Etiology

Dilated cardiomyopathy is a disorder characterized by cardiac dilation and reduced systolic function. It represents an outcome of a heterogeneous group of inherited and acquired disorders.

 nongenetic conditions

• infectious or postinfectious conditions
  • Coxsackie virus Q and B
  • Enteroviruses
  • Mumps
  • Coryne diphteroides

• Endocrine/vitamin/mineral disorders
  • Thyrotoxicosis
  • Hypothyroidism
  • Vitamin E deficiency
  • Selenium deficiency
  • Infants of diabetic mothers

• Cellular toxicity
• Anthracycline toxicity
• Hemochromatosis
• Alcohol
• Cyclophosphamide

 Genetic/familial conditions

• Infiltrative disorders - Storage disorders
  • Disorders of glycogen metabolism
    • Glycogen storage disease type IV (Andersen disease - Branchaing enzyme deficiency)

• Diminished energy production (Mitochondrial disorders)
  • Disorders of oxidative phosphorylation
    • Complex I deficiency

• Disorders of fatty acid metabolism
  • Primary or systemic carnitine uptake deficiency
  • Muscle carnitine deficiency
  • Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

• Toxic intermediary metabolite disorders
  • Proplenic acidemia
  • beta-ketothiolase deficiency

• Familial and neuromuscular conditions
  • Familial dilated cardiomyopathy (DCMP)
  • Familail dilated cardiomyopathy with conduction defects
  • Isolated ventricular noncompaction
  • X-linked dilated cardiomyopathy
    • Duchenne muscular dystrophy
    • Becker muscular dystrophy
    • Autosomal recessive muscular dystrophy

• Congenital myopathies
  • Centronuclear (myotubular) myopathy
  • Nemaline rod myopathy
  • Minicore-multicore myopathy

• Ataxias
  • Friedreich ataxia
  • Refsum disease

• Other
  • Isolated ventricular noncompaction
  • Tachyarrythmia-produced
  • dilated cardiomyopathy and sensorineural hearing loss (EYA4 germline mutations)

Loci involved

 CMD1A (1p11-q11) : mutations in the lamin A/C gene (LMNA) (MIM.150330)
 CMD1B (MIM.600884) on 9q13
 CMD1C (MIM.601493) on 10q21
 CMD1D (MIM.601494) on 1q32
 CMD1E (MIM.601154) on 3p
 CMD1F (MIM.602067) on 6q
 CMD1G (MIM.604145) on 2q31
 CMD1H (MIM.604288) on 2q14-q22
 CMD1I (MIM.604765) (2q35) : mutation in the DES gene (MIM.125660)
 CMD1J (MIM.605362) on 6q23-q24
 CMD1K (MIM.605582) on 6q12-q16
 CMD1L (MIM.606685) : mutations in the SGCD gene (MIM.601411) on 5q33
 CMD1M (MIM.607482) : mutation in the CSRP3 gene (MIM.600824) on 11p15.1
 CMD1N (MIM.607487) : mutation in the TCAP gene (MIM.604488) on 17q12

And

 mutation in the ACTC gene (MIM.102540)
 mutation in the cardiac beta-myosin heavy chain gene (MYH7) (MIM.160760),
 mutation in the cardiac troponin T gene (TNNT2) (MIM.191045)
 mutation in the cardiac myosin-binding protein C gene (MYBPC3) (MIM.600958)
 missense mutation in the phospholamban gene (MIM.172405)
 For X-linked dilated cardiomyopathy, mutations in the dystrophin and G4.5 genes have been reported.
 mutations in actin (close to the dystrophin binding domain)
 mutations in desmin, a component of the intermediate filaments, have been reported.
 EYA4 germline mutations: dilated cardiomyopathy and sensorineural hearing loss

The genes at a further 6 loci associated with autosomal dominant dilated cardiomyopathy (associated with conduction disease in 2 cases) remain unidentified.

Due to the mutations in dystrophin, actin and desmin, we have proposed that dilated cardiomyopathy is a "cytoskeletalopathy", and we are currently investigating the involvement of these genes in patients.

References

 Okazaki T, Honjo T. Pathogenic roles of cardiac autoantibodies in dilated cardiomyopathy. Trends Mol Med. 2005 Jul;11(7):322-6. PMID: #15935731#