Download Fabry Disease

May 2003 Emory Genetics Newsletter FAX
What is Your Diagnosis?
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Chief Complaint - 41 y.o. Caucasian male presents with the following history:
• Severe fatigue
• Episodic sharp pains in elbows and knees, so severe at times patient
reports "he cannot function"
• Proteinuria
• Serum creatinine of 1.6 mg/dl
• Intolerance to heat; patient claims he does not sweat
• Dark, reddish, slightly raised lesion in groin area
Past Medical History - Patient reports burning sensations in hands and feet as a child,
brought on by fever or exercise.
Current Medications - 10 mg Lisinopril qd for proteinuria.
Family History - See pedigree. Parents do not have known relatives in common.
Ethnicity: Ashkenazi Jewish
After reviewing this
information, answer the
questions below,
before reading the
answer on page 2.
46
Kidney transplant at age 44;
43
41
Hx of fatigue, proteinuria,
"irritable bowel syndrome",
What is Your Diagnosis?
hx of pains in hands/feet in
childhood; hearing loss, just and hearing loss
will feature one genetic
had heart surgery
case per month, to test
your knowledge of clinical
genetics. We hope you find
these cases interesting and 1. Your diagnosis for the proband is:
A)
Systemic Lupus Erythematosis (SLE)
educational. Questions or
B)
Raynaud's Syndrome
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C)
D)
E)
F)
G)
Fabry Disease
Gaucher Disease, Type I
Hypertrophic Cardiomyopathy
End-Stage Renal Failure
Alport syndrome
2. Which of the following would you order on your patient:
A)
Kidney biopsy
B)
Enzyme analysis
Visit Emory Genetics
C)
DNA test
on the web:
D)
Rheumatology evaluation
• www.geneticslab.emory.edu
• www.emoryhealthcare.
org/genetics
3. What is the most likely inheritance pattern of the disorder in your
patient's family?
A)
Autosomal Recessive
B)
Autosomal Dominant (one of the parents has gonadal mosaicism)
C)
X-linked Recessive (your patient's sister is a carrier, but due to Xchromosome inactivation, is symptomatic)
D)
Mitochondrial
continued
May 2003 Emory Genetics Newsletter FAX
If you answered C) for questions 1 & 3, and B) for question 2,
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congratulations! You have mastered this month's Genetic Challenge!
Lab Tests Ordered:
• Enzyme assay for alpha-galactosidase A (α-GAL A) revealed an enzyme level in leukocytes of 4 nmoles/hr/protein
(normal range 55-126)
• DNA sequencing of the α-GAL A gene detected a mutation in the coding region
• EKG showed inverted T waves, left ventricular hypertrophy (LVH) and bradycardia
Diagnosis/Impression:
Fabry disease with loss of kidney function and cardiac manifestations. Patient's brother and sister are most likely affected by
Fabry disease.
Plan:
1. Treat Fabry disease with Fabrazyme® enzyme replacement therapy at 1 mg/kg/2 weeks.
2. Obtain baseline labs (24 hour urine/creatinine clearance), echocardiogram, exercise tolerance test, and MRI if
neurological exam is abnormal.
3. Monitor kidney, cardiac, and neurological function at regular intervals.
4. Identify male and female family members at-risk to be affected by Fabry disease. Offer diagnostic testing (enzyme
analysis and DNA testing) and evaluations.
Follow-up:
On April 24, 2003, the FDA approved the first treatment for patients with Fabry Disease (http://www.fda.gov/bbs/topics/
NEWS/2003/NEW00897.html). "The new product, called Fabrazyme (agalsidase beta), is a version of the human form of
the natural enzyme produced by recombinant DNA technology. It is given intravenously. This replacement of the missing
enzyme reduces a particular type of lipid (fat) accumulation in many types of cells, including blood vessels in the kidney
and other organs. It is believed likely that this reduction of fat deposition will prevent the development of life-threatening
organ damage and have a positive health effect on patients."
About Fabry Disease:
First described in 1898 by dermatologists Anderson and Fabry, Fabry disease should be considered in males and females with
acroparesthesias, angiokeratomas, hypohidrosis, characteristic corneal and lenticular opacities, stroke, left ventricular hypertrophy, or renal insufficiency of unknown etiology.
Fabry disease is a lysosomal storage disorder caused by a deficiency of a specific enzyme, alpha galactosidase A (α−GAL
A) and characterized by the deposition of globotriaosylceramide (GL-3) in the vascular endothelium. Fabry disease is inherited as an X-linked condition, and therefore affects males in a severe manner. However, studies have found that heterozygote
females who were once considered only "carriers" also can develop symptoms of Fabry disease that range from very mild to
very severe. An affected male will transmit the gene to each daughter, who will be heterozygous for Fabry disease. The
severity of symptoms in heterozygous females can vary greatly due to the different patterns of X-inactivation in each female.
