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Year : 2018  |  Volume : 28  |  Issue : 2  |  Page : 120-123

Diagnostic clues for the diagnosis of nonsarcomeric hypertrophic cardiomyopathy (Phenocopies): Amyloidosis, fabry disease, and mitochondrial disease

1 Department of Cardiothoracic Sciences, “Luigi Vanvitelli”-Campania University; Department of Public Health, Nefrology Unit, Federico II University, Naples, Italy
2 Department of Cardiothoracic Sciences, “Luigi Vanvitelli”-Campania University, Naples, Italy
3 IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy
4 Department of Public Health, Nefrology Unit, Federico II University, Naples, Italy
5 Institute of Cardiovascular Sciences University College of London, London, UK

Date of Web Publication16-May-2018

Correspondence Address:
Giuseppe Limongelli
Department of Cardiothoracic Sciences, “Luigi Vanvitelli”- Campania University, Naples
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcecho.jcecho_2_18

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Hypertrophic cardiomyopathy (HCM) is the most common known inherited heart disorder, with a prevalence of 1:500 of the adult population. Etiology of HCM can be heterogeneous, with sarcomeric gene disease as the leading cause in up to 60% of the patients, and with a number of possible different diseases (phenocopies) in about 10%–15% of the patients. Early diagnosis of storage and infiltrative disorders, particularly those with specific treatments (i.e., Fabry disease and/or amyloidosis), means early management and treatment, with a significant impact on patients prognosis. Here, we report on four different cases of HCM, highlighting difficulties to make differential diagnosis of different forms of cardiomyopathies, and their potential impact on the management.

Keywords: Amyloidosis, Fabry disease, hypertrophic cardiomyopathy

How to cite this article:
Limongelli G, Masarone D, Verrengia M, Gravino R, Salerno G, Castelletti S, Rubino M, Marrazzo T, Pisani A, Cecchi F, Elliott PM, Pacileo G. Diagnostic clues for the diagnosis of nonsarcomeric hypertrophic cardiomyopathy (Phenocopies): Amyloidosis, fabry disease, and mitochondrial disease. J Cardiovasc Echography 2018;28:120-3

How to cite this URL:
Limongelli G, Masarone D, Verrengia M, Gravino R, Salerno G, Castelletti S, Rubino M, Marrazzo T, Pisani A, Cecchi F, Elliott PM, Pacileo G. Diagnostic clues for the diagnosis of nonsarcomeric hypertrophic cardiomyopathy (Phenocopies): Amyloidosis, fabry disease, and mitochondrial disease. J Cardiovasc Echography [serial online] 2018 [cited 2021 Oct 26];28:120-3. Available from: https://www.jcecho.org/text.asp?2018/28/2/120/232557

  Introduction Top

Hypertrophic cardiomyopathy (HCM) is the most common known inherited heart disorder, with a prevalence of 1:500 of the adult population.[1] Etiology of HCM can be heterogeneous, with sarcomeric gene disease as the leading cause in up to 60% of the patients, and with a number of possible different diseases (phenocopies) in about 10%–15% of the patients.[1],[2] Early diagnosis of storage and infiltrative disorders, particularly those with specific treatments (i.e., Fabry disease and amyloidosis [AL]), means early management and treatment, with an important impact on patients prognosis.[3],[4],[5],[6],[7] Here, we report on four different cases of HCM, highlighting challenges in the etiological definition of HCM and difficulties to make differential diagnosis of different forms of cardiomyopathies.

  Methods Top

We reviewed all the notes of patients referred to our HCM clinic in 2017. We selected four cases, in which a suspect of HCM phenocopy (HCM associated with metabolic, infiltrative, or neuromuscular disorder) has been raised, and a diagnosis has been excluded or confirmed after a comprehensive clinical evaluation.

  Results Top

Case 1

An young patient with concentric HCM and moderately reduced ejection fraction was referred to our attention after a recent hospitalization for heart failure. He was followed up for his cardiomyopathy for 8 years, and a suspect of Fabry disease was made on the basis of cardiomyopathy, proteinuria, and juvenile stroke. He had a family history of diabetes and hypoacusia (mother and maternal aunt). He suffered for exercise limitations and complained of fatigue after exercise and/or fever. The electrocardiogram (ECG) showed a short PR and signs of left ventricular hypertrophy (LVH) with repolarization abnormalities. Echocardiography showed a concentric LVH (with maximal thickness of 17 mm) and severely reduced systolic function (ejection fraction 20%) [Figure 1]. The patient had also bilateral hypoacusia, diabetes, proteinuria, and chronic kidney disease Stage 3b (glomerular filtration rate 38 ml/min/1.73 m2). The alpha-galactosidase (α-GAL) enzymatic activity was normal. The lactate/pyruvate ratio was elevated (1:25). For a suspect of mitochondrial disease, he underwent genetic analysis which evidenced a 3243 tRNAlle mutation consistent with MELAS diagnosis. Due to the severe, systemic presentation of the disease, the patients were offered a destination therapy by left ventricular assist device. He refused this possibility and died after 12 months for cardiogenic shock.
Figure 1: Echocardiography showing a left ventricle with concentric hypertrophy (a) and electrocardiogram (b) showing a short PR and signs of left ventricular hypertrophy with repolarization abnormalities

