Andrew Mattingly Jackson Jr. whirs his three-wheeled electric cart into a paneled dining room in a nursing home in Silver Spring, hurrying to join a gathering of his relatives.
Waiting for him is John Philip Mattingly, a resident of the home. He nudges his right hand against the control stick of his electric wheelchair, spinning to greet Mr. Jackson face to face. One by one, the rest arrive: Anna Mae in her wheelchair; Jay with his cane and plastic ankle braces; Bonnie and then Janet, both with a telltale hesitation in their step.
They've come to share news about children and spouses and jobs. And about the tragic legacy they all share.
For seven generations, the descendants of George Washington Mattingly, born in St. Mary's County in 1792, have been shadowed by a baffling illness that can slow, hobble and finally cripple sufferers.
Now investigators at Johns Hopkins University and the University of Pennsylvania, using the recently developed tools of molecular genetics, are trying to solve that mystery. They're hunting for the gene that causes the disorder, which affects at least 70 of about 150 known descendants of George Mattingly.
And, while it may take a year or longer, they expect to find it.
Over the past century, the family disorder has remained beyond the reach of scientific breakthroughs in medicine: in antibiotics, surgery and vaccines. That's because the disorder is not caused by a viral infection, trauma or outside cause. It lies within.
But the current revolution in genetics offers younger Mattinglys a measure of hope.
Discovery of the gene will probably yield a test that will alert potential victims. One day, it could lead to a treatment, or even a cure.
Unlike some other inherited neuromuscular diseases, the Mattingly disorder does not shorten a person's lifespan. Still, family members could face some hard questions. If a prenatal test were positive, should parents terminate a pregnancy? Would teen-agers or young adults with no symptoms really want to know they face paralysis?
Today, these issues are purely hypothetical. The Mattinglys are eager to see the Hopkins-Penn team track down the gene.
None seems more eager than Andrew Mattingly Jackson Jr., a 67-year-old retired Black & Decker manager from Hampstead.
"I'm getting to the point where I have to have an aide to dress and undress me, to shower me, to lift me off and on the john," says Mr. Jackson, talking with a reporter during a break in the gathering. "I can't bring food up to my face. I have very little use of my hands."
He grows silent, then raises his stricken hands, palms upward.
Mr. Jackson first sought treatment in 1947, after he struggled to climb ladders while serving aboard a Navy ship. At the Pensacola Naval Hospital, he was misdiagnosed with a lethal illness -- amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease -- and discharged.
A few months later, a Johns Hopkins physician told him he had Charcot-Marie-Tooth, or CMT -- a nonfatal, inherited, muscular disorder.
In 1963, researchers at the National Institutes of Health launched the first full-scale study of the Mattinglys' ailment. They, too, labeled it a form of CMT. Hopkins physicians conducted another, more limited study 13 years later, in 1976.
In these early research efforts, scientists lacked the modern tools to track down the ultimate cause of the disease -- the gene itself. But they were able to catalog its effects and compile a partial family tree that traced the illness among Mattingly descendants, confirming its genetic basis.
After his discharge from the Navy, Mr. Jackson started his own family. He had two sons.
One, Dwight David Jackson, inherited the disorder.
"We noticed something wrong with him when he was 7 or 8 years of age," Mr. Jackson recalled. "That kind of devastated me. I was thinking of what lay in store for him."
Mr. Jackson's concern for his son accelerated as his own strength ebbed.
He attended meetings of CMT sufferers. He expanded the NIH's Mattingly family tree, now an 86-page catalog of births, deaths and marriages spanning more than 300 years. He pored over newsletters published by a CMT support group, and wrote articles for it.
Jay Lane, 42, of Takoma Park, learned that he had the family illness in 1990 while reading an article Mr. Jackson wrote in a newsletter for CMT sufferers.
