Is the Generations Deep Notion That CMT Can and Does Skip a Generation Fact or Fiction? The Answer is Easy, But The Road Trip to Get There is Not.
Wherever there is an appearance of CMT skipping a generation, there is an explanation, even when getting to that explanation requires that we follow a fleeting trail of breadcrumbs. That trail, true to form for CMT, is often complex and confusing. Everything about CMT is complex and inherently confusing. The genetics and inheritance of CMT are no different. Arising from these complexities are many misconceptions. Among these is the notion that CMT can skip a generation. CMT does not and cannot skip a generation. To know the how and why requires that we unwrap some of the mysteries of CMT inheritance, and I’m here to do just that.
All the CMT experts agree that CMT does not and cannot skip a generation. Because of how the gene mutations that cause CMT are inherited, CMT cannot skip a generation. There are several variables that contribute to this misconception, and I’ll explain several.
First and foremost, we have to toss out what we know about the words “dominant” and “recessive.” Their use in genetics is different than what we’re used to in conventional use. In genetics and inheritance patterns, in the most basic sense, dominant refers to needing one copy of a mutation to cause the disease, and recessive refers to needing two. And, in our case, of course, we’ll focus only on CMT.
The term "carrier," as it relates to CMT, derives from the recessive types of CMT, whether autosomal or X-Linked (some of the Type 2’s, some of the X-Linked, all the Type 4’s, and all the Intermediate Recessives). We normally have two copies of every gene. We inherit one copy from our mom and one copy from our dad. The exception is with the X-chromosome. Males have only one X-chromosome, and this one X-chromosome is inherited from only their mom. Because males have only one X-chromosome, they have only one copy of each of the genes that live on the X-chromosome. This detail only adds to the misconception that CMT can skip a generation.
The Autosomal Recessive Conundrum
Autosomal recessive types of CMT are caused by a mutation in both copies of a gene that lives on any of the numbered chromosomes (numbered 1-22, and are referred to as the autosomes, hence, autosomal). When only one copy of the gene has a mutation, it is not sufficient to cause the associated type of CMT. When somebody has that one copy of the gene mutation, they are a "carrier" of that one copy of the mutation, but not of CMT.
Somebody who is a carrier of this one copy of an autosomal recessive mutation has a 50/50 chance of passing it on to each of their children. Their children who do inherit this one copy of the mutation will not have CMT unless they inherit the second needed copy from their other parent or unless the second needed copy occurs randomly (de novo) at conception. I'll have more on de novo CMT in a moment.
This one copy of the autosomal recessive mutation can go generations deep, but there will not be CMT unless through inheritance from the other parent or through a de novo occurrence the second needed mutation is introduced. Only then can the person have the associated autosomal recessive CMT.
If any of the children do not inherit this one copy of the mutation from their "carrier" parent, they will not have the mutation to pass onto their children, and their children cannot inherit that which the parent does not have. This sounds confusing now, but this will make sense in a moment, I promise.
The Autosomal Dominant Conundrum
The misconception of CMT skipping a generation can also come from dominant types of CMT (all the Type 1’s, most of the Type 2’s, 2 of the X-Linked types, all the Intermediate Dominants). Autosomal dominant types of CMT are caused by a mutation in only one copy of the associated gene, and this gene lives on any one of the numbered chromosomes. Because there needs to be only one copy of the mutation for there to be these types of CMT, autosomal dominant types of CMT are far more common than autosomal recessive types.
When somebody has an autosomal dominant type of CMT, they have a 50/50 chance of passing on their CMT causing mutation to each of their children, regardless of gender. When any of the children inherit this mutation, they have the associated CMT, and it is only a matter of time before symptoms start to show.
The children who do not inherit this CMT causing mutation will not have the associated CMT. They cannot pass on this CMT causing mutation to their children because they do not have the mutation to pass on.
