Unraveling the Confusion and the Chaos of the Many CMT2A Names
Science is dynamic, ever evolving, and never sits still. When it comes to CMT, and especially CMT genetics, the science is approaching warp speed. In December 1990, there wasn’t a single known cause of CMT. By Christmas Eve 1993, there were three known causes. By May 1, 1998, there were six genes discovered to have CMT-causing mutations. By the end of 2011, marking the end of the first 20 years of CMT gene discovery, researchers and scientists had discovered 55 genes having CMT-causing mutations. Today, 11 years later, scientists have discovered another 65 genes, bringing the total 120 genes discovered to have mutations that cause CMT. Sometimes, a discovery is a correction to a previous discovery. A review of published literature reveals two such corrections.
When scientists and researchers discover a new cause for CMT, they publish their findings in a research paper. The research paper is referred to as “published literature.” The phrase, “in the literature,” or “in the published literature,” refers to published research papers. The researcher or group of researchers who discover a new cause for CMT get to pick the name for their discovery. There’s a CMT naming nomenclature scientists and researchers use as a guideline for naming their discovery—the CMT-causing genetic mutation, and this name becomes known as the subtype name, as in CMT2A, for example (Raymond 2021). And this is where our story begins.
Discovering the Elusive CMT2A Cause
Before scientists found the first genetic CMT cause, there were three basic CMT types. These were CMT1, CMT2, and CMT3. Whether a CMTer had CMT1 or CMT2 depended on their nerve conduction study (NCS) results (Stojkovic, et al., 2016) (Gondim and Thomas 2019). If nerve conduction speeds were slower than thirty-eight meters/sec, amplitudes were somewhat reduced, and each nerve evaluated showed the relative same, it was CMT1. If nerve conduction speeds were faster than thirty-eight meters/second, amplitudes were significantly reduced, and there was variability between the various nerves evaluated, it was CMT2. Doctors used CMT3 as the diagnosis when CMT symptom onset was in infancy. CMT3, today, is no longer used (Bird, 1998, Updated 2022). CMT1 and CMT2, however, are in use, and the nerve conduction criteria that separate the two from one another are the same today as they were back then.
The very first discovered cause for CMT happened in 1991. Scientists discovered the genetic cause for CMT1, and aptly named this discovery CMT1A (Raeymaekers, et al., 1991). Scientists had been able to figure out by this time that there would likely be more than one cause for CMT1. This first discovery, a duplication of a tiny segment of chromosome 17, 17p11.2-p12, to be exact, Raeymaekers(1991) understandably named their discovery 1A, with the “A” indicating it was the first discovered cause for CMT1.
A year later, in 1992, researchers pinned down the exact gene implicated in CMT1A—a duplication of the PMP22 gene (Patel, et al., 1992). While the exact gene involved discovered by Patel(1992) might seem like a correction to the chromosome segment duplication discovery by Raeymaekers(1991), the chromosome segment duplication is the reason for the PMP22 gene duplication. Raeymaekers(1991) discovered the duplication, and Patel(1992) clarified the exact gene. Where scientists had predicted more than one cause for CMT1, they had also predicted more than one cause for CMT2.
With the first CMT1 discovery coming in 1991, the cause for what CMT researchers and scientists had already dubbed CMT2A remained elusive for ten years. Finally, in 2001, the breakthrough discovery everybody was struggling to find was published. Scientists working in Japan at the University of Tokyo discovered a mutation in the KIF1B gene causing CMT2 and linked their discovery to CMT2A (Zhao, et al., 2001). Finally, we had the cause for CMT2A. Or did we?
Genetic Roommates
The CMT2A-causing mutation in the KIF1B gene was discovered in just one family by Zhao(2001). While this was truly a breakthrough discovery, researchers and scientists had a challenging time finding this KIF1B mutation in other CMTers, in other families. Try as they may, it just wasn’t happening. Stephan Züchner, MD, PhD, Professor and Chairperson of the Department for Human Genetics at the University of Miami Miller School of Medicine, co-founder and CEO of The Genesis Project, tells the story in a CMT4Me podcast of how, despite all of his efforts, could not find the Zhao(2001) KIF1B mutation in any CMTer who was thought to have CMT2A. Instead, what he did discover, was a mutation in a gene at the same genetic address, and this gene is the MITOFUSIN2 gene, or MFN2 for short (Stephan Züchner 2021).
In 2004, after having identified his MFN2 discovery as the actual culprit in many CMTers who had CMT2A, Dr. Züchner published his findings as the cause for CMT2A (Züchner, et al., 2004). Although published literature doesn’t give the reason for this discrepancy between KIF1B and MFN2 in the linkage to CMT2A, the confusion likely stems from the two gene’s cytogenic address.
