Familial isolated restrictive cardiomyopathy (ORPHA:75249)
A rare genetic cardiac disease characterized by restrictive ventricular filling due to high ventricular stiffness that results in severe diastolic dysfunction in the absence of dilated or hypertrophied ventricles.
Epidemiology
The prevalence is unknown; however, from a European registry the familial form is reported to account for 30% of restrictive cardiomyopathy.
Clinical description
Clinical presentation of restrictive cardiomyopathy (RCM) is heterogeneous, with onset at any age. Dyspnea is the most common symptom, followed by edema, palpitation, fatigue, orthopnea and chest pain. The typical symptoms upon examination include jugular venous distension, elevated systemic and pulmonary venous pressures, systolic murmur, lower-extremity edema, atrial fibrillation, cardiomegaly, and less frequently atrioventricular block. In advance disease, symptoms include pulmonary congestion, hepatomegaly, ascites and edema. Diastolic volumes are normal or reduced, and whilst initial systolic function is normal or near-normal, it may deteriorate with diseases progression. The ejection fraction is typically above 50%. Mild-to-moderate tricuspid and mitral valve regurgitation is common. Bi-atrial dilatation due chronic elevation of atrial pressure usually develops which along with pulmonary venous congestion and pleural effusions can result in moderate to generalized cardiomegaly. Other changes in cardiac morphology, such as ventricular dilatation, septal and ventricular hypertrophy, typically do not occur in RCM. Myocardial biopsy typically demonstrates interstitial fibrosis, and mild to moderated myocyte hypertrophy, without evidence of amyloid deposition, eosinophil infiltration or other systemic infiltration. Death can occur suddenly or as a result of congestive heart failure, cardiac arrhythmias, or other associated complications.
Etiology
RCM is due to increased ventricle stiffness resulting in restricted ventricular filling either unilaterally or bilaterally. Most cases of RCM remain idiopathic; however, an increasing number of disease causing mutations have been identified and include the sarcomere subunits, such as troponin T (TNNT2, 1q32.1), troponin I (TNNI3, 19q13.42), alpha-actin (ACTC, 15q14), beta-myosin heavy chain (MYH7, 14q11.2), myopalladin (MYPN, 10q21.3), and filamin C (FLNC, 7q32.1) as well as kinesin-like protein KIF20A (KIF20A, 5q31.2).
Diagnostic methods
Diagnosis is made with cardiac echocardiography supported by electrocardiogram, cardiac catheterization, and endomyocardial biopsy. Typical findings on echography include enlargement of atria, normal or reduced left ventricular end diastolic dimension and/or volume, restrictive left ventricular filling pattern, normal or near normal systolic function, and normal ventricular wall thickness. Thorough hemodynamic evaluation with cardiac catheterization may be required to exclude the differential diagnosis.
Differential diagnosis
Differential diagnosis includes constrictive pericarditis and infiltrative myocardial disease such as cardiac amyloidosis, and other secondary causes of restrictive myopathy such as storage disease.
Genetic counseling
For patients with known mutation, the pattern of inheritance is autosomal dominant and, therefore, there is a 50% risk of disease transmission from an affected parent to offspring. Autosomal recessive inheritance has been observed in one family. Genetic counseling should be offered to affected families, with clinical screening of asymptomatic family members.
Management and treatment
Cardiac transplant is the sole effective procedure in treating the disease. Pediatric patients should obtain preference on the waiting list due to the high risk of sudden death and to prevent the need for heart-lung transplantation. No single drug improves prognosis of RCM. Whilst diuretics are commonly used to reduce preload, excessive reduction may decrease ventricular filling. Thus, diuretics should be limited to patients presenting with symptomatic pulmonary venous congestion and/or right heart failure. ACE (angiotensin-converting enzyme) inhibitors and vasodilators are considered detrimental for the treatment of RCM. Anti-dysrhythmic therapy or implantable cardioverter defibrillators (AICD) may be an option for patients presenting with atrial fibrillation or ischemia. Pacemaker is considered in the presence of high degree atrioventricular block. Anti-coagulants reduce the risk of thromboembolic events.
Prognosis
Prognosis is usually poor, especially in pediatric patients, with 50 percent of deaths occurring within 2 years of diagnosis. For patients 10 years of age and above, the 5-year survival rate is 64 percent.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Pr Philippe CHARRON