Where the misconception of skipping comes into play here is when somebody has a dismissively mild case. CMT can affect everybody vastly differently, and even within the same family. It is not uncommon for somebody to be the first in the family diagnosed, to then find out that a parent has it but that the parent’s was dismissively mild.
It can also be common to find out that a grandparent has/had it badly, but the parent seemingly did not. From this, some infer that the CMT skipped a generation. What really took place was that the parent was so dismissively mild that there was no reasonable reason to suspect they, too, have/had CMT. I’ll use myself as an example.
Skipper, No Skipping
I have CMT1A. CMT1A is autosomal dominant in inheritance—need only one copy of the responsible mutation to cause it. I was the first diagnosed in my family. I was diagnosed in late 2002, at 29 years old, with a Type 1 CMT, based on Nerve Conduction Study, or NCS for short. Almost one-year later to the day, I received genetic confirmation of 1A. Shortly thereafter, my dad was diagnosed, at 60 years old.
My dad was evaluated for CMT not because he was symptomatic, but because he was willing to find out if there was a family history, or if my CMT was de novo—a new spontaneous occurrence. I was very CMT-symptomatic from an early age. Like most who are the first in the family diagnosed, my diagnostic journey was eventful. In sharp contrast, my dad’s CMT was dismissively mild. Nobody ever suspected he had anything neuromuscular going on. My dad’s CMT was dismissively mild despite him having essentially the same nerve conduction characteristics as me—the typical 1A NCS results of ~19 meters/sec velocities, prolonged latencies, somewhat reduced action potential amplitudes, etc. This is a testament to nerve conduction characteristics not correlating with 1A severity. After my dad was diagnosed, something about his biological father suddenly clicked.
My dad was adopted by his stepdad when he was 6 years old. This was post-WWII Detroit, in 1948. My dad’s biological father, like most 20-something men at the time, was a WWII veteran. I never met the guy. The story is that he was a P52 pilot. My sister has his US Army Air Corp. portrait, but not much is known. The story also includes that he moved back to his hometown of London, Ontario after the war. My dad met him in the 80s and got to know him a little bit, and this is where the CMT story picks up.
My dad never talked about his biological father. He only brought him up the one time after the CMT diagnosis. My sister and I knew he existed, but this is the extent of it. My dad said that my grandfather had serious issues with his legs, and he could barely walk. He seemingly lived out his last twenty years confined to a wheelchair and drawing Veteran’s Disability because his issues were deemed to be caused by his military service. As the story goes, he started having issues in his late twenties, shortly after WWII, and shortly after moving to Canada.
It’s a safe bet that my dad’s biological father had CMT1A. My dad had it, and it’s a safe bet that he inherited it from his biological father. I inherited the 1A causing mutation from my dad. The story suggests that my grandfather, whom I never met, had a fairly severe case of 1A. My dad’s CMT was so mild that nobody ever suspected anything. I am right in the middle of the two, more severe than my dad, and less severe than my grandfather.
From the outside looking in, it’s easy to presume that CMT skipped a generation in my family. My grandfather had it bad. Some would argue that I, too, have it bad (albeit with issues, I have my legs). My dad would have never been suspected of it had I not been diagnosed. However, CMT did not skip a generation from my grandfather to me. Investigative medicine showed that my dad did have it, even though his was exceedingly dismissively mild.
CMT 1A is autosomal dominant. If you have the one copy of the CMT causing mutation, you then have the associated CMT. Symptom onset, rate of progression, severity, etc., become the question, and it is a question of when, not if. My dad had the 1A causing mutation. Despite no outwardly clinical symptoms of CMT, his nerve conduction characteristics were textbook 1A. For whatever reasons there might have been, he never developed anything CMT-consistent beyond nerve conduction characteristics. Despite an otherwise absence of symptoms, he had CMT. CMT did not skip, because CMT does not skip.
