Phenocopies of hypertrophic cardiomyopathy

Phenocopies of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by hypertrophy of the left ventricle, not related to load. It is a genetically transmitted condition. There are several mimickers of hypertrophic cardiomyopathy which can be called phenocopies of hypertrophic cardiomyopathy. Conventional form of HCM has been called sarcomeric HCM as it is due to mutations in genes encoding sarcomeric proteins [1].

Here is a small list of phenocopies of hypertrophic cardiomyopathy which is not truly exhaustive:

  1. Fabry disease
  2. Danon disease
  3. PRKAG2 Cardiomyopathy
  4. Pompe disease
  5. Cardiac amyloidosis
  6. Athlete’s heart
  7. Hypertensive heart disease
  8. DUSH – Discrete Upper Septal Hypertrophy

Fabry disease

Fabry disease is due to a mutation in the α-galactosidase A (α-GAL A) gene and is an X-linked recessive disease [2]. Left ventricular hypertrophy is noted on echocardiography due to accumulation of glycosphingolipids. Cardiac manifestations in this multisystem disease include cardiac arrhythmias, conduction system disease and left ventricular dysfunction. The left ventricular hypertrophy in Fabry disease is concentric and the treatment is lifelong enzyme replacement therapy.

Danon disease

Danon disease is a lysosomal storage disease which is transmitted as an X-linked dominant condition. Lysosome associated membrane protein 2 (LAMP2) is deficient in these patients. Hypertrophic cardiomyopathy was noted in 88% and muscle weakness in 80% of males [3]. Women are less severely affected and can have equal prevalence of hypertrophic and dilated cardiomyopathy. Authors reviewed data of 82 of their patients and 63 cases reported in literature [3]. They reported that women present about 15 years later compared to men. About two thirds of men and one third of women may have ECG features of pre-excitation in the form of Wolff-Parkinson-White syndrome. Left ventricular hypertrophy is of the concentric type, though asymmetric septal hypertrophy may occur in some.

PRKAG2 Cardiomyopathy

PRKAG2 Cardiomyopathy is an autosomal dominant condition and involves  gamma (γ)-subunit of AMP-activated protein kinase (AMPK) [4]. Left ventricular hypertrophy is due to glycogen deposition. Both WPW syndrome and atrioventricular block can occur. Hypertrophy is usually concentric, though asymmetric septal hypertrophy can occur rarely. Pacemaker implantation may be needed due to conduction system disease [5].

Pompe disease

Pompe disease is a glycogen storage disease which causes left ventricular hypertrophy. ECG is characterized by short PR interval and large QRS complexes [6]. Regression of ECG changes with enzyme replacement therapy using recombinant human acid alpha-glucosidase has been documented in infantile Pompe disease.

Massive cardiomegaly and progressive skeletal muscle disease is seen in infantile Pompe disease which is fatal. Hypertrophic cardiomyopathy due to glycogen accumulation later progresses to dilated cardiomyopathy. Left ventricular outflow tract obstruction can occur due to the hypertrophy [6].

Cardiac amyloidosis

Cardiac amyloidosis is due to extracellular deposition of amyloid material. It can cause infiltrative/restrictive cardiomyopathy [7]. Concentric left ventricular hypertrophy is noted on echocardiography. The characteristic feature in ECG is low voltage complexes in spite of hypertrophy noted on echocardiography [8]. Conduction system abnormalities, atrial and ventricular arrhythmias can occur.

Two important varieties of cardiac amyloidosis are light chain or AL amyloidosis and transthyretin amyloidosis (ATTR amyloidosis). Non hereditary form of transthyretin amyloidosis usually occurs after the seventh decade of life. 99mTc-DPD scintigraphy (bone scintigraphy) is a useful diagnostic investigation [9].

Treatment of AL amyloidosis is chemotherapy directed at clonal proliferation of plasma cells [7]. Tafamidis has been approved for the treatment of ATTR amyloidosis. Liver transplantation to remove the source of variant transthyretin has been considered the treatment of choice in younger patients with ATTR amyloidosis [7].

