53],
56], thereby attenuating the effect of ERT. Finally, ERT demonstrates uneven biodistribution, with the liver taking up the majority of the recombinant replacement enzyme, whereas the most severely affected cell types in the body such as cardiomyocytes and podocytes take up lesser amounts of the replacement enzyme
[55][52].
There is currently no evidence demonstrating the superiority of agalsidase α over agalsidase β and vice versa in clinical endpoints
[57,58][54][55]. Specifically, in the Canadian Fabry Disease Initiative, a comparison of agalsidase α and agalsidase β demonstrated no statistical difference in clinical endpoints including death, cardiac events, acute neurological events, and others
[58][55]. However, there were differences in the biochemical response between patients treated with agalsidase α and agalsidase β, with a higher risk of developing anti-drug antibodies and a greater decrease in the plasma globotriaosylsphingosine levels in patients treated with agalsidase β. In addition, there was a greater reduction in the left ventricular mass in patients treated with agalsidase β
[59][56].
Oral pharmacologic chaperone therapy, namely Migalastat, is an alternative treatment option for FD. However, since Migalastat is protein-variant specific, it is only used for patients with amenable
GLA gene variants
[60][57]. These specific
GLA variants produce highly unstable mutated α-Gal A proteins. Migalastat binds to these α-Gal A variants, thus stabilizing the enzymes by enhancing correct folding
[55][52]. This stabilization allows the mutated enzymes to be properly trafficked to lysosomes, where Migalastat dissociates, allowing it to catabolize the accumulated Gb
3 substrates
[61][58]. This therapy has been demonstrated to both increase α-Gal A activity and decrease Gb
3 inclusions
[62,63][59][60].
Despite disease-modifying FD treatments described, equal attention and care should be given to non-FD specific treatments directed towards the multi-system consequences of the condition. Due to the clinical heterogeneity of FD, a multidisciplinary clinical team with a cardiologist, nephrologist, neurologist, genetic counselor, and a medical geneticist should ideally be in place for the holistic care of FD patients. General preventative measures including pharmacological stroke prophylaxis with an antithrombic agent and lifestyle modifications such as avoidance of extremes of temperature to prevent painful crises, exercise prescription, diet, and smoking cessation should be appropriately advised. Other co-morbidities such as hypertension and dyslipidemia should be managed diligently. The management of the cardiac manifestations of FD has been summarized in .
Table 4. Management of the cardiovascular manifestations of Fabry disease.
| Structural abnormalities that can be present on cardiac imaging |
|
|
-
Identification/treatment of hypertension to prevent further increase in LV wall thickness
-
Cautious use of medications with negative inotropic effects (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, disopyramide) if LVOT obstruction present
-
Regular surveillance of valvular regurgitation and aortic dilatation
|
|
| Electrophysiologic abnormalities detected by ECG or rhythm monitoring |
|
|
-
Atrial arrhythmias may require treatment with rate control strategy (using AV nodal blockers) or rhythm control strategy (with anti-arrhythmic agents or catheter ablation)
-
Anticoagulation for stroke risk reduction is indicated in the setting of atrial fibrillation
-
Ventricular arrhythmias may require treatment with either beta-blockers, anti-arrhythmic agents, catheter ablation, or ICD therapy
-
Amiodarone should only be considered when other therapeutic options have failed since it may promote glycolipid accumulation and attenuate the effects of ERT
-
Symptomatic bradyarrhythmias including sinus node dysfunction or advanced AV block may require permanent pacing
|
|
| Other cardiovascular considerations in patients with Fabry disease |
|
|
-
ACE inhibitors or ARBs should be considered for patients with chronic kidney disease
-
Beta-blockers or non-dihydropyridine calcium-channel blockers should be used with caution given the higher prevalence of sinus node dysfunction or advanced AV block
-
Antiplatelet therapy may be indicated for primary or secondary prevention of ischemic stroke in selected patients
-
Heart failure can be treated with diuretics or LV enhancement therapy if LVEF is reduced in accordance with contemporary consensus-based guidelines
-
Chest pain due to large-vessel or microvascular disease can be managed with standard anti-anginal therapy with cautious use of AV nodal blockers as previously described
|
|
|
Hypertrophic Cardiomyopathy |
|
| |
|
|
-
High voltage QRS
-
Left atrial enlargement
-
Atrial fibrillation
|
|
| |
|
| |
|
| Cardiac Amyloidosis |
|
|
-
Heart failure
-
Bilateral carpal tunnel
-
Nephrotic syndrome
-
Macroglossia
-
Peripheral neuropathy
|
|
|
-
Low voltage QRS
-
Atrial fibrillation
-
Pseudo-infarct
|
|
| |
|
| |
|