"It all clicked then," Mr. Lane said. "My grandmother was from St. Mary's County, born and raised there, and she was a Mattingly. I just called him up and said, 'Hey, we could be related. Could we have the same thing?' "
Mr. Jackson wrote letters to Mattinglys all over the country and in England in an unsuccessful search for affected relatives. (Thomas Mattingly, the first member of the family to arrive in St. Mary's County, emigrated from England in the 1600s.)
Astonishingly, the afflicted descendants now all seem to live in Maryland. Branches of the family living in Texas and the Midwest, including that of pro baseball player Don Mattingly, apparently are not affected.
As he learned more about CMT, Mr. Jackson began to suspect that the Mattingly disorder was different. Few, if any, CMT sufferers wind up in wheelchairs. And CMT deadens sensory nerves as well as motor neurons, numbing the limbs. The Mattinglys don't lose any sensation.
Four years ago, Mr. Jackson retired from Black & Decker in Towson and turned all his energies on the illness.
"My biggest concern now is to find something that's going to help my son," Mr. Jackson said.
About two years ago, Mr. Jackson persuaded two Hopkins neurologists, David Cornblath and John Griffin, to undertake new research. They in turn recruited Dr. Philip Chance, a pediatric neurologist at the University of Pennsylvania specializing in genetic illnesses.
To help the scientists, Mr. Jackson arranged for a family reunion last June on Solomons Island, where researchers conducted interviews, physical exams and drew more than 100 blood samples so that DNA could be extracted.
Now they are using that data and the samples to hunt for the
gene.
The Mattinglys are closely watching the search.
Janet Michelle Lane, a 34-year-old member of the Mattingly clan who works at Montgomery College in Rockville, has had trouble walking since childhood. Now she is thinking about what will happen when she has a family of her own.
"We don't want to pass this on to our children," she says.
"My mother's hands are like fists, clubs," says her brother, Jay Lane, a mechanic with Prince George's County schools.
He holds up his own thin, delicate fingers, which curl slightly. "It deteriorates little by little."
Dr. David Cornblath flips through medical studies in his narrow office, located deep inside the Hopkins Hospital complex. He seems quiet, direct and intense.
He has scoured the reference books, read reports in medical journals dating to the 1890s, and talked to genetics experts.
And he's come up with a theory. He suspects that the Mattingly disorder is probably a variety of juvenile-onset ALS.
Both likely attack the body's motor neurons, which link the brain to the muscles. As these neurons die, they stop stimulating the muscles, which waste away.
Both disorders are caused by a dominant gene.
About 100,000 genes lie scattered through the 23 pairs of chromosomes packed into every human cell. Each chromosome is a gossamer coil of DNA, the chemical code that acts as a blueprint for the body. In each pair, one chromosome comes from the mother, one from the father.
In general, there are two types of genetic illness, dominant and recessive. To develop a recessive genetic illness, victims must inherit two copies of the same faulty gene, one from each parent. An example of such an illness is cystic fibrosis, which causes chronic lung infections.
In a dominant illness like the Mattinglys', victims need inherit only a single defective gene from one parent. Each child born to an affected parent has a 50-50 chance of inheriting that gene.
In both the Mattingly ailment and ALS, parts of the body controlled by the longest motor neurons -- the feet, lower legs and hands -- are the first paralyzed. In both, men seem to be more severely afflicted than women.
That's where the similarities end.
ALS, or Lou Gehrig's disease, named for the New York Yankee first baseman who died of the illness in 1941, usually strikes people over 50, spreads rapidly, and kills its victims in two to four years. Death generally results from a paralysis of the muscles that control breathing and swallowing.
The Mattingly disorder, while tragic, is neither swift nor deadly.
It starts around the ankles. Children may have trouble running and tend to trip over steps, curbs or their own feet. By the time the weakness reaches the midcalves, victims also begin to lose strength in their hands. They have trouble fastening buttons and turning keys in locks.
In their 30s, they may need ankle supports. In their 40s or 50s, canes. Then wheelchairs. But the disorder never reaches their necks and chests.
The Mattingly disorder, it seems, is always inherited. But only about 5 percent to 10 percent of the estimated 30,000 Americans with ALS have the inherited or "familial" form. Most have so-called "sporadic" cases. Their cause is unknown.
