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 3rd
or 4th decade.
Figure 1. Angiokeratoma cutaneous lesions
Cardiac disease in AFD
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 (1st, 2nd or 3rd degree block),
bundle branch block, chronotropic incompetence, atrial arrhythmias and
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
Coronary artery disease
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.
Enzyme replacement therapy (ERT)
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.
Cardiac specific therapy
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.
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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
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
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