- MS is an immune-mediated disease of the brain and spinal cord, influenced by multiple risk factors including genetics. Some rare neurological conditions can mimic MS or occur alongside it, making diagnosis challenging.
- ANZgene researchers studied 4,340 people with MS and 2,861 without MS to investigate whether rare changes in other neurological disease genes affect MS risk or severity.
- They found genetic “mimic” diseases or additional rare neurological conditions were very uncommon, and these rare genetic changes did not significantly affect MS risk or severity.
Understanding MS mimics and genetic complexity
MS is a disease where the immune system mistakenly attacks the brain and spinal cord, causing symptoms like vision problems, weakness, and balance issues.
Many factors contribute to MS risk, including environmental and lifestyle factors and genetics. In fact, more than 200 genetic changes are linked to a slightly increased risk of MS, underscoring the complex interplay between genes and other risk factors.
Some rare neurological conditions, such as hereditary spastic paraplegia (HSP), CADASIL, Fabry disease, and certain leukodystrophies, can resemble MS or occur alongside it. These “MS mimic” diseases may present with overlapping symptoms or MRI changes, complicating diagnosis and sometimes leading to misdiagnosis or delays.
How often people diagnosed with MS actually have an alternate diagnosis (MS mimic) or genetic multimorbidity (multiple genetic conditions in the same individual) is unknown. It is also unclear whether rare genetic changes linked to other neurological disease genes play a role in who develops MS or how severe it becomes.
To address these questions, researchers from the Australia and New Zealand MS Genetics Consortium (ANZgene), a genetics research platform funded and coordinated by MS Australia, conducted a large-scale genetic study. Results of the study were published recently in Genome Medicine.
What did the researchers do?
The researchers collected genetic information from 4,340 people with MS seen in specialist MS clinics in Australia and New Zealand, along with 2,861 people without MS from the same regions.
They examined the protein-coding regions of DNA, focusing on 1,680 genes already known to cause other progressive brain and nerve diseases, to identify rare genetic changes that might affect brain and spinal cord function.
When potentially significant genetic changes were found, experienced MS neurologists reviewed those individuals’ clinical histories and MRI scans in detail, without knowing the genetic findings initially, to determine whether they truly had MS, a different rare genetic disease, or both.
Finally, the team compared genetic patterns across large groups of people with and without MS, and among those with milder or more severe forms of MS, to see whether these rare genetic changes were more common in MS or associated with relapsing versus progressive disease and greater disability.
What did the researchers find?
Among the people with MS, 166 carried a genetic change significant enough to warrant closer clinical review, but detailed histories were only available for 75 of them. Of those 75, only four individuals showed clear evidence of either a genetic “mimic” disease instead of MS or a second genetic disease alongside MS. In other words, true “genetic mimics” or extra rare genetic diseases were extremely uncommon.
When the researchers looked more broadly at all 1,680 genes linked to progressive neurological diseases, they did not find strong evidence that rare genetic changes in these genes were more frequent in MS than in people without MS, or that they were associated with greater MS severity.
What is the significance of this?
For people living with MS, these results are reassuring – in a large, well‑characterised group seen in specialist MS clinics, misdiagnosis due to a genetic mimic or the presence of an additional rare genetic disease was very uncommon.
This study suggests that rare genetic changes in genes linked with other neurological diseases make little overall contribution to who develops MS or how severe the disease becomes.
However, the research also highlights that a small number of individuals can have a different genetic disease that resembles MS or have MS alongside another genetic condition. This reinforces the importance of paying close attention to “red flags” in symptoms, MRI findings, and family history.
For people with unusual clinical features, atypical scans, or strong family histories, targeted clinical genetic testing may still provide critical answers. It can help guide more appropriate treatment, reduce unnecessary exposure to MS medications, and support genetic counselling for families.
