Exploring The Inheritance Patterns of Charcot-Marie-Tooth Disease
Charcot Marie Tooth disease, or CMT for short, is a rare, complex, heterogeneous inheritable peripheral polyneuropathy. Although rare, CMT is the most commonly inherited peripheral nervous system disease. First named for the three physicians who first described the disease in 1886, Jean-Martin Charcot [shahr’kō] (1825-1893), Pierre Marie (1853-1940), both from France, and Howard Henry Tooth (1856-1925) from England, CMT as a modern-day disease name has morphed into an umbrella term that represents a wide variety of inherited sensory and/or motor neuropathies.
CMT is inheritable because each of the more than 100 CMT subtypes are caused by mutations in genes that are inheritable. We normally have two copies of every gene, with only a few exceptions. We inherit one copy from each parent. Any mutations present in the gene copy inherited from each parent are also inherited. How CMT is inherited and the chances of inheriting CMT from a parent are solely dependent on the underlying CMT-causing mutation itself. How CMT is inherited is called an inheritance pattern, and there are five inheritance patterns in all. The five inheritance patterns are autosomal dominant, autosomal recessive, X-Linked dominant, X-Linked recessive, and mitochondrial inheritance.
What’s it All Mean?
In genetics and inheritance, dominant refers to a gene with one mutation and recessive refers to a gene that has two mutations. Autosomal refers to a gene that lives on any of the numbered chromosomes (1-22)—the autosomes. X-Linked refers to a gene that lives on the X-chromosome. Mitochondrial inheritance refers to a gene that lives in the mitochondrial genome. Gender is of no consequence to autosomal inheritance, whether dominant or recessive. Chromosomal gender is a factor for X-Linked inheritance and for mitochondrial inheritance.
Chromosomal females have two X-chromosomes, having inherited one from each parent. Because there are two halves, just as there are with each of the autosomes, the rules governing X-Linked inheritance for XX-females are the same as they are for autosomal inheritance, whether dominant or recessive. X-Linked inheritance rules are different for chromosomal males. The rules are different because chromosomal males have only one X-chromosome, having inherited it from their mother, only from their mother, and never from their father. In place of a second X-chromosome, chromosomal males have a Y-chromosome, having inherited this from their father, only from their father, and never from their mother. This distinction will become evident later on. Mitochondrial inheritance is strictly maternal, that is, from mother to child, regardless of the children’s gender. There is some recent research suggesting mitochondrial inheritance is also paternal, but concrete evidence seems elusive.
Autosomal dominant inheritance is the most straightforward inheritance pattern. CMTers whose CMT is autosomal dominant in inheritance have a 50/50 chance of passing on their CMT to each of their children, regardless of gender and regardless of their children’s gender. Autosomal dominant inheritance means that the gene with the CMT-causing mutation lives on an autosome and the gene has a CMT-causing mutation in only one of its two copies. At conception, either the copy of the gene with the CMT-causing mutation will be passed on from the parent who has it, or the copy without the mutation will be passed on. It’s a 50/50 randomization. The second copy of the gene, which would not have a CMT-causing mutation, would be passed on/inherited from the other parent. A CMTer whose CMT is autosomal dominant in inheritance has a CMT-causing mutation in one of the two associated gene copies and the other copy has no CMT-causing mutation. Autosomal recessive inheritance isn’t as straightforward.
Autosomal Recessive – Sarah’s Story
A CMTer whose CMT is autosomal recessive in inheritance has a CMT-causing mutation in both copies of the associated gene, and the gene lives on one of the autosomes. When inherited, one copy of the mutation was inherited from the mother, and the other was inherited from the father. A CMTer whose CMT is autosomal recessive in inheritance usually will be the first one in the family to have CMT. This is because the associated gene must have two mutations, and when there is only one, it does not cause CMT. It’s not uncommon for people to have only one copy of an autosomal recessive CMT-causing mutation and not know it. Having just one copy does not cause CMT, as having both copies is required for causing the related autosomal recessive CMT.
From each parent, we inherit one copy of each gene that lives on any of the autosomes. Both parents each have two copies of these autosomal genes, and the copy of each that is passed on/inherited is completely randomized. Hypothetically, two parents each have one copy of a CMT-causing mutation in their PRX gene. The PRX gene lives on chromosome 19. Because each have only one copy of this mutation, neither have CMT. They don’t even know they each have this mutation. These two parents then have two children, Sarah, and Billy. Sarah has CMT4F. Billy does not. Why?
