Diagnosing More Than Just MS
- Gary Birnbaum, MD
- Apr 6
- 4 min read
Common Diseases in Clinical Cohorts -
Not Always What They Seem
Rahimov, F., Jacobs, B.M., Lee, J.S., Mahi, et al.
N Engl J Med; 2025; Issue 16 Pages 1589-1598
Introduction:
Diagnosing multiple sclerosis (MS) can be difficult. None of the symptoms or signs of MS are unique to that illness. Weakness, numbness, gait imbalance, tremors, fatigue, bowel and bladder difficulties can be caused by other illnesses. As a result, diagnosing MS is, to a large extent, based on eliminating MS “look-alikes".
Diagnostic criteria, such as the McDonald Criteria, expanded and validated over the past several decades, allow experienced clinicians to diagnose MS at earlier stages with earlier initiation of disease-modifying therapies. However, even with these tools, MS is either not diagnosed or is diagnosed wrongly. My own experiences with two board-certified general neurologists and an experienced emergency room physician, all incorrectly making a diagnosis of MS, emphasized the conclusions of multiple papers that up to 20% of persons referred to an MS specialty clinic did not have MS.
A misdiagnosis of MS can have severe consequences, not only in regard to the initiation of inappropriate MS therapies but also in not treating undiagnosed MS “look-alikes.” Further complicating the issue, persons with MS may have other illnesses that cause symptoms and signs mimicking those of MS. As a result, responses to disease-modifying therapies may be altered or insufficient, with atypical or unexpected disease progression.
To address these issues Rahimov and colleagues studied three groups of persons with autoimmune diseases, multiple sclerosis, inflammatory bowel disease, and atopic dermatitis (an inflammatory skin disease). They studied these groups for the presence of gene variants that could cause monogenic diseases (a disease that results from an abnormality of only one gene) resulting in symptoms and signs similar to the initially diagnosed Illness. Results are discussed below.
Key Points:
1. The United Kingdom has a Biobank of more than 500,000 individuals between the ages of 40 and 60 years. 9529 participants volunteered to allow access to their medical records and to have their genomes sequenced. In this group there were 1850 persons diagnosed with MS. These were designated the “discovery” group.
2. Since medical diagnoses in this group were based on electronic record data, with a risk as to the accuracy of the diagnoses, the researchers studied “follow-up” groups of individuals where the diagnoses were more stringently determined. For MS this was the Genuity Science cohort.
3. This cohort consisted of 7475 persons diagnosed with MS recruited from neurology clinics and other biobanks. Diagnoses were confirmed by trained neurologists using the revised 2013 McDonald criteria.
4. Panels of genes known to cause a monogenic disease were assembled for each of the three disease groups. Genes were chosen on the basis of their causing illnesses similar to the originally diagnosed disease. The MS panel consisted of 1673 genes associated with abnormalities of the immune system and abnormalities of the nervous system.
5. Of the 1850 persons with MS from the Biobank population, 53 individuals (2.86%) were found to have rare variant genes associated with an inherited neurologic disease other than MS. The most frequent other disease, in 11 individuals, was a vascular disease called CADASIL (autosomal dominant cerebral arteriopathy and subcortical infarct leukoencephalopathy). Multiple examples of CADASIL being misdiagnosed as MS are published. Other monogenic, inherited disease genes found were those for congenital, autosomal-dominant spinal muscular atrophy and autosomal-dominant familial amyotrophic lateral sclerosis (ALS). These data suggested that a small number of individuals diagnosed with MS either were underdiagnosed (had MS and another neurologic illness) or were misdiagnosed.
6. The authors then compared clinical histories of persons diagnosed with MS with those diagnosed with MS and a rare genetic variant. The latter group had more than a 14-fold higher incidence of dementia and a greater than 3-fold higher incidence of convulsions, indicating that these rare diseases can exacerbate clinical findings that are part of the MS spectrum.
7. Studies of persons with MS in the Genuity Science cohort, a more stringently diagnosed cohort, revealed that 88 participants (1.18%) had rare gene variants that could result in MS-look-alike illnesses. This value is less than half that of the percentage found in the Biobank group, perhaps related to the careful exclusion of individuals with other neurologic issues.
8. To again determine if having pathogenic gene variants alter the course of MS the authors looked at the severity of MS in persons with and without potentially pathogenic variants in the Genuity Science cohort. They used the “Age-related Multiple Sclerosis Severity Score” (ARMSS) for this analysis. Persons with variants had significantly more severe disease (P=0.02).
9. No data were presented regarding how the presence of variant genes in persons with MS affected responses to treatment with disease-modifying therapies. However, in persons with inflammatory bowel disease, the occurrence of gene variants resulted in an overall decreased response to therapy.
Discussion:
There are several important implications from the above study. Since making a diagnosis of MS is itself challenging, it is essential that any person initially diagnosed with MS be evaluated by a health care provider specializing in the care of persons with MS, using the latest iteration of the McDonald criteria to make the diagnosis. Sadly, as noted previously, even board-certified neurologists are not immune from misdiagnosing MS.
The incidence of possible disease-causing genetic variants in persons with MS is rare, between 1% and 3%. When should persons with MS be tested for the presence of such variants that can have a profound effect on clinical course and possibly response to treatment? Certainly in individuals with a family history of monogenic diseases. I would also suggest genome testing in individuals with atypical clinical courses, such as unusually rapid clinical progression, those with poor or refractory responses to disease-modifying therapies, and in those individuals with relatively uncommon MS symptoms such as frequent seizures or the early onset of rapidly progressive cognitive impairment.
The costs of genomic testing have drastically decreased in the past several decades and are used extensively in oncology. Should costs continue to decline, genomic testing may become part of the routine work-up for persons being evaluated for a diagnosis of MS, allowing the detection not only of unexpected diseases that may mimic MS, but also genomic variants associated with disease severity and susceptibility .
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