Progeria

• 1. Introduction

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  Progeria is a disorder so rare that the world's known cases could fill a single school bus several times over, yet it has taught scientists more about ordinary aging than almost any other condition. As of September 2020, the Progeria Research Foundation counted 179 known cases, spread across 53 countries. A study from the Netherlands put the odds at 1 in 20 million births. Hundreds of cases have been reported in medical history since 1886. The name comes from two Greek words, pro, meaning before or premature, and gēras, meaning old age. Children born with it usually look healthy at first. Then something begins to run too fast. Why does one tiny change in a single gene age a body so rapidly? Why does the mind stay sharp while the heart wears out? And why do researchers who study a few hundred children believe they may be learning something about everyone?

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• 2. A Body Ahead of Schedule

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  Around 18 to 24 months of age, the first clear signs of progeria usually appear in a child who seemed perfectly normal at birth. Growth slows. Hair falls from the whole body. The face takes on a distinctive shape, small, with a shallow, recessed jaw and a pinched nose. Some children show earlier hints, such as a failure to thrive or a patch of tight, scleroderma-like skin during the first months of life.

  As the years pass, the signs deepen. The skin wrinkles. The head looks large against a small, fragile frame. Veins show clearly across the scalp, made more obvious by the missing hair, and the eyes are prominent. Fat and muscle waste away, joints stiffen, and hips can dislocate. Kidney failure, loss of eyesight and atherosclerosis can follow.

  One thing stays untouched. Most people with progeria keep typical mental and motor function. Intelligence tends to be average to above average, so a child can look decades older than their age while thinking exactly like one. That mismatch shapes how many of them are seen, and how they choose to present themselves, as later chapters show.

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• 3. The Faulty Protein

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  In 2003, researchers pinned the cause of progeria to a single point mutation at position 1824 of a gene called LMNA, where a cytosine is swapped for a thymine. The gene normally makes a protein that helps hold the cell nucleus together. The change creates a hidden splice site in exon 11, so the cell produces a shorter than normal messenger RNA. That shortened message yields an abnormal protein called progerin.

  Normally, prelamin A goes through a series of steps before becoming lamin A. A farnesyl group is attached to one end, and later an enzyme called ZMPSTE24 snips that end away, freeing the finished protein from the nuclear membrane. Progerin lacks the cutting site. Its farnesyl group can never be removed, so the protein stays stuck to the rim of the nucleus.

  The result is a nucleus that bulges and warps, a feature called nuclear blebbing. The supporting scaffold under the nuclear envelope, the nuclear lamina, can no longer do its job. Scientists admit that the link between the misshapen nucleus and the symptoms is still not understood.

  The damage reaches beyond the nucleus. Progerin also leads to swollen, poorly working mitochondria, the cell's power plants, with low energy output and high levels of harmful reactive molecules. The reason they accumulate is not yet explained, though researchers have pointed to low levels of a regulator called PGC1-α and of a protein called LAMP2.

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• 4. One in Twenty Million

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  Progeria is an autosomal dominant disorder, which usually means a parent can pass it on. Here that almost never happens. Most cases arise from a sporadic mutation, and people with progeria rarely live long enough to have children. Only two cases are known in which a healthy person carried the mutation. One family from India had four of its six children affected.

  People with progeria do have normal reproductive development. There are known cases of women with progeria who delivered healthy offspring, so the barrier is time rather than biology.

  A rarer, atypical form also exists. In these patients, heterozygous LMNA mutations produce symptoms only in late childhood or early adolescence, and they tend to live longer. Even people with the same mutation can present differently.

  Over 1,400 variations in the LMNA gene are known. The 2003 report in Nature that described the new dominant mutation had a co-author with a personal stake, a physician named Leslie Gordon. She knew nothing about progeria until her son Sam was diagnosed at 22 months. She and her husband, pediatrician Scott Berns, went on to found the Progeria Research Foundation.

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• 5. A Window Onto Aging

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  Scientists are interested in progeria partly because it may reveal clues about the normal process of aging. Their reasoning has real evidence behind it. When one study compared cells from children with progeria against skin cells from young and elderly people, it found similar defects in the progeria cells and the elderly cells. These included more DNA damage, lower levels of certain nuclear proteins, and a loss of the tightly packed form of DNA called heterochromatin.

  Nematodes show a similar pattern. Over their lifespan, their cells develop lamin changes comparable to those in progeria, in all cells except neurons and gametes. Progerin production is also switched on in typical aging cells. Fibroblast samples from children with progeria show accelerated aging on the epigenetic clock, in both skin and blood.

