(c) 2004, The Hartford Courant

TOLLAND, Conn. - 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 have it.

By the time Nicole Clavette was 1, her mother, Donna Clavette, knew something was 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 - about 250 new cases each year.

The syndrome was first recognized in 1965, when English physician Harry Angelman described peculiar behavioral abnormalities in three patients and hypothesized that the cases 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 identified as a specific disease. Angelman patients have a normal lifespan but require 24-hour care.

In about 70 percent of 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 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."

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.

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."