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Case 2

A 51-year-old patient was referred to our cardiomyopathy clinic with a diagnosis of HCM. He suffered from hypertension and proteinuria since he was 20 years old, he had an non-ST elevation myocardial infarction at 35 years old, and he had renal failure requiring dialysis since he was 45 years old. His family history was unremarkable, except hypertension in the mother. The ECG showed q waves in infero-lateral leads and LVH. Echocardiography showed concentric LVH (maximal wall thickness 20 mm at basal interventricular septum), with normal systolic function (ejection fraction 55%), posterolateral, and apical hypokinesia. The α-GAL activity was mildly reduced (2.3 nmol/h/ml). A D313Y mutation was found by α-GLA gene sequencing, and diagnosis of Fabry disease was ruled out. The next-generation sequencing (NGS) panel for sarcomeric gene disease failed to find disease-causing mutations. The patients are currently evaluated in our cardiomyopathy clinics every 6 months.

Case 3

In April 2013, a 63-year-old male was admitted to our cardiomyopathy clinic for the diagnosis of HCM. The patient had a negative family history for cardiomyopathies and sudden death. His previous clinical history was unremarkable. The ECG showed LVH with repolarization abnormalities in lateral leads. Routine laboratory tests (including proteinuria) were normal. Echocardiography showed severe LVH with maximal wall thickness of 27 mm, Type I diastolic dysfunction, and left ventricular outflow tract obstruction of 40 mmHg at rest. Cardiac magnetic resonance showed severe symmetric LVH with evidence of diffuse late gadolinium enhancement [Figure 2] The patient underwent a systematic biochemical evaluation, according to the protocol of adult HCM in our cardiomyopathy clinic (including blood glucose, proteinuria, blood urea nitrogen, creatinine, electrolytes, lactate, ammonia, creatine phosphokinase, lactate dehydrogenase, and dry blood spot for lysosomial storage diseases and a NGS panel for sarcomeric gene disease). The enzymatic blood assay revealed no α-GAL activity in the patient's blood. Genetic analysis showed a gene mutation consistent with the diasgnosis of Anderson-Fabry disease (AFD). No sarcomeric gene mutation was found. The patients started enzyme replacement therapy (ERT).
Figure 2: Cardiac magnetic resonance imaging showing severe asymmetric left ventricular hypertrophy with evidence of diffuse late gadolinium enhancement (white arrow)

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Case 4

A 54-year-old male was referred to our clinic for a severe HCM, with preserved systolic function, and with pericardial and pleural effusion. His family history was unremarkable. He started to suffer from hypertension since he was 45 years, proteinuria at 52 years, and bilateral carpal tunnel at 53 years. He presented with HFPEF (heart failure with preserved ejection fraction): dyspnoea, elevated brain natriuretic peptide measurement (2450 pg/ml), a chest X-ray showing bilateral pleural effusion. ECG showed low QRS voltages. Echocardiography showed biventricular hypertrophy, biatrial dilation, restrictive mitral inflow pattern, systolic pulmonary pressure of 50 mmHg, and pericardial effusion; a speckle tracking evaluation showed the “apical sparing” pattern [Figure 3]. A suspect of AL was based on clinical, imaging and lab findings. Cardiac biopsy showed interstitial, subendocardial, and small artery media deposits of amyloid which were confirmed on thioflavin T staining and with immunohistochemistry and immunofluorescence characteristic of λ light chain. The diagnosis was AL, and the patients started the specific chemotherapy protocol.
Figure 3: Echocardiographic appearance of amyloidosis (a-c). Increased wall thickness of the left ventricular wall in apical four-two and three chambers, biatrial enlargement, and pericardial effusion. (a-c) Bulls-eye plot of speckle tracking showing the “apical sparing” pattern (d)

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  Discussion Top

HCM is characterized by LVH, unexplained by abnormal loading conditions.[8] Sarcomeric gene-disease is the principal cause of adult HCM, explaining up to 60% of the cases. Another 10%–15% of the patients can be affected by systemic diseases mimicking HCM and including genetic syndromes,[9] metabolic/storage,[10] mitochondrial,[11] or neuromuscular diseases.[12]

ECG and imaging findings, along with a comprehensive clinical evaluation, including family and personal history, clinical examination, and laboratory evaluation, have been suggested as an useful approach (“red flag approach”) to distinguish phenocopies from sarcomeric HCM.[13]

AFD represent a rare, but potentially treatable cause of nonsarcomeric HCM, in about 0.5%–2% of the patients.[14],[15] It is an X-linked disease of lysosomal metabolism.[1] The α-GAL enzymatic deficit. causes progressive, widespread intracellular accumulation of globotriaosylceramide, and other sphingolipids throughout the body, leading to dysfunctions in multiple organ systems.[2] Cardiac involvement, with HCM, rhythm, and conduction abnormalities, is common in AFD and generally presents by the fourth decade of life.[6] AFD should always be suspected in patients (males older than 30–35 years old and females older than 40–45 years old) with unexplained LVH, even in the absence of renal, cerebrovascular, or skin involvement.

