‘For us, this means hope’: Exploring the promise of genomic medicine

March 15--Joselin Linder and members of the DeMoe family of North Dakota both lost genetic lotteries: They carry harmful inherited mutations that will impair, and likely curtail, their lives.

But the respective protagonists of "The Family Gene" and "The Inheritance" are far more than victims. At some sacrifice to their time, comfort and even health, they have become contributors to cutting-edge genomic medicine -- a field whose inevitable advances will benefit future generations.

Linder's mutation is exceedingly rare. In fact, it exists only in her family. Its marker is a heart murmur, often barely detectable. Its pre-eminent symptom is leakage of lymphatic fluid into the lungs and other body cavities, resulting in swollen limbs, damaged organs, breathing problems and eventual starvation. The gene, located on an X chromosome, expresses less virulently in women because they carry a second, nonlethal X chromosome that may temper its effects.

The DeMoes of North Dakota are plagued by early-onset Alzheimer's disease -- a rare variation of the growing health scourge. Alzheimer's affects as many as 36 million people worldwide and about 5.3 million in the United States, but early-onset Alzheimer's represents just 1 percent of cases. It arises from three genetic mutations and typically presents between ages 30 and 50.

In rural Colombia, one extended family wrestling with this highly heritable dementia calls it "the curse." But for Alzheimer's researchers, the malady represents a scientific windfall -- an opportunity to test preventive drugs on a population known to be headed for illness.

"The Family Gene" and "The Inheritance," while concerned with explicating the relevant science, also share an unusual emotional intimacy. That intimacy takes different forms. Linder's memoir is a personal tale of loss, illness, ethical dilemmas and emotional fallout. Some of the details are harrowing. But Linder tells her story in a smart, wry voice devoid of self-pity.

"The Inheritance" is more straightforward in style, but ultimately no less involving. A model of immersion journalism, it is especially notable for its specificity and author Niki Kapsambelis' empathy. The DeMoes laid bare their lives, and Kapsambelis repays their candor with a warts-and-all portrait softened by fondness and respect.

"The Family Gene" begins with Linder's discovery of the severity of her father's illness. Dr. William I. Linder was himself a physician. But he would spend years, baffled and increasingly terrified, in a struggle with a nameless disease that could be neither diagnosed nor successfully treated.

At one point, the widow of William Linder's uncle notes that her husband had suffered similar symptoms on his way to a horrific death. Joselin Linder's great-grandmother, Mae, though longer-lived, had also experienced the disease's characteristic swelling. The family history pointed to a genetic link.

Linder uses gentle humor to distance herself, and the reader, from the grim reality of her father's condition. "We were not a family who routinely dealt with catastrophe," she writes. "We lived in Ohio." Recounting a story of a neighbor's disaster, she writes: "It's where we excelled: watching lightning strike other people's houses."

Eventually, the family makes a fortunate connection with Dr. Christine "Kricket" Seidman, a Boston-area genetic researcher with a specialty in cardiology. She recommends screening every family member for the telltale heart murmur. Out of 41 of Mae's descendants, 13 apparently have the murmur, forecasting health troubles ahead. Linder is one of them.

During her father's illness, she tries to maintain "a semblance of normalcy," attending Tufts University, finding her first serious boyfriend. But she soon swerves off course, abandoning her studies, acting out with drugs and men. "The idea of tempering my emotions, seeking any kind of balance at all, just seemed incomprehensible," she writes.

Then her medical -- and insurance -- woes begin. Months after her father's death, Linder discovers that her platelets are "alarmingly low," a condition that Seidman diagnoses as anemia. Meanwhile, her family doctor apparently has reported her heart murmur to a medical database, saddling Linder with a pre-existing condition. For a decade, in those pre-Obamacare years, she is unable to buy health insurance -- a problem solved only by marriage to a man with employer-based insurance.

Meanwhile, more relatives are stricken, the men succumbing "faster and in more devastating ways" than the women. One day, Linder's ankles swell up. Later, she discovers that she has a blocked portal vein, another symptom. Procedures to clear it ultimately fail.

