A Guide for Women Living with Fabry Disease WOMEN LIVING WITH FABRY DISEASE WOMEN LIVING WITH FABRY DISEASE

Women often place a greater women with a family history of priority on the health of their this progressive, potentially life- family than their own personal threatening disease to be tested. health. If you are a woman If you have Fabry disease and living with Fabry disease, it is experience symptoms, speak to especially important that you your doctor about appropriate care for yourself first so that you medical care. are able to care for your family. This booklet explains the signs You may have been told for years and symptoms that women with that you are “only a carrier” Fabry disease may experience, or you may feel your disease based on recent medical is not as bad as your son’s or research. It also explains why your father’s, for example. But those signs and symptoms are as the understanding of Fabry variable and may not be the disease improves, the concept same in all women with Fabry of female “carriers” is evolving. disease. We now know that females who inherit the altered gene are affected by Fabry disease and can experience life-threatening symptoms. It is important for

Wang et al. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 2007;9:34-45.

“Advocating for oneself is not easy when it comes to Fabry “When we first started going to meetings disease. I have had to talk to several employers about it, doctors and listening to different doctors talk about who don’t know about it. And my softball coach. When we’d Fabry disease, we were literally written off. get out in the heat, he’d be saying, ‘run laps’. And I’m doing I had a doctor tell me, “You’re just a carrier. what I can, but I’m overheating because I’m not sweating very You don’t have it.” I said, “Baloney, I do have it much, and my hands and feet are on fire. And he just could not and I do have symptoms.” Today, it’s not “carrier” understand that at all. I hated it. But you do what you can to get anymore. You do have the disease. You have more your point across. And if they don’t believe you, you just move support. They will listen to you .” –Jody on.” –Jessica

1 FEMALES AND FABRY DISEASE

Fabry disease is an inherited disorder another, more than they vary among What is Fabry disease? that was once thought to affect only males. They range from mild to severe, Fabry disease is an inherited disorder caused by an altered gene. A person who males. Females were called “carriers” may start later in life, and may affect inherits this gene is unable to produce enough of an essential called because it was believed that they different organ systems in different carried the gene for the disorder people. The effects of Fabry disease alpha-galactosidase A (al´-fă gă-lak´-tō-si-dās ā), or alpha-GAL. without developing symptoms. on an individual female depend on a According to a study in Australia*, number of factors. Alpha-GAL breaks down a fatty substance called Fabry disease affects an estimated 1 in If you know or suspect that there is a (glō´-bō-trī-ă-ō-sil-ser-a-mīd), or GL-3, so that it can be removed. Since a 117,000 live births, so for many years, history of Fabry disease in your family, person with Fabry disease does not produce enough active alpha-GAL, GL-3 is little clinical information was available or if you suspect you may have Fabry not removed, but instead builds up in the cells. about its effects on the body. disease, it is important to talk to your In the past 15 years, research on Fabry doctor or a genetic specialist and get Over many years, as GL-3 slowly builds up in the walls of blood vessels and disease has increased dramatically. tested. A genetic test can determine New research is demonstrating that whether you have Fabry disease. other tissues, it can cause more and more damage. Major organ systems females with Fabry disease do, in fact, Your doctor will provide you the involving the , , and brain may eventually not function properly, have a wide range of symptoms. These information needed to manage causing potentially life-threatening problems. symptoms vary from one female to your health. The most serious problems in Fabry disease usually occur in the fourth * Meikle PJ et al. JAMA. 1999;281:249-254 or fifth decade of life. However, signs and symptoms may appear much earlier. The earlier Fabry disease is recognized, the earlier disease management can begin. Remember that taking care of your health also means

nurturing your emotional well-being. Tap into a support

network, or talk to your friends, family, co-workers and

loved ones. You are not alone — there are other women

like you with Fabry disease, and support is available.

2 3 WHY DOES FABRY DISEASE AFFECT MALES AND FEMALES DIFFERENTLY?

To understand how Fabry disease Men who inherit the altered gene that affects males and females, it helps causes Fabry disease will have all the to have a basic understanding symptoms of Fabry disease. But it’s of chromosomes, genes, and a little different for women. Women inheritance patterns. who inherit the altered gene may or may not experience all the symptoms Different diseases are passed down of Fabry disease. in different ways. Fabry disease is considered an X-linked genetic Women (any daughters) may disease. This means that the altered experience only a few or all of the gene that causes Fabry disease is symptoms of Fabry disease. This holds on the X chromosome, which gets true no matter whether the daughter passed down from parent to child. inherited the disease from the father Chromosomes are in our cells and or the mother. contain our DNA. If a man with Fabry disease has children, any and all of his daughters will inherit the gene and will have Fabry disease. None of his sons will have the disease. If a woman with Fabry disease has children, she has a 50% risk (with each birth) of passing the altered gene to both sons and daughters. Any sons and daughters who inherit the gene X Marks the Spot: The altered gene will have Fabry disease. that causes Fabry disease is on the X chromosome.

