At the threshold of Don and Natalie Wallace's two-story colonial in suburban Norristown, Pa., is clear evidence that a sick child is in residence—the sign on the front door asking all visitors to please wash their hands and a small pile of disposable surgical masks in the foyer. And just beyond those telltale signs is proof of what's really at stake here. A shadow box near the front door contains a pair of child's eyeglasses, next to it is a blanket with a Wild West print and nearby a stack of bound medical records. Those things don't belong to the Wallaces' sick child. They are the mementos of a little boy who is no longer here.

In January 2001 the Wallaces' first child, Zachary George, was born, healthy and perfect. But a month before his second birthday, he contracted a virus and within 24 hours became paralyzed and lost his sight. Over the next two years, Zach seemed to rally, and on Jan. 18, 2005, a Tuesday, he celebrated his fourth birthday. Within days, though, after being rushed to the hospital with a sudden and violent immune reaction, the Wallaces' little boy was dead.

Doctors believe Zach was killed by a genetic blood disease that has no cure or even a name. Discovering its precise cause is like "finding a needle in a haystack," says Dr. Edward Attiyeh, the family's hematologist at the Children's Hospital of Philadelphia. "This is a rare form of something that is already extremely rare." But one thing the doctors do know: Despite the disease's rarity, it has struck twice in the same house. Although the couple's daughter Olivia, 4, is healthy, their youngest, Ben, 2, has the same mysterious symptoms as his brother. And so, a family that has already experienced the deepest tragedy is once more fighting for a child's survival. "We're trying to do everything right," says Natalie, 34, "because it's happening again."

From as early as she can remember, what Natalie Wallace most wanted in life was to have kids. She made her husband, Don—they met at the wedding of his sister to her brother—agree to have six of them. "All I ever wanted was to hear someone say, 'Mommy,'" she says. When Zachary was born, the family lived in a three-bedroom fixer-upper where Don refinished the floors and put in a new kitchen. "We loved that house," Natalie says. Then, on the morning of Dec. 8, 2002, Zach came down with a fever and began vomiting. "He just didn't look right," says Natalie, who took him to the ER. After an exam, Zach went home. But soon after, he had a seizure in his mother's lap, and Natalie rushed him back to the hospital. After he was transferred to Children's, doctors discovered that he had become paralyzed from the waist down and delivered a stunning prognosis: Zach might die within 24 hours. With her little boy in a coma-like state, Natalie dropped to her knees at his bedside. "I remember praying, 'Just don't take him now.'"

Zach lost his sight, remained paralyzed and stayed in the hospital for three months. But despite CT scans, MRIs and skin and muscle biopsies, doctors couldn't pinpoint what was wrong. "They were unable to understand why he couldn't walk," says Don, 33, who runs a commercial cleaning company. "We asked eight doctors 10 different ways, and they never could explain why."

Over the next year the Wallaces took Zach to specialists at Johns Hopkins and the Mayo Clinic, but no one could give them a definitive diagnosis. "At first blush, it looked like an autoimmune disease," says Dr. Thomas Crawford, associate professor of neurology and pediatrics at Hopkins. "But it was unique. Absolutely unique. I had never seen anybody who had that exact constellation of multiple organ-targeting in such a relentless and progressive fashion."

Still, over time it seemed Zach was making progress. In October, after surgery to stop blood seeping into his retinas, Natalie was amazed to see him reach deliberately for a mound of Play-Doh. That spring, at the Jersey Shore, he picked up a seashell in the sand. She asked him if he could see it. Yes, he replied, he was going to give it to his little sister. "We thought he was really starting to heal," says Natalie.

She and Don bought him a swing set, a sandbox, a playhouse. As Zach's fourth birthday approached, he did visit the hospital with a fever, but doctors checked him out and he went home. Zach celebrated his big day eating chocolate cake wearing a Spider-Man bib. The next day Natalie insisted on taking him in for blood work; before she and Zach even got home, the hospital called and told her to bring him back immediately. His blood test showed wildly elevated enzyme levels and platelets so low that he could have bled to death internally. That night at the hospital, Zach didn't talk but kept reaching his arms out. And every time he did, a family member hugged him. "We didn't know it, but he was having strokes," says Natalie today. "I was lying in bed with him, saying, 'It's okay, Zach. Mommy's right here.'"