In the pedigree on page 1, the sister (circle) should actually not be shaded in, but instead should have a 'dot' in the middle of the
circle to denote that she is heterozygous for an X-linked recessive condition. A significant number of heterozygote "carrier"
females develop symptoms and may progress to severe clinical disease. Some of the more common symptoms of Fabry
disease include:
• Acroparasthesia (episodic pain in the extremities often described as burning and/or sharp pain)
• Intolerance to extreme heat or cold
• Hypohidrosis (inability to sweat)
• Angiokeratomas (vascular cutaneous lesions) of the skin and groin area
• Corneal opacities and neurosensory hearing loss
• Postprandial pain or diarrhea, early satiety
• Renal disease leading to renal failure
• Hearing Loss
continued
page 2
• Myocardial ischemia or infarction
May 2003 Emory Genetics Newsletter FAX
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•
•
•
Concentric myocardial hypertrophy
Premature stroke
Other symptoms related to progressive microangiopathic obstructive failure of vascular beds in critical organ systems.
Clinical Overview
Although atypical variants with an intermediate presentation have been described, there are two major phenotypes found in
Fabry disease:
Classic Form - usually found in males with <1% alpha-galactosidase A (α−GAL A) activity who present in childhood (average
age at onset 4-8 years) with acroparesthesia, appearance of angiokeratoma, hypohydrosis, characteristic corneal and lenticular
opacities and proteinuria. Deterioration of renal function to end-stage renal disease usually occurs in the third to fifth decade
(average age of death 41 years). After renal transplant, most males then go on to have cardiovascular and or cerebrovascular
disease.
Cardiac Variant - males with 1-10% α−GAL A activity, usually presents in the sixth to eighth decades with LVH, myocardial
infarction, and/or cardiomyopathy. They usually do not develop end stage renal disease.
Heterozygous Females - can be asymptomatic, however, many manifest symptoms of the disease with increasing age and have
a decreased lifespan. It is unknown what percentage of heterozygote females exhibit symptoms of Fabry, but some studies
suggest it may be as high as 75%.
Because Fabry disease presents with such a wide and varied spectrum of symptoms, the disorder is often misdiagnosed or
diagnosed late, after end-organ damage such as renal failure, myocardial infarction or premature stroke has already ensued.
This disease is progressive with symptoms becoming more severe with increasing age in affected males and heterozygote
females; therefore, early diagnosis with prompt and appropriate treatment with enzyme replacement therapy may prevent
progression to irreversible damage of organs.
Diagnosis:
The least invasive and most cost-effective method of diagnosing Fabry disease in males is by α−GAL A activity in plasma,
leukocytes, and/or cultured cells. In females, this measurement is not reliable due to lyonization (the phenomenon by which
one X-chromosome is randomly inactivated in early embryonic cells, with fixed inactivation in all descendent cells first
described by geneticist, Mary Lyons), as some heterozygote females have normal α−GAL A activity. Clinical DNA testing (gene
sequencing) for the α−GAL A gene, called the GLA gene, located on Xq22, is available for females. Nearly all affected males
and females will have an identifiable mutation in the GLA gene. Over 300 mutations have been described in the GLA gene, with
most mutations "private" (i.e. they have been found in only a single family).
Pathophysiology:
All Fabry patients have a deficiency of the enzyme alpha-galactosidase A. This enzyme functions in the lysosomes of cells to
break down and remove glycolipids. Insufficient levels of α−GAL A cause the glycolipid globotriaosylceramide (GL-3; also
known as GB-3, ceramide trihexoside, or CTH), to accumulate in the lysosomes of virtually all body cells and tissues, particularly neurons, as well as renal, smooth muscle, cardiac, and vascular endothelial cells. Most of the GL-3 comes from cellular
components of degrading erythrocyte membranes. As GL-3 accumulates, the vascular endothelium both narrows and dilates
the blood vessels, causing ischemia and infarction that results in cell and organ damage.
Frequency:
The incidence of Fabry disease is approximately 1 in 40,000 males and 1 in 20,000 females. The disease is present in all ethnic,
racial, and demographic groups. This condition may be more common than originally estimated, as milder forms of Fabry
disease involving the renal system, cardiovascular system, or neurological system alone may be mistaken for conditions other
than Fabry.
page 3
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Treatment:
While there is no cure for Fabry disease at this time, enzyme replacement therapy is available. Fabrazyme® enzyme replacement therapy (agalsidase beta) reduces globotriaosylceramide (GL-3) deposition in the capillary endothelium of the kidney,
heart, and skin, and provides an exogenous source of α−GAL A in Fabry disease patients. A Fabry Registry has been established for patients to better understand the variability and progression of Fabry disease and to monitor the long-term treatment
effects of Fabrazyme® (www.fabryregistry.com).
References:
-www.genetests.org
-National Institute of Neurological Disorders and Stroke (www.ninds.nih.gov)
-Online Mendelian Inheritance in Man (OMIM) (www.ncbi.nlm.nih.gov)
If you have additional questions about Fabry disease or other lysosomal storage
disorders, call the Emory Lysosomal Storage Disease Center at (404)727-3930,
or fill out the information below, and fax this page to: FAX (404) 297-1517.
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