Charcot Marie Tooth is hereditary. We know this. It’s something that we are either born with and have, regardless of when symptoms show up. Or we are not born with it and will never have it. CMT is the most common inherited neuromuscular disease. If we have it, we can pass it on to each of our children. How CMT is inherited is determined by the underlying associated gene mutation.
CMT is inherited in one of three different ways, depending on the gene mutations that are responsible. The three inheritance patterns are autosomal (non-sex chromosome) dominant, autosomal recessive, and X-Linked (sex chromosome). To understand these, we need to first understand the basic structure of our DNA.
In an oversimplification, our DNA structure is comprised of chromosomes. Each parent passes on one half of our DNA. As such, our DNA is structured in chromosomal pairs. One side of the pair is from mom, the other is from dad. Each chromosome is home to many genes, and these genes are paired, so that there are essentially mirrored copies on each of the chromosome pairs. To visualize this, hold up your index fingers next to each other.
Holding each of your two index fingers next to each other, we’ll call these two, together, Chromosome 1. The right side of Chromosome 1 was inherited from your dad. The left side came from your mom. All of the genes on the right came from your dad, and then likewise for the left from your mom. Sometimes, each side is an exact copy of the corresponding side with each parent, and sometimes it’s not. Sometimes, CMT is caused by a mutation of a gene on only one side. This is referred to as dominant. Sometimes, CMT is caused by a mutation of both the right and left side gene copies. This is referred to as recessive.
The Patterns of Inheritance
Autosomal dominant inheritance means that only one parent needs to have the mutation in order to pass it on. When that one parent has it, there is a 50/50 chance of passing it on to each child. The Type 1s and the Type 2s are all autosomal dominant in inheritance. The European classification system, however, includes some autosomal recessive subtypes in the Type 2s.
Autosomal recessive means that it takes one copy of the mutated gene being present on each of the respective chromosome pair, having inherited one from each parent in order to have the disease. When somebody has both of these copies of disease causing mutations, they then have a 50/50 chance of passing on only one copy of that mutated gene. Their child then will not have the disease, although they have the one copy of the gene. In order to have the disease, the other parent would have to have passed on the same mutated gene. These are the Type 4s.
The Patterns of Inheritance Continued
The third inheritance pattern of CMT is X-Linked. X-Linked CMT is caused by a mutation of a gene that is found on the X-Chromosome. With X-Linked dominant, when the mom has it, she has a 50/50 chance of passing it on to each child. When the dad has X-Link dominant CMT, he will pass it on to every daughter, but he cannot pass it on to any son. Males are X Y, and females are X X. Knowing this, we randomly get one of mom’s X’s; girls get dad’s X, and boys get dad’s Y, hence dad’s not passing on their X-Linked dominant CMT to their sons. Because of the X – Y combination, and knowing that recessive inheritance takes two copies of the mutation – one on each of the chromosome pair, boys cannot have X-Linked recessive subtypes because boys do not have two X chromosomes. The X-Link subtypes are the only ones that involve gender as a factor. Currently, there are 6 named X-Linked subtypes (1 – 6).
There’s Always an Exception
When there is no family history of CMT and no family history can be identified after diagnosis, the new case is referred to as a de novo (new) case. A de novo CMT case is one that occurred on its own, without inheriting the gene mutation responsible for causing the CMT. With this de novo case, the person now has the chances of passing it on in accordance with the inheritance pattern of the particular subtype they have. There’s no clear data on how many total cases are de novo, but the literature suggests that <4% of total CMT cases are de novo. I have also read in literature that the number could be as high as ~20%. There is no clear statistic though.
My Opinion on A CMT Carrier
There is a misconception that CMT can skip a generation. CMT does not skip a generation. The phrase “skip a generation” is a misnomer when describing CMT. Often, the term “carrier” is used also. With CMT, “carrier” is, too, a misnomer. I’ll explain why.
These two misconceptions arise from the recessive subtypes. With these, if there is only one copy of the mutated gene, there is no CMT. However, the term “carrier” is sometimes used to describe that the person “carries” the gene, but does not have CMT.
The correct description would be that the person has one copy of a mutated gene that, when paired with a second copy of that mutated gene, has that subtype of CMT, but does not have CMT by having only the one mutated copy.
In this “carrier” and “skips a generation” misconception, the person has only one copy of a gene that causes CMT when paired with a second copy. In order for any of the person’s children to have these recessive subtypes, the children have to inherit the mutation from the one parent and, then, inherit a mutated copy from the other parent, or develop a de novo mutation for that second copy.
To use the term “carrier” implies that the person has something that can or will be triggered at some point, or that the associated condition is present, but is dormant. None of these describe CMT.
Of course, there are numerous conditions that harbor a “carrier” gene, or that somebody can be a carrier for without they themselves having the condition. However, CMT does not fit that definition.
One is either born with CMT and has it, or was not born with it and will never have it. When somebody does have it, they’ve always had it, even when asymptomatic, and it’s only a matter of time before symptoms do show up, even if those symptoms are never worse than dismissively mild.
The genetics of CMT are complex. Knowing the basics of CMT inheritance helps us to better understand how and why we have CMT; and how and why our children have/may have it, even when we, or our children are a de novo presentation.