By Terry Jo V. Bichell, MPH, CNM (PhD candidate)

Nashville, TN February 26, 2012

I learned, while traveling in Nigeria long ago, that the child who follows twins is supposed to bring luck, or be lucky, or carry some kind of amazing happy blessing.  I remember thinking about that luckiness when I saw Louie’s squished newborn face, just after his cord was cut.

Louie was born in February, 1999, sweet, social and sleepless just like his big sisters.  We didn’t learn until a year later, when we sought a reason for his inability to sit up and crawl and babble like all the other playgroup babies, that he was born without a crucial piece of my 15th chromosome.  He was made from a good sperm and a bad egg.  Ironic, considering that the last two of his four older sisters had come from an egg so lucky, it split in half and made gorgeous, brilliant identical twins.

The egg that made Louie had a tiny chunk missing, while the sperm was perfectly intact.  The lack of that little piece of maternal DNA, specifically the lack of one particular gene, Ube3a, causes Angelman syndrome.  Since his diagnosis, I have dreamed of Ube3a, pondered Ube3a, cursed Ube3a and pleaded with Ube3a.  Why did that little piece fall out?  Was it my Fourth of July beer drinking in the month following his conception?  Was it my bad behavior as a high school and college student? Was it a karmic curse for selfish decisions as a young adult? Was it because my parents’ neighborhood in Texas had been regularly sprayed with DDT?  Was it because, as good Christians assured me unbidden, our family could uniquely handle a child with a severe disability, and we had been chosen for this task by a higher power?

It turns out that this section of the human genome is just a weak spot in our genetic code, a chunk that is prone to falling out, or rearranging itself . These genes fall out before or during conception without regard to age, substance abuse, socio-economic status, race, ethnicity, religion or sexual preference.   It is just bad luck.

When Louie was diagnosed with Angelman syndrome, we were told, with variable sensitivity, that he would have severe epilepsy and severe mental retardation, now referred to as an intellectual disability by “People-First” terminology.  We were told that he might never walk, he might never eat normally or toilet-train, he would be hyperactive, sleepless and a danger to himself during the long sleepless nights.  With good care, he would live a normal lifespan and, he would never speak a word.  It seemed to my husband and me to be pretty bad luck.

Or was it? My husband is a pediatric heart surgeon, and his patients are babies born with only half a heart, or hearts with a missing piece, or a twisted section, or a mismatched middle.  Usually, he fixes their enormous cardiac bad luck, and these delicate babies come out of the ICU to be pink and vibrant.  They grow up and play sports and come back to visit and shake his hand.

I never doubted that there would also be a way to fix the missing piece of Louie’s DNA.

Louie was lucky to be born a mere 2 years after brilliant scientists Art Beaudet and Joe Wagstaff had identified maternal Ube3a as the source of Angelman syndrome.  They had also found that the normal companion gene on the paternal 15th chromosome, was turned off, as it is in everyone.  All of us leave our father’s Ube3a to rest, using only our mother’s Ube3a to do what needs to be done.  So, Louie was missing the Ube3a that I should have given him, and his father’s Ube3a was just sitting there, perfectly good, but dormant.

It seemed possible, plausible, to be able to get that paternal Ube3a off the couch and into the kitchen.  All we needed to do was turn it on somehow, and maybe Louie would walk, eat, sleep well, and speak.

My husband and I used all our medical wherewithal to help the brilliant scientists move their ideas about awakening the paternal gene into clinical trials and real kids.  Despite all the best efforts, nothing worked.  The paternal Ube3a stayed a snooze.  I went back to school at the age of 50, to join the quest for the holy gene grail myself, as a PhD student in neuroscience, convinced that the cure lay almost visible, reachable, just over the next hump.  And it was.

In an amazing stroke of good fortune, two young scientists, Ed Weeber in Florida and Ben Philpot in North Carolina, joined the fray and independently went to work on the problem.  In December 2011, right before the holidays, both published papers.

The gentleman in North Carolina had designed one of those simply beautiful experiments that I can now appreciate as a neuroscience student.  He used dishes of cells from a genetically engineered mouse that would glow yellow only if the paternal Ube3a was turned on.  Then, he poured a selection of 2000 known neuroactive medications and compounds onto the cells and waited to see which ones would glow.  I imagine him grabbing the plate with one yellow well from a naive undergraduate student and shouting, “Eureka!”.  Or maybe he simply figured it was a mistake and sent the poor beleaguered student back to the lab to repeat the experiment until he was convinced by the evidence.  Amazingly, unexpectedly, one drug, a brain cancer drug, Topotecan, allowed the paternal Ube3a to activate, turning the cells yellow.  Philpot had found a way to cure Angelman syndrome.  The cure.

But what does it mean to cure a person with a developmental disability?   Hasn’t the brain developed in an abnormal way?  Many people with Angelman syndrome have microcephaly, small heads.  Doesn’t that mean that their brains haven’t grown enough?  Doesn’t that mean that the disorder is irreversible?

