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Concentric hypertrophy and fibrosis

Case presentation

A 45-year-old Caucasian male was referred to our outpatient department for evaluation of episodes of paroxysmal pain in his left arm radiating to the chest. The pain was present at rest since two weeks, each episode lasted a few minutes and was not related to physical exertion. However, the pain aggravated upon movement of his left arm. He did not experience nausea, dyspnea or diaphoresis.
Myocardial Disease

Physical examination showed no abnormal findings, except for extensive periumbilical angiokeratomas (fig. 1), a tender left arm on palpation. Laboratory tests did not demonstrate any abnormal findings and an ECG showed signs of left ventricular hypertrophy and a right bundle branch block pattern (fig. 2).

Fig. 1 Periumbilical angiokeratomas

Fig. 2 ECG showed sinusbradycardia, signs of left ventricular hypertrophy and a right bundle branch block pattern.

The differential diagnosis of chest pain is extensive and ranges from musculoskeletal conditions to cardiac diseases. Since our patient demonstrated rather atypical symptoms and laboratory tests showed no abnormalities, coronary artery disease was not the first option. Because his left arm was tender and the pain was aggravated by movement of his arm, a musculoskeletal problem was

thought to be the most likely cause of his complaints. Upon inquiry, the patient told that he works as a truck driver and had driven long distances lately. Consequently, his complaints were attributed to occupational overstrain of the left arm and physical therapy was recommended.
For further evaluation of the left ventricular hypertrophy accidently found on ECG, an echocardiogram was performed. It demonstrated concentric hypertrophy with a maximum wall thickness of 14 mm, a preserved left ventricular ejection fraction and a grade II diastolic dysfunction. On cardiovascular MRI (fig. 3), left and right ventricular hypertrophy and a high intensity signal suggesting fibrosis in the mid- and basolateral segment were detected.

Fig. 3 CMR showed concentric ventricular hypertrophy and mid- and basolateral fibrosis (not visible)


1. What do you think would be the diagnosis?
2. What would be the next step to confirm your diagnosis?
3. What therapy would you recommend?


1. What do you think would be the diagnosis?


Ventricular hypertrophy is often a result of increased resistance to contraction of the ventricles and occurs when there is long-term hypertension or aortic valve disease (especially aortic stenosis). In rare cases, ventricular hypertrophy is caused by a congenital heart disease as hypertrophic cardiomyopathy.
Since our had a history of a normal blood pressure, long-standing hypertension was a less probable cause of the ventricular hypertrophy. An important argument is that the patient also had right ventricular hypertrophy.
The combination of angiokeratomas, signs of concentric left ventricular hypertrophy and a right bundle branch block pattern of ECG and fibrosis on MRI suggest the presence Fabry disease. Upon inquiry it appeared that his brother was diagnosed with Fabry disease.

Fabry disease (or Anderson-Fabry disease) is an X-linked glycolipid storage disease. As a result of α-Galactosidase A deficiency, globotriaosylceramide (Gb3) accumulates in lysosomes in a wide variety of cells; primarily in kidneys, heart and brain. Progression of disease leads to progressive tissue damage and organ failure and survival is greatly reduced.(1) As it is an X-linked disease, it was thought that only males could be affected by this gene defect but the disease is detected in women as well, although often later in life and less fulminant.(2)
Clinical manifestation of the disease start in childhood or adolescence and frequently seen symptoms are severe neuropathic pains in the limbs, hypohydrosis, angiokeratomas, renal manifestations as proteinuria and polyuria and gastrointestinal symptoms as diarrhoea and vomiting.(3) Cardiac involvement is often seen as ventricular hypertrophy, coronary artery disease, aortic and mitral insufficiency and conduction defects.(4)  The ventricular hypertrophy is a relatively early finding in Fabry’s disease and may be misdiagnosed as a hypertrophic cardiomyopathy, although hypertrophy in Fabry disease is usually symmetric instead of asymmetric as frequently seen in hypertrophic cardiomyopathy.(5)
ECG findings in Fabry disease consist of signs of left ventricular hypertrophy, a short PR interval and a prolongation of the QRS complex, often with a right bundle branch block pattern.(6)

2. What would be the next step to confirm your diagnosis?


The diagnosis of Fabry disease is usually confirmed in males if there is a low α-Gal A activity detected in leukocytes or plasma. In women and in males with an atypical presentation or marginal α-Gal-A activity, diagnosis is confirmed by genetic testing. Thus far several hundreds of mutations have been identified.(7)
Renal manifestation of the disease can be seen as proteinuria. In addition, kidney biopsies might help in confirming the diagnosis as extensive renal glycolipid accumulation can be observed. 

Laboratory tests in our patient showed lowered levels of α-Gal-A (1.0 nmol/mg.hour) and genetic testing ultimately confirmed the diagnosis of Fabry disease in our patient: a hemizygous mutation c.1156C>T of the GLA gene on chromosome Xq22 was found.

3. What therapy would you recommend?


The only treatment available for Fabry disease is enzyme replacement therapy with recombinant human α-Gal-A. Enzyme replacement therapy significantly improves neuropathic pain and significantly decreases mean ventricular wall thickness and left ventricular mass. In addition, treatment with recombinant human α-Gal-A showed a trend for a slower rate of decline in kidney function when compared to placebo treatment.(8)
In case of sole cardial manifestation of the disease it is also recommended to start immediately with enzyme replacement therapy.
Eng et al. found that enzyme replacement therapy clears microvascular endothelial deposits of Gb3 from the kidneys, heart, and skin, hereby reversing the pathogenesis of the main clinical manifestations of Fabry disease.(9)


Recombinant human α-Gal-A was started in this patient. He receives intravenous enzyme replacement therapy once per two weeks to slow the progression of the disease.


  1. Wanner C. Fabry disease model: a rational approach to the management of Fabry disease. Clin Ther 2007; 29 Suppl. A: S2-5.
  2. Wang RY, Lelis A, Mirocha J, et al. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 2007 Jan; 9 (1): 34-45.
  3. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, Linhart A, Sunder-Plassmann G, Ries M, Beck M. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34(3):236.
  4. Nagueh SF. Fabry disease. Heart. 2003;89(8):819.
  5. Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, Elliott PM. Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation. 2002;105(12):1407.
  6. Mehta J, Tuna N, Moller JH, Desnick RJ. Electrocardiographic and vectorcardiographic abnormalities in Fabry's disease. Am Heart J. 1977;93(6):699.
  7. Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, Goldfarb L, Brady RO, Balow JE, Austin Iii HA, Kopp JB. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine. 2002;81(2):122
  8. Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, Finkel R, Packman S, Bichet DG, Warnock DG, Desnick RJ, Fabry Disease Clinical Trial Study Group. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007;146(2):77.
  9. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ, International Collaborative Fabry Disease Study Group. Safety and efficacy of recombinant human alpha-galactosidase A--replacement therapy in Fabry's disease. N Engl J Med. 2001;345(1):9.

Notes to editor

Presented by: Susan Stienen, Research Fellow, Academic Medical Center, Department of Cardiology, Room C01-315, Meibergdreef 9,1100 DD Amsterdam and Prof. Dr. Yigal Pinto,Heart Failure Research Center, University of Amsterdam,The Netherlands.
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.

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