Make the Diagnosis: CTX and Early-Onset Cataracts
Ernst Schaefer, MD, professor of medicine at Tufts University School of Medicine in Boston and chief medical officer and laboratory director at Boston Heart Diagnostics, recently presented a session at the National Lipid Association Scientific Sessions on cerebrotendinous xanthomatosis (CTX). The condition is often marked by early-onset cataracts in adolescents and young adults. He spoke about the impact of the condition, what ophthalmologists should know about the associated cataracts, and treatment options.
Question:
You were part of a presentation that took place at the National Lipid Association Scientific Sessions, titled, “The Hidden Impact of Sterile Disorders: Differential Diagnoses in CTX and other Lipid Disorders.” What were the key highlights and takeaways from that session?
Ernst Schaefer, MD:
The key highlights and takeaways were that you have to think of the diagnosis, and this is a disease where often the diagnosis is missed until people are in their 30s. By then, they’ve often developed pretty bad neurologic disease. It’s important to make the diagnosis much earlier because we know now that we can prevent the disease if we identify it, diagnose it, and treat it.
Question:
Can you talk about genetic testing for CTX and the potential differential diagnoses?
Ernst Schaefer, MD:
The first step is how these cases present. They often present in childhood with diarrhea and learning problems, and then in their teens they often, more than two-thirds of them, develop premature cataracts. At that point, it’s important to think of the disease, and the genetic diagnosis is made by sequencing the gene that’s specific for cerebrotendinous xanthomatosis.
It’s a defect in a gene that’s important for forming bile acids, if you will, from cholesterol. When that does not happen, bile acids aren’t made and cholestanol builds up. You can diagnose the disease by measuring cholestanol and other sterols in the bloodstream at Oregon Health Sciences University, Dr. Andrea DeBarber. You can make the genetic diagnosis at the gene locus CYP27A1 by getting DNA sequencing done by Prevention Genetics in Marshfield, Wisconsin.
Question:
What are the challenges in distinguishing CTX from other lipid disorders, and what can be done to ensure earlier diagnosis and management in patients with CTX?
Ernst Schaefer, MD:
The other thing that I have not mentioned is that these cases often present, about 80% of them, with unusual cholesterol deposits or xanthomas on their tendons of their hands and their Achilles tendons and on the elbows. Most patients that have cholesterol deposits or xanthomas have high blood cholesterol levels, but these patients don’t. They tend to have normal cholesterol levels.
If the doctor sees a patient with a normal cholesterol level, say about 200 mg/dL, and yet they have these cholesterol deposits, then they should think of this disease, cerebrotendinous xanthomatosis, also abbreviated as CTX.
Question:
Early-onset cataracts are a common feature in patients presenting with CTX. Can you talk about the importance of educating physicians on this? How can physicians connect these cataracts with a potential CTX diagnosis?
Ernst Schaefer, MD:
Yeah, that’s a very important question. I think now the ophthalmologists have become increasingly aware of the presence of very premature cataracts. When you see cataracts in a 15-year-old child or young adult, then you should think of this disease, because most cataracts occur in people who are over the age of 65.
Premature cataracts, one of the diseases that causes this is CTX. It’s really important to make the diagnosis, especially at that stage, because these people have a block in producing bile acids. Giving them the bile acid that they don’t make, like chenodeoxycholic acid or chenodeoxycholate, which is readily available at a dose of 250 mg, 3 times a day, orally, stabilizes the disease and prevents the progression of the disease.
It’s especially important in preventing the neurologic disease because if this disease is not diagnosed and not treated, many of these people end up in wheelchairs by the time they’re in their 30s and then they die from the disease in their 30s or 40s. Whereas if you diagnose them, let’s say, in their teens, I have several patients that have now been on treatment for more than 20 or 30 years and are doing just fine.
My colleague, Dr. Gerald Salen, was a pioneer in this field, and when he died, he passed on many patients to me. He died unfortunately at the age of 85, but he made huge contributions to this field.
Question:
Once CTX is suspected due to the presence of early onset cataracts, what should clinicians do?
Ernst Schaefer, MD:
There’s a leukodystrophy foundation, but as I mentioned, sending a sample of urine and a sample of serum or blood to the Oregon Health Sciences University Laboratory in Portland, Oregon, Dr. Andrea DeBarber. They will run the testing, actually, free of charge because they’re funded by a different source. The same goes for the genetic testing at prevention genetics.
They’re also funded because there are foundations and companies that are interested in making sure that the diagnosis is made and that these patients are identified and treated. I should say that there was a very nice paper by Dr. [Sharon] Friedman and colleagues in the Journal of the American Medical Association, several years ago on premature cataracts in these cases of CTX.
Question:
Can you talk about chenodeoxycholic acid and its use in patients with CTX?
Ernst Schaefer, MD:
Because there’s a block in the formation of the bile acid, chenodeoxycholate, this allows other products to build up, byproducts of cholesterol metabolism like cholestanol, which accumulates in the brain and in tendon xanthomas and causes significant … and also in the eyes. But there are other metabolites as well, some of which can readily be picked up, not only in the blood but also in the urine.
If you give these patients the bile acid, they do not make, it suppresses the of these byproducts and stabilizes and prevents further development of the disease. Chenodeoxycholic acid, or cholate CDCA, is the treatment of choice, and the standard dose is 250 mg given orally 3 times a day, and it’s available through Mirum Pharma.
One of the things about this disease that is [that] makes it a little harder sometimes is not all the patients will get the premature cataracts. Not all the patients will get the unusual large xanthomas. That sometimes makes it hard to diagnose the condition. But certainly if somebody has premature cataracts, they should think of this disease. Certainly if somebody has tendon xanthomas with normal cholesterol, they should certainly think of this disease.
