A 54-year old patient with Fabry disease, mechanical valve prosthesis in mitral position, and history of kidney transplant was admitted for obstructive hydronephrosis and bradycardia with junctional rhythm (30-35/min).
Figure 1 ECG on admission with junctional rhythm
The mitral valve disease, newly diagnosed conduction abnormalities, as well as the chronic renal failure as the reason for kidney transplantation, have all been attributed to the patient’s primary inherited metabolic illness - Fabry disease.
Upon admission, TTE was performed and showed the following findings:
Video 1 TTE on admission
Video 2 Four chamber view on admission TTE
Figure 2 Severe biatrial dilatation on TTE
Despite isoprenaline therapy and discontinuation of bradycardia medication, junctional rhythm persisted. Given the good systolic function of both ventricles, the patient was indicated for single-chamber pacemaker implantation. With regards to the patient’s kidney drainage and thus heightened infection risk along with looming haemodialyzation therapy, MICRA (electrode-less) pacemaker was deemed the most suitable option.
Video 3 Skiascopy during MICRA insertion
The pacemaker was successfully implanted via right femoral vein to the apical portion of the right ventricular septum since the patient presented with midventricular obstruction of the left ventricular septum during the procedure.
The patient was then transferred back to the nephrology department for the follow-up treatment of hydronephrosis.
Fabry disease (FD) is an X-linked lysosomal storage disease (caused by a variety of mutations in the GLA gene on Xq22.1) with an incidence of about 1:120000, but mutation incidence is as high as 1:1250.
The cause of the classical variant stands the lack of alpha-galactosidase activity, which results in the accumulation of globotriaosylceramide (Gb3) in cells of various systems. This causes the disease’s wide-spread multi-systemic effects, namely paresthesias, skin and eye, cardiovascular, cerebrovascular and renal disorders.
The mean age of onset of the first symptom is before 10 years of age. Atypical variants of FD involve residual enzyme activity, resulting in milder, more often than not restricted to only one organ, symptoms with a later onset, usually between 40 and 60 years of age.
Undiagnosed patients with FD can be detected by screening in at-risk populations, such as patients with end-stage renal disease, unexplained myocardial hypertrophy or early stroke (18-55 years of age).
On the forefront of FD stands facial dysmorphism, also described as ‘Fabry facies’, characterized by periorbital fullness, bushy eyebrows, recessed forehead, pronounced nasal angle, bulbous nasal tip, full lips, broad alar base. It is possible that these features become more pronounced with age in regard to the accumulation of Gb3.
Figure 3 Fabry facies
The most common subjective symptom is neuropathic pain, with the average onset of about 15 years of age. It begins in the extremities and radiates proximally with the trigger being any physical or emotional stress.
Skin abnormalities, namely angiokeratomas, teleangiectasia and sweating abnormalities (an-/hypo-/hyper-hidrosis) are among the most commonly observed FD symptoms and hence lead to diagnoses being made in the dermatology departments. Another hallmark of FD are whorl-like opacities resulting from changes in the subepithelial layers of the cornea, also known as cornea verticillata.
Figure 5 Angiokeratomas
Figure 5 Cornea verticillata
Progressive cardio- and renovascular abnormalities are among the most common causes of death in all patients with FD. A so-called ‘Cardiac variant’ has also been recognized in a large number of patients, who present with a late-onset phenotype manifesting mostly as a left ventricular hypertrophy (LVH) or hypertrophic cardiomyopathy (HCM). The absolute majority of cardiovascular symptoms of FD begin manifesting between 30 and 40 years of age. The heart is the most susceptible tissue for Gb3 accumulation of the whole body and therefore presents with a broad spectrum of symptoms, among which angina pectoris, palpitations, syncope, dyspnoea and heart failure are the most notable.
Symmetrical progressive LVH is the predominant finding, diagnosed by imaging techniques (echocardiography, MRI) and ECG (hypertrophy voltage criteria), although a small portion (5%) of patients develop asymmetrical septal hypertrophy. While LV systolic function is usually within normal range, diastolic dysfunction is very typical. Increased oxygen demand from the hypertrophic muscle, along with endothelial infiltration and dysfunction causes significantly reduced coronary flow reserve. Although this leads to recurrent angina pectoris in a portion of patients, actual myocardial infarction is very rare in patients with FD and selective coronarography usually does not reveal coronary stenotic lesions.
