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I contacted Debra Johnson of the Fabry's orgaization and asked her if she could help us understand the differences between HCM and Fabrys. The gave me such a wonderful answer I have simply posted it here.
I wish to thank Debra for her prompt and through reply to my question.
Lisa
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I have been working on an answer to your question, “How can I tell if HCM is a manifestation of Fabry Disease?”
Diagnosing Fabry is not simple or straight forward. The manifestations can be quite variable. There are also documented cases of cardiac and renal variants. One example of a research article is called "An Atypical Variant of Fabry's Disease in Men with Left Ventricular Hypertrophy" can be found at http://content.nejm.org/cgi/content/short/333/5/288. Another example is "An atypical variant of Fabry's disease with manifestations confined to the myocardium." http://<a href="http://www.ncbi.nlm....=Abstract</a>.
For some patients obvious Fabry symptoms will be present. Fabry has characteristic dermatological finding called angiokeratomas. This is can cause a rash like appearance of small red to purple dots around the belly button and swim suite area. Sometimes they can be larger, slightly raised and almost wart like. The other outward sign is a particular eye finding seen by slit lamp exam. It is a corneal dystrophy (cornea verticillata); also vessel tortuosity can be apparent. Other symptoms such as hand and foot pain, lack of sweating, frequent GI problems and others can be an indicator. Some patients will have few or no obvious Fabry symptoms but most do.
For males the easiest way to diagnose Fabry disease is with an enzyme assay. They will typically show between 0-5% enzyme activity. With a male identified, the gene mutation analysis can identify the coding error in the enzyme genetic sequence responsible for Fabry disease. Then looking for that specific sequence can be used to identify female members of the family.
Historically females have been referred to as "carriers", this use is very misleading in Fabry disease. Many doctors are now acknowledging female "carriers" as patients who suffer from many of the debilitating effects of Fabry disease. To diagnose a female, usually looking for a family history, a male with Fabry is the quickest way. For females, an enzyme assay can be inconclusive. Females can have low enzyme levels in their blood and may not show symptoms, while other females can have near normal enzyme levels in their blood and still experience symptoms. Medical research has shown there is a definite connection between the enzyme and the disease; however, the exact mechanism is very complex. A renal biopsy showing an accumulation of abnormal glycoshinglipid is indicative of Fabry; however, the lack of such evidence does not preclude a diagnosis of Fabry. Please see one example of renal pathology slides for reference at http://<a href="http://www3.us.elsev...as37_4.htm</a>
Another reference about diagnosis can be found on the website called OMIM: Online Mendellian Inheritance of Man http://<a href="http://www.ncbi.nlm....?id=301500</a>
Kint (1970) showed that the activity of alpha-galactosidase is deficient in leukocytes of male patients with Fabry disease and that carrier females can be identified by this method. Moser (1983) considered the urinary trihexoside assay, described by Cable et al. (1982), to be the most reliable way to identify carriers of Fabry disease. Kirkilionis et al. (1991) described a Nova Scotia kindred known to contain 30 affected males and 50 possible female carriers. They found that there was no major alteration of the gene but that it was linked to the rarer allele (frequency = 0.20) of the polymorphic NcoI site located 3-prime to the gene. This helped carrier identification; all of 17 obligate carriers examined were identified, including 6 who were not identified as carriers by enzyme assay.
Another reference about Fabry disease can be found at http://genetest.org at http://genete...bry/index.html.
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There are links to recent research articles and support organizations on the website http://www.fabry.org.
General Information about Fabry Disease from the Fabry Support & Information Group
Fabry Disease:
Fabry disease results from abnormal deposits of a particular fatty substance (called globotriaosylcera-mide) in blood vessel walls throughout the body. The primary defect, which allows this to occur, is the inherited deficiency of the enzyme, alpha galactosidase A, which is normally responsible for the breakdown of globotriaosylceramide.