CMT4F is caused by autosomal recessive mutations in the PRX gene. CMTers who have CMT4F, have a mutation in both copies of their PRX gene. Sarah has CMT. Her genetic testing revealed that she has a CMT-causing mutation in each copy of her PRX gene, and therefore has CMT4F. Sarah was the first in the family diagnosed. Nobody in the family had ever heard of CMT, and nobody else has any hint of CMT. Following Sarah’s genetic confirmation, her brother, Billy, and both parents underwent genetic testing. Genetic testing revealed both parents each have a CMT-causing mutation in one copy of their PRX gene, but the other copy each parent has does not. Billy’s testing revealed he doesn’t have any CMT-causing mutations in his PRX gene.
Sarah’s parents each have one copy of an autosomal recessive CMT-causing mutation in their PRX gene. Neither parent has CMT. Neither parent has CMT because having only one copy of an autosomal recessive CMT-causing mutation is insufficient to cause the associated autosomal recessive CMT. The autosomal recessive CMT in this case is CMT4F. Each parent having only this one copy of this mutation means they are each a genetic carrier of this mutation but not of CMT, and not of CMT4F. Both parents, each having this mutation in only one copy of their PRX gene, had a 50/50 chance of passing on their one copy to Sarah, and they each had a 50/50 chance of passing on their one copy to Billy. Overall, both Sarah and Billy had a 25% chance of inheriting both CMT-causing mutations (one from each parent). Sarah randomly inherited her mother’s PRX gene copy that has the mutation instead of the PRX gene copy that does not, and she randomly inherited her father’s PRX gene copy that has the mutation instead of the PRX gene copy that does not. Billy, on the other hand, inherited the opposite PRX gene copies from each parent.
A CMTer who has an autosomal recessive CMT has a CMT-causing mutation in each copy of the associated gene. Because of this, each of their children will inherit one copy of this CMT-causing mutation, regardless of gender. Sarah’s children will each randomly inherit one of her PRX gene copies. Because both copies have a CMT-causing mutation, each of Sarah’s children will inherit from Sarah one copy of her CMT-causing mutation. However, Sarah’s children will not have Sarah’s autosomal recessive CMT. Instead, they will be a genetic carrier of one copy of this CMT-causing mutation, but not of CMT, just like Sarah’s parents. Billy, on the other hand, has no CMT-causing mutations in either of his two PRX gene copies. He can’t pass on to his children genetic mutations he does not have. Therefore, his children will not be a genetic carrier of his family’s autosomal recessive CMT-causing PRX gene mutation.
X-Linked CMT is so called because the gene with the CMT-causing mutation lives on the X-chromosome. Unlike autosomal CMT, chromosomal gender is a factor with X-Linked inheritance patterns. Chromosomal gender is a factor because chromosomal females have two X-chromosomes, inheriting one from each parent while chromosomal males have only one X-chromosome, inheriting it only from their mother and never from their father. In place of a second X-chromosome, chromosomal males have a Y-chromosome, inheriting it only from their father and never from their mother. Chromosomal female = XX, and chromosomal male = XY. This is the easiest part of X-Linked inheritance, whether X-Linked dominant or X-Linked recessive.
Chromosomal females who have X-Linked dominant CMT have a CMT-causing mutation in one copy of a gene that lives on the X-chromosome. Their other copy of the associated gene, which lives on their second X-chromosome, does not have a CMT-causing mutation. Chromosomal females who have X-Linked recessive CMT have a CMT-causing mutation in both copies of the associated gene—one gene copy on each of their two X-chromosomes. For chromosomal females who have X-Linked CMT, whether dominant or recessive, the rules that govern the inheritance pattern are the exact same as they are for autosomal inheritance, whether dominant or recessive, respectfully. There is no difference between autosomal dominant and X-Linked dominant, or autosomal recessive and X-Linked recessive, except for where the gene lives—on an autosome or on the X-chromosome. The rules, however, are different for chromosomal males who have X-Linked CMT, whether dominant or recessive.
