Diverse phenotypic expression associated with the same genetic variant in female heterozygote patients of Anderson-Fabry disease: a case series

Abstract

Background: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder resulting from a mutation of alpha-galactosidase A gene (GLA), causing deficiency in alpha-galactosidase activity. The enzyme deficit can lead to storage of globotriaosylceramide in various organs including heart. Studies suggest that vasospastic angina (VSA) is associated with AFD.

Case summary: This clinical case series aimed to present two female patients with AFD, including progressive cardiac involvement: a 50-year-old woman (patient number 1) and a 39-year-old woman (patient number 2) who are siblings with a male AFD patient harbouring p. Arg342Glu missense variant in alpha-galactosidase A gene (GLA), who suffered VSA and subsequent ventricular fibrillation. Enzymatic tests and genetic analysis confirmed AFD in both female patients and histological tests revealed globotriaosylceramide deposits in their hearts. In patient number 1, a 12-lead electrocardiography and transthoracic echocardiography revealed cardiac hypertrophy. Coronary angiography revealed no organic coronary artery stenosis and vasospasms was induced by spasm provocation test. In patient number 2, no signs of cardiac hypertrophy were found, and coronary arteries had no organic stenosis with negative spasm provocation test. Both patients received enalapril therapy and enzyme replacement therapy (ERT).

Discussion: Different phenotype of AFD was occurred even with the same genetic variant in female heterozygote patients. The duration of exposing accumulation of Gb3 might affect cardiac hypertrophy and vasospasms. Coronary angiography with acetylcholine provocation test should be considered in female AFD patient, especially in case with cardiac hypertrophy.

Keywords: Anderson–Fabry disease; Cardiac hypertrophy; Case series; Vasospasms.

Figure 1

Electrocardiography at the time of diagnosis: (A) electrocardiography showed sinus rhythm and left ventricular hypertrophy with repolarization disorder. Transthoracic echocardiography at the time of diagnosis: (B) The top shows end diastole, and the bottom shows end systole in the long-axis view. At the time of diagnosis, transthoracic echocardiography showed that the left ventricular motion was normal, and left ventricular hypertrophy in lateral wall was observed.

Figure 2

The top shows coronary angiography in left coronary arteries from the right anterior oblique (RAO) view (RAO 30, Caudal 30). The bottom shows ECG at the examination. (A) No significant coronary stenosis was found. ST depression and repolarization abnormalities found on ECG before intracoronary acetylcholine infusion. (B) Coronary artery spasms were induced following intracoronary acetylcholine injection (100 μg) in the left coronary artery (black broad arrow) and proximal segment of 6 and 11 (black arrows). Electrocardiography showed ST depression by 0.15 mm in the inferior leads compared to those of electrocardiography at rest.

Figure 3

Biopsy of the right ventricular wall: (A) Vacuolated myocytes in cardiomyocytes (haematoxylin–eosin staining) Cardiac magnetic resonance imaging at the initiation of enzyme replacement therapy: (B) The slide shows end systole at the basal inferolateral wall in the short-axis view. Cardiac magnetic resonance imaging showed left ventricular apical hypertrophy and the late gadolinium enhancement is exhibited (white arrow).

Figure 4

Coronary angiography in left coronary arteries from the RAO view (RAO 30, Caudal 30) (A) No significant coronary stenosis was found in the coronary arteries in control coronary angiography. (B) Coronary artery spasms were not induced following intracoronary acetylcholine injection (100 μg) in the coronary artery.

Figure 5

Endomyocardial biopsy of the right ventricular wall (A) Vacuolated myocytes in cardiomyocytes (haematoxylin–eosin stain). (B) The annual substrate accumulates in the endothelial cells (electron microscopy).