Anderson-Fabry disease (AFD) is a multi-system, X-linked lysosomal storage disorder first described in 1898. In AFD, there is a deficiency of the enzyme a-galactosidase A resulting in accumulation of the glycosphingolipid, globoytiaosylceramide (Gb3), in blood vessels, tissues and organs including skin, eyes, heart, kidneys, brain and peripheral nervous system. Life expectancy can be shortened up to 20 years in males and 15 years in females.

 

The incidence of AFD has been estimated to be between 1 in 40,000 to 1 in 117,000 worldwide (1). However, its incidence is felt to be greater than this as there are those with some residual enzyme activity with slow progression to disease resulting in cardiac or renal variants with delayed presentation. In a newborn screening study, there was a higher incidence of later onset AFD (1 in 3100 male births) (2). The prevalence of AFD in ESRD on haemodialysis is 0.2-1.2%. In a recent, large European study, the prevalence of AFD in unexplained HCM was 0.5% (3). Higher prevalences of AFD in HCM of up to 12% have been noted in studies but this may be due to referral bias to specialist centres that were involved in the study.

 

Up to 500 mainly point mutations of the GLA gene have been identified on chromosome Xq22.1. An affected male will pass the disorder to all his daughters but none of the sons will be affected. An affected female will have a 50% chance of passing the disorder to both her sons and daughters. Variable expression is commonly seen within and between families.

 

The multi-systemic symptoms vary in age of onset, severity, rate of progression and organ manifestations. In males, AFD tend to present with more severe symptoms and at an earlier age than women. There is a variable presentation in women with some having minimal symptoms whilst others having severe symptoms. This may be partially explained by the random inactivation of X chromosome.

In the first decade, especially in males, symptoms include acroparesthesia (burning neuropathic pain, especially at the extremities), febrile crises, hypohidrosis (lack of sweating), intolerance to heat, GI disturbances and cutaneous angiokeratomas (see figure 1). Neurological manifestations (stroke, autonomic dysfunction, hearing loss) and proteinuria develop form the second decade. Cardiac symptoms manifest later clinically in the 3^rd or 4^th decade.

 

 

Figure 1. Angiokeratoma cutaneous lesions

 

In the heart, Gb3 accumulates in cardiomyocytes, conduction system cells, valvular fibroblasts, vascular endothelium and smooth muscle cells. This accounts for only 1-2% of total cardiac mass. Another postulated mechanism is the accumulation of Gb3 results in cellular dysfunction by stimulating intracellular signalling pathways that lead to hypertrophy, necrosis and fibrosis.

These patients commonly present with symptoms of dyspneoa, palpitations, angina and syncope. In a large registry study, Fabry Outcome survey, cardiac symptoms were reported by 69% of males and 65% of females (4).

 

LVH is the commonest structural cardiac abnormality seen in AFD. Its prevalence increases with age and occurs earlier in males. In the early stages, these patients have concentric remodelling which develops over time into hypertrophy, mainly concentric hypertrophy. These patients tend to develop cardiac symptoms.

ECG changes include LVH by voltage criteria. ST segment abnormalities and T wave inversion are also seen in up to a third of AFD with normal LV morphology, which may be a reflection of Gb3 accumulation in cardiac tissue. On ECHO, there may be increased LV wall thickness, which tends to be concentric. There may also be a binary appearance of endocardial border due to Gb3 endomyocardial deposition, which is non-specific to this condition. RVH has been noted in up to a third of AFD patients. Ejection fraction is usually well preserved but LV diastolic dysfunction is common. Tissue Doppler imaging (TDI) tends to be affected even before the development of LVH and should be used to assess for early cardiac involvement (5). On CMR, there may be LGE especially on the basal posteroinferior LV wall, which typically spares the subendocardium. LGE has been associated with a lack of LV mass regression with enzyme replacement therapy.

 

A short PR interval occurs in 40% of patients. This is due to an accelerated AV conduction and is reversible with enzyme replacement therapy. Other abnormalities include bradycardia (1^st, 2^nd or 3^rd degree block), bundle branch block, chronotropic incompetence, atrial arrhythmias and ventricular arrhythmias.

 

There is aortic and mitral valve thickening and regurgitation due to valvular deposition of Gb3 resulting in fibrosis and calcification. Mild aortic root dilatation has also been reported.

 

Half the AFD patients report angina although the majority have normal coronary angiograms. Possible explanations for angina symptoms include thickening of blood vessel walls due to Gb3 deposition, endothelial dysfunction, reduced coronary flow reserve and increased myocardial oxygen demand due to increased LV mass.

 

Diagnosis in men can be made by measuring blood level of a-galactosidase activity, which is low or absent. However, in females, gene sequencing is preferred as they can have normal enzyme activity. Other diagnostic options include Gb3 concentration in urine/plasma and renal/cardiac biopsy.

 

 

Patients should be referred to specialist centres for treatment and monitoring of AFD. It is also very important to screen family members.

 

Recombinant a-galactosidase A has been available in Europe since 2001. Two intravenous preparations are available: agalsidase a and agalsidase b. There is evidence that ERT decreases cardiac mass, improves LV function, decreases frequency of pain crises, improves pulmonary and GI symptoms, increases sweating, improves hearing and sensation and slows down renal deterioration. There is also more benefit when ERT is started at milder degrees of LVH and before the development of severe renal impairment (1, 6).

Currently, there is no reliable biochemical marker to monitor the effectiveness of ERT in treated patients. There are ongoing trials using pharmacological chaperones and substrate inhibitors to increase the residual a-galactosidase A activity in patients with AFD.

 

Patients with angina should be treated with conventional anti-anginals although one must be cautious as beta-blockers and calcium-channel blockers may exacerbate bradycardia. In LV dysfunction, ACE inhibitors or ARBs should be prescribed and CRT could be used to improve dyssynchrony. Patients in AF/flutter need to be considered for warfarin and sotalol therapy. Amiodarone should not be used as first line therapy for AF as it may interfere further with lysosomal metabolism. Symptomatic bradycardia requires a pacemaker and an ICD for VT (5).  

 

In summary, AFD is a multi-system disorder that varies in age of onset, severity and rate of progression that should be considered especially in patients with early onset renal impairment, stroke or heart disease in the absence of traditional risk factors.

 

1. Zarate YA, Hopkin RJ. Fabry's disease. Lancet. 2008 Oct 18;372(9647):1427-35.

2. Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006 Jul;79(1):31-40.

3. Elliott P, Baker R, Pasquale F, Quarta G, Ebrahim H, Mehta AB, et al. Prevalence of Anderson-Fabry disease in patients with hypertrophic cardiomyopathy: the European Anderson-Fabry Disease survey. Heart. 2011 Dec;97(23):1957-60.

4. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004 Mar;34(3):236-42.

5. O'Mahony C, Elliott P. Anderson-Fabry disease and the heart. Prog Cardiovasc Dis. 2010 Jan-Feb;52(4):326-35.

6. Schiffmann R, Kopp JB, Austin HA, 3rd, Sabnis S, Moore DF, Weibel T, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001 Jun 6;285(21):2743-9.