Chromosomal males who have X-Linked CMT have a CMT-causing mutation in a gene that lives on the X-chromosome. Chromosomal males have only one X-chromosome. They don’t have a second X-chromosome for a second copy of the associated gene. For X-Linked dominant CMT, this is easy. However, despite having only one copy of each X-Linked gene, and despite recessive inferring a mutation in each of two copies of a gene (not one), chromosomal males can have X-Linked recessive CMT. Because chromosomal males have only one X-chromosome and therefore only one copy of each X-Linked gene, having an X-Linked recessive CMT-causing mutation in their only copy of the associated gene is sufficient for causing the associated X-Linked recessive CMT. In a sense, for chromosomal males, X-Linked CMT isn’t dominant or recessive in inheritance. It’s just simply X-Linked inheritance. The genetic properties of dominant and recessive don’t apply, per se, because chromosomal males have only one X-chromosome and therefore only one copy of each X-Linked gene.
Chromosomal males who have X-Linked CMT will pass their X-Linked CMT-causing mutation to each of their chromosomal female children without exception. Conversely, they will not and cannot pass it onto any of their chromosomal male children. Chromosomal males pass on their only X-chromosome to their chromosomal female children, and they pass on their Y-chromosome to their chromosomal male children. If the X-Linked CMT is an otherwise X-Linked recessive CMT, their chromosomal female children would be a genetic carrier of this one X-Linked recessive mutation, but not CMT, just as though it was an autosomal recessive CMT. If the X-Linked CMT is an otherwise X-Linked dominant CMT, their chromosomal female children would then also have the associated X-Linked dominant CMT.
A chromosomal female who is a genetic carrier of one copy of an X-Linked recessive CMT-causing mutation has a 50/50 chance of passing on this mutation to each child. A chromosomal female child who inherits this one copy of an X-Linked recessive CMT-causing mutation will also be a genetic carrier of this mutation, but not of CMT. A chromosomal male who inherits this one copy of an X-Linked recessive CMT-causing mutation will have the associated CMT because they have only one X-chromosome and therefore only one copy of each X-Linked gene and having only one is sufficient to cause the associated X-Linked recessive CMT.
De Novo – Cori’s Story
CMT is inheritable, yes. One does not have to have inherited it in order to have it though. A CMTer whose CMT was not inherited from a parent has CMT that is caused by a spontaneous and random gene mutation that occurred at or shortly after conception. CMT that was not inherited from a parent is called a de novo, or new case. A de novo CMT case is not uncommon. Many CMTers who are the first in their family diagnosed are usually a de novo case. There are situations in which not everything is as it appears though.
It’s not uncommon for recessive CMT-causing genetic mutations to go undetected. When a CMTer has a de novo recessive CMT, whether autosomal or X-Linked, it might not be a truly de novo case. Often, as with Sarah’s story up above, a first-in-the-family CMTer who has a recessive CMT inherited one-half of their recessive CMT-causing mutation from each parent. The parents usually have no idea they have these mutations. Usually, genetic testing in these situations reveals that each parent has one copy of the recessive CMT-causing mutation, and this genetically explains how the CMTer came to have their recessive CMT, like how Sarah up above did. Sarah’s wasn’t a random spontaneous mutation. However, there are times when this is not the genetic case.
Cori is genetically confirmed to have CMT4C. CMT4C is caused by autosomal recessive mutations in the SH3TC2 gene. Cori, like many CMTers who have recessive CMT, is the first diagnosed in her family. No other family members have any signs, symptoms, or even the slightest inkling of CMT. Family genetic testing revealed that Cori’s mother has one of Cori’s two SH3TC2 mutations, and Cori’s father doesn’t have any mutations in this gene. One of Cori’s siblings has the same mutation as their mother, and the others have no mutations in this gene. How is it then that Cori has CMT4C since only her mother has only one CMT-causing mutation, and why does her mother and one sibling not have CMT?
Autosomal recessive CMT is caused by a gene that lives on an autosome having two CMT-causing mutations, with one mutation on each of the gene’s two copies. The SH3TC2 gene lives on chromosome 5. CMT4C is caused by this gene having two CMT-causing mutations, with one mutation on each of the gene’s two copies. These things add up the make CMT4C autosomal recessive in inheritance. Cori’s mother has just one of these two CMT-causing mutations. Having just one is insufficient to cause CMT. One copy of her SH3TC2 gene has a CMT-causing mutation, and the other copy does not. This means that each of her children had a 50/50 chance of inheriting this one mutation. Each of her children would either get her SH3TC2 copy with the mutation, or the copy without. Cori and one of her siblings inherited this one mutation, and Cori’s other sibling did not. Why is Cori the only one in her family with CMT?
