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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.

SUBMITTER: Laney DA

PROVIDER: S-EPMC5740039 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The Impact of Fabry Disease on Reproductive Fitness.

Laney Dawn A DA Clarke Virginia V Foley Allison A Hall Eric W EW Gillespie Scott E SE Holida Myrl M Simmons Morgan M Wadley Alexandrea A

JIMD reports 20170322

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 fitnes ...[more]

PMID: 28324326

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Project description:Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.

Project description:IntroductionControl of the mosquito Aedes albopictus is confounded by its behavior due to females preferring to oviposition in small natural and artificial containers that are often difficult to remove or treat with insecticides. Autodissemination strategies utilizing highly potent insect growth regulators (IGRs) have emerged as promising tools for the control of this container-inhabiting species. The intended goal of autodissemination approaches is to use mosquitoes to self-deliver an IGR to these cryptic oviposition locations. Previous studies have focused on the efficacy of these approaches to impact natural populations, but little focus has been placed on the impacts on mosquitoes when exposed to non-lethal doses of IGRs similar to the levels they would be exposed to with autodissemination approaches.MethodsIn this study, the impact of non-lethal doses of pyriproxyfen (PPF) on the reproductive fitness of Ae. albopictus was investigated. Female and male Ae. albopictus mosquitoes were exposed to non-lethal doses of PPF and their fecundity and fertility were measured. To examine the impact of non-lethal doses of PPF, the expression of the ecdysone-regulated genes USP, HR3, and Vg, which are involved in vitellogenesis, was determined.ResultsOur results demonstrated a significant reduction in female fecundity and in the blood feeding and egg hatching rates upon exposure to non-lethal doses of PPF. Oocyte development was also delayed in PPF-treated females. Furthermore, exposure to non-lethal doses of PPF altered the expression of the genes involved in vitellogenesis, indicating disruption of hormonal regulation. Interestingly, PPF exposure also reduced the sperm production in males, suggesting a potential semi-sterilization effect.DiscussionThese findings suggest that non-lethal doses of PPF could enhance the efficacy of autodissemination approaches by impacting the reproductive fitness of both males and females. However, further research is needed to validate these laboratory findings in field settings and to assess their practical implications for vector control strategies.

Dataset Information

The Impact of Fabry Disease on Reproductive Fitness.

Publications

The Impact of Fabry Disease on Reproductive Fitness.

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