Science / Medicine : Deft Diagnosis : Segawa’s Dystonia Mimics Cerebral Palsy but Is Treatable
By successfully treating a little-known disorder that is often misdiagnosed as cerebral palsy, researchers are gaining valuable insight into an entire class of chronic neurologic conditions, including Parkinson’s disease.
The disease, known as Segawa’s dystonia, may afflict as many as 10,000 people in the United States but often goes unrecognized. Like cerebral palsy, the crippling disorder is marked by tremors and rigidity. But unlike most other neurological disorders, Segawa’s is readily treated with small doses of L-dopa--the drug used to treat Parkinson’s.
A dramatic example of Segawa’s--and of the ability of L-dopa to alleviate it--may be seen in the case of Kimberly Nelson of Trinity, N.C.
When she was 7, Kimberly developed what her mother, Brenda, called a “funny walk. Her balance was not real good and she would fall down frequently.”
By the time she was 14, Kimberly had to hold onto walls or another person to walk and could travel only a short distance. She usually walked on her toes to maintain her balance, her head bent distinctly to the left, her left arm had started “turning in” and her left hand often involuntarily clenched into a fist.
Ron and Brenda Nelson took her to hospitals throughout the country. “Everything they did--tests, CAT scans, myelograms, MRIs--came back normal; there was nothing they could find anywhere,” said Brenda Nelson. “We were at a dead end.”
After a chance conversation with a physician friend in church, the family visited the National Institutes of Health, where they met neurologist John K. Fink. Fink and his colleagues suspected that Kimberly had Segawa’s.
To test their theory, they gave her a tablet of L-dopa, the drug normally used to treat Parkinson’s disease that has been used successfully on Segawa’s patients for more than 20 years. Brenda recalled that an hour or two later, as the family walked through the NIH lobby on the way to dinner, “She said, ‘Look, Dad! I can walk without holding on. I can keep my balance now.’ It was like a miracle had taken place in front of our eyes.”
That was in December, 1989. Kimberly has been on L-dopa ever since and now has “no symptoms at all.” The high school sophomore played on the softball team at school last year, is active in her youth group and last month was inducted into the National Honor Society. In short, she is able to do everything that other girls her age do.
Miraculous as it may seem, Kimberly’s recovery is not unusual. Virtually all patients with Segawa’s exhibit a similar renaissance when given the drug, and the effects are long-lasting, according to a report in the most recent issue of the journal Neurology. Unfortunately, “the majority of people, including most neurologists, are simply not familiar with it (Segawa’s),” said Fink, who is now at the University of Michigan Medical Center in Ann Arbor.
(Similar, dramatic recoveries of comatose patients given L-dopa have been documented by neurologist Oliver Sachs of the New York Department of Health in the book “Awakenings” and in the movie of the same name. Those patients, however, suffered from encephalitis--sleeping sickness--unrelated to Segawa’s, and their recovery was only temporary.)
Fink estimates that as many as 10,000 people in the United States may suffer from Segawa’s without knowing it, with women about 2 1/2 times more likely to have the genetic disorder than men. In many cases physicians are not able to make any diagnosis. In others, it is mistaken for a psychological problem. But most often it is misdiagnosed as cerebral palsy, he said.
Fink and other researchers are searching for more patients with Segawa’s, both to help them and to learn more about the unusual disease. “Once we figure this out,” he said, “it will be a model for understanding other inherited neurological or psychiatric disorders, such as Parkinson’s disease.”
Some researchers think Fink’s estimates of prevalence may be a little too high. But, noted neurologist Roger C. Duvoisin of the University of Medicine and Dentistry of New Jersey in New Brunswick: “I’m sure there’s more of it than we recognize. . . . I often think and wonder what has happened with patients we’ve missed in the past.”
“There are certainly lots of cases, it’s just a question of recognition and diagnosis,” added neurologist Torbjoern G. Nygaard of the Columbia-Presbyterian Medical Center in New York City, lead author of the Neurology paper.
Many of the symptoms of Segawa’s dystonia do mimic cerebral palsy, which usually results from a brain injury before or during birth. An estimated 750,000 Americans suffer from cerebral palsy, for which there is no effective therapy. Leg spasticity inhibiting the ability to walk occurs in both disorders. “Virtually every one of the (Segawa’s) patients I’ve seen had been told he or she had CP,” Fink said.