What if both parents of a CMTer absolutely do not have CMT, but a grandparent absolutely does? Surely, then, CMT skipped a generation, right? CMT, in this situation still has not skipped a generation.
The De Novo Conundrum
CMT is inheritable. This much is a given. However, CMT does not have to be inherited in order to have CMT. When there is no genetically established family history, that is, the CMTer did not inherit their CMT causing mutation from a parent (or from both parents in cases of autosomal recessive CMT), the CMTer's CMT is referred to as a de novo (new) case. A de novo case is one in which the underlying causative gene mutation occurred spontaneously without having been inherited.
A CMTer whose CMT is a de novo case passes on their CMT causing mutation according to the inheritance pattern of the mutation: autosomal dominant, autosomal recessive, X-Linked dominant, or X-Linked recessive. How does this apply to the notion of CMT skipping a generation?
Hypothetically, Grandpa Bob has CMT. Dad (Tom) does not. However, Tom's son, Bill, does. Tom's wife, Cathy, does not have CMT. Tom and Cathy do not have CMT, but their son, Bill, does. Because Tom's dad, Grandpa Bob, has CMT, it obviously skipped a generation, right? No, the CMT did not skip a generation. Why not?
Situation One
Bill was diagnosed with CMT when he was 20 years old. He received genetic confirmation of the CMT1B causing autosomal dominant mutation in his MPZ gene at 21. Grandpa Bob had received genetic confirmation of his CMT years ago. Tom never showed any signs of CMT, so he was never evaluated. With Bill's genetic confirmation, both Tom and Cathy get tested. Neither of them have Bill's CMT causing genetic mutation. Low and behold, Bill has the same mutation that Grandpa Bob has though. This is proof that CMT skipped a generation, right? No, it did not skip a generation.
Although Bill has the same CMT1B causing mutation as Grandpa Bob, Tom does not. Because Tom does not have the mutation, he could not have and did not pass it on to Bill. Bill's CMT1B causing mutation, instead, and albeit the same mutation as Grandpa Bob, is a de novo occurrence, having occurred spontaneously at conception. The chances of this happening are exceedingly rare, but never zero.
Situation Two
Grandpa Bob has an autosomal recessive type of CMT, we'll say CMT2A2B, and he has genetic confirmation of the responsible compound heterozygous mutation in his MFN2 gene. His son, Tom, has no signs of CMT, and was never tested. However, Tom's son, Bill, is diagnosed with CMT, and then genetically confirmed to have, coincidentally, the same compound heterozygous mutations in his MFN2 gene as Grandpa Bob. Obviously, CMT skipped a generation, right? No, CMT did not skip a generation.
After Bill received genetic confirmation of CMT2A2B, Tom and Cathy were tested. It turns out that Tom has in his MFN2 gene one mutation of the two needed to cause CMT2A2B, and Cathy has the second in her two MFN2 gene copies. It's a safe bet that Tom inherited his copy from his dad, Grandpa Bob. Because Tom has only one of the needed mutations that, when there is both in the same person cause CMT, he does not have CMT. Cathy, also, with only one of the needed mutations in her MFN2 gene, does not have CMT. But, because Tom has one of the mutations, but not CMT, CMT skipped a generation because Grandpa Bob and Bill both have CMT, right? No, CMT did not skip a generation.
Bill has CMT2A2B because he inherited one of his two CMT causing mutations from his dad, Tom, and the other from his mom, Cathy. Unbeknownst to everybody, both Tom and Cathy were "carriers" not of CMT, but of one copy each of a mutation, that when both are present in the same person, causes CMT2A2B. Tom and Cathy each having only one of the 2A2B causing mutations in their MFN2 genes do not and cannot have CMT. Bill, though, having both copies, has CMT2A2B. Because Tom and Cathy each have just one of the mutations, there was a 25% chance that Bill would inherit both copies, and then have the associated CMT.
