The Impact of Fabry Disease on Reproductive Fitness

Abstract

Fabry disease (FD) is a pan-ethnic, X-linked, progressive lysosomal storage disorder caused by pathogenic mutations in the GLA gene. Published case reports and abstracts suggest that decreased reproductive fitness may occur in males with FD. In order to understand the impact of FD on reproductive fitness and increase the accuracy of reproductive genetic counseling, this study examines a large, multi-centered population of individuals with FD to determine if males have reduced reproductive fitness. Study data were collected on 376 patients through two, gender-specific surveys distributed across the United States and Canada. The number of biological live-born children among individuals with FD was compared to statistics from the general population. Information was also collected on reduced sperm count, depression, pain, use of assisted reproductive technology, and reproductive choice. On average, females affected by FD had more biological live-born children (1.8) than males affected by FD (1.1). However, males affected by FD had an increased mean number of biological children (1.1) compared to the mean number of biological children fathered by men in the United States (0.9). Sixteen of the 134 males with FD reported oligospermia, which suggests that an infertility work up may be indicated for males having difficulty impregnating their partners. In our large multicenter sample, males and females with FD do not exhibit reduced reproductive fitness; on average they have more biological children than the general population in the United States. This information should assist clinicians in providing accurate reproductive genetic counseling and treatment for individuals with FD.

Appendices

Summary

Males and females with Fabry disease do not exhibit reduced reproductive fitness; on average they have more biological children than the general population in the United States.

Compliance with Ethics Guidelines

Allison Foley, Myrl Holida, Scott Gillespie, Eric Hall, Morgan Simmons, Alexandrea Wadley, and Virginia Clark declare they have no conflicts of interest.

Dawn Laney consults for Genzyme and Shire, and is a study coordinator in clinical trials sponsored by Genzyme, Amicus, and Protalix. She has also received research funding from Alexion, Amicus, Genzyme, Pfizer, Retrophin, Shire, and Synageva. Grant funding to conduct this investigator initiated studies was provided through an educational grant from Genzyme, A Sanofi company. These activities are monitored and are in compliance with the conflict of interest policies at Emory University School of Medicine.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentations (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study. This chapter does not contain any studies with animal subjects performed by any of the authors.

Contributions

Planning of this study, oversight, data collection, analysis, and reporting of work were coordinated by Dawn Laney. Statistical analysis and manuscript authorship by Scott Gillespie and Eric Hall. Subject recruitment, data collection, and manuscript creation review by Alexandrea Wadley. Data analysis and manuscript review and editing by Morgan Simmons and Allison Foley. Subject recruitment and manuscript authorship/review by Myrl Holida and Virginia Clarke.

Appendix 1: FIT Survey Sample Questions. Questions Were Presented to Be Answered as Self-Response Multiple Choice, Yes or No, and Free Response Answers