A ected Father Non-A ected Mother Non-A ected Father A ected Mother Inheritance Pattern

XY XX XY XX When a male inherits an X chromosome with the altered gene, he produces little or no alpha-GAL, and he develops

XX XX XY XY symptoms of Fabry disease. A female has two X chromosomes,

XX XX XY XY 50-50 chance that 50-50 chance chance daughters will be a ected that sons will be a ected (50% risk) (50% risk) All daughters No sons so even if she has one altered gene, she has a second gene that will be a ected will be a ected (100% risk) (0% risk) can produce alpha-GAL. However, females often will experience When the father is affected, all of his When the mother is affected or has the daughters will have the altered gene. altered gene, she has a 50-50 chance symptoms of Fabry disease. This is because the amount of alpha- Daughters may experience only a (like the flip of a coin) with each birth few symptoms or many symptoms. of passing the altered gene on to her GAL a female produces depends on a process called X-inactivation. The affected father will not pass the sons and daughters. Daughters who have 4 gene on to any sons, and therefore, inherited the altered gene may experience 5 no sons will be affected. only a few symptoms or many symptoms. PROBLEMS ASSOCIATED WITH FABRY: INFO FROM THE FABRY REGISTRY

About the Fabry Registry The analysis highlighted in this section About X-Inactivation and The Fabry Registry is an includes disease data on 1,132 males, Why Fabry Disease is international database, sponsored 1,055 females. Depending on her Different for Women and administered by Sanofi X-inactivation pattern, a female’s Genzyme, that collects information symptoms may include: 14% of males (n = 156) had reached Why is it that women experience end-stage renal disease (ESRD), Fabry disease differently from men? on Fabry disease patients. Heart1 requiring dialysis or transplantation Why is it that each woman with Fabry The Fabry Registry has been Heart problems are reported to at an average age of 39 and 38 years, disease is different and may or may established in order to better be the most common serious respectively. A lower percentage of not have all the symptoms of the understand the progression and manifestation of Fabry disease in female patients than males had kidney disease? management of Fabry disease, as well as the different ways in which females who participated in the problems of any type. However, when females did have kidney problems, they The altered gene that causes Fabry Fabry disease affects men and Fabry Registry. Females with Fabry occurred at a similar or only slightly disease is on the X chromosome. women. disease reported heart problems higher age than reported in males. Women have two X chromosomes, almost as often as males with the whereas men only have one. For men What Fabry disease disease, although they were older Skin1 who have Fabry disease, their only X symptoms when these problems developed. A painless, purplish skin rash called affect females? chromosome is Heart problems observed included angiokeratomas were seen in about Some females with Fabry disease the one that has the altered gene. angina (constricting pain in the chest), 18% (n = 200 males; n = 188 females) of remain healthy throughout their And that X chromosome is in every irregular heartbeat, an enlarged left both male and female patients in the lives, while others experience the one of his cells. ventricle, and heart attack. Regular Fabry Registry. full range of disease symptoms. exams, including electrocardiography 1 But in women, the altered gene For most, symptoms occur later Gastrointestinal and echocardiography, are In the Fabry Registry, 21% (n = 226) of is only in one of the two X and are less severe than in males, recommended for women with Fabry females reported abdominal pain and chromosomes they have. In every cell but this is not always true. disease, because heart disease can 19% (n = 199) reported diarrhea; 13.4% only one of the two X chromosomes develop even when there are no (n = 152) of males reported abdominal has been activated – it may or may obvious symptoms. pain and 11.9% (n = 135) reported not be the one with the altered gene. diarrhea. This is a completely random process Cerebrovascular1 that occurs before birth. Only cells In the Fabry Registry, stroke was Eye2 that have an activated X chromosome reported by 4.2% of females (n = A distinctive pattern on the cornea that with the altered gene will be affected 44) and 6.7% of males (n = 76), at an typically does not affect vision, called by Fabry disease. average age of 44 and 40, respectively. corneal whorling or corneal verticillata Transient ischemic attack (TIA, have been reported in almost all males Since women can have symptoms of sometimes called a “mini stroke”) was with Fabry disease, and in 70% of Fabry disease to different extents, all actually more common among females, females. This pattern can only be seen women with the altered gene should and was reported by 3.9% of females (n with a slit lamp, an instrument used by be seen regularly by their doctors. = 41) and 1.7% of males (n = 19). eye doctors. We’ll talk more about this in the Quality of Life1 upcoming pages. Kidney1 Both males and females in the Fabry Many female patients in the Fabry Registry reported lower quality of life Registry reported experiencing than the general population, especially significant kidney problems, when they are in their mid 30s and demonstrated by (excess older. Quality of life is measured using protein in the urine) and reduced a widely accepted questionnaire called kidney function. In the Fabry Registry, the SF-36, which has been used to 19% of females (n = 121) had chronic evaluate quality of life in people with a kidney disease stage 3 or higher, wide range of chronic health conditions. compared to 34% of males (n = 207). 6 7 In addition, 2% of females (n = 23) and HOW IS FABRY DISEASE DIAGNOSED?

