On Thursday we challenged Well readers to solve the difficult case
of twin sisters who, in the prime of youth, developed a weakness that
forced them to use their arms to rise from a chair. Nearly 300 of you
wrote in with thoughts on this difficult case.
Many of you recognized
that this was likely to be a genetic disorder, though I greatly admired
the “House”-ian thinking that led to a host of possible reasons why two
sisters, living in different states, might develop the same symptoms
independent of their shared DNA. It took this patient, Katie Buryk, four
years to get her answer, which was:
Late onset Tay-Sachs disease
Although several of
you made this difficult diagnosis, the first to do so was George
Bonadurer, a second year medical student at Mayo Medical School in
Rochester, Minn. He says he recently read about this disease in a book
of unusual cases that had come to the Mayo clinic for help. This is
actually Mr. Bonadurer’s second win of this contest. Strong work!
Katie Buryk finally received a diagnosis for the mysterious muscular weakness she has suffered since childhood.
By Colin Archdeacon on Publish Date May 8, 2015.
The Diagnosis
Tay-Sachs disease was first identified by two physicians, independently, in the 1880s. Dr. Warren Tay was an ophthalmologist in London. Dr. Bernard Sachs was a neurologist in New York City. Each described a disease in infants that caused profound weakness, blindness and, usually by age 4, death. Careful consideration of cases over the following decades showed that the disease was inherited and often seen in children of Ashkenazi descent. Studying the patterns of inheritance, it became clear that both parents had to have the abnormal gene and that each of their children would have a one in four chance of being born with the disease.The terrible manifestations of the disease derive from an inherited inability to make an essential protein in the brain. This protein acts to break down discarded components of the cells. Without this protein, these discarded cell parts accumulate, interrupting normal nerve and brain cell functioning. This mechanism and the missing protein was identified in 1969, allowing for the development of a test for carriers. Since the development of this test, the incidence of Tay-Sachs in the United States has dropped by 90 percent.More recently, genetic studies of the disease have shown that there are dozens of mutations of the gene that makes this protein. Some mutations will prevent the body from making any of the essential chemical, called hexosaminidase A, resulting in the infant form of the disease initially identified. Other mutations allow the body to make some version of the protein, and these patients will develop signs of the disease at a later age. In patients with one of these delayed forms of the disease, known as juvenile Tay-Sachs and late onset Tay-Sachs, the manifestation of the disease as well as its progression can be quite varied. Most will have problems with balance as well an abnormal gait, and some abnormalities of speech. Some will have psychiatric problems as well.All varieties of Tay-Sachs are seen more commonly in three populations: people of Ashkenazi descent, as was initially described, as well as those of French Canadian and Louisiana Cajun heritage. It is much less common in the latter two groups than it is in the Ashkenazi population. However, not everyone who has Tay-Sachs is from one of these groups. According to the patients’ parents, they are neither Jewish, nor Canadian, nor Cajun.
How the Diagnosis Was Made
Dr. Cristina Drafta, the patient’s neurologist, sent the young woman to be tested for spinal muscular atrophy, or SMA, a genetic disorder which, while rare, is the most common genetic cause of diffuse weakness. Those with SMA are born without the ability to correctly make an important structural protein in the spine that allows the brain to communicate with the muscles in the body. As with Tay-Sachs, there is a range in disability. Those born with none of this protein have extreme weakness and die in early infancy. Those born with a defective version of the protein may develop weakness later in life. The genetic test showed that the patient did not have any of the most common genetic abnormalities linked to SMA.Still, the SMA expert the patient saw was intrigued by her case. He thought she might have some kind of autoimmune disorder in which the patient’s natural defense system had mistakenly started attacking the nerves going to the muscles. He treated the patient with IVIG, a treatment made up of antibodies taken from thousands of blood donors, which is often used in the treatment of some autoimmune disorders. However, the infusion made the patient sick and didn’t help her weakness. Discouraged, the young woman returned to Dr. Drafta.
Searching for the Right Gene
The doctor felt pretty certain that the patient had some type of genetic defect that was affecting the nerves and the muscles, but there are many such diseases. And now that it was clear she didn’t have the most common defect, it seemed ridiculous to test her for each of the others, one disorder at a time.Getting her entire genome sequenced seemed the more direct route to the answer they sought, but because the test is wildly expensive, her insurance company was not eager to pay for it. So Dr. Drafta referred the patient to a clinic at Columbia University that specialized in neuromuscular diseases. Maybe they could figure out which of the diseases she was most likely to have.After an initial evaluation at the clinic, the doctors there agreed with Dr. Drafta – the best and most efficient way to get a diagnosis for this patient was to sequence the entire genome and look for a known genetic abnormality associated with one of these diseases. The patient was a little worried; would her insurance company pay? If not, she wasn’t so sure that she could afford to get the test, though of course, she would if she had to.A definitive diagnosis would be the only way to know if there was any effective treatment for this slowly progressive weakness. Don’t worry, the genetic counselor assured her. They had a lot of experience helping insurance companies understand when and why such extensive testing was needed. They took a sample of blood from Katie, as well as from her twin and both her parents. They would need to look for a gene that was shared by both twins. And that gene needed to have a matching version in each parent. It was a complicated assessment and usually took months.The patient had already made an appointment with the Mayo Clinic. She went and saw several doctors there and had many, many tests. At the end of her visit, they told her that they were not able to make a diagnosis. They had considered late onset Tay-Sachs, but she had only mildly reduced levels of hexosaminidase A and this, they thought, was not sufficient to cause her weakness. It turns out they were wrong.
A Diagnosis and a Plan
Katie finally got a call from the genetics lab, some four months after they had collected her blood. They had an answer. Could she come in to talk with them? And perhaps she should bring a friend.Hearing this, Katie’s heart sunk. She was eager for an answer, but the fact that they wanted to break the news to her in person told her that the news was bad. When she heard the diagnosis, Katie began to cry. She had read about this disease. It was very bad news.By the time she told her parents, Katie was done crying. As her mother wept, Katie sat perfectly composed; she had a plan. This was an orphan disease. There were too few people with the disease for any drug company to want to devote the time and money to look for a treatment. Maybe they didn’t need a drug company; she would raise the money herself to help fund this research, by creating the Katie & Allie Buryk Research Fund. Whatever that research uncovers might not be done in time to give her the help she wanted — though she certainly hoped it would — but it would help the people who came after her. And anything she could do to make this easier for somebody was worth doing.In the meantime, there was a drug available that made the hexosaminidase A she had – because she did have some – work better. This medication, originally (and still) used as a drug to fight malaria, has been shown to slow the progression of the disease. Her sister is planning to take part in a study looking at another medication.
Staying Strong
Katie still goes to work every day. Stairs are her biggest problem day to day, but she has organized her life in New York City to avoid them. She walks to work. There is an elevator in the building to take her to her floor. If she is too tired to walk home at night she will take the bus, or sometimes a taxi.Before she goes anywhere she makes sure that if there are stairs, there is a way to avoid them. And she works out as many days as she can. She is going to work hard to maintain the strength she still has. It is going to be a long road, she knows, and she wants to be strong enough to take it.
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