Familial isolated dilated cardiomyopathy (ORPHA:154)
A rare familial cardiomyopathy characterized by the dilation of left ventricle and progressively impairing of systolic ventricular function, in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. The disease may cause heart failure or arrhythmia. The disease is isolated when no additional atypical cardiac or extracardiac manifestations are present.
Epidemiology
The prevalence and incidence of Familial isolated dilated cardiomyopathy (FDC) is unknown; however, the incidence of dilated cardiomyopathy (DCM) is estimated between 1/12,000-28,000 worldwide; the prevalence of dilated cardiomyopathy is estimated at 1/2500; FDC is reported to make up about 20-30% of DCM case (range 2-65%).
Clinical description
The disease is defined by the presence of two major clinical criteria: left ventricular (LV) fractional shortening less than 25% and/or LV ejection fraction less than 45% with LV end diastolic diameter greater than 117% of the predicted value (corrected for age and body surface area based on Henry's formula), in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. The disease can develop at any age, in either sex. LV mass is often greatly increased in this disorder but LV wall thickness is normal. Symptoms of heart failure may be present as well as arrhythmias. Other presentations include the incidental detection of asymptomatic cardiomegaly and symptoms related to coexisting conduction disturbance or thromboembolic complications. Typically, there is a history of DCM in the family.
Etiology
Around 30-40% of FDC has an identified genetic origin attributed to over 50 genes, a number that is constantly increasing as new genes are discovered. Most mutations include titin (TTN; 15-27%), lamins A/C (LMNA; 6%), Beta-myosin heavy chain (MYH7; 4.20%), myopalladin (MYPN; 3.50%) and cardiac troponin T (TNNC1, TNNI3 and  TNNT2; 2.90%).
Diagnostic methods
Clinical screening of relatives, in particular first degree relatives, of primary DCM cases using electrocardiogram (ECG) and echocardiography allow the identification of familial FDC. Two or more affected relatives with dilated cardiomyopathy meet the above major criteria for the disease. Cardiac catheterization and CT or MRI scan are used also. Genetic screening of the family is also possible.
Differential diagnosis
Differential diagnosis include the various non-genetic causes of dilated cardiomayopathy, such as cardiac AL amyloidosis or senile amyloidosis, peripartum cardiomyopathy, sarcoidosis, myocarditis, autoimmune cardiomyopathy.
Antenatal diagnosis
Fetal echocardiography, B and M-mode, is the main diagnostic tool to determine the neonatal outcome. A hemodynamic evaluation can be performed by Doppler mode. Antenatal diagnosis is very rare due to the manifestation of the pathology later on during adult life. Fetal echocardiography is therefore not widely recommended unless there is a family history of neonatal case. Prenatal genetic testing may be considered on a case-by-case basis in the context of a pathogenic variant identified in the family.
Genetic counseling
Familial dilated cardiomyopathy is primarily an autosomal dominant disease, but autosomal recessive, X-linked and mitochondrial forms have also been described. Genetic counseling is therefore possible. The transmission outcome is 50% in an autosomal dominant case and 25% for a recessive transmission.
Management and treatment
The pathology is treated with a combination of medications, depending on the symptoms. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta-blockers, diuretics, digoxin, blood-thinning medications are used. The management of alimentation is important in affected families, and exercise and healthy habits are essential.
Prognosis
The prognosis of dilated cardiomyopathy is very poor in the absence of therapeutic management but mortality is largely reduced by medical and non-medical treatments. The prognosis may be influenced by the associated mutations.

                            Last update: 
                            September 2020


                            - Expert reviewer(s): 
                            Pr Philippe CHARRON