Figure 6 ECG stripe showing significant left ventricular hypertrophy
Figure 7 MRI showing diffuse left ventricular hypertrophy
Electrophysiological abnormalities are also very commonly involved in FD, on ECG typically with high voltage and short PR interval due to accelerated AV conduction or preexcitation (which occurs often among lysosomal storage diseases in general). Conduction system dysfunction; bundle branch and AV blocks of varying degrees, progressive sinus node dysfunctions occur, among others, with disease progression and very often require pacemaker implantation. Palpitation and arrhythmias, such as supraventricular tachycardia or atrial flutter and fibrillation accompany later stages of the disease.
Figure 8 Typical ECG of a patient with Fabry disease: short PR intervals, left ventricular hypertrophy and prominent ST depressions and T-wave inversions
Infiltrative changes within valvular fibroblasts cause also valvular involvement, most commonly resulting in mitral valve prolapse, usually with only mild to medium regurgitation, but occasionally requiring surgical valve replacement. Echocardiography usually reveals valvular thickening and deformation.
Figure 9 Echocardiogram showing mild thickening of the mitral valve leaflets (arrows), with also significant thickening of the septum
Figure 10 Colour doppler echocardiogram showing mild to moderate mitral regurgitation, with noticeable bilateral atrial dilatation
Among renovascular abnormalities, otherwise unexplained proteinuria/albuminuria are especially alarming. The disease manifests through isosthenuria with progressive deterioration of renal funcion to end-stage renal disease, which, unless counteracted by therapy, results in the death of the patient. Cerebrovascular involvement includes thrombosis, transient ischemic attacks, basilar artery ischemia and aneurysms, seizures, hemiplegia and other serious neurological symptoms. A neurologic phenotype including decreased overall motor performance has been also cited. Gastrointestinal and pulmonary abnormalities are also of common occurrence.
Due to the basic genetic principles, it was initially thought that Fabry disease is an illness mostly exclusive for the male population and females serve their role as carriers. Nevertheless, it was recently discovered that heterozygous females may (based on individual factors) experience milder forms of Fabry disease. They are usually subject to painful neuropathies and isolated skin lesions, although disturbances of corneal opacity have been observed in about 70-80% of otherwise asymptomatic heterozygous females.
Figure 9 Fabry disease diagnosis algorithm
The primary blood test for the diagnosis of Fabry disease assesses the activity of the alpha-galactosidase A enzyme. Another blood test, which detects the presence of a fatty substance called lyso-Gb3, also can be performed and may indicate the severity of the disease. Finally, the blood sample can be used for genetic testing that looks for mutations in the GLA gene and may help confirm Fabry disease.
Diagnosis of cardiovascular involvement
Electrocardiography usually shows:
Echocardiography is the most useful method for diagnosing and monitoring FD-related cardiomyopathy.
Cardiac-MRI provides an accurate assessment of LV size, mass and geometry, gadolinium contrast enhancement can help visualize myocardial fibrosis.
Endymyocardial biopsy may be considered in some variants patients, high residual enzyme activity (>10%) or low lyso-Gb3 levels to confirm or exclude FD as the cause of LVH. It is however not a recommended method for treatment efficacy follow-up.
Electrophysiological study is recommended in patients with persistent or recurrent SVT to guide therapy.
Laboratory tests aids detection of non-cardiac conditions that cause or exacerbate ventricular dysfunction.
Standard, yet still fairly new treatment for FD is enzyme replacement therapy (ERT), which aims to supply a recombinant version of the genetically deficient enzyme. It has been shown to significantly alleviate the cardiac, renal, and neuropathic effects of FD. The enzyme is administered every 2 weeks. Novel therapy based on pharmacological chaperone is now available for FD patients of certain variants. Many studies have demonstrated a benefit in FD patients when ERT is initiated early.
Cardiologic treatment involves standard measures of reducing cardiovascular risk (e.g.: statins, antihypertensive therapy). Beta-blockers should be used only with great caution, as they have been proved to aggravate symptomatic bradycardia and AV conduction impairment in some patients - dihydropyridine Ca blockers are deemed the safer and more effective therapy. Antiaggregation in all patients with cardiac symptoms, anticoagulation in patients with supraventricular rhythm disturbances. Septal alcohol ablation can be also considered for patients with LVOT obstruction.8,9
Patients also profit from effective pain management. Prophylaxis of secondary complications is in the gestion of adequate dispensarisation. Other complications should be treated in accordance with protocols of the respective departments, with kidney transplant due to end-stage renal disease among the most significant.
Authors: Michal Pazderník, Vojtěch Berka