Zebras Exist, Too!

Keywords
Fabry Disease/complications; Infant, Newborn, Diseases; Hypertrophy, Left Ventricular; Cardiomyopathy, Hypertrophic/diagnostic, imaging; Enzyme Replacement Therapy; Rare Disease

Fabry disease (FD) is a rare X-linked hereditary lysosomal storage disease caused by deficient activity of the enzyme alpha-galactosidase A that leads to the accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart, brain, and kidneys.¹ In FD, cardiac damage begins early and progresses subclinically before the appearance of symptoms and generally manifests as left ventricular hypertrophy simulating hypertrophic cardiomyopathy (HCM).² Recent studies have demonstrated a prevalence of FD of up to 5% in patients whose initial diagnosis was HCM.³ After the introduction of enzyme replacement therapy, FD deserves special attention in the differential diagnosis in patients with unexplained ventricular hypertrophy and HCM, as it is a heart disease that requires specific treatment. However, early diagnosis and treatment are essential to prevent the progression of the disease by reducing cardiovascular event rates.⁴-⁶

With the aim of investigating the clinical and exam differences between HCM and DF, the study of Akhan et al.⁷ retrospectively evaluated 60 patients with HCM and 40 with FD. In this population, with a similar average age, the authors showed, in general, that the characteristics of the two cardiac conditions share more similarities than differences, making diagnosis a challenge in clinical practice.

The authors indicated that the HCM group presents more significant structural and functional cardiac changes, resulting in more pronounced symptoms and the need for drug interventions.⁷ These findings corroborate the pathophysiological mechanism implicated in the origin of both diseases, while in HCM mutations in cardiac sarcomere genes trigger hypertrophy, disarray, and fibrosis, in FD, the deposition of Gb3 in cardiomyocytes activate inflammatory and neurohormonal mechanisms involved in the formation of hypertrophy and tissue fibrosis, although indirectly and to a lesser extent.⁸ The decrease in the glomerular filtration rate was more significant in FD since renal impairment occurs progressively and early; however, it is important to highlight that in this context of diagnosis differential, it is a finding that must be carefully considered.⁹ The ECG findings indicated that they have little value for differentiating between the two heart diseases. Something relevant to be considered was the QT interval, which was shorter in the FD group, suggesting that this measure may be more relevant than reducing the PR interval (PQ) for diagnosing FD, as also demonstrated by Namdar et al.¹⁰

"When you hear hoofbeats, think of horses, not zebras." (Dr. Theodore Woodward 1940), but remember: zebras exist too! In the challenging scenario of rare diseases such as FD, neglecting the possibility of this diagnosis can result in delays and diagnostic errors, reducing the benefits of specific treatment. Therefore, a good detailed history, especially with the family pedigree, together with a thorough physical examination and recognition of differences (often subtle) in complementary exams, are the only steps that lead us to meet the zebras.

Referências

• ¹
  Pieroni M, Moon JC, Arbustini E, Barriales-Villa R, Camporeale A, Vujkovac AC, et al. Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week. J Am Coll Cardiol. 2021 Feb 23;77(7):922-36. doi: 10.1016/j.jacc.2020.12.024
  » https://doi.org/10.1016/j.jacc.2020.12.024
• ²
  Ommen SR, Nishimura RA, Edwards WD. Fabry disease: a mimic for obstructive hypertrophic cardiomyopathy? Heart. 2003 Aug;89(8):929-30. doi: 10.1136/heart.89.8.929
  » https://doi.org/10.1136/heart.89.8.929
• ³
  Fernandes F, Antunes MO, Hotta VT, Rochitte CE, Mady C. Doenças de Depósito como Diagnóstico Diferencial de Hipertrofia Ventricular Esquerda em Pacientes com Insuficiência Cardíaca e Função Sistólica Preservada. Arq Bras Cardiol. 2019;113(5):979-87. doi: 10.36660/abc.20180370
  » https://doi.org/10.36660/abc.20180370
• ⁴
  Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, et al. Fabry disease revisited: management and Treatment recommendations for adult patients. Mol Genet Metab 2018;123(4):416–27. doi: 10.1016/j.ymgme.2018.02.014
  » https://doi.org/10.1016/j.ymgme.2018.02.014
• ⁵
  Linhart A, Germain DP, Olivotto I, Akhtar MM, Anastasakis AM, Hughes D, et al. An expert consensus document on the management of cardiovascular manifestations of Fabry disease. Eur J Heart Fail. 2020;22(7):1076–96. doi: 10.1002/ejhf.1960
  » https://doi.org/10.1002/ejhf.1960
• ⁶
  Germain DP, Elliott PM, Falissard B, Fomin VV, Hilz MJ, Jovanovic A, et al. The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: a systematic literature review by a European panel of experts. Mol Genet Metab Rep. 2019;19:e100454. doi: 10.1016/j.ymgmr.2019.100454
  » https://doi.org/10.1016/j.ymgmr.2019.100454
• ⁷
  Akhan O, Kis M, Güzel T, Zoghi M. Differences Between Two Distinct Hypertrophic Cardiac Conditions: Fabry Disease versus Hypertrophic Cardiomyopathy. Arq Bras Cardiol. 2024; 121(1):e20230229. DOI: https://doi.org/10.36660/abc.20230229
  » https://doi.org/10.36660/abc.20230229
• ⁸
  Yousef Z, Elliott PM, Cecchi F, Escoubet B, Linhart A, Monserrat L, et al. Left ventricular hypertrophy in Fabry disease: a practical approach to diagnosis. Eur Heart J. 2013 Mar;34(11):802-8. doi: 10.1093/eurheartj/ehs166
  » https://doi.org/10.1093/eurheartj/ehs166
• ⁹
  Del Pino M, Andrés A, Bernabéu AÁ, de Juan-Rivera J, Fernández E, de Dios García Díaz J, et al. Fabry Nephropathy: An Evidence-Based Narrative Review. Kidney Blood Press Res. 2018;43(2):406-21. doi: 10.1159/000488121
  » https://doi.org/10.1159/000488121
• ¹⁰
  Namdar M, Steffel J, Jetzer S, Schmied C, Hürlimann D, Camici GG, et al. Value of electrocardiogram in the differentiation of hypertensive heart disease, hypertrophic cardiomyopathy, aortic stenosis, amyloidosis, and Fabry disease. Am J Cardiol. 2012 Feb 15;109(4):587-93. doi: 10.1016/j.amjcard.2011.09.052
  » https://doi.org/10.1016/j.amjcard.2011.09.052

Publication Dates

• Publication in this collection
  08 Mar 2024
• Date of issue
  2024

History

• Received
  03 Dec 2023
• Reviewed
  18 Jan 2024
• Accepted
  18 Jan 2024