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Confounding presentation phenotype in familial cardiomyopathy

The proband is a 42-year-old male diagnosed with idiopathic dilated cardiomyopathy few years ago and followed-up in another Centre. Clinical reports of the 1st evaluation were unavailable.
In March 2009 the coronary angiography documented absence of significant stenoses. He underwent ICD implantation on March 6th, 2009.
Myocardial Disease

In April 2009 he had an episode of acute heart failure as result of therapy discontinuation on his own. He mentioned he had dyspnoea on mild efforts, orthopnoea and gain of weight. The echocardiogram showed severely depressed left ventricular systolic function (EF 15%). An increased and dishomogeneous echo-reflectance of the myocardium suggested the hypothesis of infiltrative cardiomyopathy. Peri-umbilical fat biopsy was described as positive for amyloid. The sample was untreacble.

The patient came to our attention at the end of July, 2009; the diagnostic suspect was cardiac amyloidosis; alternatively,  storage disease (i.e. Anderson-Fabry Disease).
July 31st, 2009:

Electrocardiography (figure 1): incomplete right bundle branch block, ST abnormalities ( in inferior leads) and repolarization abnormalities (negative T waves in inferior leads and in C4-C6);


ECG of the proband

Figure 1. ECG of the proband. Diffuse ST-T abnormalities with áST in the peripheral inferior leads and negative T waves in inferior leads and precordial C4 to C6. Isolated ventricular ectopic beat. ECG voltage criteria for left ventricular hypertrophy (Sokolow-Lyon).

(figure 2):
left ventricular dilation (LV end-diastolic diameter 72 mm, LV end-diastolic volume 262 ml) with severe impairment of systolic function (EF 15-20%), interventricular septum thickness 10 mm (basal segment) and of irregular echo-reflectance of the myocardium and diffuse hypokinesis. Moderate-to-severe mitral regurgitation due to leaflet tethering;

Echocardiogram of the proband

Figure 2. Echocardiogram of the proband. (A) Parasternal short axis view: left ventricle dilation, irregular echo-reflectance of the septum, thinning of the posterior wall, mild  left atrium dilation. (B) apical four-chamber view: left ventricular dilation, normal right ventricle; in the right ventricle evidence of the catheter of the ICD. (C) Color-Doppler from the apical four-chamber view showing the mitral regurgitation.  

Right Cardiac catheterization: mild-to-moderate pulmonary hypertension (systolic pulmonary arterial pressure 38 mmHg), mild increase of wedge pressure (10 mmHg);

  • Endomyocardial biopsy: focal myofibrillolysis, myocyte disarray, interstitial fibrosis. Absence of inflammation, thrombosis and interstitial deposits.
  • Biochemistry:


      Result:   Normal range:
    B-type Natriuretic Peptide   424 pg/ml   0-50
    Total CPK 197 mU/ml   24-190
    CK-MB  35 mU/ml   5-24
    Troponin I 2.155 ng/ml   0-0.04

The patient gave his informed consent to genetic and molecular analysis and a blood sample was collected with this scope.
Drug therapy with diuretics, beta-blocker and ACE-inhibitor was progressively up-titrated and the patient improved gradually till functional NYHA class II. BNP mildly diminished to about 200 pg/ml. Ejection fraction of the left ventricle improved up to 35%.

1) Do you agree with the diagnosis of idiopathic dilated cardiomyopathy vs the original diagnosis of infiltrative disease?
2) Would you suggest further biochemical examination or instrumental evaluations?
The family screening only included a younger brother who came to our attention on December 18th, 2009. He  described an atypical episode of chest pain in 2001 for which he was admitted to the Emergency Department. The clinical report was not available. According to the description, the biochemical analyses were negative, the ECH showed incomplete right bundle branch block and no signs of myocardial ischemia. He was said that the his heart showed “initial dilation”.

A Cardiac MRI was performed October 1st, 2009 and showed left ventricle with evidence of severe asymmetrical hypertrophy with maximum thickness 21 mm in the septum; dilation of the left ventricle and diffuse hypokinesis. Small areas of hyper-enhancement in the interventricular septum and anterior basal wall of the left ventricle. Delayed enhancement from endo- to epicardium in the inferior and lateral wall and in the interventricular septum (basal and medium segments). The conclusion indicated the possibility of a infiltrative cardiomyopathy.

