Regression in Kleefstra Syndrome

One of the most devastating aspects of Kleefstra Syndrome – and something KS parents fear the most – is regression, meaning the loss of developmental skills, including cognitive, language, motor, adaptive or self-help skills, typically occurring post puberty.

People with KS work extremely hard to make gains in those areas, so the possibility of suddenly losing them is terrifying – and heartbreaking when it happens.

Dr. Siddharth Srivastava (Dr. Sid) at the Kleefstra Syndrome Clinic at Boston Children’s Hospital has seen about 70 KS families, but says it’s difficult to pinpoint the prevalence of regression, in part, because people’s definitions of it vary. A KleefstraSyndrome.org survey in 2018 with 179 respondents reported 21% had experienced regression.

One family’s story

Julie and Ted Drake’s 17-year-old daughter Amber, who has KS, experienced a regression when she was 14.

Amber started experiencing a number of physical and psychological symptoms, including periods of psychosis and very abnormal eye movements. Doctors weren’t quite sure exactly what was causing her symptoms or how to treat them.

“It was absolutely awful,” Julie remembers. “We didn’t know what was happening to her.” Julie knew that a Kleefstra regression was a possibility, but felt like she was in “no man’s land” as doctors tried to figure out how to help Amber.

Amber underwent multiple EEGs to determine whether her eye movements were seizures or an autoimmune response caused by KS. Specialists at multiple hospitals were in contact with each other to monitor Amber’s progress, and were eventually able to rule out anti-NMDA receptor encephalitis and neuroblastoma as potential contributing causes.

Meanwhile, Amber was experiencing hallucinations and severe anxiety. “Because she’s mostly nonverbal, it was really hard to figure out what was going on with her,” Julie says. “It was horrible.”

Gradually, Amber did start to get better. But by February of that year, she still wasn’t quite back to her usual self, so her doctors decided to try a medication usually used to treat schizophrenia.

“She has continued to get better,” Julie says. “We still don’t know whether it was because of [the medication] or if she would’ve gotten better on her own.”

What causes regression?

Dr. Sid says there is not a clear-cut explanation of what causes regression.

“We have speculated about factors that may be implicated, such as having a specific genotype, the presence of seizures or EEG abnormalities, or hormonal fluctuations or changes, but those are just hypotheses and they have not yet been tested sufficiently.

“I think the things we should study more are: one, genotype; two, sex –male/females –; three, presence of neurodevelopmental diagnoses such as autism; and four, presence of neurological diagnoses such as epilepsy,” said Dr. Sid. “I wonder if those four factors may be related one way or the other to regression? We need to collect more data and better understand it.”

Sleep and regression

Dr. Sid said regression in KS often begins with significant sleep issues.

“When people describe regression, they’re often referring to a cluster or sequence of events that can include insomnia that can last for days on end that is proceeded by neuropsychiatric issues including – but not limited to – catatonia, psychosis (which is hearing things or seeing things that are not there), worsening OCD or new emergent OCD, worsening mania or new mania symptoms, worsening agitation and aggression – followed by a decline or loss of developmental skills.”

The Translational Neuroscience Center at Boston Children’s has received a grant for a study of KS patients titled, “A sleep-associated neurodevelopmental collapse” to determine if there is an interface between sleep and neurodevelopment. More specifically, researchers are trying to determine if a deletion or mutation of EHMT1 disrupts circadian rhythm. The study has begun and is still enrolling patients.

“It’s curious that in prototypical regression with Kleefstra Syndrome, it starts off with striking insomnia,” said Dr. Sid. “A body has a natural circadian rhythm which regulates what time we go to sleep, what time we wake up – and what if there’s some sort of disruption to that internal clock that sets off the cascade of events that leads to this? If we can better understand what’s going on mechanistically, can we actually intervene and do something about it before it leads to regression?”

Treating regression

Currently if a KS patient appears to be entering a regression phase, Dr. Sid typically takes the following steps.

“First step is I usually do a workup to screen for medical, inflammatory, infectious, and other causes that can precipitate this. Specifically, a workup can include things like an MRI of the brain, an EEG to look for evidence of seizure activity, blood work to look for any inflammatory states, autoimmune conditions that can present like this, specifically, autoimmune encephalitis. I also look for any kind of hormonal fluctuations or dysregulation, specifically thyroid hormone changes.

“The second thing is if there is true psychosis – meaning hallucinations (hearing things, seeing things that are not there) – then I think there could be a rationale for considering use of certain medications such as the antipsychotic drug Olanzapine which has been utilized in Kleefstra Syndrome, though there needs to be more research studying it. If there isn’t psychosis per se, then teasing apart other aspects of the neuropsychiatric issues determines what might be the best treatment plan.”

Reasons for hope

Despite the remaining mysteries surrounding regression in KS, Dr. Sid is hopeful.

“I’ve seen families who’ve had regression and recover from it – recover to their baseline,” said Dr. Sid. “I’m hopeful as well because there’s a lot of work in the scientific community these days with our group and others trying to better understand this really devastating symptom as part of this broader condition. I’m hopeful that one day we’ll not just be able to understand it more – but actually do something about it and have more precise treatments and targeted therapies that may even prevent this in the first place.”

As for Amber, she continues to make progress with her verbal speech since her regression a few years ago.

“We have been very excited that she has been able to put some new words together that she could not before,” said Julie. “She is very motivated to use her voice and loves going to speech therapy. She always tries her hardest when it comes to working on her sounds. We are most proud of Amber for her perseverance to try to talk, get her needs met and do the things she enjoys.”

Amber is currently enjoying her senior year of high school where she is a cheerleader. She also does a dance class at another high school and she loves basketball, so she just joined a Special Olympics team.

Julie’s advice to other KS families regarding regression is, “Get established with a psychiatrist and neurologist, if you aren’t already, while your child is young or first diagnosed so that if it does happen you aren’t on a year-long wait for an appointment or your only option is the emergency room.

“If your loved one is going through a period of psychosis or regression reach out to Dr. Sid and the Boston Children’s Hospital Kleefstra Clinic to help come up with a plan for treatment. Even if you live in another state and cannot get an actual appointment a physician-to-physician consult could be beneficial.

“Also, to prevent regression from happening or stop it we need to know as much as possible about KS. Families can help the KS community by contributing to the Ciitizen natural history study, doing the surveys for Rare-X/Global Genes and joining research studies that are being conducted around the world.”