Can discuss the genetics of CAH—specifically, how specific alterations affect clinical presentation, the pathophysiology of CAH, and its therapeutic implications?
It was known by the early 19 eighties that there were uh several different en enzymatic uh defects that uh could cause congenital adrenal hyperplasia. And when I say congenital adrenal hyperplasia, I'm referring to an inherited inability to uh synthesize uh cortisol. Uh owing to some sort of enzymatic uh defect. Cortisol is synthesized from uh cholesterol in five different enzymatic steps. I'm not going to uh air, draw the pathways uh here. Uh But suffice it to say that suffice it to say that uh uh that 90 plus percent of uh cases of ch are caused by 21 hydroxy deficiency, meaning an inability to add an oxygen atom onto the uh 21 position of uh of the steroid uh nucleus. Uh That is that is the next to last step. Uh going to cortisol uh biosynthesis uh with that particular enzymatic deficiency, not only can you not make cortisol uh but if the blockade is completed, you also cannot make uh aldosterone. And so those individuals uh have both cortisol and aldosterone deficiencies. Next, most common in, in, in most populations is 11 hydroxylase uh uh deficiency um where uh you can make cortisol but you can make, in fact, make high levels of uh of uh the oxy corticosterone, which has um salt retaining activity. And so that those individuals do not develop salt wasting. Uh They may uh in fact develop hypertension but in, but in general, it's very unusual for those kids to uh have problems with a lot of electrode abnormalities in the neonatal period. Uh Other forms are, are much rarer uh uh lipoid hyperplasia. Uh I I is a defect uh that involves uh importation of cholesterol and to Michon for, for, for the, the whole synthetic uh uh process and you can't make any steroids at all. Um That that condition is can also lead to uh potentially fatal electrode abdomen in the uh NATO period. And uh 70 hydroxy deficiency and free beta hydroxysteroid hydrox deficiency are all pretty rare and um on biochemical grounds, these uh forms have all been uh defined uh uh pretty much by the uh by the early 19 eighties. So, uh going back to 21 hydroxy deficiency, it was also recognized uh that uh this could be sent in uh forms of varying severity. And uh there were like three or four names that were given to this the most severe form where you cant make aldosterone is referred to as salt wasting uh disease. Uh If you uh had a severe enough enzymatic deficiency that you had high levels of androgens and females were were being virilize. But uh there's no problem with, with aldosterone synthesis that's referred to as simple viral disease, salt wasting of neural disease. Together are uh termed a classic cah. And then you have nonclassic ch which is a uh much milder form of the disease which um in many cases is in fact, entirely asymptomatic. Uh but in some uh leads to um signs of androgen uh excess uh developing during childhood or uh even something that's first detected in uh adults. But where uh you make adequate amounts of, of, of, of uh cortisol and all Doster and you don't have uh signs of uh of any kind of uh of hormone uh in sufficiency. And uh those were mild enough that they were detected, in fact, in family studies and in families where there are people with more severe disease, which is why it was uh intuited that uh that those were simply IIC variants. Uh they probably do do due to milder mutations. So, um it was uh first uh determined in around about 1980 that the disease was linked to um the HL A complex which is on the short arm of chromosome six and um controls of various tissue types. Uh It happened that there was a kid with, with cah, we needed a bone marrow transplant when they, when they looked at when they started doing family studies, as they realize there were several of the kids with cah and, and they were actually a identical and um then started looking at, at, at other families. It was, it was actually really very elegant uh classical uh uh genetics and immunobiology to, to figure that out. And um so I, so I had a very good uh linkage data. Uh meaning we knew where the gene was when we started uh trying to identify the gene uh specifically. Um And uh we also had at least one family where we were pretty sure that uh that patient had a homozygous deletion of the gene. Um because they were also missing several other proteins known to be in the a a complex. So it's very, it's wonderful. If you have, if you have a normal cell line, you have a cell line that, you know, that doesn't have a particular gene that makes it, you know, pretty easy to make sure that you have the right gene. Um the enzyme had been isolated um uh biochemically. And so we were able to uh replicate the enzyme purification and that gave us the uh the reagents to uh to be able to isolate uh the gene initially from a cow, uh adrenal glands. And uh we were then able to use that to show that. Yeah, it was the right gene, it was deleted in uh in uh patients uh in certain patients with, with, with cah and, and we could then go on to identify uh various mutations. Uh what that work showed was as we suspected that mild and, and, and more classic disease were, were in fact due to mutations, ovarian severity with uh salt wasted disease. Meaning that you had uh that you carried two mutations that basically, basically completely knocked the enzyme simple fertilizing disease. Meaning that you had at least one mutation that had maybe 1% of normal activity and a non plastic disease having at least one mutation that had, let's say, 20 to 50% of normal activity if you have one normal gene and you're just a carrier and then you're, then you're completely, uh, asymptomatic. So, uh, so we had all that worked out probably by the, uh, by the late 19 eighties.
