
  
  
• Long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD): Alpha & Beta subunits
  • Muscle: Rhabdomyolysis; Myopathy
  • Hepatic
    • Hypoketotic hypoglycemia
    • Metabolic encephalopathy
  • Retinitis pigmentosa
  • Laboratory: Abnormal organic acids
  
  
• Carnitine-acylcarnitine translocase deficiency
  l Autosomal Recessive
  
  • Muscle: Myopathy
  • Cardiomyopathy
  • Hepatic
    • Hypoketotic hypoglycemia
    • Metabolic encephalopathy
  • Laboratory: ± Abnormal organic acids
  
  
• Short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADH; SCHAD; HADHSC)
  l Chromosome 4q22-q26; 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
  • 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
  l CGI58 gene ; Chromosome 3p21; Recessive
  
  • Nosology: NCIE2 ; Chanarin-Dorfman disease ; Ichthyosiform erythroderma
  • CGI58 protein
    • Widely expressed: Skin, lymphocytes, liver, skeletal muscle, & brain
    • α/β hydrolase fold
    • Similar to esterase/lipase/thioesterase subfamily
  • Clinical features
    • Onset: Birth; Collodion babies
    • Ichthyosiform erythroderma: Fine white scales; Erythematous background; All over body
    • Hepatomegaly
    • Other organ systems: Variable
      • External ears: Thick; Small; Malformed
      • Deafness
      • CNS: Mental retardation
      • Muscle
        • Weakness: Proximal; Slowly progressive
        • Myopathy: Triglyceride storage
      • Eyes: Strabismus; Ectropion
  • Laboratory
    • Lipid droplets in granulocytes ± skin
    • Serum CK: Mildly elevated (2x to 3x)
    • Liver function tests: Mildly elevated (2x to 3x)
  • Also see
    • Triglyceride disorders
    • Lipid disorders
  
  
• Neutral lipid storage disease with myopathy⁷
  l Adipose triglyceride lipase (PNPLA2) ; Chromosome 11; Recessive
  
  • Epidemiology: Netherlands, French & Algerian females
  • Genetics
    • Mutations: Missense & Truncation
  • PNPLA2 protein: Lipase
    • Activated by CGI-58
    • Major role in degradation of cytoplasmic triglycerides
  • Onset
    • Age: Childhood or Adult
    • Psychomotor retardation
    • Weakness
  • Clinical
    • Myopathy
      • Delayed walking (66%)
      • Weakness: Distal or Proximal; Asymmetric; Difficulty walking
    • Heart: Cardiomyopathy (33%); Abnormal EKG (100%)
    • Liver: Hepatomegaly
    • CNS: Mental retardation (Mild) (66%)
  • Laboratory
    • Serum CK: High
    • Serum transaminases: High
    • Triglyceride storage: Leukocytes
    • Muscle: Lipid storage
  • Also see
    • Triglyceride disorders
    • Lipid disorders