A gene’s cytogenic location (address) is the distinct location within a chromosome where a gene lives. Both the KIF1B gene and the MFN2 gene live on chromosome 1. Specifically, both genes live at 1p36.22. Chromosomes are divided into two basic parts (segments): a short arm (p) and a long arm (q). The “p” and “q” are always lower case. Each arm is subdivided into bands (a number) and sub-band (another number), with the “band” and “sub-band” being separated by a decimal point.
In cytogenic location expression, 1p36.22, for example, the first number (1 – 22, or an X or Y) is the chromosome, and everything starting with either a “p” or a “q” and after is the specific location within the chromosome. Putting it all together, 1p36.22 is the house number, street, city, and postal code for both the KIF1B and the MFN2 genes. They are literal genetic roommates.
The Confusion Sets In
After the KIF1B association to CMT was discovered, we had a genetic confirmation for CMT2A. Things were great for a few years. Then came the MFN2 discovery that was proven as the actual gene with the responsible mutation. One would think that this was it, that KIF1B would see itself out, that MFN2 was the way. This would be the easiest outcome, but nothing is ever easy with CMT.
At some point after Dr. Züchner’s MFN2 discovery, CMT2A as a subtype name split into two. Published literature doesn’t give a date, but the KIF1B-associated CMT2A discovery became known as CMT2A1, the MFN2-associated CMT2A discovery became known as CMT2A2.
CMT2A1 was the name used for KIF1B-associated CMT2A because this discovery came first. CMT2A2 was used for MFN2-associated CMT2A because this discovery came second. Keep in mind, both actually referred to the same thing after the Züchner(2004) MFN2 discovery proved that the earlier KIF1B discovery by Zhao(2001) was incorrect. Everybody became used to this bit of confusion and all was well for a few years, until a new MFN2 discovery in 2011 changed it all up, again.
CMT2A, regardless of which gene we’re associating with this subtype, is caused by an autosomal dominant mutation in its associated gene. To add to the CMT2A confusion, scientists discovered an autosomal recessive CMT-causing mutation in the MFN2 gene. The scientists who made this discovery named it CMT2A2B (Polke, et al., 2011). If the autosomal dominant Züchner(2004) MFN2 discovery is called CMT2A2, it makes sense that the autosomal recessive Polke(2011) discovery should be called CMT2A2B, right? The “B” simply indicates the discovery follows Züchner(2004), because not confusing.
Let’s review real quick. 2A1 equals autosomal dominant KIF1B. 2A2 equals autosomal dominant MFN2. 2A2B equals autosomal recessive MFN2. Now that we have a handle on the origins of the many names, there’s another monkey wrench to throw into the mix, because why not?
Clarifying the Confusion
Everybody was used to the confusion of CMT2A1, CMT2A2, and CMT2A2B. The CMTer community wasn’t a huge fan, but we had a handle on it. Published literature doesn’t give a date, but by c.2013, CMT2A2 morphed into CMT2A2A. CMT2A1 remained as the association to KIF1B. With the autosomal recessive MFN2 Polke(2011) discovery being known as CMT2A2B, in what was likely an effort to clear up all the confusion, the autosomal dominant MFN2 Züchner(2004) discovery morphed into CMT2A2A. Because, again, not confusing.
For a period of time, we had CMT2A1, CMT2A2, and CMT2A2A all referring to the exact same thing. CMT2A2 and CMT2A2A are literally the same thing linked to the same mutations in the same gene. Another way to look at CMT2A2 and CMT2A2A, in a hopefully not confusing way, is autosomal dominant MFN2-associated CMT, which we can shorten to AD-MFN2-CMT. Who am I kidding? That’s even more confusing! Am I right? A solution is on its way though.
By the late 20-teens, scientists, researchers, CMT experts, and practicing clinicians alike were trying to come up with a solution to this CMT2A multiple name conundrum. One paper suggested scrapping the long used naming conventions in favor of an inheritance pattern-gene format, as in AD-MFN2-CMT (Magy, et al.,2018). While this works for scientists, researchers, doctors, etc, asking a CMTer to explain to somebody what AD-MFN2-CMT is is a huge ask, especially with complex gene names such the SH3TC2 gene, which would translate to AR-SH3TC2-CMT (AR = autosomal recessive). It’s so much easier to say and explain CMT4C (Senderek, et al., 2003). Have no fear, a solution is on the horizon.