At our centre, he underwent:

  • Electrocardiography (figure 3): deep and large (>40 msec) Q waves in inferior leads; diffuse repolarization abnormalities with negative T waves in DIII and in C4-C5; 


Electrocardiogram of proband’s brother 

Figure 3.
Electrocardiogram of proband’s brother. Evidence of Q waves in inferior leads and repolarization abnormalities both in peripheral and precordial leads.

Echocardiography (figure 4): enlarged left ventricle (end-diastolic diameter 70 mm, end diastolic volume 209 ml); asymmetric left ventricular hypertrophy: septal thickness 15 mm, corresponding to a z score (according to Henry’s formula based on age and BSA) of 5.6 (normal z score ranges from -2 to +2); thinning of posterior wall. Reduced left ventricular systolic function (EF 30%). Hypertrabeculation non fulfilling the criteria for left ventricular non-compaction. Mild mitral regurgitation due to leaflet tethering;


Echocardiographic  examination of proband’s brother

Figure 4.
Echocardiographic  examination of proband’s brother. (A) Parasternal short axis view. (B) apical four chamber view. (C) Apical three chamber view. Worth of  notice the thinning of the posterior wall just at the basis of the papillar muscle..


  • Biochemistry:

        Result:   Normal range:
      B-type Natriuretic Peptide   87 pg/ml   0-50
      Total CPK 306 mU/ml   24-190
      CK-MB  39 mU/ml   5-24
      Troponin I 0.224 ng/ml   0-0.04


    • Endomyocardial biopsy  (January 10th, 2010): hypertrophic myocytes and presence of focal interstitial fibrosis; presence of rare and focal optically empty myocytes. Normal expression of Dystrophin. Ultrastructural study documented the absence of amyloid and of intra-myocyte osmiophilic deposits that could be consistent with the diagnosis of AFD.

    (January 10th, 2010): hypertrophic myocytes and presence of focal interstitial fibrosis; presence of rare and focal optically empty myocytes. Normal expression of Dystrophin. Ultrastructural study documented the absence of amyloid and of intra-myocyte osmiophilic deposits that could be consistent with the diagnosis of AFD.

    The patient  was given beta-blockers, ACE-inhibitors and low doses of furosemide and spironolactone. He reported mild improvement in the subsequent weeks.

      3) Would you change the diagnostic hypothesis of familial DCM on the basis of the additional information coming from the proband’s brother?
      4) Considering the peculiar evidence on the endomyocardial biopsy of the proband’s brother, which gene would you screen in the two brothers?



    Recapitulation about the diagnostic work-up

    The patient was first addressed to our attention with the specific request of discriminating between two possible diagnosis: amyloidosis vs. storage disease (Anderson Fabry Disease).

    1. Amyloidosis

    We excluded this diagnostic possibility ab initio for more than one reason, on the basis of hystoric data and of instrumental data:

      • the proband is 42 years old; the age by itself does not exclude the diagnosis of amyloidosis but makes it unlikely especially because the clinical history dates back years before our evaluation
      • there were no K or L light chain bands; Bence Jones protein was absent;
      • both parents are healthy, with normal cardiac and renal function;
      • the echocardiogram recorded on July 31st, 2009 showed severe left ventricular dilation with normal LV wall thickness;
      • the ECG registered at our Centre on July 31st, 2009 (see figure 1 of case presentation) showed positive Sokolow-Lyon criteria for LV hypertrophy.

         2.  Storage disease  (in particular, Anderson-Fabry disease)

    The diagnosis of Anderson-Fabry disease was unlikely because of severe LV dilation, hypokinesia, absence of hypertrophy, absence of extracardiac features of the disease. Nonetheless, due to the specific request of colleagues who addressed the patient to our attention we tested plasma dosage of alpha-galactosidase A activity, which resulted in the normal range.

    The patient underwent EMB as per routine in potential candidates to HTx. The following characteristics of the proband could be considered for a Dystrophn defect:

    1. the severe LV dilation associated with severe systolic dysfunction
    2. the presence of T waves modification on ECG in the inferior and lateral leads (see figure 1 of case presentation)
    3. the biochemistry abnormalities such as the mild CK and CK-MB increase and the more evident Troponin I increase (see Biochemistry table of the proband in the case presentation).
    4. the absence of male-to male transmission of the disease in the family. Before family screening and genetic testing we couldn’t exclude X-linked inheritance.

    The endomyocardial biopsy showed normal dystrophin immunostain.