But there are breakthroughs to cheer: A postdoctoral fellow in the Seidman lab maps the variant gene. Technology can now detect it and keep it from being passed to the next generation. Seidman develops a hypothesis about the disease mechanism, which implicates an improperly functioning liver. There is as yet no cure -- nor even a name -- for the disease. But Linder, while postponing childbearing, resolves to enjoy her life as best she can.

Like "The Family Gene," "The Inheritance" is partly about the impact a genetic disease has on entire families -- even relatives who are not afflicted. At the center of Kapsambelis' narrative are two remarkably courageous women: Gail DeMoe and her daughter Karla.

Gail's husband, Galen "Moe" DeMoe, is "a hard drinker, a harder worker, and one of the best-liked men in the oil fields" of Tioga, N.D. Gail, with her "ribald sense of humor," is an even more popular figure. The couple has six children and a household filled with noise and laughter.

But, by 1973, Moe's forgetfulness and confusion are sufficiently worrisome that Gail takes him to a neurologist, who makes the Alzheimer's diagnosis. Over time, his temper turns violent; his children fear him and regard him as abusive. Gail blames his rages on the disease, saying she remembers a different man. But as his belligerence worsens, she finally sends him to a state mental hospital. He dies in a nursing home.

Carrying a gene associated with early-onset Alzheimer's is a guarantee of disaster: Everyone who has it will develop the disease, and so will approximately half that person's offspring. Moe's family, however, is particularly unfortunate: Of his six children, only Karla has been spared.

Kapsambelis tells the extended family's story in pointillist detail, perhaps too much so for some readers. A DeMoe family tree helps keep the relationships straight, while a generous array of photographs underlines the poignancy of their fate.

"The Inheritance" is equally concerned with the history of Alzheimer's research. Dr. Francisco Lopera, who spent years traveling the dangerous back roads of Colombia to investigate the disease, emerges as an especially sympathetic figure. Kapsambelis is also a fan of the University of Pittsburgh's Dr. Bill Klunk, a pioneer of brain imaging.

The case of Dr. Pearson "Trey" Sunderland III, chief of geriatric psychiatry at the National Institute of Mental Health, is more complicated. For all his brilliance and personal charm, Sunderland was compromised by a consulting relationship with the pharmaceutical company Pfizer, manufacturer of Aricept. Sunderland promoted the Alzheimer's drug without disclosing the extent of his financial ties to Pfizer, and eventually pleaded guilty to a criminal conflict of interest.

Kapsambelis carefully lays out the somewhat arcane internecine disputes within the field -- between, for instance, those who attribute Alzheimer's primarily to amyloid plaques and those who fault tau tangles.

She notes that early intervention is the holy grail of Alzheimer's research -- which is why families like the DeMoes, who carry an autosomal dominant gene mutation, are so important. The DeMoes, who worked with both NIMH and Pitt, are now part of the Dominantly Inherited Alzheimer's Network, a major international study aimed at finding drugs to prevent or halt the disease.

Most won't benefit directly from the study, and traveling to Pittsburgh for batteries of tests has at times strained their health. But the DeMoes remain highly motivated. "If their bodies could help science ferret out an answer," Kapsambelis writes, "they might save their children."

The younger DeMoes -- Gail's grandchildren and their cousins -- have faced difficult decisions about whether to submit to genetic testing, and whether to have children. Relatives already diagnosed have lost not just memory and jobs, but all but their most steadfast friends. Their caregivers sometimes have had to resort to deception to move them to nursing homes. "No matter what decisions you make, you never feel good about them," Karla says.

To both the Linders and the DeMoes, medical genetics offers the possibility of a reprieve. "We now understand the gene and its impact on our bodies," Linder writes. "For us, this means hope, and the chance to change our fate."

The DeMoes, too, are waiting, as clinical trials of potential Alzheimer's drugs proceed. "Tragedy would intertwine with their blessings," Kapsambelis writes, "until they found the thread that would lead them out of the labyrinth."

Julia M. Klein was a finalist for the 2016 National Book Critics Circle's Nona Balakian Citation for Excellence in Reviewing.

'The Family Gene' -- By Joselin Linder, Ecco, 261 pages, $28.99

'The Inheritance' -- By Niki Kapsambelis, Simon & Schuster, 344 pages, $26

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