At some point, and again, published literature doesn’t provide a date, CMT2A1, CMT2A2, and CMT2A2A were merged into simply CMT2A, which is where we are today. The KIF1B association to CMT was officially retracted in 2020 (Clinical Genome Resource 2020). Today, any internet search returns for CMT2A, CMT2A1, CMT2A2, and CMT2A2A all refer to the same thing—they are synonymous with one another. Any internet search return or mentions of CMT2A that is caused by KIF1B mutations is synonymous with CMT2A that’s caused by MFN2 gene mutations, but the KIF1B association should be disregarded. CMT2A2B is still CMT2A2B.
Although the KIF1B association to CMT has been retracted, the KIF1B gene still is present on some CMT genetic test panels. Should a CMT genetic test result include a KIF1B mutation, the MFN2 gene needs to be re-examined and in a much closer analysis, especially if the MFN2 gene was not included in the gene panel. While there are KIF1B mutations that are associated with causing different diseases, scientists no longer consider the KIF1B gene to have any connection to any neuromuscular disease (Charcot-Marie-Tooth Association (CMTA) 2020).
Beyond the CMT2A confusion, there are two additional subtypes caused by mutations in the MFN2 gene. In total, various mutations in the MFN2 gene are associated with causing four CMT subtypes. In addition to CMT2A and CMT2A2B, certain mutations in this gene are associated with a particularly severe subtype called CMT2B4 (Nicholson, et al., 2008), and certain mutations in this gene are associated with the subtype called HMSN-6A (Züchner, et al., 2006). HMSN is the acronym for Hereditary Motor and Sensory Neuropathy. Despite its name, this is a CMT subtype (Reilly, 2000). Although there are four different subtypes associated with the MFN2 gene, each subtype is caused by different mutations within the gene.
Remember the Second Correction?
In 2009, scientists discovered mutations in the MED25 gene were causing CMT, and they named their discovery CMT2B2 (Leal, et al., 2009). The same lead author later discovered the data was flawed. In 2018, Leal published a correction to the MED25 discovery. It turns out the actual culprit is mutations in the PNKP gene (Leal, et al., 2018). Rather than everybody going haywire and producing a new subtype name, the subtype simply remained CMT2B2. The likely reason for the confusion? You guessed it. The two genes are roommates, with both living at chromosome 19q13.33. Any internet search returns for MED25-associated CMT2B2 are synonymous with PNPK-associated CMT2B2.
Genetic tests haven’t yet caught up with this correction and still include the MED25 gene without having added the PNKP gene. Like KIF1B vs. MFN2, a test result that identifies a CMT-causing MED25 mutation should examine the PNKP gene in close detail.
In Closing
If CMT is nothing else, it is confusing, and the CMT2A naming saga lives up to CMT’s confusing ways. Out of the many CMT2A names, CMT2A, CMT2A1, CMT2A2, and CMT2A2A, one unifying name has emerged: CMT2A. Today, each of the now formers are known simply as CMT2A. When researching symptom profiles, any finding of CMT2A1, CMT2A2, or CMT2A2A refers to and is synonymous with CMT2A. If you’ve been diagnosed with CMT2A1, CMT2A2, or CM2A2A, the diagnosis is the same as CMT2A and each are interchangeable with one another. Today, we have only two simple CMT2A subtypes: CMT2A, or course, and CMT2A2B. What’s the difference?
CMT2A is caused by autosomal dominant mutations in the MFN2 gene and CMT2A2B is caused by autosomal recessive mutations in the MFN2 gene. Beyond these two, different autosomal dominant mutations in the MFN2 gene cause the CMT subtype called HMSN-6A, and different autosomal recessive mutations in this gene cause the early onset and often severe CMT2B4.
CMT isn’t about genes, per se. Rather, CMT is about certain mutations in certain genes. Having a mutation in a gene that has CMT-causing mutations doesn’t necessarily mean the mutation is causing CMT. It takes the right mutation, and when multiple subtypes are caused by mutations in a single gene, such as with the MFN2 gene, the mutation itself dictates which subtype the CMTer has. It’s important to note, not every mutation in a CMT-associated gene causes CMT. Some mutations are benign and harmless.
About the Author
Kenneth Raymond is a CMTer who was first diagnosed with CMT1 in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has devoted his life since diagnosis to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers. As a member of the Charcot-Marie-Tooth Association’s Advisory Board, Kenneth is a CMT genetics expert, a CMT-related respiratory impairment expert, and is a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT. Kenneth is also the founder of Experts in CMT, whose goal, through education and awareness, is to improve the lives of those who are living with Charcot-Marie-Tooth disease.
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