When the White House announced it was exploring leucovorin as a treatment for autism, the calls from families started pouring in: “Can you prescribe leucovorin for my child?”
We experience versions of this frequently: an unproven treatment gains momentum on social media, and we as physicians must become informed enough to counsel families who are counting on us for answers. Not surprisingly, a recent analysis published in The Lancet showed a 71% increase in outpatient leucovorin prescriptions for a few months after the White House suggested the drug as a potential autism treatment.
The White House’s promotion of leucovorin suggested that millions of people with autism have an ultra-rare condition called cerebral folate deficiency (CFD). The Lancet report captures exactly what concerned me when I heard the announcement: that physicians would feel compelled to prescribe an unproven treatment, predicated on an underlying diagnosis that most children with autism almost certainly do not have.
In reality, FOLR1-CFD — for which leucovorin is an appropriate off-label treatment — is so rare that less than 100 cases total have been reported worldwide. For people with this condition, mutations in the folate transporter gene FOLR1 prevent folate from being transported into the brain. Low cerebral folate levels cause people with untreated CFD to have more than just autism. They also have severe cognitive impairments, developmental regression, epilepsy, and movement disorders. This kind of CFD can be treated with leucovorin, a folate derivative that enters the brain through a different mechanism that doesn’t require the FOLR1 transporter. The diagnosis of FOLR1-CFD is confirmed with a combination of genetic testing and a spinal tap to measure folate levels in the brain.
In addition to asking about leucovorin, families are also inquiring about testing their children for autoantibodies against the folate transporter. The premise is that autoantibodies inhibit the FOLR1 transporter, which leads to CFD and autism. This is an interesting idea, but that doesn’t make it true. The blood test, which is only available from one commercial lab, has a cute name (Folate Receptor Autoantibody Test or FRAT), costs hundreds of dollars, and is not covered by insurance. Not only does the test have a high false positive rate, but the presence of an autoantibody alone does not equate to having an autoimmune disease. Using a positive folate receptor antibody test to diagnose a child with CFD would be like using a positive antinuclear antibody (ANA) test to diagnose lupus.
In the months since the White House announcement, one of the largest randomized, placebo-controlled studies on the use of leucovorin to treat autism was retracted for data inconsistencies. In addition, the American Academy of Pediatrics, the Society for Developmental and Behavioral Pediatrics, and the Child Neurology Society released guidelines recommending against leucovorin for autism treatment and recommending against folate receptor autoantibody testing for people with autism. And even though the White House reversed its stance on leucovorin for autism and acknowledged that there is insufficient evidence of its efficacy, the damage was already done.
What Do We Tell Families?
When I step back, it’s clear that families are asking about leucovorin the same way they inquire about gluten-free diets, stem-cell tourism, and broccoli extract. I take every one of these conversations seriously, because the underlying question — is there something treatable? — is the one I’m also asking.
I educate families that profound autism is a symptom of 1,000 rare neurogenetic diseases. I now routinely offer genome sequencing to families to understand if their child has one of these conditions. It’s a noninvasive test (just a cheek swab) — no lumbar puncture required. I tell families that doing a “spellcheck on the DNA” is the first step in their diagnostic and treatment journey.
Identifying the cause of each child’s disability is becoming increasingly important because we are entering the era of precision medicine for neurodevelopmental disorders. A growing number of autism-associated conditions already have treatments available or treatments being tested in clinical trials.
I tell families that getting the right diagnosis is what puts their child in line for when treatments become available for their condition. If testing reveals a treatable cause for their child’s disability, we can act on it immediately. If their condition isn’t treatable today, rapid advances in precision medicine mean it may be tomorrow. And if current testing does not provide an answer, we can retest in a few years once technology and our understanding of neurogenetics have advanced.
For families who aren’t able to obtain genetic testing clinically, I recommend they enroll in a study to obtain testing on a research basis.
Families of autistic children are navigating long wait times with a limited number of neurodevelopmental specialists and real gaps in treatment for core features of autism. They deserve the best that science and medicine have to offer. That doesn’t include prescribing drugs without scientific evidence, which are unlikely to help and could even cause harm.
Audrey C. Brumback, MD, PhD, is a pediatric neurologist specializing in autism spectrum disorder at Dell Medical School at The University of Texas at Austin.
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