Metabolic Defect
The body continuously performs metabolic processes, which produce, recycle and remove vital compounds. In patients with Fabry disease one such common compound formed of three sugars and a fatty substance (globotriaosylceramide) does not get broken down due to the missing or non-functioning enzyme alpha galactosidase A. Sense this fatty compound (lipid) is not being broken down and removed it begins to accumulate. Thus, Fabry disease is often referred to as a "storage disorder" due to this abnormal accumulation. In patients with Fabry disease, this accumulation occurs primarily in the blood and in the walls of blood vessels. As the abnormal storage of this fatty compound increases with time, the channels of these vessels become narrowed, leading to decreased blood flow and decreased nourishment of the tissues normally supplied by these vessels. This abnormal process occurs in blood vessels throughout the body, particularly affecting vessels in the skin, kidneys, heart, brain and nervous system.
Disease Inheritance
Fabry disease is an inherited disorder. The defective gene is on the X-chromosome, which is one of the two chromosomes that determine an individual's sex. Females have two X chromosomes, one inherited from each of their parents. Males have one X chromosome inherited from their mother and one Y chromosome inherited from their father. A female with Fabry receive one X chromosome with a defective gene and one X chromosome with the normal gene, and thus often has some protection from the major manifestations of the disease. This is not always the case though as there is a high degree of variability in females. Males with Fabry disease receive only one abnormal X chromosome that contains the abnormal gene and thus express the disease.
All male and female children of an affected female have a 50% chance of inheriting the defective gene from their mother. If the father is the one carrying the Fabry gene all female children will inherit the defective gene and all male children will not. The inheritance pattern of Fabry disease is called X-linked inheritance. Fabry disease occurs in all ethnic groups. It is estimated that one person in 40,000 has Fabry disease.
Clinical Symptoms
Males
Typically, the disease begins in childhood with episodes of pain and burning sensations in the hands and feet. In addition, young patients often develop a spotted, dark red skin rash (angiokeratomas) seen most densely from the umbilicus to the knees, a decreased ability to perspire, and a characteristic change on the cornea of the eye which does not affect vision. The painful episodes may be brought on by exercise, fever, fatigue, stress, or change in weather conditions.
The disease is slowly progressive and symptoms of kidney, heart and/or neurologic involvement usually occur between the ages of 30 to 45. Many patients are first diagnosed when the accumulated storage material begins to affect kidney or heart function. Therefore, it is important to annually monitor kidney function by blood and urine tests because kidney disease is a major complication that can occur in affected males.
A common heart symptom in Fabry patients is mitral valve prolapse, which is a benign condition that is present in approximately 10% of the normal population. More serious, but rarer, complications of Fabry disease include heart disease and strokes.
Other symptoms may include varying degrees of abdominal discomfort; frequent bowel movements shortly after eating, joint pain, back pain primarily in the kidney region, or ringing of the ears (tinnitus).
Females
Females may show a wide range of clinical manifestations. Some individuals remain completely asymptomatic and have normal levels of a gal a while some are as severely affected as hemizygous males. This variability is most likely to be caused by random inactivation of one copy of the X-chromosome in each cell. The most common symptom of Fabry disease seen in heterozygous females is corneal dystrophy, which occurs in around 70% of females. Other symptoms that have been reported in females with Fabry disease include: angiokeratomas, acroparesthesias, anhidrosis, gastrointestinal disturbances, vascular lesions in the conjunctiva and retina, kidney disease, autonomic and other neurological complications such as tinnitus and vertigo, cardiovascular abnormalities, cerebrovascular abnormalities, fatigue. Women may often be misdiagnosed as having lupus or other conditions.
Children
Although the signs and symptoms of Fabry disease generally appear during childhood, the diagnosis may often be missed. The earliest symptoms of Fabry disease in children are usually pain and angiokeratomas. The pain may, however, be dismissed as 'growing pains', while angiokeratomas may be overlooked during a routine clinical examination, particularly if they are confined to locations such as the backs of the ears. Cardiac and renal involvement can also begin in childhood, thus early diagnosis and careful monitoring are necessary. Other symptoms include Hypohidrosis (inability to sweat), GI symptoms that mimic chronic inflammatory bowel disease, recurrent nausea and vomiting, vertigo, tinnitus, headaches, fevers.
Additional information can be found on the Fabry Support & Information Support Group web site
http://www.fabry.org.
I wish to thank Debra for her prompt and through reply to my question.
