CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 1, January/February 2011
38
AFRICA
Review Article
Cardiac abnormalities in Anderson-Fabry disease and
Fabry’s cardiomyopathy
RP MORRISSEY, KJ PHILIP, ER SCHWARZ
Summary
Fabry’s disease is an X-linked lysosomal storage disease
most often associated with renal dysfunction and death
due to renal failure in patients’ fourth and fifth decades of
life. However, cardiac manifestations including arrhythmias,
angina and heart failure are common and probably under-
recognised. Furthermore, Fabry’s disease is now recognised
as also affecting female carriers, who manifest signs later
than males. A variant of Fabry’s has been identified that
only affects cardiac tissue, which presents as an unexplained
hypertrophy of the left ventricle in middle-aged patients,
possibly with women more affected than men.
Given that epidemiological studies report a prevalence of
Fabry’s cardiomyopathy among middle-aged patients with
cardiac hypertrophy to be anywhere from one to 12%, it
is reasonable to screen these patients for alpha-galactosi-
dase A deficiency. Although mortality data is lacking from
randomised, controlled trials of galactosidase replacement
therapy, there are some reports of improvement in cardiac
endpoints. Therefore patients with known Fabry’s disease
should be screened early for cardiac involvement, as treat-
ment benefit may not be seen once cardiac fibrosis has
developed.
Keywords:
Fabry’s, Anderson-Fabry, left ventricular hypertro-
phy, restrictive cardiomyopathy, tissue Doppler imaging, cardiac
MRI (CMR), late/delayed gadolinium enhancement
Submitted 4/8/09, accepted 13/8/09
Cardiovasc J Afr
2011;
22
: 38–44
Fabry’s disease is one of roughly 40 lysosomal storage disorders
that result in the accumulation of glycoproteins. Also called
Anderson-Fabry disease, Fabry’s is caused by mutations in the
GLA gene, which encodes alpha-galactosidase A, resulting
in accumulation of glycosphingolipids, specifically globotria-
oslyceramide, within the lysosomes.
1
This accumulation leads to
cellular dysfunction, particularly in the endothelium, resulting
in hypo-perfusion of tissues and further inflammation. The most
frequently involved organs include the kidneys, heart, peripheral
nerves and skin.
2
Although an X-linked condition, heterozygous
females as well as hemizygous males can be affected.
Anderson-Fabry disease, or angiokeratoma corporis diffusum,
was independently described by Johann Fabry in Germany and
William Anderson in England in 1898 in separate dermatology
journals.
3,4
However, it was not until 1963 when it was classified
as a storage disorder,
5
and 1967 when the enzymatic defect was
identified.
6
More recently, an atypical variant of Fabry’s, which
presents as cardiac hypertrophy in middle-aged adults has been
identified.
7
The incidence of Fabry’s disease is estimated to be 1:55 000
male births,
1
however, due to the constellation of presenting
symptoms as well as some mutations allowing limited alpha-
galactosidase A activity, the actual incidence of Fabry’s, includ-
ing atypical, sub-clinical or late-variant phenotypes is likely to be
much higher, even as high as 1:3 100 male births.
8
Manifestations of Fabry’s disease are directly related to accu-
mulated glycosphingolipids in tissues. Clinical symptoms usual-
ly present in childhood with painful neuropathy of the hands and
feet, nausea and abdominal pain.
2
Angiokeratomas, collections
of enlarged cutaneous capillaries, specifically of the trunk,
increase in number and size with age. Proteinuria and eventual
renal failure result from the accumulation of glycosphingolipids
in the tubular epithelial, glomerular and endothelial cells, result-
ing in both focal and diffuse glomerulosclerosis and microvas-
cular dysfunction. Males progress to renal failure by their fourth
decade and females by their fifth decade if untreated.
9
Transient ischaemic attacks and strokes are 12 times more
common than the general population in males between the ages
of 25 and 44.
2
Other neurological symptoms include decreased
hearing, anhydrosis, abnormal peripheral sensation, e.g. temper-
ature, pin-prick, and the neuropathic pain previously mentioned.
Corneal opacities can also develop, although these usually do not
affect vision. As will be discussed subsequently, manifestations
of cardiac involvement include palpitations, dyspnoea or angina,
usually secondary to an arrhythmia or myocardial hypertrophy.
Female ‘carriers’ or heterozygotes can also be affected
and more often have cardiac manifestations.
10
Signs of organ
dysfunction due to glycosphingolipid accumulation also present
later in women, with neurological features presenting at a mean
age of 16 years and cardiac and renal involvement manifesting
at mean ages of 33 and 37, respectively.
11
The mechanism by
which women are affected by this X-linked condition is most
often attributed to X-inactivation; however, this has been called
into question.
12,13
One group reports the median cumulative age of death as
Division of Cardiology, Department of Medicine, Cedars-
Sinai Medical Centre and David Geffen School of Medicine
at UCLA, Los Angeles, California, USA
RYAN P MORRISSEY, MD
KIRAN J PHILIP, MD
ERNST R SCHWARZ, MD, PhD, FESC, FACC, FSCAI, ernst.