Grandpa Bob’s MFN2 gene has a mutation in each of the gene’s two copies. Grandpa Bob randomly passed on one of his two MFN2 copies to Tom. Because both copies of Grandpa Bob’s MFN2 gene have a mutation, the copy that Tom inherited from Grandpa Bob has one of the two mutations needed to cause CMT2A2B. Tom’s mom had no mutations in her MFN2 gene, so Tom’s other copy, which was inherited from his mom, has no mutation. Hence, Tom does not have CMT2A2B. Neither of Cathy’s parents had CMT, so it is decided that Cathy’s only MFN2 mutation copy was a de novo occurrence for her.
With the genetics and inheritance patterns of the genetics that, together, dictate the CMT family situation of Grandpa Bob, Tom, Cathy, and Bill, we can see how and why CMT did not skip from Grandpa Bob, over Tom’s generation, and land with Bill. Once we look beneath the hood, and examine the details, we see that the genetic patterns of CMT do not permit CMT to skip a generation.
X-Linked CMT perhaps provides the best argument supporting the notion that CMT can skip a generation. However, much like our example of Bill’s family, there is a reasonable explanation for what transpires.
The X-Linked Conundrum
X-Linked CMT gets its name from the genes that cause it. Each of the genes that cause X-Linked CMT live on the X-chromosome. The X-chromosome is one of two chromosomes that determine gender—the other is the Y-chromosome. Together, the X and Y chromosomes are called the sex chromosomes. Females have two X-chromosomes. Males have one X-chromosome and one Y-chromosome. Because of this, unlike all the other types of CMT, gender plays a role in X-Linked CMT, in both inheritance and in reported disease severity.
X-Linked CMT can be either dominant or recessive in inheritance, and these are termed X-Linked dominant and X-Linked recessive. Like autosomal dominant, X-linked dominant types of CMT need only one copy of a gene mutation in order to cause the associated CMT; and, like autosomal recessive CMT, X-Linked recessive needs two, but with an exception. Dominant is still dominant, and recessive is still recessive. The difference is only with the gene living on the X-chromosome vs the associated gene living on one of the numbered chromosomes.
Gender plays a role in inheritance and reported disease severity in X-Linked CMT because of the number of X-chromosomes females have compared to males. Females have two X-chromosomes and males have one. Females inherit one of their X-chromosomes from their mom, and one from their dad. Males inherit one X-chromosome from their mom, and they inherit their Y-chromosome from their dad.
Females, because they have two X-chromosomes, can only pass on an X-chromosome to each of their children. The one of her two X-chromosomes that gets passed on is completely randomized. Her children’s dad will pass on either his one X-chromosome or his one Y-chromosome. When he passes on his one X-chromosome, the children are female. When the dad passes on his Y-chromosome, the children are male. Because of this gender-determining combination, there can be no male-to-male inheritance of X-Linked CMT.
When a male has X-Linked CMT, he cannot pass it onto any of his sons because he passes on only his Y-chromosome to his sons, and not his X-chromosome, without exception. However, when a male has X-Linked CMT, he will pass it on to every daughter because he passes on his X-chromosome, and all the genes living on his X-chromosome, to every daughter, without exception. What I mean here by including “without exception” refers only to the Y-chromosome being passed onto to his sons, and the X-chromosomes being passed onto his daughters. The CMT part gets tricky and is different for males than it is for females.
For all intent and purpose, for females, the rules that govern X-linked dominant and X-Linked recessive CMT inheritance are the exact same as those regarding autosomal dominant and autosomal recessive. When a female has an X-Linked dominant CMT (X1 or x6), the associated gene has a mutation in only one of the two gene copies, just as in autosomal dominant types of CMT. When a female has an X-Linked recessive CMT (X2, X3, X4, or X5), both copies of the associated gene have a mutation, just as in autosomal recessive types of CMT.