    Family screening

    1. The younger brother of the proband showed hypertrophic phenotype (both on echocardiography and on CMR imaging); this finding empowered the hypothesis that the diagnosis in the family was HCM, still typical in the brother but evolved through dilatation and dysfunction in the proband.
      The younger brother shared with the proband biochemical abnormalities (see Biochemistry table of the proband’s brother in the case presentation) and other characteristics in ECG and echocardiography, confirming that the cardiomyopathy was familial.
    2. Parents: both mother and father underwent clinical screening (ecg, echo, biochemical testing) that gave negative results: in fact the father showed confounding hypertension and a max wall thickness of 10 mm.
    3. The oldest brother showed normal echocardiographic and ECG, normal biochemical data with the exception of very mild increase of lactic acid values (27.1 mg/dl, normal laboratory range 5.7 – 22 mg/dl).

    Considering the HCM hypothesis as the most likely, we tested sarcomeric gene associated with HCM and we found a mutation in MYBPC3 gene, reported as associated with HCM[1].
    The genetic cascade screening did not confirm the segregation of the mutation with the phenotype  in the family because the carrier father showed normal ECG and echocariographic findings, as well as normal biochemical indexes. The mother tested negative.  (Figure 1).

     ESC Working Group Myocardial & Pericardial Diseases Newsletter

    Figure 1. Family pedigree

    + = genetic test positive for the MYBPC3 mutation found in the proband;
     = genetic test negative for the MYBPC3 mutation found in the proband

    Further considerations about the genetic mutation found and the clinical phenotype

    The MYBPC3 mutation is described as causative mutation [1]. MYBPC3 is known as one of the most frequently involved sarcomeric genes in familial hypertrophic cardiomyopathy characterised by moderate hypertrophy of the left ventricle, with progressive development of hypertrophy and late onset of symptoms [2].
    In our family however, the proband came to our attention with a dilated phenotype and LV dysfunction. The younger brother showed mild asymmetrical hypertrophy, with evidence of concomitant hypokinesia and early LV dilation. The father was “healthy” carrier of the MYBPC3 mutation at the age of 74 years. He only showed LV wall thickness at the upper-normal range (10 mm, concentric) with a confounding history of arterial hypertension.
    The echocardiographic study in  mother, who had negative MYBPC3 test, showed septal thickness of 10 mm, posterior wall of 9 mm, and impaired left ventricular diastolic function.

    Due to the lack of segregation of the mutation with the phenotype in the family, we completed the screening of sarcomeric genes that gave negative results. The presence of minimal lactic acidosis in the oldest brother, the coexistance of DCM and HCM phenotype in two affetcted members of the same generation and the potential matrilineal inheritance led to the analysis of mtDNA.

    Progression through the case resolution

    We identified a mtDNA mutation, known to be associated with cardiomyopathy, which was transmitted from the mother to the three sons (figure 2).

     ESC Working Group Myocardial & Pericardial Diseases Newsletter

    Figure 2. Family pedigree

    + = genetic test positive;
    - = genetic test negative
    (red: mtDNA mutation; blue: MYBPC3 mutation)


    We interpret these data as suggestive of HCM (MYBPC3) evolving through DCM (MtDNA), with neither mutation sufficient by itself for causing the cardiomyopathy. The follow-up of the brothers with the double mutation will provide confirmation (or not) of this hypothesis.


    1. Andersen PS, Havndrup O, Bundgaard H, Larsen LA, Vuust J, Pedersen AK, Kjeldsen K, Christiansen M Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: total or partial haploinsufficiency. Eur J Hum Genet. 2004;12:673-7.
    2. Andersen PS, Havndrup O, Bundgaard H, Moolman-Smook JC, Larsen LA, Mogensen J, Brink PA, Dupont Børglum A, Corfield VA, Kjeldsen K, Vuust J, Christiansen M. Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations. JMG 2001;38:e43

    Notes to editor

    F.I. GambarinPresented by F.I. Gambarin, A. Serio, M. Pasotti, L. Tavazzi* and E. Arbustini
    Centre for Inherited Cardiovascular, Diseases, Molecular Diagnostic Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
    *Research Unit, GVM Care and Research, Cotignola, Italy

    (This material is original; it has not previously published and is part of a research on Hypertrophic Cardiomyopathies supported by funds from Cariplo Foundation and Health Ministry granted to EA).
    The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.