In 1993, researchers discovered that some with familial ALS have a defect in something called the SOD-1 gene, which produces an enzyme called the superoxide dismutase.
The enzyme neutralizes "free radicals," corrosive molecules produced by the body's normal metabolism. Unless the body's defenses intercept them, these molecules can rip through healthy cells.
After extracting the Mattingly family's DNA this summer, the Hopkins-Penn team sent samples to Harvard researchers for analysis. There was no sign of the SOD-1 gene.
That hunch was unfounded.
Still, scientists suspect the Mattingly disorder is a previously unknown form of another genetic ailment.
They just haven't been able to find the link.
"What's unusual about it is, if you go back in the literature and look at juvenile ALS, or other early-onset motor systems diseases, there are virtually no cases that are anything like this," said Dr. Cornblath.
In a University of Pennsylvania laboratory with blond wooden cabinets and glass walls, a cardboard box sits on a counter. Inside the box are about 100 spike-shaped plastic vials that contain the DNA of two-thirds of the living descendants of George Washington Mattingly.
Wielding a device that looks like a cross between a syringe and a squirt gun, neurologist Mena Scavina removes tiny drops of DNA from the vials.
Dr. Philip Chance, 41, watches from a stool.
Since 1992, working alone or in collaboration with others, Dr. Chance has nailed down the genetic basis of five different
inherited peripheral nerve disorders, including four varieties of CMT.
He has a personal stake in his work.
In high school, the soft-spoken Tennessee native was diagnosed with an inherited form of Charcot-Marie-Tooth, ending his hopes of becoming a professional musician.
The muscle wasting caused by CMT has left his wrists slim, his fingers delicate. "If you want to be a symphony clarinetist," he said, "you don't want CMT."
To start the hunt for the Mattingly gene, Dr. Chance examined segments of chromosomes where the genes for other inherited neurologic illnesses reside.
That process ruled out the most common forms of CMT, familial ALS and juvenile-onset ALS.
Now the researchers are conducting a chromosome-by-chromosome search.
"It's kind of a fishing expedition," Dr. Chance said.
In a vast ocean.
Think of each chromosome as a spiral staircase of DNA, with two interlocking molecules that form each step. There are 6.6 billion of these steps in the 46 chromosomes in every human cell.
These molecules are called nucleotide bases. There are four of ++ them: A (for adenine), T (for thymine), G (for guanine), and C (for cytosine). One step might consist of the pair AT, for example, for adenine and thymine.
Like the software that runs computers, genes are simply a form of information. They code that information into strings of bases that serve some function, such as ordering the production of a protein.
They are very small and difficult to find.
Unwound and stretched out, a single cell's worth of DNA would be about 6 1/2 feet long. That strand would be more than 37,000 times thinner than the human hair.
Imagine that this cell's worth of DNA was long enough to stretch across the United States. An average-sized gene, consisting of 30,000 base pairs, would span only about 31 feet.
Genetic defects can be caused by the substitution of one base pair for another, called a point mutation. On our continent-spanning DNA, that mutation would cover only 1/160th an inch.
Dr. Chance and his University of Pennsylvania team must genetically map the disorder -- that is, identify which chromosome it's on and roughly where on the chromosome it's located. They're looking for signposts called "markers": some detectable trait usually inherited with a disease.
Color blindness can be such a signpost. In some families, it is inherited along with hemophilia. That's because the gene that causes one lies very close to the gene that causes the other.
But markers tied to obvious traits are rare. To track down most genes, investigators have to use much harder-to-see signposts, patterns in the sequences of bases.
Over the years, scientists have pinpointed a whole series of these signposts, which are short base sequences.
There are about a thousand of them, more or less evenly spaced along the chromosomes.
What makes them useful is that, while they are found in the same general location in everyone's chromosomes, they vary slightly from individual to individual.
