Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction, due to a variety of causes that are frequently genetic. They can be either confined to the heart and often leading to cardiovascular death or progressive heart failure-related disability. The most common cardiomyopathy is hypertrophic cardiomyopathy (HCM) caused by variants in sarcomeric  genes, characterized by left ventricular hypertrophy in the absence of another cardiac, systemic, or metabolic disease capable of producing the magnitude of hypertrophy evident. A key pathophysiological aspect of HCM is diastolic dysfunction, which can be severe enough to determine a restrictive left ventricular filling pattern, raising problems of differential diagnosis with primary restrictive cardiomyopathy (RCM).

Some familial forms of primary RCM have been described in patients carrying variants in sarcomeric genes traditionally associated with HCM, and HCM and primary RCM may coexist in the same family. This scenario is further complicated by classifications that group cardiomyopathies based only on ventricular morphology and function irrespective of etiology. According to these phenotypic classifications, some infiltrative and storage diseases may be listed as either HCM or RCM depending on the degree of hypertrophy observed and left ventricular filling pattern.


Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease caused by a broad variety of genetic variants involving mostly proteins of the cardiac sarcomere. Given its prevalence of 1:500 in the general population, it is considered the most common genetic cardiovascular disease.


Primary Restrictive Cardiomyopathy

Primary RCM is a rare myocardial disease characterized by normal or decreased volume of both ventricles associated with biatrial enlargement, normal left ventricular wall thickness, impaired ventricular filling with restrictive physiology, and normal or near-normal systolic function. Since the first report of a familial form caused by a cardiac troponin I (TNNI3) variant, primary RCM was believed to be a sarcomeric disease and was labeled together with HCM as a sarcomeric cardiomyopathy according to a genomic/postgenomic classification.


Cardiomyopathies with either Hypertrophic or Restrictive Phenotype

Some infiltrative and storage diseases may present as phenocopies of either HCM or primary RCM, according to the degree of hypertrophy observed and left ventricular filling pattern. If maximal left ventricular wall thickness is at least 15 mm, they must be differentiated from sarcomeric HCM. Otherwise, the restrictive physiology inherent to the pathological process of myocardial infiltration or storage yields a phenotype similar to that of primary RCM. Unmasking the underlying disease and going beyond the ventricular morphology and function, is crucial in order to establish prognosis, guide reproductive choices, and offer specific therapy to the patient. Age of onset is among the factors to consider for differential diagnosis: for instance, glycogen storage diseases are more common in infants, whereas ATTRwt amyloidosis involves predominantly men over the age of 65 years.

Amyloidosis - Amyloidosis is a systemic syndrome that represents the archetype of the infiltrative form of RCM. Extracellular deposition of insoluble amyloid fibrils involves a variety of organs including the heart, leading to cardiomyocyte separation, cellular toxicity, and apoptosis.

Storage Diseases - Fabry disease is a lysosomal storage disease with an X-linked recessive inheritance caused by variants in the GLA gene, that determine an absent or deficient activity of lysosomal alpha galactosidase A.

Glycogen Storage - Diseases  Glycogen storage diseases are a group of inherited genetic disorders that cause glycogen to be improperly accumulated in the body. Although they are listed as cardiomyopathies that can also have a restrictive phenotype [7,51], patients affected with glycogen storage diseases typically show a marked left ventricular hypertrophy and must be differentiated mainly from HCM.



HCM and primary RCM have a similar genetic background as they are both sarcomeric cardiomyopathies, and significant phenotypic overlap can exist between them. Patients with HCM and primary RCM may coexist in the same family and a new category of HCM with restrictive physiology has been recently described. One hypothesis is that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this delicate scenario some infiltrative and storage diseases may show either a hypertrophic or restrictive phenotype (HCM and primary RCM phenocopies) according to left ventricular wall thickness and filling pattern. Establishing a correct diagnosis is of paramount importance for cascade family screening and therapy.