The connection between ataxia and cerebrotendinous xanthomatosis: how to treat
Yaz Kisanuki, MD, of the Department of Neurology at The Ohio State University Wexner Medical Center, talks about his personal experience connecting ataxia to cerebrotendinous xanthomatosis and why chenodeoxycholic acid is currently the “best” available treatment.
Question:
Can you talk about cerebrotendinous xanthomatosis (CTX) and the associated ataxia patients can experience?
Yaz Kisanuki, MD:
I learned [about] this disorder during my residency a long time ago at the University of Michigan. My former mentor taught me specifically that this is the disease that does not happen so often as a clinical practice, but you do not want to miss this group of patients because there is a few available medication, which is not yet approved from the FDA standpoint, but still available to slow down the progression or even to stop the progression if diagnosed early. After I finished my training and I came to the current institute, I think about maybe about 2 to 3 years down in my practice, I saw the first patient. I strongly remember that he’s still in the twenties, getting close to thirties and unfortunately he’s already quite symptomatic, developed cataracts around the age of 20, but unfortunately the ophthalmologist who saw him, this is always some issue, like pediatric ophthalmologists often recognize this rare disorder very carefully. They’re not going to just treat the cataracts only. They usually push further to do the workup, but unfortunately, whoever did the cataract surgery probably did not recognize this disorder. He finished the treatment, replaced the lens, but he’s completely not worked up.
Then later he began showing the neurological disorders, including ataxia. By the time I saw him, he unfortunately quite at advanced stage, wheelchair-bound, and he’s already showing a cognitive disorder as well. His speech is significantly affected. He also had that very classic like tendinous xanthoma in his Achilles tendons and the family and the patient was saying that, “Oh, well, we like to see the orthopedics to try to get the treatment.” I basically say, “I don’t think this is going to be an orthopedic issue. You have some potential rare genetic disorder.” We did the workup and of course the testing was positive.
I mean, it was a biochemical testing. We did it, and then we started on the treatment. Unfortunately, his condition was well advanced, so he later I think after about 3, 4 years later, he suffered from the aspirational pneumonia and [went] on to be deceased very young age. After that I diagnosed probably about 2 to 3 more adults… Actually 4 more adult patients in my clinic. Some of those adult onset patients are very kind of not so typical presentation. They do came from the primarily neurologic disorder without having the cataract nor xanthoma sometimes. That’s what atypical presentation can be, so that when it comes to the fresh case of the relatively young adult or middle-age adult onset of progressive ataxia, I would say that we should at least screen, but least keep some this disease in mind because there is available testing to get the diagnosis. But if you don’t know anything about it, then you have no clue how to diagnose this disorder. That’s how important it is.
Question:
What treatment or management options are there for patients with CTX with and without ataxia related symptoms?
Yaz Kisanuki, MD:
Probably the best available medication to directly slow down or suppress the progression is the chenodeoxycholic acid. There’s a similar compound called cholic acid is also available. Both are not completely approved [from] the FDA standpoint. However, historically, we’ve been using one of these. From the limited case series that we already noticed that these are the first-line medications. Now, sometimes these medication can be combined with the HMG-CoA reductase inhibitor such as statin to try to improve the efficacy. But I think still the bottom line is that chenodeoxycholic acid is probably the first choice. I think from my limited experience, I’m going to say, cholic acid can have a little bit less side effect in terms of the GI and liver enzyme side effect. But when it comes to the suppression of the toxic metabolite due to this enzymatic deficiency from the CTX, I would say chenodeoxycholic acid is still superior.
Now, obviously this patient can manifest the variety of the symptoms, so ataxia is one of the probably most disturbing symptoms. For the ataxia-wise, the management of the ataxia-related symptoms are not so much different from the other type of ataxia patients. Sometimes, we use the beta blockers such as propranolol or sometime primidone to try to suppress the tremors. They also develop the spasticity mainly in their legs and these can be treated by the antispasmodic medications such as baclofen or tizanidine, whatever the choice of those medications. Now, they also can develop the peripheral neuropathy on top of it, and those neuropathy symptoms can be quite disturbing because of the paresthesia. For those symptoms that still… I mean, we use the very typical standardized like neuropathic pain management, including pregabalin, gabapentin, or tricyclic antidepressant or even SSRI such as duloxetine, nortriptyline, amitriptyline, you name it, basically.
The rest of the symptom managements are not particularly unique to the CTX population, but I think the main take-home message is the chenodeoxycholic acid. Now this is still, I’m going to say preliminary and it’s not completely official result yet, but there is actually the recent conducted clinical study to try to seek for the FDA approval for the chenodeoxycholic acid over the CTX because the chenodeoxycholic acid is still currently only approved for the gallstone treatment. But these days, gallstone treatment is done by the other medications. Speaking of the practical usage wise, chenodeoxycholic acid is more likely only spared for the CTX patient these days.