The next morning, with Don and Natalie at his bedside, Zach Wallace died. In the aftermath of his death, "it felt like the end of the world was a week away," says Don, who had always made Zach's scrambled eggs and cheese and given him piggyback rides at the beach while chasing seagulls. "Don wasn't right for months," says Natalie. "I didn't think he was gonna make it. It was the most brutal time."

Father Edward Windhaus, the priest who baptized and buried Zach, believes that the Wallaces' marriage, and religion, are what saved them. "I know the pain that goes on in their hearts very quietly," he says. "If they didn't have each other, I don't know how they would be able to handle all of this. They have tremendous trust and faith in God." And there was reason for real joy in the house: "We knew we were pregnant before Zach passed," says Don. "We were having our third child. We were having another little blessing."

In August 2005, Natalie gave birth to an apparently healthy baby boy. But at five months Ben woke from a nap and, to Natalie's horror, showed a clear first symptom of the disease that had killed his brother. "He looked right past me, and I knew that he had already gone blind," she says. "The same thing was happening." Dr. Edward Attiyeh and colleagues now believe that the brothers' illness is genetic, the result of inheriting as-yet-unidentified genes from their parents. Most likely, the genes interrupt the production by the body of a vital protein and cause the immune system to overreact to the slightest challenge. The task is to find exactly what went wrong among the body's 25,000 genes to produce that abnormality. Though there has not yet been another confirmed case of Ben's disease, Attiyeh is in contact with genetic researchers internationally who are conducting studies on the effects of missing genes. "Whenever we hear of a gene that might be the culprit, we test for it," he says.

In fact, if there is anything positive to emerge from Zach's death, it is that it has provided clues for his little brother's treatment as well. Every week, Ben gets fresh frozen plasma transfusions—a shotgun approach that gives him all the possible proteins he could be missing. "It's hard to say what's going to happen," says Attiyeh, "but I'm very optimistic that replacing the missing proteins is going to keep Ben out of danger."

On one recent visit to the clinic, Ben hops out of his stroller in the waiting room and accidentally knocks down a little girl. "I'm sorry," Natalie tells the toddler matter-of-factly. "He can't see." During the course of the afternoon, Ben pulls out his IV, and Olivia fusses that she wants to go home. Exhausted, at one point Natalie says, "I can't do this anymore." But by the time the receptionist asks if Ben will need an appointment for the following week, her resolve is back. "Yes," says Natalie. "For next Wednesday. And every Wednesday, until we figure out what he has."

There have been signs that the treatment is working. Although Ben is legally blind, he is beginning to make out big block letters and colors, "which is a beautiful thing," says Natalie. "When Ben says, 'Oh, that's yellow,' it's like, 'Thank you, Lord.'" Even more remarkably, after Ben got sick with a cold in September, he recovered without having to go to the hospital—for the first time in his life. "He held his own," says Natalie proudly, "and that is a true blessing. Maybe this means his immune system is getting stronger. Maybe our treatment is the right treatment."

Until they know that for certain, they can only hope. Natalie, upbeat even when the news is discouraging, and Don, quiet and devout, focus on making sure that illness isn't the dominant theme in his life. "I spoil him," says Natalie. "His favorite treat is Gummy Bears. We try not to give him too many. But I'll give him a couple, and Don will give him 10 because he loves them so much."

Natalie and Don know only too well that the loss of a child is irrevocable and will never be forgotten. Zach's photographs are in every room of their house, and on summer nights, when she's being tucked into bed, Olivia calls out "Good night, Zach ..." through her open window because "I miss him when he goes away." But there are also ways of moving on. If the Wallaces have learned anything, they say, it is that the best way to honor the loss of a child is by loving the ones who live. "I know that someday I'll be with Zach again," says his mother. "But right now, I live for my children who are here."