Doctors said the boy was suffering from teenage psychosis. What he really had was a rare genetic condition.

By Jamie Talan,

When he was 15, Adrian Batson walked into the family room one morning with a glazed look. He was always chipper, but on that day he stared into the mirror and asked, “Mom, why is there a skeleton in the mirror?” Tonya Batson, his mother, thought he was joking. “Oh, Adrian, there’s no skeleton in the mirror.”

His gaze pierced the glass. He looked down at his hands. “Mom, why do my arms and my legs look like a skeleton?”

She looked up hoping to see a smirk and then hear his hearty laugh, but there was nothing. He was silent. He just stared. She would come to know this look well.

For the next year, Adrian was in and out of the psychiatric wing at the University of Kansas and at a nearby private psychiatric facility, and no one could tell her why he was seeing things that were not there, and what was wrong with him. The last hospitalization that year led to a dangerous mix of antipsychotic drugs that landed him in the emergency room at Children’s Mercy Hospital in Kansas City.

Fortuitously, pediatric neurologist William Graf was on call that day and walked into the room where the teenager was moaning and his body would not stop shaking. Graf had already read the charts and studied his medical history. As he looked at Adrian, he noticed what all the other doctors had not: the boy’s prominent nose with squared-off nasal tip, low nasal bridge, small mouth, small chin, high-arched palate, small rounded ears and flat feet.

He turned to Adrian’s mother and grandmother. “I know what’s wrong with Adrian,” he said.

Adrian’s psychosis was actually a symptom of a genetic disease called velocardiofacial syndrome, or VCFS, Graf said. The boy’s slight physical anomalies were some of the 180 physical and behavioral features that have been described in the syndrome. One in 5,000 people are born missing a small piece of genetic material on chromosome 22. For most people, it is discovered at birth because of obvious heart and facial defects, but some, like Adrian, have very subtle signs. Graf immediately ordering a genetic test. It came back positive.

Discovering the cause

VCFS is a disorder that often goes undetected and misdiagnosed as a form of childhood schizophrenia, a diagnosis that can lead to years of mistreatment — as in Adrian’s case — or is sometimes never figured out.

Almost 45 years ago, Robert J. Shprintzen, a speech-language pathologist, first identified these children when he worked in a craniofacial program at Montefiore Medical Center in New York. There were a dozen children.

“You line them up and they look like brothers and sisters,” he said. Some people coined the term Shprintzen’s syndrome, but he liked the more descriptive velocardiofacial syndrome. He followed these 12 children as they grew up and was surprised when a third of them developed psychosis in early adolescence.

Graf trained under Shprintzen, and he became an expert in the syndrome. He and others who work with these patients believe that many children diagnosed with schizophrenia actually have VCFS. Graf had studied the missing piece on chromosome 22 and believed that it had something to do with dopamine, a brain chemical that is often abnormally high in psychosis. He conducted spinal taps in some of his patients to get samples of cerebrospinal fluid and looked for dopamine metabolites, a byproduct of dopamine. These patients had extraordinarily high levels of brain dopamine metabolites.

Graf had used a drug called Demser — its chemical name, metyrosine — successfully in a patient with a debilitating movement disorder that has also been linked to abnormal regulation of dopamine. Metyrosine had been used as far back as the 1960s to treat a rare adrenal tumor that caused excessive amounts of norepinephrine and epinephrine.

Like dopamine, these neurotransmitters are all catecholamines, and he took a gamble that the drug might also help get rid of the excessive dopamine in the brains of these young people with VCFS. He tried it in five patients in the throes of psychosis. While one person dropped out of the study, the other four showed dramatic improvement within two to three weeks.

Scientists who study the syndrome believe that the missing piece of the chromosome makes it difficult for the brain to balance its normal concentration of dopamine, and over time it builds up to toxic levels. Metyrosine is not an antipsychotic, and while many misdiagnosed VCFS patients receive prescriptions for psychoactive medicines, most don’t work and often can have serious side effects.