Not necessarily.  It is a question of structure versus function.  If the Angelman brain is built differently than the typical brain, then a cure might be farfetched.  Whole neural pathways would have to be unwound and rewound, channels filled in and re-dug, branches built where none had reached before.  Maybe not impossible to fix, but nigh.

On the other hand, if Angelman syndrome is a synaptic disease, and all the neurons are there but misconnecting, like diplomats without a translator, then maybe a cure could supply the missing ingredient and the neurons would jump into action. A few days before Philpot’s research came out just before Christmas 2011, Dr. Ed Weeber published a separate study on another strain of adult Angelman mice. Weeber delivered the Ube3a gene into the brains of these mice and Angelman behaviors normalized.  That’s right!  Full-grown mice with the mouse form of Angelman syndrome get better when you supply the gene they are missing. So, it isn’t structural.  It’s synaptic!

Weeber showed that Angelman syndrome can be reversed, and Philpot found the drug that can reverse it.  What luck!

Hold your breath.  There is no way to know if the drug Philpot identified will improve Angelman symptoms in humans until we try it in humans.  But, what all this means is that it is possible that sometime in the near future we could give Topotecan, or some other drug like it, to a kid with Angelman syndrome, maybe even a teenager, maybe even Louie, and reverse the symptoms.

What does that mean?  Will Louie lean forward and say, “Pass the salt, please.”?  Will he run and jump?   Will he dream?  Maybe he’ll tell us all the things that have been bothering him all this time, recount all the conversations we’ve had in front of him and the cusswords we’ve said to other drivers while he has been in the backseat, sweetly smiling.

Louie has lived 13 years in silence, coddled and catered to. Oh, we’ve worked him hard, taught him to sight-read flashcards, and communicate a bit through signs and an iPAD.  We’ve dragged him to swim classes and hippo therapy and every other technique that showed any promise.

He’s learned a lot all these years, but what about all the lessons he’s missed, things he hasn’t learned or understood, playmates and friends he’s never had, sports he’s never played?   Even in the most active and conscientious family, the life of an intellectually disabled non-verbal child is severely restricted.

Thankfully, smiling a lot and being happy is another well-known symptom of Angelman syndrome.  Will a “cure” cause Louie to be as anxious and crabby and irritable as the rest of us?

Does it matter? If Louie had been born with no legs, and a fantastic medical team had invented a form of artificial limbs that could be permanently implanted, we would have jumped to get him a pair.

If Louie had been born with half a heart, we would have sent him to a hotshot surgeon to manufacture the other half out of his own muscle and tissue.

If Louie had been born with the gene for Huntington’s disease and a drug was discovered that could stall the inexorable brain deterioration caused by the mutation, we wouldn’t hesitate to give it to him.

Strangely, people I know are having a very hard time with the idea of giving Louie a drug that might cure his mental retardation. Experts on developmental disabilities squirm, as if I am suggesting that we cure Louie’s ethnicity.  Educators continue to insist, as they always have, that pushing Louie to learn academic skills is a waste of time.  Friends balk, assuming that a brain disorder can’t really be “cured”, and that I am living in a state of rose-colored denial.

Other parents of children with Angelman syndrome take offense, stating that AS is not a ‘disease’, like diabetes or cancer.  How not?

It is perfectly acceptable to speak about a cure for cancer, knowing that there might be lasting effects of tumors even when they have been removed and that strong chemotherapy drugs might cause terrible side-effects.

But it is very very controversial to speak about a cure for the mental retardation, or intellectual disability, of Angelman syndrome.

I have been told not to use the irresponsible word, “cure”.  I have been told to say, instead, “very potent treatment”, because the word “cure” might lead naïve parents to assume that their children will actually jump up, play the piano or basketball, and get a driver’s license, and we don’t know what the drug will really do.

That is exactly the point.  We don’t know what the drug might do.

It might let Louie’s synapses suddenly kick in, make connections faster, remember ideas better, retrieve knowledge, move muscles.  And all of that might still not allow him to speak or stop his seizures, but it might allow him to “think stronger”, and perhaps that would be sufficient to call it a cure.

The brain is a part of our body, a simple organ. As anyone with treatable depression will tell you, treatment makes them feel more like themselves than they do when they are depressed..

A cure for depression would be a godsend.  Angelman syndrome, like depression or alcoholism is a brain disorder It seems to me more irresponsible, more lazy, more selfish, NOT to talk about a cure for Angelman syndrome, and face the inevitable side-effects and disappointments that come along with any brain drugs.

We have to wind our minds around the idea that mental retardation, at least the kind caused by Angelman syndrome, might be cured.  In our lifetimes.

We have to keep an open mind about what will happen in Louie’s mind when he gets the “very potent treatment”.  We have to continue to educate him as well as we can, in case he is building memory stores that can be unlocked someday.  We have to expose him to as many social situations as we can, in case he can learn to communicate well some day.  We have to prepare him to be cured.

Louie is not Angelman syndrome, he just has it, like other people have asthma or diabetes or alcoholism.  He will still be Louie without Angelman syndrome, or with more controlled Angelman syndrome.

He will still be Louie if he is less intellectually disabled.  And he will be incredibly lucky.