  Progeria does not copy old age in every way. Other conditions, such as Werner syndrome, Cockayne syndrome and xeroderma pigmentosum, change a few aspects of aging but never all at once, so they are called segmental progerias. Patients with progeria show no neurodegeneration and no predisposition to cancer. They also avoid cataracts and osteoarthritis, which are linked to accumulated damage.

  Overall, symptoms develop as if aging ran eight to ten times faster than normal. The DNA repair question remains open, since progeria may not be directly caused by defective repair.

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• 6. Chasing a Treatment

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  In November 2020, the U.S. Food and Drug Administration approved lonafarnib, the first drug aimed at the disease's root problem. It belongs to a class called farnesyltransferase inhibitors, which block the enzyme that attaches progerin to the nuclear rim. A phase II trial using it had begun in May 2007. In a 2018 trial analysis, treated patients had a mortality rate of 3.7 percent, against 33.3 percent for untreated ones, at a median follow-up of 2.2 years.

  The drug comes as capsules taken twice a day. Side effects include nausea, vomiting, diarrhea, infections, decreased appetite and fatigue. It may cost US$650,000 per year, which puts it out of reach for most families, and it was unclear how United States insurance would cover it.

  Other approaches have been tried. Doctors treat complications with coronary artery bypass surgery and low-dose acetylsalicylic acid, and growth hormone has been attempted. In cells, rapamycin removed progerin through autophagy, while sirolimus abolished nuclear blebbing, though only in the laboratory. Morpholinos were used in mice and cell cultures to cut progerin production.

  Mouse work has gone further. In 2020, base editing targeted the mutation in a mouse model. In 2023, a study designed a peptide that stopped progerin from binding to BubR1, a protein known to regulate aging in mice.

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• 7. Naming the Disease

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  In 1886, the English surgeon Jonathan Hutchinson first described progeria. Hastings Gilford described it independently in 1897. The pairing of their names gave the condition its full title, Hutchinson-Gilford progeria syndrome.

  For more than a century, research yielded very little. Before the late 20th century, little was known about the syndrome. Before a genetic test for LMNA mutations became available, misdiagnosis was common. Other conditions look similar, including Werner syndrome, Cockayne syndrome, Hallermann-Streiff syndrome and Wiedemann-Rautenstrauch syndrome, so the test now confirms what the eye alone cannot.

  Without a cure, the average life expectancy was 13 years as of 2003. At least 90 percent of patients die of complications of atherosclerosis, such as heart attack or stroke. Severe cardiovascular problems usually develop by puberty. Recent medicinal advances enabled one patient to live to age 28, a milestone that later lives would surpass.

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• 8. Lives Beyond the Diagnosis

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  In 1987, fifteen-year-old Mickey Hays appeared with the actor Jack Elam in the documentary I Am Not a Freak. The two had met during the filming of the 1986 film The Aurora Encounter, in which Hays played an alien. Their friendship lasted until Hays died in 1992, on his 20th birthday. Elam said, "You know I've met a lot of people, but I've never met anybody that got next to me like Mickey."

  Sam Berns, the son of the foundation's founders, became an activist. He was the subject of the HBO documentary Life According to Sam, and on the 13th of December 2013 he gave a TEDx talk titled "My Philosophy for a Happy Life." Hayley Okines, from England, spread awareness of the condition. Adalia Rose Williams, born on the 10th of December 2006, shared her everyday life as a YouTuber and vlogger before she died on the 12th of January 2022, aged 15.

  Others worked in creative fields. Leon Botha, a South African painter and DJ known for work with the hip-hop duo Die Antwoord, died in 2011, aged 26. Margaret Casey, a freelance artist, died on the 26th of May 1985, at 29, after being taken to Yale New Haven Hospital with respiratory problems. Amy Foose died at 16 in 1985, and her brother, the car designer Chip Foose, started a foundation in her name called Amy's Depot. The Progeria Research Foundation gives out the Amy Award in her honor.

  Sammy Basso, an Italian biologist, studied the disease that he lived with. He was born on the 1st of December 1995 and died on the 5th of October 2024, aged 28, as the longest-living survivor of the condition. Tiffany Wedekind of Columbus, Ohio, was believed to be the oldest survivor at 44 years old as of September 2022.

  Fiction has borrowed the condition too. Orlando Gardiner, a character in Tad Williams' tetralogy Otherland, plays a barbarian called Thargor online and dies at 14. The play and Tony-winning 2021 Broadway musical Kimberly Akimbo, by David Lindsay-Abaire, follows a 16-year-old girl with a progeria-like disease. A Catalan girl, Alexandra Peraut, inspired a children's book called Una nena entre vint milions, meaning A girl in 20 million.

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