Fragile X marks the spot. (Part I in a series)
It occurs to me that I’ve never actually told The Boy’s story, and therefore a story of my family, from the molecular level.
That story begins at the far end of the human genome, at the 23rd pair of chromosomes, where X, as always, marks the spot.
Fragile X — it’s the most common heritable form of mental retardation and the most common known cause of autism. If autism’s boat is being buffeted by the storms of controversy and debate, Fragile X has found safe harbor from the high winds. Because Fragile X is unerringly genetic, its diagnosis unambiguous amidst the bluster of potential causes for the majority of autism cases. Fragile X is a mutation on the X chromosome that delays development, impairs cognition, and can cause a range of health problems and, of course, autism.
In all the turbulence of the autism debate, where no one can agree, where no compass reliably points north, still it is accepted that Fragile X is the cause of some five percent of autism cases. And consequently no one talks about it. Fragile X is practically lost in that cove away from the storm. Because while the cause of the Fragile X mutation is not clear, its effects are well-documented. How uninteresting. So, ironically, being understood makes it unknown.
The human genome is a vast galaxy of traits — the three billion base-pairs that make up the coiling snakes of its double helix spell out some thirty-thousand genes. Those base-pairs are chemical letters that get arranged along the DNA in order to spell out instructions for the organism. One gene is an arrangement of hundreds or thousands of these letters that, when the code is translated, produce proteins that make up every cell and tissue and organ in the living thing.
Our story takes us out to the distant neighborhoods of the X sex chromosome, the yin to the Y chromosome’s yang. At the end of the X there is a base-pair sequence of chemical letters, CGG (cytosine-guanine-guanine), that in most people repeats anywhere from five to 55 times. But with the Fragile X mutation, that sequence can repeat hundreds of times, with a whole range of effects. Fifty-five to two-hundred repeats of the sequence causes a premutation, which can manifest in dementia, tremors, premature menopause. If that CGG sequence repeats more than two-hundred times, that person has the full Fragile X mutation. This is the Boy’s address.
All those repeats on the long arm of the X chromosome make it look dangerously bent, and thus the mysterious and strangely elegant name for a little-known mutation — Fragile X.
And those repeats effectively shut off a gene that produces a protein which acts as a kind of wrangler (in the parlance of our Wild Western genome) for other proteins. These other proteins control the growth of brain cells; when that wrangler gene doesn’t get produced, the other proteins run wild, the varmints: brain cells develop all wrong and developmental hijinks ensue.
From such forges was born The Boy.
A part of my life has been lived with the recognition of a genetic bullet dodged — my mother had two X’s — one Fragile, one not. These were apportioned to The Boy and me. My CGG repeats are within the normal range; his are beyond the frontier of the two-hundred mark.
I live on the lee side of a coin toss that would have changed everything; he lives on the flip side, everything changed. I’d once thought that these were odds that couldn’t be challenged.
But treatments that get that wrangler protein working again are being tested on people now, with exciting effects. Even as the storm rages outside the safe port, research is happening with Fragile X that could affect autism and perhaps other neurological diseases. It’s entirely possible that Fragile X research could find a way to contain the high winds of the autism debate, maybe even still them.
Nov 10th, 2009 7:30pm
