information - posted again for new members

[Guest guest]

Jeroen kindly prepared this information for us back in November.

I am posting it again as I think it will provide useful information for new member of the group.

Regards

Shireen

London, England

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From: jeroenkleinen, Sent: 11 November 2005 14:13

Hi everybody,I read the recent posts about type I and type II BPES and infertility. I noticed that there are a lot of questions and uncertainties. Maybe I can clarify one and other. I have a degree in medicine and although I am now specializing in psychiatry, I am familiar with general medicine matters. Moreover, recently I spoke with Dr. Debaere, who's a world expert on genetic research in BPES.First I'd like to explain something about genetics.

Humans have 46 chromosomes. We have 2 Sex chromosomes, XX (female) or XY (male), and 44 autosomal chromosomes. Each parent Passes 23 chromosomes (22 autosomal and 1 sex chromosome) so you get 23 chromosome "couples".Chromosomes consist of DNA. Specific regions on chromosomes are called genes. There are a lot of genes (eye-colour, hair-colour, ...etc).

In our cells there is a sophisticated system that can translate the information which is encoded in the DNA, the building material of genes, and form proteins. So a gene actually stands for a specific protein (like there is a gene for insulin). How do genetic disorders arise? Genetic disorders arise when there is a mutation (change) in the DNA within a specific gene region. This alters the gene and, thus, alters the protein which is formed. This is important. For example insulin which is different from normal insulin might not be able to lower blood sugar levels.

Once a genetic disorder has arisen, which can happen spontaneously, it can be passed from parents to children. Genetic disorders can be "dominant" or "recessive". When a genetic disorder is dominant only one of the two genes in the gene couple (the one from father or the one from mother) has to be altered to give rise to the disorder. When a genetic disorder is recessive both the father and the mother need to pass an altered gene to give rise to the disorder.What about BPES?

BPES is an autosomal dominant genetic disorder. The gene is called FOXL2 and is located on chromosome 3. Chromosome 3 is an autosomal chromosome and the fact that the disorder is dominant means that you only need to have one altered gene to get the disorder. The different types (I and II) of BPES were first described in 1983 (Zlotogora). Type I includes the four major features (blepharophimosis, ptosis, epicanthus inversus and telecanthus) and female infertility caused by premature ovarian failure (POF). Type II includes only the four major features.

The difference between Type I and II is the position on which the DNA, and thus the gene, is mutated (altered). There are several (at least 21) known mutations of the FOXL2 gene. Depending on the location these mutations give rise to a shortened protein or an extended protein. The ones that give rise to a shortened protein cause type I and the ones that give rise to an extended protein cause type II.

For some mutations it's not clear which type they cause. During a genetic investigation, which takes about three months, they try to find a known mutation to see if they are able to tell which type of BPES the affected person has.What about the management of POF?

Management of POF needs to address the two major medical issues: hormone replacement therapy (HRT) and infertility.HRT: Oestrogen and progesterone replacement therapy is usually indicated. No comparative data are available to guide estrogen use in young women as most studies on HRT involve post-menopausal women, but the advantages often outweigh the possible side-effects.Infertility: No effective treatment for infertility exists. Adoption and oocyte (egg) donation are among the available options. However, more recently there are some new therapies under investigation.

Ovarian tissue and oocyte cryopreservation (freezing in) hold promise for fertility preservation in the women most likely to undergo ovarian failure. Adolescent girls with BPES who have a risk of developing POF could be candidates for ovarian (not necessarily the complete ovary so it's not necessary to cause surgical menopause) cryopreservation. This cryopreserved ovarian tissue can be used in two ways: retransplanting and in vitro stimulation. The first live birth after retransplantation was reported in 2004 (this was not a woman with BPES). Note that these techniques are not (yet) applied on a large scale.Women with POF often reach menopause when they are 25-30 years old.

In the old days, when women conceived at a younger age, this was not necessarily a problem. Nowadays most women start a career and think of children at an older age which makes POF more of an issue.

Endocrinologic and gynecologic follow-up are advised in affected females in whom the BPES type is unknown or in whom BPES type I is suspected based on a positive family history or suggestive FOXL2 mutation.I myself had a blood sample taken one and a half month ago. We are planning to have more kids and we just want to know which type I have to be as prepared ad possible. I do not have the result yet. It takes about three months.I hope I was of any help. If some things are unclear please ask questions.Greetings,Jeroen.