Early Onset Familial AD
Interview: A Diagnostic Odyssey
In this conversation with Gabrielle Strobel, the husband of a 39-year-old mother of three recounts how the couple spent nearly 2 years with erroneous diagnoses and useless treatments of his wife's condition until she was correctly diagnosed with early onset familial AD (eFAD). All names are pseudonyms.
ARF: Brad, what were the very first signs you noticed in Megan?
Brad: Her limp, in July 2004. Looking back, I now recall memory lapses that spring, but we chalked them up to having too much on her mind. In August, her brother noticed forgetfulness and that made me think there might be more to it. We saw an orthopedist, who could not find anything to explain her limp. Then we saw a chiropractor, and she recommended we see a neurologist. It was a community-based neurologist who initially thought of a brain or spinal cord tumor, but the spinal tap and blood work and MRI were negative. The neuropsychological test at that time did show mild to severe impairment in some areas. Megan had been at the top of her class in high school and college and had home-schooled our kids. I should have given those tests more weight right away but did not know better at the time.
ARF: Did you get a diagnosis then?
Brad: The neurologist diagnosed conversion disorder. [MedlinePlus, an online encyclopedia run by the U.S. National Library of Medicine defines conversion disorder as "a psychiatric condition in which emotional distress or unconscious conflict are expressed through physical symptoms." An alternate name is "hysterical neurosis."] I should not have believed that. I've seen stressed people get depressed and forgetful but that does not come with a limp. The neurologist assured me that sometimes people get stomachaches or headaches when they are stressed, so it could just be an unusual case. The neurologist knew about her memory loss but just did not think of Alzheimer's.
ARF: How severe was her memory loss at the time?
Brad: Mild. But Megan often had trouble finding the doctor's office, for example, even though she was familiar with the route. She got disoriented. He knew that. That should have been a sign.
So we started down the depression route. We also saw a psychiatrist, who prescribed antidepressants. She tried various different ones. We went to psychotherapy sessions once a week. I was eagerly anticipating changes but nothing happened. She might be a little bit more engaged and I was trying to hang on to that, but meanwhile her walking was getting more labored and she was having trouble with her balance. The neurologist said that today's antidepressant drugs have faster onset and should take us 60 percent toward recovery, and psychotherapy and removing stress from our lives would do the rest.
ARF: Did it?
Brad: No. We de-stressed wherever we could. We did not worry about things left undone in the house, went on a cruise while her parents watched the kids for 3 weeks. We really went stress-free into the winter of 2005, but she kept deteriorating. I went back to the neurologist several times, but he kept telling me that I had not given the therapy enough time.
We had called the nearest academic medical center in August but had to wait 3 months for our first appointment in November. In the meantime, I quizzed our neurologist about every possible explanation I could find, like vascular dementia or hormonal deficiencies. He talked about various rare diseases he'd considered, but AD was not one of them. He did say that as a community-based physician he had exhausted all his avenues, and that the academic center might find even rarer diseases. Except AD isn't that rare. I would like to follow up again with him now, just to make him aware.
ARF: At the university medical center, where did you start out?
Brad: At a palliative care clinic. Our psychiatrist referred us, perhaps because the head of the clinic is a psychiatrist. The psychiatrist at the clinic also went down the conversion disorder route, and talked about teaching us how to cope with stress. He prescribed the antipsychotic Risperdal. Megan had no psychotic symptoms. In her interview at the clinic, she clearly was having trouble recalling words, remembering the psychiatrist's questions.
ARF: What happened next?
Brad: I was getting frustrated. I pressed the psychiatrist and then we got to see Dr. Myer [a pseudonym for a noted academic AD specialist]. He knew right away Megan had a neurologic disease. After 2 minutes, Dr. Myer noticed weakness on her left side. He was upset about the Risperdal prescription and took her right off it. He took her blood and called us the next morning that her iron levels were high and that she needed a test for hemochromatosis (see Medline) [a disease of iron overload; for links between hemochromatosis and dementia, see ARF Discussion; comments at Collingwood et al., 2005]. She tested positive for having a double copy of a hemochromatosis disease gene. A liver biopsy confirmed the disease and she then had phlebotomies to get her blood iron levels back down to normal.
ARF: Did you think you had your explanation? After all, hemochromatosis is only rarely associated with early onset AD.
Brad: Initially, yes. But there was a lot more. Her hemochromatosis was not typical, and Dr. Myer soon found that Megan also has an alpha-1 antitrypsin (AAT) mutation. In the spring of 2006, he did a PET scan of her brain. He showed us that one brain area was less active on the left side of her brain. Her weak side was also the left, so you would have expected less activity in the right side of the brain. He said this resembles a pattern I've seen in AD, but you are too young for AD. We decided to test first for ApoE, which came back negative for the high-risk E4 allele. Then for APP and that came back negative, but then the presenilin-1 came back positive. Then she started on Aricept, and on high-dose statin because her cholesterol is high as a family trait.
ARF: Megan, did you notice an improvement on those drugs?
Megan: I can't tell. … I feel pretty good. I try to think positive. … Nobody knows what is going to happen later. I don't know.
ARF: What is it like when you can't recall something that you know you knew at some point?
Megan: It is frustrating. … I tell people that I am good at going forward but not good at going backward. If somebody asks me about something that was yesterday, I won't know. But if you talk to me about tomorrow, that will be fine. I understand that is a problem. I try not to worry too much about it. I just try to do as much as I can.
ARF: What was the low point?
Megan: When I found out about the Alzheimer's. I am praying that it will get better.
ARF: Brad, knowing what you know now, what do you want to see change?
Brad: I want the community-based physicians to not go straight to depression when they encounter something they can't explain, especially when there is no history of depression in that person. As I was reading up on MS, vascular dementia, and even Parkinson's, people sometimes get sent down the depression route first. It wastes precious time and frustrates the patient and family.
Doctors in community settings have become more aware that depression is common, but they are not aware that AD, too, is not that rare, at least not in people in their fifties and even forties. I have had to learn that, and physicians should all know it, too.
If it's not depression, the family really needs to go to an academic medical center. I don't understand why our neurologist did not refer us there earlier. Why did he hold on to the depression diagnosis for a full year when it obviously was not working?
I also think they could have noticed the iron component earlier. It was a straightforward blood test. Apparently, unless a patient comes in with anemia, community-based physicians will not test iron if the symptoms are psychiatric, as they thought initially. But hemochromatosis is not that rare, either.
ARF: You were articulate and persistent in your dealings with your physicians. If you had been less forceful, would you have seen Dr. Myer?
Brad: No. If I was like many people who tend to accept what the doctor says as final, we'd still be going to psychotherapy.
Editor's note: Cases where a person has separate independent mutations for hemochromatosis and for eFAD are rare. Even so, doctors should be aware of the genetic complexity of eFAD. Researchers have associated hemochromatosis genes and high brain iron levels with an increased risk for Alzheimer disease, and they are beginning to study how additional genetic changes can interact with eFAD mutations to lower the age when a person with eFAD mutations develops the disease (e.g., Connor and Lee, 2006; Lehmann et al., 2006; Schmechel et al., 2006).
NEXT: Genetic Testing and Counseling for Early Onset Familial Alzheimer Disease