Genetics and Genomics
by Michelle F. Pflumm, PhD
Addison Lennon met all her early milestones: she sat up on time, crawled on time and walked on time. At about 4 months, however, she had a seizure, and her parents started to worry. By 9 months, her head appeared small for her age.
Her neurologist reassured the family that Addison could still be within the lowest 5 percent of the normal range. “We were thinking she was typical,” says Kari Lennon, “she would be in that 5 percent.”
At 15 months, however, Addison had another seizure that was a lot more severe. She had been tested for everything. No one could pinpoint the cause of her so-called microcephaly, or small head.
Kari spent countless hours online in search of answers. “How I could fix Addie? How could I make her better?”
Reassured that Addison’s condition was likely caused by a virus her mother had contracted during pregnancy, the Lennons went on to have three boys, Sam, Jack and Brooks.
A new brother: Brooks
Shortly after his arrival, the Lennons knew that Brooks had the same disease as his sister. His head was small and as he grew, he too fell below the normal range. Could there be a genetic cause?
Kari remembered, from one of her late-night Internet searches, a clinic at Children’s Hospital Boston that specialized in hereditary forms of microcephaly. The clinic team, led by Christopher Walsh, MD, PhD, and which included Edward Gilmore, MD, examined the children. Addison and Brooks did not have any known heritable brain disease.
“Ed and I looked at each other and said, ‘maybe these children have Microcephaly with Seizures,’” recalls Walsh.
Discovered two years earlier by the Walsh team, Microcephaly with Seizures, or MCSZ, is an extremely unusual form of microcephaly in which the brain is of smaller size but is otherwise structurally normal. People with MCSZ have seizures, but typically many more than Addison and Brooks were experiencing. The team therefore suspected that the children had a mild form of MCSZ. The disease, however, had never been seen outside of the Middle East.
Undeterred, the team sequenced the children’s PNKP gene, the critical gene altered in MCSZ. Both Addison and Brooks had mutations, in both copies of the gene. But one of these mutations had not been seen before, and since it didn’t wipe out the function of the gene, the team simply could not be sure that Addison and Brooks had MCSZ.
The phone call
Brooks’s condition worsened. His seizures were uncontrolled. He was in intensive care every other week. And in the chaos, the Lennons learned that they were expecting another child.
The Lennons found themselves in a Catch-22. To knowingly bring another child into the world with this genetic condition was unthinkable to them. However, they would not terminate the pregnancy unless they were sure that their future child would have the disease.
Kari’s obstetrician urged the family to reach out one more time to the Walsh team. Perhaps they had identified the cause of their children’s microcephaly. “My husband sent an email from the car after we meet with her,” Kari recalls. “We heard back from Brenda Barry with the Walsh Lab the next morning asking to speak with us that evening as they did have news to share with us.”
Just weeks before, the team had completed biochemical studies on cells derived from Addison and Brooks, and they now had evidence confirming that the two had MCSZ. Eleven weeks into Kari’s pregnancy, the growing fetus was tested and found to be free of the MCSZ mutations its siblings had.
The Lennons’ MCSZ, so rare, could only be detected by studying large families with shared ancestry on the other side of the world. One of the two MCSZ mutations that Addison and Brooks each carried had been previously identified in the Walsh lab’s studies of Middle Eastern families.
“We never would have found this gene in the U.S.,” says Walsh. “We needed to go over to the Middle East to make a difference here.”
The day the Lennons’ new baby was born, they sent an email to the Children’s clinic, announcing that she would be named Grace Gilmore, in part for the neurologist on the Walsh team, and expressing their gratitude for a healthy baby.
“I cannot remember a better day since I became a doctor,” says Walsh. “For a geneticist, this is as good as it gets.”
And Kari Lennon, knowing what is behind her children’s condition, can finally sleep at night. “We are so lucky,” she says. “They have just given us the biggest gifts in the world. A diagnosis for Addison and Brooks and a baby that is healthy.”