As reported by The Hartford Courant, August 31, 2004.

No Laughing Matter

By William Hathaway

Children with Angelman syndrome used to be called "happy puppets" because they tend to laugh with ease, flap their arms like marionettes and never talk.

Nearly 40 years after the syndrome was first described to skeptical doctors, scientists know what causes the rare and devastating developmental disorder. And by studying it, researchers have stumbled on new insights into a number of similar genetic diseases, as well as autism and epilepsy.

However, as with investigations of many rare disorders, understanding Angelman won't necessarily improve the lives of people who suffer from it.

By the time Nicole Clavette of Tolland was a year old, her mother, Donna Clavette, knew something was very wrong. Nicole almost never slept, her motor control was poor and she sometimes burst out laughing in the middle of the night.

Doctors told first-time parents Donna and Mark to relax, that Nicole just might be developmentally delayed. But by the time she was 2, her doctors were concerned, too. Her movements were jerky, and she had seizures, which led one doctor to suggest Nicole had cerebral palsy. But her puppet-like mannerisms and peculiar laughter led Donna Clavette to suspect something else.

It took more than a year of consultations with medical experts before tests confirmed that within Nicole's DNA, a segment of chromosome 15 was missing - the telltale genetic sign of most Angelman syndrome cases.

The mystery of Nicole's illness was solved, but scientists are still baffled by some aspects of the syndrome, which is estimated to afflict about one in 15,000 children born - about 250 new cases a year.

The syndrome was not recognized until 1965, when English physician Harry Angelman described peculiar behavioral abnormalities in three patients and hypothesized they were linked to a single but as-yet unnamed disease. The children with their flapping arms and laughter reminded Angelman of an oil painting by Gian Francesco Caroto, "Boy With a Puppet."

It wasn't until the early 1980s that Angelman was recognized as a specific disease. Angelman patients have a normal lifespan but require 24-hour care for the rest of their lives.

In about 70 percent of the cases, there is a missing genetic sequence on chromosome 15. Humans have 23 pairs of chromosomes on which all genes are located. The deletion linked to Angelman is only found on the maternal chromosome. This mystified scientists because sexually reproducing organisms come with maternal and paternal copies of each chromosome.

Genes on the chromosomes from both parents are activated seemingly at random in the developing child. This genetic redundancy is nature's way of protecting against developmental disorders. If a gene on one chromosome is damaged or missing, then the other copy can be activated.

But in Angelman and about a dozen other similar diseases, that does not happen.

At the University of Connecticut Health Center, geneticist Marc Lalande wants to understand why.

"Why go through millions of years of evolution to get a second copy [of a gene] and shut one down?" Lalande said. "That is the million-dollar question."

Studying Angelman syndrome offers a window into understanding genetic imprinting - the process that determines which of the parental genes will be activated early in development, he said.

"If you muck with the imprinting process, you perturb development, and that is crucial in a lot of human disease states," Lalande said.

For instance, a nearly identical deletion of chromosome 15 - but from the paternal gene - leads to a totally different disease, Prader-Willi Syndrome. Like Angelman kids, children with Prader-Willi are mentally retarded, but they tend to be short in stature and lack muscle tone. While some Angelman children have little appetite, Prader-Willi children often cannot stop eating.

Studying abnormalities on chromosome 15 also has led scientists to the genetic origin of one form of autism, long sought by researchers. While genetic causes of most forms of autism remain elusive, Angelman gave scientists a view about how such links might work.

As many as 3 percent of people with autism also have an Angelman deletion, but with this twist: They carry an extra chromosome 15, according to Dr. N. Carolyn Schanen, a geneticist at the University of Delaware.

Like most children with autism, but unlike Angelman kids, these particular autistic children often form unusual attachments to objects and can be socially aloof. However, compared with others with autism, these children "are more puppy-like in their behavior, and they sometimes lick you," Schanen said.

"This research might be broadened to help understand the molecular underpinnings of autism," she said.

The study of Angelman syndrome also has produced valuable leads into the study of epilepsy, a much more common disorder.

In a significant subset of Angelman cases, a key neurotransmitter system in the brain known as GABA is abnormal, said Dr. Edward Novotny, a pediatric neurologist at Yale University School of Medicine. People with this form of Angelman are especially prone to seizures - 1,500 a day in one of Novotny's patients. Novotny is using imaging studies to try to figure out just what is happening in the brains of these patients. The knowledge may one day help doctors find the best way to treat different forms of epilepsy, including the one found in Angelman.

Donna and Mark Clavette know that research is unlikely to significantly improve their daughter's life. Nicole, now 15, isn't able to speak, although she smiles and engages with her family members. She also needs to sleep in a special enclosed bed to protect her.

The genetic defect set off a chain reaction of events during Nicole's early childhood development that would be difficult if not impossible to undo.

"That would be a realistic assessment," said Dr. Robert Greenstein, professor of pediatrics in the division of human genetics at the UConn Health Center and Connecticut Children's Medical Center.

But that hasn't stopped the Clavettes from enrolling Nicole in at least three different scientific studies involving Angelman.

The studies help them understand the strange world she inhabits, her parents say.

"If we can contribute in any way to the advancement of science when it comes to this, we'll do it," Mark Clavette said. "If it can help somebody else, it's worth it."

And scientists investigating rare diseases believe the research one day will help, Greenstein said.

"Even though it may be an esoteric disease," he said, "when we learn the genetic keys to an illness, it will lead to better diagnosis and treatment down the line."