Athlete’s heart

Athlete’s heart is the physiological hypertrophy which occurs due to the increased load in trained athletes. Simple way to differentiate it is by deconditioning which reduces the hypertrophy. But this may not always be acceptable. Family history of sudden cardiac death may point to genetic sarcomeric HCM [2]. Systolic mitral annular velocity of <9 cm/s has been shown to have 87% sensitivity and 97% specificity for differentiating physiological from pathological left ventricular hypertrophy in a study [10].

Hypertensive heart disease

Hypertensive heart disease with left ventricular hypertrophy can sometimes be difficult to differentiate from sarcomeric HCM. ‘Pseudo’ SAM (systolic anterior motion of mitral valve) has been described in hypertensive heart disease. It has been differentiated by the late occurrence in systole compared to true SAM [11].

Discrete upper septal hypertrophy (DUSH)

Discrete upper septal hypertrophy has been thought to be either a localised hypertrophy due to pressure overload or a forme fruste of sarcomeric HCM. Tissue Doppler indices E’ (Ea) and E/E’ ratio have been shown to be useful in differentiating DUSH from HCM with fair sensitivity (75%) and good specificity (90%) [12]. E’ was lower and E/E’ higher in those with HCM.


  1. Crilley JG, Boehm EA, Blair E, Rajagopalan B, Blamire AM, Styles P, McKenna WJ, Ostman-Smith I, Clarke K, Watkins H. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol. 2003 May 21;41(10):1776-82.
  2. Sankaranarayanan R, J Fleming E, J Garratt C. Mimics of Hypertrophic Cardiomyopathy – Diagnostic Clues to Aid Early Identification of Phenocopies. Arrhythm Electrophysiol Rev. 2013 Apr;2(1):36-40. 
  3. Boucek D, Jirikowic J, Taylor M. Natural history of Danon disease. Genet Med. 2011 Jun;13(6):563-8.
  4. Arad M, Benson DW, Perez-Atayde AR, McKenna WJ, Sparks EA, Kanter RJ, McGarry K, Seidman JG, Seidman CE. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest. 2002 Feb;109(3):357-62.
  5. Arad M, Maron BJ, Gorham JM, Johnson WH Jr, Saul JP, Perez-Atayde AR, Spirito P, Wright GB, Kanter RJ, Seidman CE, Seidman JG. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med. 2005 Jan 27;352(4):362-72. 
  6. Ansong AK, Li JS, Nozik-Grayck E, Ing R, Kravitz RM, Idriss SF, Kanter RJ, Rice H, Chen YT, Kishnani PS. Electrocardiographic response to enzyme replacement therapy for Pompe disease. Genet Med. 2006 May;8(5):297-301.
  7. Martinez-Naharro A, Hawkins PN, Fontana M. Cardiac amyloidosis. Clin Med (Lond). 2018 Apr 1;18(Suppl 2):s30-s35. 
  8. Quarta CC, Kruger JL, Falk RH. Cardiac amyloidosis. Circulation. 2012 Sep 18;126(12):e178-82. 
  9. Lee J, Kim K, Choi JO, Kim SJ, Jeon ES, Choi JY. 99mTc-DPD scintigraphy and SPECT/CT in patients with AL and ATTR type amyloidosis: Potential clinical implications. Medicine (Baltimore). 2020 Jan;99(4):e18905. 
  10. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol. 2001 Jul 1;88(1):53-8.
  11. Doi YL, McKenna WJ, Oakley CM, Goodwin JF. ‘Pseudo’ systolic anterior motion in patients with hypertensive heart disease. Eur Heart J. 1983 Dec;4(12):838-45. 
  12. Chen-Tournoux A, Fifer MA, Picard MH, Hung J. Use of tissue Doppler to distinguish discrete upper ventricular septal hypertrophy from obstructive hypertrophic cardiomyopathy. Am J Cardiol. 2008 May 15;101(10):1498-503.