For example, one person might have 20 copies of the sequence CA (a cytosine followed by an adenine) at a specific spot. A second, unrelated person might have 30 copies of CA at about the same spot. A third may have 40, or 100, or whatever.
Here's how researchers follow the signposts:
Say a Mattingly man with the family's disorder has 20 repeats of CA at a specific site on a particular chromosome. Say his wife has 40 repeats in the same spot.
Using special chemicals called restriction enzymes, researchers can snip segments that include the CA markers from the couple's DNA samples.
With simple laboratory techniques, researchers can compare the lengths of these segments. The husband's will be shorter, because he carries fewer repeats of CA.
Suppose this 20-repeat marker shows up in some of the couple's children, but only in those who inherit the disorder from their father. All the healthy children share the mother's 40-repeat sequence.
Maybe the 20-repeat marker is inherited along with the gene for the Mattingly disorder, and the gene lies near it. But maybe it is just a coincidence. Look at the next generation, then the next and then at other branches of the same family.
If the 20-repeat marker keeps popping up in people with the disorder, you've mapped the general location of the gene.
"It's the kind of thing that given enough time you'll figure out," Dr. Chance said. "It's just a question of whether we will hit it on the 10th marker we study, or will it take 100 markers?"
Even then, researchers will know where the gene is only within a few million base pairs.
"You use more and more markers to zero in on, progressively, a smaller interval," Dr. Chance said. "It's like you're interested in finding someone. You find the city, the part of the town, then the block, then the room, then the part of the room."
Once the suspect gene is cornered, so to speak, researchers have to figure out how it differs from a healthy gene.
Some mutations are easier to spot than others. Some are caused the addition or deletion of scores or hundreds of base pairs. Others are caused by the change in a single base pair.
To spot tiny errors, researchers must use their most powerful biochemical magnifying glasses, and make a base-by-base comparison of the gene under scrutiny with a normal one.
Once they find the error, they must still figure out the defective gene's modus operandi.
Does the Mattinglys' faulty gene fail to produce a chemical that protects the motor neurons? Or does it produce too little of the chemical? Too much? Does it tell the body to make a chemical that attacks the neurons?
Using their discovery, researchers will probably devise a prenatal test and will launch a search for treatments.
"But the ultimate goal is to use the research as an approach to gene therapy," said Dr. Chance.
That means a corrected version of the gene might one day be inserted into afflicted Mattinglys. Or a gene might be introduced to counteract the destructive effects of the faulty gene.
It wouldn't be simple. It may, in fact, be impossible. Still, that's what scientists are aiming for.
Dr. Nancy Wexler stands before the molecular biologists and medical geneticists gathered at a Washington hotel for the annual Human Genome Conference and raises an issue that may confront the Mattinglys.
"If you say, 'Do you want to be tested?' " she said, "that is not a neutral question."
Dr. Wexler's mother and three of her maternal uncles all died of Huntington's disease, a late-onset brain disorder that triggers uncontrollable shaking and confused thinking. It is always fatal.
A professor of clinical neuropsychology at Columbia University, Dr. Wexler herself has a 50 percent chance of inheriting the illness. At 50, she is about the same age as her mother was when the first signs appeared. She has declined to say whether she has been tested.
Her family's experience inspired her, 15 years ago, to go to the Lake Maracaibo region of Venezuela, home of the world's largest concentration of Huntington's victims.
Like Andrew Mattingly Jackson, she organized an effort to collect medical histories and blood samples from victims and their families. Using that data and DNA, researchers mapped the Huntington gene to a general location on chromosome 4 in 1983. Scientists finally isolated the gene itself 1993.
Families with inherited illnesses are "enormously committed to having these genes found," she said. When radio stations reported the discovery of the gene for Lou Gehrig's disease, she said, members of these families "pulled off the road to cry with jubilation."
Treatments and cures, meanwhile, are elusive. Usually, the first practical benefits are a pre-natal test and tests to identify people destined to develop the illness.
These tests have been available for Huntington's disease for about a decade. But Dr. George Annas, professor of health law at Boston University, said 94 percent of the people who are at risk for the disorder, and who seek genetic counseling, decide they'd rather not know.