Lisa
******************************************
I have been working on an answer to your question, “How can I tell if HCM is a manifestation of Fabry Disease?”
Diagnosing Fabry is not simple or straight forward. The manifestations can be quite variable. There are also documented cases of cardiac and renal variants. One example of a research article is called "An Atypical Variant of Fabry's Disease in Men with Left Ventricular Hypertrophy" can be found at http://content.nejm.org/cgi/content/short/333/5/288. Another example is "An atypical variant of Fabry's disease with manifestations confined to the myocardium." http://<a href="http://www.ncbi.nlm....=Abstract</a>.
For some patients obvious Fabry symptoms will be present. Fabry has characteristic dermatological finding called angiokeratomas. This is can cause a rash like appearance of small red to purple dots around the belly button and swim suite area. Sometimes they can be larger, slightly raised and almost wart like. The other outward sign is a particular eye finding seen by slit lamp exam. It is a corneal dystrophy (cornea verticillata); also vessel tortuosity can be apparent. Other symptoms such as hand and foot pain, lack of sweating, frequent GI problems and others can be an indicator. Some patients will have few or no obvious Fabry symptoms but most do.
For males the easiest way to diagnose Fabry disease is with an enzyme assay. They will typically show between 0-5% enzyme activity. With a male identified, the gene mutation analysis can identify the coding error in the enzyme genetic sequence responsible for Fabry disease. Then looking for that specific sequence can be used to identify female members of the family.
Historically females have been referred to as "carriers", this use is very misleading in Fabry disease. Many doctors are now acknowledging female "carriers" as patients who suffer from many of the debilitating effects of Fabry disease. To diagnose a female, usually looking for a family history, a male with Fabry is the quickest way. For females, an enzyme assay can be inconclusive. Females can have low enzyme levels in their blood and may not show symptoms, while other females can have near normal enzyme levels in their blood and still experience symptoms. Medical research has shown there is a definite connection between the enzyme and the disease; however, the exact mechanism is very complex. A renal biopsy showing an accumulation of abnormal glycoshinglipid is indicative of Fabry; however, the lack of such evidence does not preclude a diagnosis of Fabry. Please see one example of renal pathology slides for reference at http://<a href="http://www3.us.elsev...as37_4.htm</a>
Another reference about diagnosis can be found on the website called OMIM: Online Mendellian Inheritance of Man http://<a href="http://www.ncbi.nlm....?id=301500</a>
Kint (1970) showed that the activity of alpha-galactosidase is deficient in leukocytes of male patients with Fabry disease and that carrier females can be identified by this method. Moser (1983) considered the urinary trihexoside assay, described by Cable et al. (1982), to be the most reliable way to identify carriers of Fabry disease. Kirkilionis et al. (1991) described a Nova Scotia kindred known to contain 30 affected males and 50 possible female carriers. They found that there was no major alteration of the gene but that it was linked to the rarer allele (frequency = 0.20) of the polymorphic NcoI site located 3-prime to the gene. This helped carrier identification; all of 17 obligate carriers examined were identified, including 6 who were not identified as carriers by enzyme assay.
Another reference about Fabry disease can be found at http://genetest.org at http://genete...bry/index.html.
----------------------------------------------------------------------------------------------------
There are links to recent research articles and support organizations on the website http://www.fabry.org.
General Information about Fabry Disease from the Fabry Support & Information Group
Fabry Disease:
Fabry disease results from abnormal deposits of a particular fatty substance (called globotriaosylcera-mide) in blood vessel walls throughout the body. The primary defect, which allows this to occur, is the inherited deficiency of the enzyme, alpha galactosidase A, which is normally responsible for the breakdown of globotriaosylceramide.
Metabolic Defect
The body continuously performs metabolic processes, which produce, recycle and remove vital compounds. In patients with Fabry disease one such common compound formed of three sugars and a fatty substance (globotriaosylceramide) does not get broken down due to the missing or non-functioning enzyme alpha galactosidase A. Sense this fatty compound (lipid) is not being broken down and removed it begins to accumulate. Thus, Fabry disease is often referred to as a "storage disorder" due to this abnormal accumulation. In patients with Fabry disease, this accumulation occurs primarily in the blood and in the walls of blood vessels. As the abnormal storage of this fatty compound increases with time, the channels of these vessels become narrowed, leading to decreased blood flow and decreased nourishment of the tissues normally supplied by these vessels. This abnormal process occurs in blood vessels throughout the body, particularly affecting vessels in the skin, kidneys, heart, brain and nervous system.