In males, a lack of alpha-GAL activity Where can I find support if I shows that they inherited the altered receive a positive diagnosis? gene. Males can usually be diagnosed Getting tested for Fabry disease can through a blood test that measures be emotionally stressful. Many people alpha-GAL enzyme activity. in families with Fabry disease have Females, however, can have normal already seen close relatives become to low-normal levels of alpha-GAL affected with the disorder. News that enzyme and still have Fabry disease. they actually carry the altered Since the X-inactivation pattern may gene can lead to depression and be different in different organs such as even despair. the heart or kidney, females may have Emotions elicited by test results can one or more severely affected organs produce changes in feelings among but still have nearly normal alpha- family members. Someone who is GAL in their blood. For females with carrying the altered gene may feel normal to low-normal alpha-GAL, a anger, while one who is not may feel genetic test is needed for an accurate guilt for not having a disease that diagnosis. afflicts a close relative. A parent may can confirm or rule feel guilty for passing the disease on out the presence of Fabry disease. A to a child. negative test can relieve uncertainty, These feelings are understandable. while a positive test can allow a If you are considering testing or person to pursue medical options. have received a positive diagnosis, Because Fabry disease is progressive, ask your doctor for help in finding early intervention is important. the support you need, or contact your Sanofi Genzyme Case Manager How should testing be handled at 800-745-4447 (option 3) or in Fabry families? genzymesupportservices.com for When one person in a family is assistance in finding support in diagnosed as having Fabry disease, your area. it is likely that others are also at risk. If you receive a positive diagnosis, a genetic specialist can help you determine who else in your family might be affected by Fabry disease “When I was a teenager, I knew that I could pass Fabry disease on if and who should consider testing. I had children, but I thought the only symptoms I would experience Sanofi Genzyme Patient Education Liaisons can help you better were that my hands and feet would hurt when I got a , understand the testing, genetic counseling, and disease management along those lines. But women can have more than just the mild options available to you and your symptoms. When my mother passed away, she’d had a stroke. She family. Contact Sanofi Genzyme at 800-745-4447 (option 3) or 617-768- had some , she had multiple heart problems. And, I 9000 (option 3) for more information. still think when she passed away they didn’t attribute all that to Fabry disease, but in my mind that’s what caused it.” —Kelly 8 9 WHAT SUPPORT IS AVAILABLE?

Recommended Sanofi Genzyme is committed to helping meet the needs of women and Medical Assessments families who are living with Fabry disease. As part of this commitment, we provide resources and information to help patients advocate for their Because Fabry disease is progressive — comprehensive care. meaning it can get worse over time — females with Fabry disease should have regular medical assessments in addition to yearly physical Please contact Sanofi Genzyme for: exams, even if they feel fine. • Patient resources and advocacy groups to help connect patients and their Since some of the symptoms of Fabry disease families to others living with Fabry disease may only be recognized through specific medical evaluations, it is important for females with Fabry • Resources regarding diagnostic testing and genetic counseling disease to have regular assessments with their • Fabry disease information and educational resources doctor — especially to monitor their heart, brain and kidney function. Talk to your doctor and • Personalized support from a Sanofi Genzyme Case Manager including helping ask your Sanofi Genzyme Case Manager for a you understand health insurance options and coordinating with your copy of the “Taking Better Control of Fabry Disease” booklet to learn more about healthcare providers these assessments. • For more information contact your Sanofi Genzyme Case Manager, 800-745-4447 (option 3) or genzymesupportservices.com

Sanofi Genzyme Patient & Caregiver Portal genzymesupportservices.com If you or a loved one is living with Fabry disease, managing your time “A lot of information and energy is important. The Patient & Caregiver Portal was developed

on Fabry disease says girls are just to provide you with the convenience of 24/7 online access to the personalized support and information you need. carriers, they will not have the disease.

