Clues to Zika damage might lie in cases of twins
Doctors study differences between fraternal, identical.
On the bed next to her brother, Ana Vitória da Silva Araújo acted like the 1-year-old she was. She smiled and babbled. She played with a stuffed whale. She plucked the pacifier from her brother’s mouth and the burp cloth from his shoulder.
Her brother, João Lucas, seemed unaware of her, his eyes closed, his mouth making sucking motions. It was typical behavior for a newborn. But João Lucas is the exact same age as Ana Vitória — they are twins.
João Lucas was born with microcephaly and other serious problems, the result of his mother being bitten by a Zika-infected mosquito during pregnancy. But the virus that attacked his brain in the womb apparently spared his sister.
The siblings are one of nine sets of twins identified in Brazil’s Zika crisis, and scientists hope they can shed light on how the virus works generally and why it inflicts ruthless damage on some babies and not others.
Twins often yield clues to medical mysteries because their biological similarities allow scientists to identify relevant differences. Determining why one twin became infected in the womb while the other did not may illuminate how Zika crosses the placenta, how it enters the brain, and whether any genetic mutations make a fetus more resistant or susceptible to Zika infection.
Until recently, Brazil’s Zika twins seemed to follow a pattern, said Mayana Zatz, a geneticist and molecular biologist at the University of São Paulo. The cases include two sets of identical twins, and both babies in each pair have microcephaly, she said. There are also six sets of fraternal twins, in which one twin has microcephaly, while the other appears unaffected.
Since identical twins share one placenta while fraternal twins almost always have separate placentas, Zatz and other experts suggested that the Zika virus may have penetrated one placenta and not the other.
Perhaps the virus entered through a weak spot in one placenta’s membrane, said Dr. Ernesto Marques, an infectious disease expert at the University of Pittsburgh and the Oswaldo Cruz Foundation in Recife, Brazil. Or if one fetus “kicked the placenta,” he said, inflammation from that bruise on the membrane could become a portal.
But one set of twins has broken the pattern. Those twins are fraternal and had separate placentas — but both have microcephaly and other Zika complications. “The boy is more affected than the girl, but both are severe,” Zatz said.
That case complicates the theory. Dr. Vanessa van der Linden, who helped discover that Zika causes microcephaly and has treated some of the twins, said one explanation might be that in some fraternal cases Zika crossed both placentas, but the twins had genetic differences that influenced why only one became infected or “why the babies reacted differently to the virus.”
Marques suggested another possibility: that an impaired twin was exposed to Zika before the mother’s body or the placenta developed immune responses against the virus and that the second fetus was infected slightly later.
“It should reach both at an equal time,” he said. “However, if the virus hit one of the babies before the mother actually had developed protective immune responses, you have a problem.”
Zatz’s lab has drawn blood from affected and unaffected twins, and is growing brain cells from their stem cells. She is testing to see which of those cells are susceptible to Zika infection. That could show whether some twins have genetic predispositions that make Zika infection more likely. Ultimately, Zatz expects to find an interplay of factors that can vary in each twin pregnancy. “I believe,” she said, “the explanation will be complex.”
For now, why João Lucas is devastated by the virus and his sister is not remains a mystery.
When João Lucas and his twin sister were born in August 2015, their mother, Neide Maria Ferreira da Silva, was unaware he had microcephaly or brain damage, she said. He was born first and was temporarily placed in an oxygen chamber because of breathing problems. And the maternity hospital’s “deformation doctor,” a physician specializing in newborns with deficiencies, recommended he see a geneticist. But da Silva thought any problems would be mild, she said.
She had already given birth to 10 children, starting when she was 17. It took a month before she brought João Lucas to the geneticist, who said “his brain, it wasn’t like ours,” da Silva, 42, recalled. “It was going to be always very small.”
She was shocked. “I didn’t feel sad or upset,” she said. “I thought about how it was going to be when he grows up” and realized “I will have to take care of him more than the other kids.”
But his symptoms began overwhelming her. “He would fall asleep, and five minutes later he would start screaming,” she said.
Da Silva was especially alarmed by João Lucas’ seizures, which made him “get purple” and look “like his eyes were going to jump out.”
Sometimes he became so agitated, he would scratch himself in the face, da Silva said. “Blood would come out.” Unable to cope with his care, da Silva started bringing him to a neighbor’s cousin, who began caring for him. The caregiver, Valéria Gomes Ribeiro, 46, brought the baby to his first appointment with a neurologist. The doctor prescribed clonazepam, an anti-anxiety drug, to calm him, but Ferreira still found that when João Lucas was home, something often went wrong. He developed pneumonia and eating problems, even what she called “an emotional fever” because he seemed to miss Ribeiro, da Silva said.
Da Silva’s 11-year-old daughter became pregnant and had an abortion, prompting a child protection agency visit. After da Silva told the caseworker that a friend was caring for her Zika baby, the agency investigated and initiated proceedings to remove João Lucas from her home. To keep him from being placed in a shelter, both women and the state agreed that João Lucas would live with Ribeiro, while Ana Vitória stayed with da Silva. Under court order, João Lucas spends Sundays at his biological mother’s house.
Ribeiro, who has adorned João Lucas with a bracelet and necklace hung with a good-luck charm called a “figa,” tries to keep up with his many appointments. They include visits with a psychologist who shows João Lucas a panel of black and white squares to stimulate vision and rubs him with a sponge studded with Popsicle sticks to stimulate touch.
On a visit last fall to Ribeiro’s emerald green house on a dirt street, where the 23rd Psalm hangs on a yellow wall, Ana Vitória toddled around, clutching a piece of spongy cake with one hand, thumping a table with the other. Reaching for her brother’s mouth, she touched the green tape that therapists apply around his lips, fingers, back and chin to relax tight muscles. Da Silva waved a rattle before João Lucas, but he did not respond.
So far, Ana Vitória — like the other fraternal twins without obvious brain damage — appears unimpaired, but doctors are monitoring her and the others. At Ana Vitória’s one-year exam, she was slightly behind developmentally. Her vocabulary was limited and she was slow to point to her mother when the doctor asked, da Silva said.
That could be unrelated to Zika, but, she noted, “The doctor never said it’s 100 percent sure that she doesn’t have a problem.”