FIT survey	Sample question asked
Males
Part 2. General Questions	“Do you have any biological children?” Yes: _____ Number of boys ____ Number of girls _____ No, but I have adopted children No, I do not have any children biological or adopted
	“Have you ever gotten one of your partners pregnant?”
	“Have you ever had difficulties getting your partner pregnant?”    Yes (please describe) __________________    No    I have never tried to make my partner pregnant
	“Have you ever experienced issues with infertility?”
	“Have you ever been used assisted reproductive technology?”    Yes, my partner took hormones to increase ovulation    Yes, we used a donor egg    Yes, we used a donor sperm    Yes we used in vitro fertilization    Yes, we used in vitro fertilization and preimplantation genetic diagnosis    No, we have never used assisted reproductive technology
Part 3. Medical History	“Have you ever experienced any of the following health issues?” Hypertension/High Blood pressure, beginning at age ___ Burning pain in your hands/feet, beginning at age ___ Fabry pain crises, beginning at age ___ Depression, beginning at age ___ Anxiety, beginning at age ___ Panic Attacks, beginning at age ___ Kidney failure, beginning at age ___ Liver disease, beginning at age ___ Erectile dysfunction, beginning at age ___ Low sperm count, beginning at age ____ No, none of the above.
	“Do you take any medications for high blood pressure?”    Yes, ______________ (medication) beginning at age ___________
	“Have you ever been treated for cancer or a tumor?”
	“Have you ever worked in a job that included frequent exposure to industrial chemical, pesticides, lead, heavy metals, or radiation/Xrays?”
Part 4. Family History	“Did you know that you had Fabry disease before you considered having children?”
	“If you did know that you had Fabry disease prior to having children, did having Fabry disease affect your decision to have children?”
	“Anything else about your reproductive history or having babies while living with Fabry disease that you think we should know?”
Females
Part 2. Medical History	“Have you ever experienced any of the following health issues?” Burning pain in your hands/feet, beginning at age ____ Depression, beginning at age ____ Kidney failure, beginning at age ____ Polycystic ovaries, beginning at age ___ Abnormal uterine shape Endometriosis, beginning at age ___ An STD such as herpes, which one? ___ Other chronic health issue(s) (other than Fabry disease) not mentioned above
Part 3. Reproductive History	“Have you ever been pregnant” If yes, number of times and how old were you during the first trimester of each? If no, have you ever tried to become pregnant?
	“At what age did you begin having your periods?”
	“Have you ever had difficulties getting pregnant?”    Yes (please describe _________)    No    I have never tried to become pregnant.
	“Have you ever had any concerns about your ability to have children?”
	“Have you ever experienced any issues with infertility?”
	“Have you ever been evaluated for infertility concerns?”
	“Have you ever been used assisted reproductive technology?”    Yes, I took hormones to increase ovulation    Yes, I used a donor egg    Yes, I used a donor sperm    Yes, I used in vitro fertilization    Yes, I used in vitro fertilization and preimplantation genetic diagnosis    No, I have never used assisted reproductive technology
	“Have you ever experienced menopause?”
Part 4. Pregnancy History	“How many times have you been pregnant?”
	“Have you ever had a miscarriage?”
	“Have you ever had an elective termination of a pregnancy?”
	“Have you ever had a termination of a pregnancy for medication reasons?”
	“How many children have you given birth to ___boys ___girls?”
	“Were any of your children stillborn or died soon after birth?”
	“Do you have any adopted children?”
Part 5. Family history	“Did you know that you had Fabry disease before having children?”
	If you did know that you had Fabry disease prior to having children, did having Fabry disease affect your decision to have children?

Appendix 2: Reproductive Decision-Making and Fabry Disease (Selection of Free Response Answers)

Impact reported on the reproductive decision-making process of the knowledge that they had Fabry disease	Patient quotes
No negative impact	“No, it <having Fabry disease> didn’t matter … My wife and I discussed Fabrys, and decided we wanted at least 2 children.”
	“No, not at all. My dad always told me he had enjoyed his life and was glad he was born and hated when his dad told him if he knew his boys would have Fabrys he wouldn’t have had them.”
	“No, but it has changed that decision for some of my family members. I figure my life, even though not easy, is worth it. So my kids if they got it would feel the same way. Some of my family have a harder time with that feeling.”
Mixed impact	“Yes, from age 18 I was certain I did not want children because I did not want the disease to continue. I was the youngest person in my family that had Fabry and the disease would end with me. My brother had two kids, but male, so I would be the last of it. But then I got married and I changed my mind and wanted children.”
Negative impact	“The treat<ment> is great for many reasons, but the pain from neuropathy is not controlled enough for me to be comfortable in having a child who could possibly go through the type of pain I did growing up.”
	“YES … I had a tubal ligation at age 24”
	“Once I knew I had Fabry it was sort of the final straw in deciding if we should have kids or not. I felt selfish possibly bringing a child into the world with Fabry. I know this doesn’t take into consideration all of the other facets of a child, and that if my mom had chosen that, then I wouldn’t be here. But for me I would feel so guilty watching a child suffer the symptoms of Fabry, knowing I chose that for them, in sense.”