Identifying and Diagnosing Genetic Leukodystrophies as MS Mimics


Alise Carlson, MD, a resident at Cleveland Clinic, discussed her presentation from ACTRIMS Forum 2021 on the misdiagnosis of adult-onset genetic leukodystrophies as multiple sclerosis.

Alise Carlson, MD

Alise Carlson, MD

Leukodystrophies are a group of rare, progressive, genetic diseases that affect the brain, spinal cord, and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter of the brain. Adult-onset genetic leukodystrophies (gLD) are rare, difficult to diagnose, and can be overlooked in the diagnostic evaluation of potential multiple sclerosis (MS) mimics.

At the Americas Committee for Treatment and Research in MS (ACTRIMS) Forum 2021, February 25-27, Alise Carlson, MD, presented a study that described the clinical and imaging features of patients with gLD initially misdiagnosed with MS. Among the 19 patients included in the cohort, the most common presenting symptoms were spastic paraplegia (37%) and headache (16%). Carlson and her colleagues identified a number of gLD diagnoses from the patient cohort and concluded that adult-onset gLD should be part of the differential diagnosis of MS and suspected patients with progressive neurological symptoms, negative oligoclonal bands (OCBs), and atypical white matter abnormalities (WMAs).

Carlson, a resident at Cleveland Clinic, sat down with NeurologyLive to discuss her presentation, including the major differences in gLDs compared to MS at diagnosis, the negative effects of misdiagnosis, and what research needs to be evaluated next. She also discussed ways of raising awareness of these gLDs and whether this is an area of study that garners enough attention.

NeurologyLive: What inspired you to conduct this study? And do you feel as though that this may be an area that doesn't Garner full attention?

Alise Carlson, MD: The discussion surrounding MS misdiagnosis has been ongoing for many years. The MS diagnostic criteria has evolved over time to allow for earlier and more accurate diagnosis, but when these criteria are applied to atypical situations or patients with atypical presentations, the rate of misdiagnosis increases. As one might imagine, the criteria can be fulfilled by many other neurologic diseases. Genetic leukodystrophies have been long recognized as part of this differential, but due to the relative infrequency with which neurologists encounter these patients in clinical practice, they can be very diagnostically challenging.

Can you detail the major differences in these gLDs compared to MS at diagnosis?

Genetic leukodystrophies are a genetically determined group of disorders. They’re rare and highly heterogenous. Similar to MS, they do affect the CNS (central nervous system) white matter, but in general, these disorders are poorly understood due to the relative frequency. In almost all cases, these leukodystrophies are sub-acute and progressive as opposed to relapsing remitting. For that reason, the largest change of error is mistaking one of these conditions for primary progressive MS.

Further complicating things, the clinical presentation of examination findings in patients with genetic leukodystrophies are usually nonspecific. Again, emphasizing that the clinical history and diagnostic evaluation can be very helpful in keying providers into thinking about potentially MS mimics, specifically again, for patients with atypical clinical presentations, negative oligoclonal bands, and atypical MRI findings. All of these things should definitely ring a bell for an MS mimic and potentially cue into a genetic leukodystrophy. We are working to further classify imaging characteristics, which might prompt a more focused evaluation for some of these conditions. We know that MRI pattern recognition can be very helpful in not only diagnosing MS but diagnosing many of these MS mimics and narrowing down the differential diagnosis.

How can we raise awareness of these gLDs in the clinical care setting? Does this need to be implemented more in the educational stages?

As we have begun to recognize this group of disorders more and more over time, and the genetic testing, particularly whole exome sequencing, has become less expensive and readily available, we have been able to make these diagnoses more rapidly and in a shorter timeframe over recent years. That being said, the diagnostic process is still time sensitive. It’s important to have this group of conditions in mind when considering MS for that reason. Getting these patients on therapy early is important. Some of these therapies may only be effective early on in the course of the disease. As we begin to expand our capability for diagnosing these conditions, there are of course, things that we haven’t even recognized at this point. However, we will take more steps as we refer these patients to the medical genetics’ teams and things of that sort. In the meantime, we need to again, emphasize the importance of taking a detailed clinical history, including a family history, asking about the co-occurrence of atypical symptoms which might key us into these conditions.

What role can genetics play in these disorders?

In some instances, these patients will carry a family history, which might be suggestive of an underlying genetic condition that’s inheritable and been passed down through generations. Sometimes these conditions, however, are de novo, meaning they won’t have a family history, and can develop them sporadically. We’re hoping that with increased recognition of these conditions, that we’ll be able to key in on some of the more salient clinical features. What are the MRI patterns that should prompt us to think a bit more about some of these conditions? Then we can appropriately refer these patients or get our medical genetics teams involved to ultimately reach the correct diagnosis.

What are some of the major negative effects with misdiagnosing a patient with MS who actually may have a gLD? And vice versa.

When we label someone with multiple sclerosis, our second step is always what disease-modifying therapy do we need to put this patient on? If that diagnosis is incorrect, we may be exposing these patients to unnecessary immunosuppressive therapies. Receiving these therapies can very cost intensive and time intensive as well, whether they need to travel for infusions or again just simply paying for these medications. On the flip side, if we miss the diagnosis of 1 of these genetic leukodystrophies, we may be missing our effective time window for treatment for some of these conditions. These treatments vary widely. There are some therapies for certain conditions, as well as the growing field of gene therapy. If we don’t catch these conditions early enough in the course, we reach a point where they’re not so effective for the patient.

Are there any aspects within this field that need more extensive research?

The bottom line is to keep in mind that part of MS diagnosis is ensuring that there is no better explanation for the symptoms with which your patient is presenting. It’s our job as clinicians to make sure that we’re doing a good job formulating that differential diagnosis and investigating all of those potential MS mimics. In terms of future direction, we’re working on trying to better classify and characterize these MRI findings, specifically in this patient cohort, that might help us better recognize which patients might fall into this category. We’re currently working on this through a multicenter, worldwide study. Hopefully, we’ll be able to glean some information from that study.

Has the prevalence of these specific rare diseases been observed yet? Or is this an area that needs more updating?

That’s something that we don’t have a lot of information on at this point. As we are gaining more access to these genetic tests that will help us identify these conditions, I think we will gather additional prevalence data over the coming years, which hopefully will help us see the bigger picture in terms of where these patients are presenting, how they’re presenting, and what we can do for them.

Transcript edited for clarity. For more coverage of ACTRIMS 2021, click here.

Carlson A, Nadjar Y, Cohen JA, Macaron G. Adult-onset genetic leukodystrophies misdiagnosed as multiple sclerosis in clinical practice. Presented at ACTRIMS Forum 2021; February 25–27. Session S1.4
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