Disease Inheritance
Fabry disease is an inherited disorder. The defective gene is on the X-chromosome, which is one of the two chromosomes that determine an individual's sex. Females have two X chromosomes, one inherited from each of their parents. Males have one X chromosome inherited from their mother and one Y chromosome inherited from their father. A female with Fabry receive one X chromosome with a defective gene and one X chromosome with the normal gene, and thus often has some protection from the major manifestations of the disease. This is not always the case though as there is a high degree of variability in females. Males with Fabry disease receive only one abnormal X chromosome that contains the abnormal gene and thus express the disease.
All male and female children of an affected female have a 50% chance of inheriting the defective gene from their mother. If the father is the one carrying the Fabry gene all female children will inherit the defective gene and all male children will not. The inheritance pattern of Fabry disease is called X-linked inheritance. Fabry disease occurs in all ethnic groups. It is estimated that one person in 40,000 has Fabry disease.
Clinical Symptoms
Males
Typically, the disease begins in childhood with episodes of pain and burning sensations in the hands and feet. In addition, young patients often develop a spotted, dark red skin rash (angiokeratomas) seen most densely from the umbilicus to the knees, a decreased ability to perspire, and a characteristic change on the cornea of the eye which does not affect vision. The painful episodes may be brought on by exercise, fever, fatigue, stress, or change in weather conditions.
The disease is slowly progressive and symptoms of kidney, heart and/or neurologic involvement usually occur between the ages of 30 to 45. Many patients are first diagnosed when the accumulated storage material begins to affect kidney or heart function. Therefore, it is important to annually monitor kidney function by blood and urine tests because kidney disease is a major complication that can occur in affected males.
A common heart symptom in Fabry patients is mitral valve prolapse, which is a benign condition that is present in approximately 10% of the normal population. More serious, but rarer, complications of Fabry disease include heart disease and strokes.
Other symptoms may include varying degrees of abdominal discomfort; frequent bowel movements shortly after eating, joint pain, back pain primarily in the kidney region, or ringing of the ears (tinnitus).
Females
Females may show a wide range of clinical manifestations. Some individuals remain completely asymptomatic and have normal levels of a gal a while some are as severely affected as hemizygous males. This variability is most likely to be caused by random inactivation of one copy of the X-chromosome in each cell. The most common symptom of Fabry disease seen in heterozygous females is corneal dystrophy, which occurs in around 70% of females. Other symptoms that have been reported in females with Fabry disease include: angiokeratomas, acroparesthesias, anhidrosis, gastrointestinal disturbances, vascular lesions in the conjunctiva and retina, kidney disease, autonomic and other neurological complications such as tinnitus and vertigo, cardiovascular abnormalities, cerebrovascular abnormalities, fatigue. Women may often be misdiagnosed as having lupus or other conditions.
Children
Although the signs and symptoms of Fabry disease generally appear during childhood, the diagnosis may often be missed. The earliest symptoms of Fabry disease in children are usually pain and angiokeratomas. The pain may, however, be dismissed as 'growing pains', while angiokeratomas may be overlooked during a routine clinical examination, particularly if they are confined to locations such as the backs of the ears. Cardiac and renal involvement can also begin in childhood, thus early diagnosis and careful monitoring are necessary. Other symptoms include Hypohidrosis (inability to sweat), GI symptoms that mimic chronic inflammatory bowel disease, recurrent nausea and vomiting, vertigo, tinnitus, headaches, fevers.
Additional information can be found on the Fabry Support & Information Support Group web site
http://www.fabry.org.
For the 5% or so of HCM sufferers whose HCM is caused by Fabry, this approval is very good news indeed--for the first time, something can be done about all aspects of the disease, including the HCM and its attendant (at least in my case) debilitating symptoms. 
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