Sometimes, Dr. Wexler said, medical professionals mishandle the information. One person with a history of psychiatric problems was told, over the phone, that a test for Huntington's was positive. He committed suicide, she said.
While the Mattingly illness isn't fatal, it can be devastating. Family members may face many of the same issues.
Parents who learn, after having children, that they have any inherited illness may feel guilty about having put others at risk, Dr. Wexler said. Children who have no symptoms, but are told they carry the disease gene, can feel confused or stigmatized.
Researchers point out that genetic tests can be a tremendous relief to people who find they are not at risk. Others may want to know about their health status so they can better plan their lives. Some couples who would never have had children now do so, because of prenatal screening.
But Dr. Wexler says that doctors and others tend to push testing as a kind of treatment even where it's not helpful.
"People are told, 'If you're worried about getting it, go take a test," she said. "That's the American way."
Back in the nursing home, John Philip Mattingly, one of the oldest and most seriously afflicted members of the family, sips ice water and recalls, in a raspy voice, the lineage of his illness.
"My father had it," says the 72-year-old former bacteriologist with the state Department of Agriculture. "He was in a wheelchair for 25 years. Dad had five brothers, and two of them had it."
As a boy, John Philip often stumbled and fell. As he reached manhood, his feet and hands began to weaken. For years, he thought his problems were the result of a childhood bout with scarlet fever.
He didn't discover until he was middle-aged that his slow-motion tumble into paralysis was part of the Mattingly family legacy. "In those days, we did not know anything about this condition," he said. "It really was a mystery."
Mr. Mattingly's cousin, Anna Mae Wuenschel, sits in a wheelchair, pushed by her husband.
Over the past two years, the 72-year-old retired State Department employee has broken her right hip and her right leg in separate falls at their Silver Spring condominium.
When she was 35, she thought the weakness in her joints was arthritis. By the time she was 53, in 1975, she was tripping every afternoon.
The State Department sent her to the NIH for treatment. Doctors there didn't realize that she was a member of the extended Mattingly clan. They couldn't find anything wrong.
About five years ago, she was told she had the same disorder as her cousin, John Philip Mattingly. And, she discovered, her son had it as well.
She wishes there had been a test when she was younger.
"I would want to know," she said. "If I'd have known I had this, I would have traveled more. I love to travel."
There was one thing she would not have done.
"I would not have had children," she said. "I don't think it would be fair. It's bad enough now, the way the family is, without passing it on further."
Bonnie Mattingly Beardsley, who is now 46, sees things differently.
One day in 1974, she drove to the NIH. The same neurologist who diagnosed her father, John Philip Mattingly, asked her a few questions and watched her flex her ankles. He quickly confirmed her fear: She had the same genetic ailment. She was five months pregnant with her first child.
L "I teared up and said, 'What about my baby?' " she recalled.
A 50-50 gamble, the doctor said. "Do you want this baby?" he asked.
"I do very much," she said.
"Then go home and have a happy baby, and what comes, comes," he said.
Her toddler, Nick, looked "fat, round, happy, healthy," she said. But she noticed he couldn't stand from a squat without pushing off with his hands. Her doctor confirmed her fear: He had the Mattingly disorder.
All his life, she said, Nick has been willing to struggle. He struggled to wrestle in junior high school, and failed. He struggled to become an actor, and succeeded.
Today he is enrolled in a Florida college, spending the year in London in an acting program.
Ms. Beardsley never regretted her decision to have Nick. Later she gambled and had another child, a daughter, who was not affected.
"It comes back to the basic premise that, just because everybody doesn't walk the same, their life is still valuable," she said.
"I wish I didn't have" the disorder, she said. "I wish my son didn't have it. It bothers me a lot. I'm starting to feel my world is limited by it, and that really bothers me, bugs me, irritates me.
"But I'm still glad I'm here."
DOUGLAS BIRCH is a reporter for The Sun.