And here I have my daughter with raging ,

burning hands and feet, not being able to move for

four or five days, missing school. It took a long time

to find someone who would listen, and it was very

frustrating. Her gym teacher thought she was just

lazy, you know, and she’s passing out from heat

exhaustion.” —Heather

10 11 WOMEN LIVING WITH FABRY DISEASE

Alpha-galactosidase A Enzyme X-inactivation (alpha-GAL) (al´-fă gă-lak´-tō-si-dās ā) A protein produced by the body A small structure in most cells acting A phenomenon in which one of two An enzyme that is ineffective, missing that acts to chemically change other as the chemical plant of the cell. X chromosomes in every cell of a or present in inadequate amounts substances. are involved in contain and make various female’s body is inactivated. The in people with Fabry disease. It is breaking down or chemically altering enzymes that digest or break down process of X-inactivation is random, normally found in the lysosomes. substances so that the body can use substances. In Fabry disease, GL-3 which helps account for variation in or excrete them. Enzymes are typically builds up in the lysosomes. the symptoms of females who carry Angiokeratomas named by adding an “—ase” to the end the Fabry disease gene on only one Dark-red to blue skin lesions, which of a word that describes the enzyme. Lysosomal storage disorder X chromosome. may be flat or slightly raised, that are A disease resulting from the storage usually found in the area below the Fabry disease or accumulation of material in X-linked disease waist and above the knees in patients A caused by a the lysosomes. Fabry disease is a A genetic disease in which the altered with Fabry disease. deficiency of the enzyme alpha- lysosomal storage disorder. gene is carried on the X chromosome. galactosidase A. Fabry disease is an X-linked disease. Carrier Protein A person who carries the gene for Gene The building blocks of cells involved a disease without experiencing A piece of DNA that codes for a in all essential life functions (for symptoms. particular substance. Each gene example: cell growth, energy occupies a specific location on a production, metabolism). Cerebrovascular chromosome, which defines a person’s Of or relating to the blood vessels that bodily makeup and function. Proteinuria supply the brain. Excessive protein in the urine. Genetic Chromosome Affecting or affected by genes Stroke A threadlike strand of DNA and (genetic disorder). A sudden loss of brain function caused protein in every plant and animal cell. by a blockage or rupture of a blood Chromosomes carry the genes that GL-3 vessel to the brain. define a person’s bodily makeup (for An abbreviation for example: hair and eye color, disease globotriaosylceramide. Whorling expression). A star burst pattern commonly Globotriaosylceramide found on the cornea of people with Cornea (glō´-bō-trī-ă-ō-sil-ser-a-mīd) One Fabry disease. The thin transparent outer covering of type of glycosphingolipid compound the eyeball. which accumulates in the blood vessel X chromosome walls of people with Fabry disease The sex chromosome associated with Corneal as a result of a deficiency in alpha- female characteristics. All females Of or relating to the cornea. galactosidase A. typically have two X chromosomes while males typically have only one DNA Glycosphingolipids X chromosome. An abbreviation for deoxyribonucleic Fatty substances. There are many acid, the storehouse of all hereditary different types of glycosphingolipids; characteristics. All chromosomes are in the case of Fabry disease, certain made up of genes, and genes are glycosphingolipids cannot be broken made of DNA. down, and thus accumulate, due to an 1. Wilcox W, Oliveira J, Hopkin R, Ortiz A, Banikazemi M, Feldt-Rasmussen U, et al. Females with Fabry disease enzyme deficiency. frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008;93(2):112-28.

2. Desnick R, Brady R. Fabry disease in childhood. J Pediatr 2004;144:S20-6. 12 13 AN ONGOING COMMITMENT

For more than 30 years, Sanofi Genzyme has been committed to researching and developing products for people living with lysosomal storage disorders such as Fabry disease. Providing comprehensive and confidential support services that address the unique needs of those living with Fabry disease is part of this ongoing commitment.

Connect with a Sanofi Genzyme Case Manager online: genzymesupportservices.com

fabrycommunity.com

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