Anticipation in TNR expansions

[Phloston]

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Kaplan QBank says that expansion of the TNR in Fragile-X from pre-mutation to mutation length is much more likely to occur during oogenesis versus spermatogenesis.

For some reason, I had had the impression that the male, not the female, is more important for anticipatory-based expansions in Huntington's.

In Fragile-X, this has nothing to do with the fact that infected individuals tend to be males from female carriers.

Could someone please explain the mechanism regarding why or why not the male versus female is more likely to induce anticipation for TNR expansions?

Cheers,

 

[Myxedema]

Let's assume we have a proband female with mental ******ation due to fragile X syndrome. Her carrier mother and her mother's brother were also found the carry the mutation, but both of them are phenotypically normal. In this scenario, the mother's brother and the mother both carry premutations (~50-200 repeats), making the brother a carrier male. During the mother's oogenesis, trinucleotide repeats were amplified and this new amplified mutation was transmitted to the daughter. Now, the daughter has an X chromosome with full blown mutation. Full mutations can cause mental ******ation in females as well (30-50%).

 

[Phloston]

I'm not so sure that really addresses the question.

However I have generally appreciated your input, Myxoedema (your username stresses me out because we spell it "oedema" over here).

 

[Myxedema]

I'm not so sure that really addresses the question.

However I have generally appreciated your input, Myxoedema (your username stresses me out because we spell it "oedema" over here).

Yeah, but I felt you've already answered it yourself. In HD, expansions tend to occur during spermatogenesis, whereas in fragile X, expansions tend to occur during oogenesis. As to why, I don't think anybody know that yet.

Apart from that, fragile X syndrome has premutations, whereas HD has not. In HD, expansion of repeats causes anticipation. However, in fragile X syndrome, in addition to anticipation, premutations can cause additional diseases, such as premature ovarian failure in females and a Parkinson-like movement disorder with ataxia in males.

 

[da Vincis World]

In males X comes from mom....wouldn't it have to occur during oogenesis?

 

[Myxedema]

In males X comes from mom....wouldn't it have to occur during oogenesis?

Females can be effected in fragile X syndrome as well (i.e. female "carriers" can have mental ******ation). So it has some differences from other X-linked diseases.

Still, we don't know why this expansion tends to occur during oogenesis in females (I know it's tempting to say 'Because it's X-linked', but like I've said, this is no ordinary X-linked disease). We also don't know why nucleotide expansion occurs during spermatogenesis in HD.

 

[da Vincis World]

I am aware that women are affected. However in order for any male to be affected it must occur in oogenesis, so it is occurring in oogenesis at least 50% of the time.

As far as why.......way beyond the scope of this test.

 

[Phloston]

I actually wouldn't say this is beyond the scope of the Step1. I've been PMed by people who've mentioned some quite bizarre material having appeared on their tests.

As far as I'm aware, Huntington's DOES have premutations. When I worked in a genetics clinic during my undergrad, 35-39 was considered the premutation range on all official lab reports. If you mean, however, that no phenotypic manifestations occur within the premutation range in HD, that's different.

Fragile-X is also not considered X-linked recessive. I've seen it come up in a practice question somewhere as X-linked DOMINANT. This is because up to 50% of carrier females have a degree of mental ******ation (this latter part I learned from one of the explanations in Kaplan QBank). I'm therefore assuming that skewed X-inactivation may account for one of the mechanisms regarding why some females do not demonstrate the adverse phenotype.

 

[da Vincis World]

Ive taken the test and I agree that there are certainly some really tough/odd questions. The odds of you posting one of those questions and then getting that question on your actually test are extremely low.

The way you get those super odd questions correct is to have an excellent foundation and then being able to logically think through the problem.....not memorizing every esoteric detail.

 

[da Vincis World]

Phloston,
When are you taking this beast? By the detail of your questions you seem to be pretty far along in your studies.

 

[Myxedema]

I actually wouldn't say this is beyond the scope of the Step1. I've been PMed by people who've mentioned some quite bizarre material having appeared on their tests.

As far as I'm aware, Huntington's DOES have premutations. When I worked in a genetics clinic during my undergrad, 35-39 was considered the premutation range on all official lab reports. If you mean, however, that no phenotypic manifestations occur within the premutation range in HD, that's different.

Yes, I also mean premutations in fragile X causing premature ovarian failure and a neurodegenerative disorder.

Fragile-X is also not considered X-linked recessive. I've seen it come up in a practice question somewhere as X-linked DOMINANT. This is because up to 50% of carrier females have a degree of mental ******ation (this latter part I learned from one of the explanations in Kaplan QBank). I'm therefore assuming that skewed X-inactivation may account for one of the mechanisms regarding why some females do not demonstrate the adverse phenotype.

I'm frustrated with this as well. Some books, like Robbins, purposefully avoid calling it recessive/dominant and simply state: 'X-linked, predominantly affects males'. UpToDate does this as well. Other resources list it as "X-linked dominant with variable penetrance". Some even list it as "X-linked recessive" (Rubin's Pathology, 6th edition, p. 252). The same goes for OTC deficiency as well: Some list it as X-linked dominant, some as X-linked recessive.

 

[Phloston]

December 14th

 

[Phloston]

In general, I would say that any TNR is NOT a recessive disease, because they are perfect examples of dominant-negative effect mutations, NOT null-allele ones.