D.T. Max - The Family That Couldnt Sleep: A Medical Mystery

CONTENTS

For Sarah

Dove andrai tu andr anchio

e dove starai tu io pure star

Now all my hours are trances;

And all my nightly dreams

Are where the dark eye glances,

And where thy footstep gleams,

In what ethereal dances,

By what Italian streams.

EDGAR ALLAN POE, The Assignation

Protein, so far as we know, does not replicate itself all by itself, not on this planet anyway. Looked at this way, the [prion] seems the strangest thing in all biology and, until someone in some laboratory figures out what it is, a candidate for Modern Wonder.

LEWIS THOMAS

INTRODUCTION

I n October 1997, Stanley Prusiner, a professor at the University of CaliforniaSan Francisco who had spent twenty-five years studying prions, went to Stockholm to receive the prize he called the big one from the King of Sweden. His great achievement was to show that the prion (pronounced pree-on), the infectious agent responsible for bovine spongiform encephalopathy, or mad cow disease, Creutzfeldt-Jakob disease, and a disease in sheep called scrapie, was not a virus or a bacterium but a protein, a nonliving thing. Protein, as the name suggests, is prime, proto matter. (These agents, one prion researcher told a documentary film interviewer, are almost immortal.)

The fifty-five-year-old Prusiners discovery, the Swedish academy noted, introduced a new biological principle of infection into science. Over the years, Prusiner, an ambitious man, had developed a taste for good wine and food. Now the Swedish elite entertained him at their finest restaurants while the press pursued him for his photograph and his ideas. The moment was just as hed always dreamed it would be. Asked by the newspapers what was left now that he had the top prize in science, he said his new goal would be to work towards an effective therapy for prion diseases. In 1998, he told an Israeli newspaper he thought hed have a cure in five years.

Three years later, in 2001, when a family in the Veneto, the Italian region of small towns and farms outside Venice, held its first family reunion, Prusiners words were on their minds. Family reunions are rare in Italy, because they are unnecessary: Italian families already do everything together; you cant reunite something that never disperses. This family had a special reason for its gatherings, thoughmany of its members carry a gene for a dreadful disease. Of noble origin, the family counts doctors, engineers, industrial managers, and a well-respected academic among its number.

But this family is cursed. For at least two centuries, its members have suffered from an inherited prion disease called fatal familial insomnia that strikes them, usually in their fifties, killing by depriving them of sleep. FFI is an autosomal dominant mutation, which means that a child of a parent with FFI has a 50 percent chance of getting it, too. In the general population the chance of having FFI is one in 30 million; within the affected branches of this Italian family, it is one in two.

The symptoms of FFI are remarkable and grim. Typically, one day in middle age, the sufferer finds that he has begun to sweat. A look in the mirror will show that his pupils have shrunk to pinpricks and he is holding his head in an odd, stiff way. (I write he for clarity, though men and women are equally affected.) Constipation is common, the women suddenly enter menopause and the men become impotent. The sufferer begins to have trouble sleeping and tries compensating with a nap in the afternoon, but to no avail. His blood pressure and pulse have become elevated and his body is in overdrive. Over the ensuing months, he tries desperately to sleep, sometimes closing his eyes but never succeeding in falling into more than a light stupor. FFI sufferers are sometimes able to enter a half sleep that is like a parody of the agitated dream sleep some people experience just before waking, but they cant go deeper to get real rest. Their exhaustion is immense, beyond comprehension.

Once the sufferer can no longer sleep, a downward progression ensues, as he loses his ability to walk or balance. Perhaps most tragic, the ability to think remains intact; sufferers know what is happening. At first, they can talk about it and even write down their thoughts. After a few more months, some lose this level of functioning. Once their bodies shut down, only the desperate look in their eyes shows that they know what is going on. But others can talk and reason until the end. In the terminal phase, usually about fifteen months after the disease has begun, they fall into a state of exhaustion resembling a coma and die. When I began this work, Pierluigi Gambetti, the director of the national prion surveillance center at Case Western Reserve University School of Medicine in Cleveland, one of the discoverers of the disease, told me, I used to think Alzheimers was the worst disease you could get. But to see a loved one disintegrate in front of your eyesand for that person to know it is happening? Somehow, the fact that it is so rare makes it even worse, it seems to me. I think now even a car accident would be less cruel.

This Italian family is one of a handful of families in the world afflicted with fatal familial insomnia. They can trace their disease back to the mid-eighteenth century, possibly to a Venetian doctor who lived near the Jewish ghetto, and with certainty from him to an aristocrat in the Veneto named Giuseppe and down to Vincenzo in the 1880s, Giovanni in the 1910s, Pietro in the 1940s, Assunta, Pierina, and Silvano in the last three decades of the twentieth century and on toto whom? That question hangs over the group at its annual reunions.

In a sense, the answer is known. In the early 1990s, the University of Bologna, whose neurological institute specializes in sleep, tested many of the members of the family for the genetic mutation that causes FFI and has the results in its files. So who will die is known, although in what order family members will perish is not. And that someone will die soon is all but certainat least thirty members of the family have died from FFI in the last century, fourteen since 1973, seven in the past decade. Among living family members, the laws of probability suggest that at least a dozen more carry the mutation that causes the disease.

Many lethal genetic diseases disappear on their own, because they bring about death before the carriers of the mutation can reproduce, but not FFIat least not in this family. Because the disease usually strikes its sufferers after their childbearing years, and because most members of this family still decide to have children, FFI will live on through them. The decision to bring a child into the world who may die a horrible death in middle age is a difficult one. Bologna weighed this equation at the time it conducted its genetic tests and decided it would not inform the members of family whether they had the mutation or not so they could not use the information in making reproductive decisions. The family gave its consent to being kept ignorant, and to my knowledge no family member has terminated a pregnancy out of fear of passing the syndrome on.

Bologna framed the familys problem, but it did not solve it. Family members still must wait for the tautly held head and pinpoint pupils that are the first sign of the disease, then the sweating and shivering that follow, the handkerchief always on the brow or the shirt that has to be changed at midday or the sudden menopause, and the awful next step, when the sufferer begins not to sleep.