Charcot-Marie-Tooth disease (CMT) is named after the three doctors who first described the disease in 1886: Jean-Martin Charcot (shar-coh), Pierre Marie, and Howard Henry Tooth. Today, CMT refers to any peripheral neuropathy with a genetic cause, whether or not the specific genetic mutation is known.
Affecting 1 in 2,500 people, CMT is a rare disease but also the most common inheritable peripheral neuropathy. It is inheritable because the genetic mutations that cause CMT can be passed from parents to children. These genetic mutations follow one of five inheritance patterns, determined by where the mutation occurs and how many mutation copies are needed.
The five inheritance patterns of CMT are:
- Autosomal dominant
- Autosomal recessive
- X-linked dominant
- X-linked recessive
- Mitochondrial inheritance
What Do These Mean?
- Autosomal: The mutated gene is on one of the 22 numbered chromosomes (not the sex chromosomes).
- X-linked: The mutated gene is on the X chromosome.
- Dominant: A single copy of the mutated gene is enough to cause CMT.
- Recessive: Two copies of the mutated gene (one from each parent) are needed to cause CMT.
- Mitochondrial: The mutation is in mitochondrial DNA, passed only from the mother to her children.
We normally have two copies of every gene, one inherited from each parent, with very few exceptions. Whether one or both gene copies are mutated and where the gene is found determines the inheritance pattern and the likelihood of passing on CMT.
Autosomal Dominant Inheritance
In autosomal dominant CMT subtypes, such as CMT1A, CMT1B, and CMT2A, only one copy of the gene needs a mutation to cause CMT. Each child of an affected individual has a 50% chance of inheriting the mutation, regardless of gender. The majority of CMT subtypes follow this inheritance pattern. If a child does not inherit the mutation, they will not develop CMT and cannot pass it on to their children.
Autosomal Recessive Inheritance
In autosomal recessive CMT subtypes, such as CMT4A, CMT4C, and CMT-SORD, both gene copies must carry mutations to cause CMT. Typically, one mutation is inherited from each parent. Children of an affected individual are not at risk of inheriting CMT unless the other parent also carries a mutation in the same gene.
Having only one mutated copy of the gene does not cause CMT. These individuals, often called “carriers,” do not develop CMT and cannot pass it on to their children unless their partner also carries a mutation in the same gene.
When both parents carry one mutation in the same autosomal recessive CMT-causing gene, each child has a 25% chance of inheriting both mutations and having CMT.
X-Linked Dominant Inheritance
In X-linked dominant CMT subtypes, which are CMTX1 (aka CMT1X or CMTX), CMTX6, and CMT-DRP2, the gene with the mutation is located on the X chromosome. For individuals with two X chromosomes (chromosomal females), a mutation in one copy of the gene causes CMT. For individuals with one X and one Y chromosome (chromosomal males), a mutation in their single copy of the gene causes CMT.
When a chromosomal female has X-linked dominant CMT, each of her children has a 50% chance of inheriting the mutated gene and having CMT. In contrast, a chromosomal male with X-linked dominant CMT will pass the mutation to all of his daughters, who will have CMT, but none of his sons, as males pass their X chromosome only to their daughters.
X-Linked Recessive Inheritance
In X-linked recessive CMT subtypes, such as CMTX4 and CMTX5, the gene with the mutation is located on the X chromosome. For individuals with two X chromosomes (chromosomal females), a mutation in both gene copies is required to cause CMT. For individuals with one X and one Y chromosome (chromosomal males), a mutation in their single copy of the gene causes CMT.
Although recessive inheritance usually requires mutations in both gene copies, individuals with one X chromosome have only one gene copy. As a result, a single mutation is sufficient to cause X-linked recessive CMT in chromosomal males.
When a chromosomal female has X-linked recessive CMT, her sons will inherit the mutation and have CMT. At the same time, her daughters are only at risk if the other parent also carries a mutation in the same gene.
A chromosomal male with X-linked recessive CMT will pass the mutation to all his daughters, who will carry the mutation but not have CMT unless the other parent also carries a mutation in the same gene. None of his sons will inherit the mutation, as males pass their X chromosome only to their daughters.
Mitochondrial Inheritance
Mitochondrial inheritance applies to CMT-ATP6, the only CMT subtype caused by a mutation of a mitochondrial DNA gene. The mt-ATP6 gene is located in the mitochondrial DNA (denoted by “mt”) and is inherited exclusively from the mother.
When a mother has CMT-ATP6, all her children will inherit the gene mutation and have CMT. In contrast, a father with this subtype cannot pass the mutation to his children, as mitochondrial DNA is inherited only from the mother.
Common Questions About CMT Inheritance
Inheritance patterns explain how CMT-causing mutations are passed down through families, but not every case fits neatly into these categories. Questions often arise about whether CMT can occur spontaneously or appear to skip a generation. Understanding these nuances provides clarity for individuals and families navigating CMT genetics.
Can I Have CMT Without Inheriting It?
Yes, having CMT without inheriting it from a parent is possible. In these cases, CMT is caused by a random and spontaneous mutation in a gene at or shortly after conception. This is known as a “de novo” mutation, meaning “new.”
When a de novo mutation causes CMT, it can be passed on like inherited cases. The chances of passing on de novo CMT depend on the inheritance pattern of the specific subtype.
Can CMT Skip a Generation? Does It?
No, CMT cannot and does not skip a generation. Before genetic discoveries in CMT began in the early 1990s, it sometimes appeared to skip a generation. However, advancements in genetic research, including the Human Genome Project and CMTA-driven genetic discovery initiatives, have significantly expanded our understanding of CMT inheritance.
Today, genomic science confirms that CMT does not skip a generation. Even in cases where it seems to, there is always a genetic explanation, though it may not be immediately evident. CMTA’s commitment to funding genetic research continues to uncover these explanations and improve our understanding of CMT genetics.
Next Steps in Managing CMT
Knowing the inheritance patterns of CMT empowers individuals and families to navigate their diagnosis confidently. While the complexities of CMT inheritance can feel overwhelming, expert guidance and resources are available to help at CMTA Centers of Excellence.
CMTA Centers of Excellence are multidisciplinary clinics specializing in CMT care, where patients and their families can receive comprehensive care that includes genetic counseling and tailored management plans.
Visit the CMTA Center of Excellence directory today to find your nearest center and take the next step in your journey. [link or button to directory]