But Segawa’s has several unusual characteristics that set it apart from cerebral palsy and other neurological disorders. Most unusual is that the symptoms are usually least severe in the morning, becoming more incapacitating through the course of the day.
Because of this diurnal variation, Segawa’s is often mistaken for an emotional problem. “Children get up in the morning, get dressed and walk to school,” Fink said. “By midmorning, the school nurse calls to say they are unable to walk. Parents are often told it is an emotional disorder such as separation anxiety or regression.”
The other major factor that distinguishes Segawa’s from cerebral palsy is that the former often runs in families, while the latter virtually never does.
U.S. researchers have identified more than a dozen large families in which the disorder is common. These families are particularly important in the quest for the cause of the disease because studies of their DNA (deoxyribonucleic acid, the genetic blueprint of life) will eventually enable researchers to find the particular gene that is defective. Such studies of families have been used by other researchers to identify the causes of a variety of genetic disorders, such as muscular dystrophy and cystic fibrosis.
But that solution is far from close. “Right now, we don’t even know which chromosome it (the defective gene) is on,” Nygaard said.
Cases of Segawa’s have been sporadically reported in the medical literature since at least 1947, Duvoisin said, but the first complete description of the condition and its response to L-dopa was produced by neurologist Masaya Segawa of the Segawa Neurological Clinic for Children in Tokyo in 1971. He called it “hereditary progressive dystonia.” Segawa “has spent the last two decades going to meetings around the world and talking about his patients,” Nygaard said, and his name has thus become closely associated with the disorder.
Dystonia is a neurological disorder characterized by powerful, involuntary muscle spasms that jerk parts of the body into unusual postures. Between 100,000 and 200,000 people in the United States suffer from dystonia, according to UCLA neurologist Charles Markham, medical director of the Dystonia Research Foundation. Segawa’s, which may account for no more than a few percent of all dystonia cases, is the only form of the disorder that responds to L-dopa.
Researchers have identified the approximate location of the genetic defect that causes the most common form of dystonia. But researchers have shown that that gene, located on chromosome 9, is not the cause of Segawa’s dystonia.
The changes induced by Segawa’s in the brain are apparently very subtle. Victims of the disorder show no mental abnormalities and studies conducted by neurologist Donald Calne of the University of British Columbia in Vancouver with positron emission tomography show no difference in brain activity between Segawa’s patients and healthy individuals.
But as is the case with Parkinson’s victims, there is a deficiency of dopamine in the brains of Segawa’s patients. Dopamine is a neurotransmitter, a brain hormone that is involved in the control of muscle activity by brain cells. It is deficient to a much greater extent in patients with Parkinson’s disease, and the amount of L-dopa required for Segawa’s is only about one-fifth the amount required for Parkinson’s.
Nevertheless, researchers believe that similar mechanisms may be at work in the two diseases and that their findings on Segawa’s may lead to new treatments for Parkinson’s as well. But at this stage, Fink said, it would be premature to speculate what those treatments might be.
In the Neurology paper, Nygaard and neurologists Stanley Fahn of Columbia and C. David Marsden of The National Hospital in London report on studies of 66 patients with Segawa’s. The majority, 61 of the patients, showed no return of symptoms after as long as 22 years of treatment with L-dopa.
Four men and one woman showed some “wearing off,” a less satisfactory response to the drug, after the first few years of therapy. Nygaard speculated that these five did not have true Segawa’s, but may have had a form of Parkinson’s disease.
Research also has shown that the brains of Segawa’s victims are deficient in biopterin, a chemical that is necessary for the synthesis of dopamine. Fink speculated that the defective gene is the blueprint for a protein important in the synthesis of biopterin.
While Segawa’s dystonia is both rare and rarely diagnosed, patients with the disorder might provide clues to many other disorders. “That’s what we’re hoping,” Fink said, “that cures for a whole class of neurological diseases will be discovered.”
“If we can find out what causes (Segawa’s),” said neurologist Matthew Brin of Columbia, “it may give an insight into what causes dystonia in general and why some people develop Parkinson’s. . . . We’re always looking for insights into the cause of that condition.”
Search Is On for Segawa’s Victims
Neurologist John K. Fink is searching for other victims of the disorder, and constantly flies around the country to visit patients who can’t come to see him. Fink asks that people who think they or a family member have the disease write to him. He will send them information about the disease and where to go for an evaluation.
His address is:
J. K. Fink MD
Neuroscience Laboratory Building
1103 E. Huron Street
Ann Arbor, MI 43104-1687
