FABRY DISEASE
Fabry disease
(Anderson-Fabry disease) is a rare disease caused by a deficiency in the enzyme
ceramide trihexosidase (α-galactosidase A). Fabry disease is also known by its
alternative descriptive name, angiokeratoma corporis diffusum. It is inherited
in an X-linked recessive pattern and is classified as a lysosomal storage
disease. The defect in this enzyme causes a lack of proper metabolism of
globotriaosylceramide (ceramide trihexoside) and accumulation of this lipid in
various tissues throughout the body. Fabry disease affects the skin, kidneys,
cardiovascular system, eye, and neurological system. There is no known cure,
but advances in enzyme replacement therapy have shown promising results. Males
are more severely affected; females can be affected to varying degrees or can
act as carriers of the disease. Fabry disease has been estimated to occur in 1
of every 50,000 males. There is an increase in the mortality rate, with the
average age at death for a man with classic Fabry disease being 40 years.
Clinical Findings: The clinical
manifestations of Fabry disease have a slow onset during childhood; the average
age at onset is 5 to 6 years. Acroparesthesias are the initial presenting
symptoms in most children. Patients have severe pain in the hands and feet that
is episodic in nature and can last from minutes to hours or, in extreme cases,
days. The pain is often described as a burning sensation. Episodes of stress
can induce the acroparesthesias. This is accompanied by bouts of hypohidrosis
or, less commonly, anhidrosis. This inability to sweat properly may lead to
heat exhaustion and heat intolerance. Patients also eventually develop varying
degrees of hearing loss.
The
cutaneous findings consist of numerous angio- keratomas in unusual locations.
These fine, red, hyper- keratotic papules occur on the trunk and lower
extremities and are almost always located between the umbilicus and the knees.
The number of angiokeratomas continues to increase with time, eventually
reaching hundreds to thousands. The mucous membranes may also be involved with
angiokeratomas. Presentation of a child or a young adult with multiple angio- keratomas
should prompt the clinician to consider the diagnosis of Fabry disease and to
search for any other symptoms consistent with the disease. If the diagnosis of
Fabry disease is made, patients should be referred to a specialty center that
cares for these patients.
The most
characteristic ocular finding is that of cornea verticillata. This is a
whorl-like corneal opacity that can be observed only by slit-lamp examination.
They do not impede vision.
With
time, patients begin to develop progressive kidney disease. The earliest sign
is often asymptomatic proteinuria. Continued kidney damage eventually leads to
chronic renal failure and end-stage renal disease. Maltese cross shaped deposits are
often found in the urine sediment from patients with Fabry disease and
represent lipid accumulations. Cardiovascular changes can be seen and lead to
ischemic heart disease. Stroke and cerebral vascular disease are common and
cause a significant amount of mortality in these patients.
The
diagnosis of Fabry disease can be made by evaluating the plasma for
α-galactosidase A activity. Males with classic Fabry disease have less than 1% of
proper enzyme activity. DNA gene sequencing can be performed to isolate the
exact genetic defect. Genetic testing is the only reliable way to diagnosis
females with the disease, because female carriers do have some plasma enzyme
activity.
Treatment: Many medications can
be used to treat the acroparesthesias, and they typically come from the
antiseizure class of medications. Phenytoin and gabapentin are used to help control the frequency
and duration of the episodes. In the past, there were no specific therapies for
Fabry disease. End-stage renal disease often required kidney transplantation.
Enzyme replacement therapy has been available since 2003 and has begun to have
an impact on morbidity in these patients. Long-term studies are needed to make
any conclusions regarding their effects on mortality.