So far, the only solution

For many of them, metyrosine has become their only option to avoid hallucinations. The drug is used off-label and has not been federally approved for VCFS. Aton Pharma, the company that made the drug, was bought out by Valeant Pharmaceuticals in 2010. (The company was renamed Bausch Health Cos. in 2018.) Immediately, the drug was no longer available. Families and doctors pressed the company to restart production. The price tag ballooned from $1,000 a month to tens of thousands of dollars for a hundred pills, and the company set up a patient assistance program to help defray the high costs for people without insurance. Some patients have to take up to five tablets a day.

The drug is still often hard to find, and many families say that their children relapse into psychosis when they are not on the drug.

The company is working “to ensure that patients have access to our medicines when they need them,” said Lainie Keller, vice president of corporate communications for Bausch. “Through our patient assistance programs, eligible patients can receive our prescription products, including Demser, at no cost.”

Just wanting to be normal

Emily Cain, a 25-year-old woman who lives with her parents in New York, was diagnosed with VCFS at 7. She started experiencing psychosis as a young adult. She responds well to metyrosine, but the family said it has been a roller coaster trying to secure the drug.

“Every time we are running low, we fear another relapse if we can’t get the medication,” said Kevin Cain, her father. When they could not get the drug, their daughter would pull on her ears and scream all day and night.

Last May, Emily was without the medication for a month — and then again from September through December. The screaming and ear pulling returned with a vengeance only to stop within days when they finally were able to get the drug. But they were able to get only 100 pills, and her father was recently calling pharmacies around the country to buy more.

For Adrian, metyrosine also has changed everything.

After Graf prescribed the medication and his system cleared of the antipsychotics he had been prescribed, Adrian’s hallucinations quickly subsided, and Adrian was able to return to high school.

But as with Emily, Adrian, now 28, struggles when he runs out of the drug and can’t refill it immediately.

“When we can’t get the medicine, he relapses and it is ugly,” Tonya Batson said. “He can get physical. He’s never been the same since the symptoms he experienced on the antipsychotics when he was a teenager.”

When he’s well, Adrian likes to play piano and guitar and listen to jazz. “I know he just wants to be normal,” she said. He “often asks to return to his life before this disease.”

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On the hunt for VCFS
In 1974, when Robert Shprintzen was a young speech pathologist at Montefiore Medical Center, he was introduced to a dozen children with similar presentations: cleft palates, heart problems, immune disorders and developmental delays that would ultimately lead to learning disabilities. He published a paper describing this new syndrome.
Other scientists had chronicled children with identical features — DiGeorge syndrome, for instance — but ultimately it was agreed that they were talking about the same syndrome and kids. They called it velocardiofacial syndrome, or VCFS.
Almost two decades later, Shprintzen got a call from parents who said that their son, with VCFS, had been diagnosed with childhood schizophrenia. Then, another call came through. And then a third — this one from a family who had been in his initial study with his first dozen patients. He cleaned off his desk and got to work calling every other family in his original study.
These children were now in their teens and he was stunned when a third of them said that, out of the blue, their teenage child had begun having night terrors, anxiety, obsessive behaviors, paranoia and hallucinations. By this time, he had accumulated another hundred cases of young people diagnosed with VCFS in his files, and he started calling those families as well.
After he published this new finding in 1992, he got a call from Peter Scambler, a physician and geneticist at University College London whose career is focused on congenital malformations. He was studying babies with DiGeorge syndrome and asked Shprintzen to send blood samples of the children in his initial study for genetic testing. That is what allowed Scambler to identify a missing piece on chromosome 22q11.21 as the likely culprit. This finding garnered a lot of interest, in large part because it provided a possible genetic explanation for psychosis in people with schizophrenia.
It would be about seven years before scientists working on the Human Genome Project sequenced chromosome 22, which was later officially linked to genetic forms of schizophrenia. There have since been dozens of genes on many chromosomes associated with a risk for schizophrenia.
People with VCFS do not have schizophrenia, of course, and some doctors like to say it is a “unique form of schizophrenia,” said pediatric neurologist William Graf, who now works at the University of Connecticut. They have a genetic condition that results in hallucinations because of a build up of dopamine over time.
Understanding the details of this psychosis was extremely important to Shprintzen, who went on to establish the Virtual Center for VCFS, a charitable organization that analyzes cases at no cost.
The scientist, now retired from academia, continues to log cases into his database, which now includes detailed medical and personal histories of 1,400 VCFS patients.

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