Wednesday, March 07, 2012

Times Are Changing

When I first started reading medical journals (mostly focusing on chromosome disorders), I was about 14 years old. Now, I'm 22. Therefore, I have personally lived through almost 10 years of medical history. As such, I've recently noticed some changes.

The first thing is a change in the style of the journal articles. It used to be that (not counting common well-described conditions like Down Syndrome) the vast majority of articles about chromosome disorders were single case studies. In other words, a group of clinicians writing about a single patient they had, while reviewing other single case studies of individuals with overlapping chromosome disorders in hopes of delineating a phenotype.

Occasionally, you'd see a different style of study, where doctors screened a large number of patients selected for a certain trait or collection of traits (such as cognitive disability plus physical anomalies) and looked for chromosome disorders in all of them. Then they'd give a sparser description of several cases who were detected as having chromosome disorders, as well as providing statistical data on how common chromosome disorders are in a certain category of patients. This kind of study, in the past decade, has become more common, until now it's the most common kind of study into rare chromosome disorders.

Another shift is in the 'chromosomal phenotype'. Originally, the 'typical' child with a rare chromosome disorder was felt to be an individual with multiple congenital anomalies and moderate to profound cognitive impairment. However, our technology for detecting chromosome disorders is more fine-tuned, and we can now find very small copy number variants - and many of these conditions show a milder phenotype than this. It's been long known that some individuals with chromosome disorders have mild cognitive impairment, such as the higher end of the spectrum for Down Syndrome. But now many people with normal IQs are diagnosed with chromosome disorders as underlying causes of a myriad of conditions such as dyslexia, ADHD, schizophrenia, isolated epilepsy, even simple depression. The 'chromosomal phenotype' is a whole lot broader than people used to think, if you include the smallest chromosome disorders.

These copy number variants show another quirk, which used to be rare among chromosome disorders but is found increasingly more and more often. This is when the same chromosome disorder present in an affected child is found in an unaffected parent as well. It used to be assumed that this was just coincidence - the chromosome disorder was a benign variant and the kid had something else as well. But large statistical studies show that many of these conditions are more commonly found in disabled populations than in normal controls. Given the individual variability seen in such well-described conditions as Down Syndrome, this could reflect a spectrum where the higher functioning end is indistinguishable from normal. Furthermore, many affected individuals have several unrelated copy number variants, whereas their unaffected relatives more often have only one, suggesting that there may be an additive effect between different copy number variants.

Another change, which probably results from sequencing the human genome, is that nowadays doctors can say things like 'the following five genes are included in this deletion, and here are the biochemical pathways impacted by those genes'. This means that even if there's never been a report of that particular deletion (or duplication) before, they could give a reasonably educated guess as to what specific impact the condition will have. If one of the genes is expressed in heart tissue, for example, then the kid might have a heart defect. (This is in contrast to the overly pessimistic 'kid will be profoundly retarded and die in infancy' stock prognosis that often used to be given for rare chromosome disorders.) There's also a database of copy number variants, called DECIPHER, that helps doctors find out if this particular condition has been seen before.

And lastly, attitudes are shifting. I've seen several articles in medical journals about the societal issues around rare genetic disorders, such as whether trisomy 13 and 18 survivors really do have a poor quality of life, how people with Down Syndrome feel about prenatal screening, or what life is like for parents who reject prenatal diagnosis or termination. Doctors are starting to get that their implicit attitudes about disability impact on the kind of care they give to patients, and not necessarily in a good way. They can be amusingly (and depressingly) naive at times, but they really are starting to get it.

I've seen a slice of history, and overall, I think I like what I'm seeing.


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