Indeed, an isolated HCM can be a rare presentation of AFD.[7] Atypical forms of AFD, predominantly affecting the heart, were reported almost a century after the original descriptions of the condition.[16] The underlying pathophysiology of the cardiac variant of AFD disease is incompletely understood; however, it is clear that different mutations in GLA gene are implicated.[17] On the other hand, the absence of systemic involvement may be cause of diagnosis in advanced/end stage of the disease with little benefit of ERT.[18]

Indeed, patient n. 3 came to our attention for unexplained LVH, without any clinical sign of a systemic disease. No systemic involvement has been noted. In addition, the severity of hypertrophy and fibrosis and presence of ventricular arrhythmias is not a classic presentation of the disease, except in patients with end-stage disease. The absence of enzyme activity in a dry blood spot analysis, lately confirmed on plasma, suggested the diagnosis of AFD.

On the other hand, the presentation of case 2 is more typical of classic AFD, with early and progressive renal disease, and cardiovascular involvement presenting later in life (HCM and coronary artery disease). However, he showed a D313Y mutation, which is not considered a disease-causing mutation for AFD. Indeed, among the currently known over 600 pathogenic GLA gene mutations,[19] the D313Y (Exon 6, c.937G. T) mutational variant has been reported to cause only mild clinical symptoms in observational case reports,[20] suggesting a good prognosis and no need of specific therapy.[21],[22],[23]

Mitochondrial disease, including MELAS, MERRF, or Friedreich ataxia, can also be part of the spectrum of nonsarcomeric HCM.[24],[25] Case 1, previously suspected to have a glycogen storage disease, presented with a typical clinical picture of mitochondrial disorder, including diabetes, deafness, exercise limitations, and matrilineal inheritance. Except deafness, the other features are totally in contrast with the diagnosis of AFD. Targeted genetic analysis showed a 3243 tRNA lle mutation, related to MELAS phenotype.

AL is a group of disorders characterized by the storage of amyloid content in the interstitium of different body organs including the heart.[26] The diagnosis of AL is challenging; however, new imaging techniques (as 99 mTc-DPD scintigraphy scan and cardiac magnetic resonance) along with cardiac biopsy are the mainstay.[27]

In case 4, bilateral carpal tunnel and visceral effusion, along with cardiac features (low QRS voltages, HCM with restrictive physiology and apical abnormal speckle tracking pattern), are a pathognomonic picture of AL, which unfortunately have the worse prognosis despite treatment.[26]

  Conclusions Top

General physician and cardiologists need to be aware of the heterogeneous clinical presentation of HCM and associated disorders (phenocopies) since an early suspicion means early and tailored management in rare disorders, which is the main determinant of the patient's prognosis.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Desnick RJ, Wasserstein MP. Fabry disease: Clinical features and recent advances in enzyme replacement therapy. Adv Nephrol Necker Hosp 2001;31:317-39.  Back to cited text no. 2
Meikle PJ, Ranieri E, Simonsen H, Rozaklis T, Ramsay SL, Whitfield PD, et al. Newborn screening for lysosomal storage disorders: Clinical evaluation of a two-tier strategy. Pediatrics 2004;114:909-16.  Back to cited text no. 3
Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet 2006;79:31-40.  Back to cited text no. 4
Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, et al. Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338-46.  Back to cited text no. 5
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Authors/Task Force members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733-79.  Back to cited text no. 8
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Elliott P, Baker R, Pasquale F, Quarta G, Ebrahim H, Mehta AB, et al. Prevalence of Anderson-Fabry disease in patients with hypertrophic cardiomyopathy: The European Anderson-Fabry Disease survey. Heart 2011;97:1957-60.  Back to cited text no. 14
Monserrat L, Gimeno-Blanes JR, Marín F, Hermida-Prieto M, García-Honrubia A, Pérez I, et al. Prevalence of fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2007;50:2399-403.  Back to cited text no. 15
von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hübner G, Olsen EG, et al. An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med 1991;324:395-9.  Back to cited text no. 16
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Kim JH, Lee BH, Hyang Cho J, Kang E, Choi JH, Kim GH, et al. Long-term enzyme replacement therapy for Fabry disease: Efficacy and unmet needs in cardiac and renal outcomes. J Hum Genet 2016;61:923-9.  Back to cited text no. 18
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Lenders M, Duning T, Schelleckes M, Schmitz B, Stander S, Rolfs A, et al. Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene. PLoS One 2013;8:e55565.  Back to cited text no. 20
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