Exon 7 Non Classical mutation. (October 2003)

The way I understand it is this: No, the V281L mutation is not found only in Ashkenazi Jews. However, of those who happen to have this mutation, a disproportionately large percentage happen to be Jews of Eastern European origin. (I’ll paste in a few references below.)

OF COURSE I don’t mind you asking where I get my information! In fact, I would caution you not to accept what anyone says at face value unless sources or references are given (except when something is obviously in the realm of "experience"). I do try to give sources as much as possible, but it can be time consuming to go back, find them, scroll to where the pertinent sections is, then cut and paste, etc......admittedly I often just dont have the time or get lazy! At the same time, I try not to state anything that sounds sort of factual, unless I am pretty certain I can back it up at a later time, if asked.

As for my interest in this whole thing: No, I don’t have a medical background. My interest is purely personal. When my son was first diagnosed, I was frustrated that I couldn’t find any information anywhere. But then I discovered the Internet. Finding that was like opening Pandora’s Box...LOL! I went crazy when I found the Pub-Med site......soooooo much information only a click away!! I have felt compelled to read and research as much as possible since then.

I think I am also "driven" to do so because the first year of my son’s treatment was nothing if not a wild roller coaster ride. We changed doctors, then changed back again; also added, subtracted, and changed medication countless numbers of times. I saw my son undergo a drastic personality change twice during that period. I was certain he was going to end up either in a mental institution or in jail when he grew up. The doctors were telling us vastly different things.......in order to figure out what was going on, who to believe, and how to make the best decisions for my son so that we could move forward, I HAD to understand what was going on. So, it was also pure, unadulterated panic and desperation that "drove" me to it!

I am fortunate that there is a medical library at a top university relatively close by. Sometimes abstracts don’t give you the full story, so if I really want to see the full length version of something, I can copy it from the medical journals there. I don’t go very often, but when I do, I will spend a number of hours and copy as many relevant articles as I can by scanning the bibliographies. I have been able to gather more than a hundred articles that way.

I am also fortunate that we have a great peds endo who is willing to fill in the gaps. For e.g. in the area of genetics, I was curious what all the weird letters and numbers stood for in the names of the different mutation, e.g. "V281L." So, I simply asked him! However, his answer only made sense because I had read enough about the topic ahead of time to understand what he was talking about.

I feel that learning about anything is a many-layered process. It’s not always possible to get it all right or "get" ALL of it, the first time around. I guess all we can do is keep plugging on......Anyway, hope that answers your question! Now you probably know more about me than you really cared to know! (Next time I’ll tell you how the tea leaf reader fit into all this, when I had just about given up all hope....LOL!!)

Val-281 $->$ Leu (V281L). V281L occurs in all or nearly all patientswith nonclassic 21-hydroxylase deficiency who carry the HLAhaplotype B14;DR1, an association that is presumably due toa founder effect (see Section VI.J) (206). In certain populations(such as Jews of Eastern European origin) this is a very commongenetic polymorphism with a gene frequency of more than 10%(191, 192); in contrast, direct molecular screening of normal newbornsin New Zealand yielded a carrier frequency of 2% (195). Overall,approximately 70% of all nonclassic alleles carry the V281L mutation(210, 334)..........

High frequency of nonclassical steroid 21-hydroxylase deficiency.

Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI.

Department of Pediatrics, New York Hospital-Cornell Medical Center, New York 10021, USA.

Nonclassical steroid 21-hydroxylase deficiency is an autosomal recessive disorder that is defined by clinical and hormonal criteria that distinguishes it from the classical 21-hydroxylase deficiency. No estimates of the gene frequency of nonclassical 21-hydroxylase deficiency, also called attenuated, late-onset, acquired, and cryptic adrenal hyperplasia, have been published thus far. Here, we have used HLA-B genotype data in families containing multiple members affected with nonclassical 21-hydroxylase deficiency together with the results of quantitative hormonal tests to arrive at estimates of gene and disease frequencies for this disorder. We found nonclassical 21-hydroxylase deficiency to be a far more common disorder than classical 21-hydroxylase deficiency, which occurs in 1/8,000 births. The prevalence of the disease in Ashkenazi Jews was 3.7%; in Hispanics, 1.9%; in Yugoslavs, 1.6%; in Italians, 0.3%; and in the diverse Caucasian population, 0.1%. The gene for nonclassical 21-hydroxylase deficiency is in genetic linkage disequilibrium with HLA-B14 in Ashkenazi Jews, Hispanics, and Italians, but not in Yugoslavs or in a diverse, non-Jewish, Caucasian group. The penetrance of nonclassical 21-hydroxylase deficiency gene in the HLA-B14 containing haplotypes was incomplete. Thus, nonclassical 21-hydroxylase deficiency is probably the most frequent autosomal recessive genetic disorder in man and is especially frequent in Ashkenazi Jews, Hispanics, Italians, and Yugoslavs.

PMID: 9556656 [PubMed - indexed for MEDLINE]