When a female has X1, only one of her two copies of her GJB1gene has a mutation. When a female has X6, only one of her two copies of PDK3 gene has a mutation. When a female has X2, X3, X4, or X5, then both copies of the associated gene have the responsible mutations. The rules are quite literally the same as autosomal dominant and autosomal recessive. When a female has an X-Linked dominant CMT, there is a 50/50 chance that she will pass it on to each of her children, regardless of gender, just as in autosomal dominant CMT. When a female has X-Linked recessive CMT, things change a little bit.
When a female has X-Linked recessive CMT, let’s say X4 for example, both copies of her AIFM1 gene have a mutation. These two mutations, when together in the same person, causes CMTX4. She will randomly pass on one of her two AIFM1 gene copies, and its mutation, to each of her children. This is where the similarities to autosomal recessive end.
When a female has X-Linked recessive CMT, both copies of her associated gene have the responsible mutation. She will pass on one copy of that associated gene and its mutation to each of her children. Her female children, inheriting this one copy, will not have the associated CMT unless they inherit the required second mutation from their dad or develop it spontaneously—de novo. Each of her male children, however, will have the associated CMT. This is where a lot of the confusion regarding X-Link CMT skipping a generation comes from.
Despite recessive inferring that there must be two mutations, one in each of the two copies of the associated gene, when it comes to X-Linked recessive types of CMT, males can have it even though males have only one copy of the associated gene being that they have only one X-chromosome. A male who has an X-Linked recessive CMT cannot and will not pass it on to any son, but he will pass on his one copy of the associated gene, with its mutation, to every daughter. Like the daughter who receives the one copy from her mom who has an X-Linked recessive CMT, she won’t have the associated CMT. Rather, she’ll be a carrier of that mutation.
Down the road, when she has children, she will have a 50/50 chance of passing on this mutation to each of her children. When the children are female and inherit this one copy of the recessive mutation, they will only be a carrier of the mutation. When the children are male and inherit this one copy of the recessive mutation, because they have only one X-chromosome, it is sufficient to cause the associate X-Linked recessive CMT.
As confusing as all this X-Linked recessive stuff is, the CMT does not skip a generation. It all comes down to the mutations, how they are inherited, and how they affect females vs males. Adding to this X-Linked conundrum, males who have an X-Linked dominant type of CMT (X1or X6) tend to be far more severely affected than females who have X-Linked dominant CMT. This is thought to occur because females have a buffer, of sorts, with having a second X-chromosome ergo a second and unmutated copy of the associated gene. This, too, can give the appearance of CMT seemingly skipping a generation. But for the reason we’ve discussed, the CMT does not skip a generation.
It’s All About the Mutations, and Not About The CMT
CMT is not about genes, per se. Rather, CMT is about mutations in genes. I do submit that an argument can be made that if a gene has a mutation that causes CMT, that gene with that mutation is then a CMT gene. Regardless of which argument, because these genes are inherited, the genetic mutations that cause CMT are inheritable. Hence, CMT is inheritable. The notion that CMT can skip a generation infers that, by whatever mechanism, CMT selectively affects only some generations, but not others. This is not the case though.
In order to have CMT, somebody must have the genetic mutation that causes the associated type of CMT. Genetic mutations cannot and do not skip a generation. If somebody does not have the CMT causing mutation (whether dominant or recessive, autosomal or X-Linked), they do not have CMT and they cannot pass it on—their children cannot inherit it from them. Regarding the mutations that cause CMT, when they are inherited, they are only inherited from a parent and not from any other family member. The mutations do not and cannot skip over a parent, nor do they come from an aunt, uncle, or cousin. The mutations that cause CMT are inheritable, but they are different and separate from heritable traits (inheritable traits, depending on author).
There are other variables and considerations that have spurred the misconception that CMT can skip a generation. They are each along the same lines though. Each familial situation where CMT has seemingly skipped a generation can be phenotypically and genotypically explained. Sometimes those explanations are easy, and sometimes they are complex and confusing, but the scenarios can be explained.