Cori’s mother, like Sarah’s, is a genetic carrier of one copy of an autosomal recessive CMT-causing mutation. Cori’s one sibling is also. Neither have CMT because their one mutation in the SH3TC2 gene is insufficient to cause CMT. It takes having two mutations in this gene to cause CMT. Cori also inherited her mother’s one SH3TC2 mutation. Cori has CMT. Specifically, Cori has CMT4C. Cori inherited only one copy of her CMT-causing mutation from her mother. Cori’s father has no CMT-causing mutations in his SH3TC2 gene. This means that Cori’s second CMT-causing mutation in her SH3TC2 gene occurred randomly spontaneously on its own at or shortly after conception. Cori’s second, non-inherited SH3TC2 mutation is a de novo mutation. Because Cori has this de novo mutation as the second CMT-causing mutation in her SH3TC2 gene, but other family members have only one CMT-causing mutation in this gene, Cori is the first and the only member of her family to have CMT. Because Cori has two mutations, one in each of her two copies of the SH3TC2 gene, each of Cori’s children will randomly inherit one of Cori’s two mutations. Her children, however, will not have CMT, but will be a genetic carrier of one copy of an autosomal recessive CMT-causing mutation.
Mitochondrial DNA – The Lonely One
We have two genomes. One is nuclear DNA, or what is referred to as DNA, or regular DNA. The other is mitochondrial DNA. Nuclear DNA is found in the nucleus of all our cells. Hence, nuclear DNA. Nuclear DNA holds over 20,000 genes that are found on 23 pairs of chromosomes. This is the DNA everybody is familiar with. Mitochondrial DNA, on the other hand, is found in the mitochondria of our cells.
Mitochondrial DNA contains only 37 genes. Thirteen of these genes are responsible for making enzymes involved in oxidative phosphorylation. Oxidative phosphorylation is a process that uses oxygen and simple sugars to create a chemical called adenosine triphosphate (ATP). ATP is mitochondria’s main energy source. There is one subtype of CMT, ATP6-associated CMT (ATP6-CMT), caused by mutations in the ATP6 gene. The ATP6 gene lives in mitochondrial DNA. Can you guess why the gene is named ATP6? Because this gene lives in mitochondrial DNA, the inheritance pattern of ATP6-CMT is mitochondrial inheritance. Mitochondrial DNA is inherited from only the mother, never from the father (refer to the earlier mention), and a mother passes on her mitochondrial DNA equally to each of her children.
There are no CMT genes and CMT isn’t about genes, per se. Rather, CMT is about mutations in genes. The term given to describe a gene that has a CMT-causing mutation is CMT-associated gene. An argument can be made that a gene with a CMT-causing mutation constitutes a CMT gene, but it comes down to personal preference. CMT is an extremely complex and diverse disease, and the genetic causes are just as diverse. While CMT is the most commonly inherited rare disease, a CMTer does not have to have inherited it in order to have it. How CMT is inherited is determined solely by the underlying responsible genetic mutation. The underlying responsible genetic mutation not only determines the inheritance pattern, but also determines the specific subtype.
As of publication, there are 120 discovered CMT-associated genes plus five additional chromosomal locations suspected of having a gene with a CMT-causing mutation, but the exact gene has not yet been identified. These discoveries account for 155 individual CMT subtypes that are organized into 14 Type categories. Autosomal dominant CMT encompasses 81 subtypes. Autosomal recessive CMT makes up 67 subtypes. X-Linked dominant CMT has 3 subtypes. X-Linked recessive has 6 subtypes. One CMT subtype is inherited via mitochondrial DNA. To date, there are no discovered CMT-associated genes found on chromosome 13 nor on the Y-chromosome. Should scientists discover a CMT-associated gene on the Y-chromosome, it would constitute a chromosomal male-to-chromosomal male inheritance only, as only chromosomal males have a Y-chromosome.
The genetics of CMT are forever growing as are the understandings of CMT genetics. While all causes are not yet known resulting in the causes of CMT not yet being fully described or understood, the inheritance patterns of CMT are well understood and described. Scientists, physicians, clinicians, and CMT genetic experts don’t necessarily need to know the exact genetic cause of a CMTer’s CMT to identify its inheritance pattern. A carefully reviewed detailed family history can reveal a likely inheritance pattern when the investigator has the specialized training needed to understand and see the patterns. Once the underlying genetic mutation is identified, however, its inheritance pattern and what the inheritance pattern potentially means for the CMTer comes to full light, as the underlying responsible mutation determines the CMT’s inheritance pattern.
About the Author
Kenneth Raymond is a CMTer who was first diagnosed with Type 1 CMT 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 and is a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT.