PCDH19 FLE causes severe drug-resistant epilepsy as well as a spectrum of developmental, intellectual, and behavioral problems in girls and women. PCDH19 FLE can occur de novo or can occur within families passed from women to their daughters or asymptomatic sons or from carrier fathers to daughters.
The most defining symptom in PCDH19 are the seizures. They tend to be extremely resistant to drug therapies and come in clusters that occur over regular intervals (once every week, month, or number of months). The seizures tend to onset in infancy or very early childhood, and, often, the early seizures are accompanied with severe apnea. In fact, many of the early seizures are confused with episodes of choking or aspiration. Over time the girls with PCDH19 tend to exhibit multiple seizure types including general clonic tonic, atonic, complex partial, myoclonic, and absence.
The girls with PCDH19 also exhibit behavioral problems. They tend to be spirited, willful, and fearless...they also seem to have friendly, smiling personalities when they are feeling good. When they are not doing well, they can be aggressive. Many exhibit autism, autistic features, obsessive-compulsive behaviors, anxiety. They also tend to have marked issues with sleep disturbance and difficulty falling asleep.
They also have a wide spectrum of developmental delays. Some are delayed from infancy while others regress with seizure onset. Some do not experience delays. Many exhibit some degree of speech delay or difficulty. Many show some signs of mild hypotonia and many general delays in motor and motor planning skills. There are two cases of girls with severe hypotonia who require feeding tubes (Esmé is one of these cases). Some, but not all, of the girls also experience a spectrum of cognitive delays, intellectual disability, and learning disorders.
PCDH19 FLE is diagnosed via genetic testing. A variety of mutations of PCDH19 (on the X chromosome) can cause the symptoms of PCDH19.
There is no cure for PCDH19 FLE. The girls are treated with a wide variety of anticonvulsants with varying degrees of success. No one medication seems to be particularly helpful in preventing seizures in this population. Some relief may be offered by Vagal Nerve Stimulators. The girls are also treated for the various behavioral symptoms.
The Cute Syndrome raises funds for PCDH19 FLE (also on Facebook)
Insieme per la Ricerca PCDH19 – ONLUS is an Italian organization that raises money for PCDH19 research
Dr. Jack Parent at the University of Michigan researches PCDH19
The International Ion Channel Epilepsy Patient Registry
Esmé and the Cute Syndrome
The Symptoms of PCDH19
Our baby was born in early 2011. Before we knew her, before we gave her a name, it was clear that something was wrong. She wasn't breathing well or making much noise and she was very floppy...and she was swept away into a special portion of the nursery. In her first hours our birth team worked to transfer Esmé to another hospital where she could be treated in a Neonatal Intensive Care Unit (and to discharge her mother), we hoped it would be a quick stay--that it would be "nothing." But as the days in the NICU went by it was clear that Esmé struggled with low tone and with feeding difficulties...and that the doctors suspected she had some sort of genetic condition.
In the first few months home with Esmé she struggled to eat or gain any weight. She was so little and so very weak. Holding her felt like holding a rag doll: light and floppy. But from her first moments she was so intensely alive. Her eyes were loving and communicative, her smile brilliant. She couldn't hold up her head, but she could direct a room. Her reflux was unlike anything I could have imagined. She would vomit unspeakable amounts of food and shudder in pain afterward, sweating through her clothes, crying in her tiny voice with a permanently wrinkled forehead.
And, strangely, she purred...all the time. In retrospect, this should have clued someone in, but her doctors seemed unconcerned. The only person who knew it was a problem was the speech therapist who started seeing Esmé through Early Intervention...to this day she remains one of the most loyal and attentive members of Esmé's medical team.
Unfortunately, at three and a half months Esmé developed severe chemical (aspiration) pneumonia and went into cardiac and respiratory arrest due to ongoing aspiration (when food goes into your lungs). Thankfully, with the help of Esmé's aunt we got her to the ER just in time. She received chest compression and was resuscitated by an amazing team of doctors and nurses. She spent two weeks in the Pediatric ICU, a portion of that time she was on a ventilator. While there she received surgery to place an abdominal feeding tube (g tube) and an anti-reflux surgical stomach wrap (fundoplication) in order to prevent her from aspirating while eating by mouth and preventing reflux and vomiting.
Unfortunately, within a month of this surgery Esmé was able to vomit again, having destroyed her fundoplication by constant retching induced by an allergy to her formula and irritation from the fundoplication. We were able to help her retching by starting on a blenderized diet, but the fundoplication coming apart created a herniated portion of her stomach to sit above the diaphragm, in her chest cavity, and had the unfortunate side-effect of increasing her reflux, retching, vomiting, and discomfort.
At 8 months Esmé had what we are fairly certain was her first seizure...
We were told, however, based on our description of the event and a normal 30 minute EEG, that it was not a seizure.
Several months later, the day after Christmas 2011, when Esmé was 11 months old, she had several "spells" in which she stopped breathing, shook, turned blue, and then appeared to recovery quickly, but sleepily. We called 911 and, although she looked good when they got to us, she had another "spell" in the ER: stiffening, turning blue, elevated heart rate, and desaturation. By the time she was admitted to the Pediatric Intensive Care, she seemed fine. A day of EEG showed nothing problematic, and we were told she had neurological reflux and discharged.
A week later she had ten "spells" in one day. We put her in the car and drove her to Boston Children's Hospital. Again she had one "spell" in front of hospital staff--everyone agreed that these looked a lot like seizures. The EEG was, again, essentially unremarkable.
Over the next months things continued like this: Esmé would have spells about once a week. The spells looked like seizures, but EEG after EEG was normal, even when she had a spell while connected. Fortunately we had a doctor at the time who stuck it out with us. She said: If it looks like a seizure, it's probably a seizure. We tried medications, but they either made Esmé sick or they did nothing. All the while she kept having between three and ten seizures in a cluster every week or so...like clockwork...which we were told was VERY unusual.
Finally one year after her first seizure, weeks of EEG monitoring and seven medications later, Esmé finally had a seizure on EEG that was large enough to read. And then she had another one. And just like that we had definitive proof of what we (and the medical team that knew Esmé well) had known all along: Esmé was having seizures. They were just very deep and difficult to pick up...and Ezzy really wouldn't have it any other way than to keep everyone guessing for awhile.
Several months after that we were finally given our first genetic diagnosis of PCDH19 Female Limited Epilepsy. Esmé is one of approximately 100 known diagnosed cases of PCDH19 FLE. Admittedly this was a great relief and extraordinarily devastating. It was especially difficult to swallow since we were also told that PCDH19 FLE would explain her drug resistant epilepsy and aspects of her developmental delay, but that the known presentations of the disorder do not include low tone and the feeding issues Esmé has had. This means that she may have a second disorder.
Over the years we have had more than one medical professional say that Esmé is the lowest tone child they have ever held or worked with.
When I say low tone, which is also referred to as hypotonia, I am not describing her strength. Esmé has be remarkably strong (although she does tire quickly). She can fight off the efforts to hold her still for medical procedures with startling power. What low tone refers to is her involuntary muscles. It means that if you extend her muscles beyond what they should do, she doesn't contract in resistance automatically. It means that she refluxes like crazy and doesn't have the coordination to swallow easily or safely. It means she cannot produce a large variety of sounds. It means that her joints slide out of place. It means that she can find herself in a full split with her feet facing the wrong direction.
In a more global sense, Esmé's hypotonia has significantly delayed her physical milestones. She was unable to hold up her head until she was a year old. At two she was still unable to sit without support. She uses a gait trainer and other adaptive equipment to help her gain independent mobility.
It does not appear as though Esmé's low tone would be explained by her diagnosis of PCDH19 Female Limited Epilepsy. However, as more cases of PCDH19 FLE are identified, it may prove to be on the spectrum of the disorder. In the meanwhile, we continue our search to identify another disorder and/or genetic mutation that may be contruibuting to Esmé's struggles.
Our story of getting diagnosed can feel like the stuff of an epic poem, with so many twists and turns and adventures. There is little doubt of who the hero of this story is. My daughter Esmé has battled with joyful determination through the various challenges that have appeared in her short 2 1/2 years. As a result, she has inspired everyone around her to be more loving, stronger, and more knowledgable than they ever thought possible.
Contributed by MOM Hillary Savoie- to follow Esmé you can find her on her webpage, blog or on Facebook