Charcot-Marie-Tooth (CMT) disease encompasses a group of inherited neurological disorders that impact the peripheral nerves. These nerves extend from the brain and spinal cord to the limbs, controlling movement and sensation. The ways in which CMT is passed down through families are diverse, making its inheritance patterns complex. Understanding whether a specific type of CMT is dominant or recessive, or follows another pattern, is important for individuals and families affected by the condition.
What is Charcot-Marie-Tooth Disease?
CMT affects the peripheral nerves, which transmit signals between the brain and the rest of the body. Damage to these nerves can lead to muscle weakness and reduced sensation, particularly in the arms, legs, hands, and feet. The condition is progressive, meaning symptoms worsen over time.
Common symptoms include muscle weakness and loss of muscle bulk in the lower legs and feet, often resulting in high foot arches, curled toes (hammertoes), and footdrop. These issues can cause an awkward gait, frequent tripping, and falls. As the disease advances, symptoms may extend to the hands and arms, impacting fine motor skills. CMT is caused by genetic mutations that disrupt nerve cell function or structure.
Understanding CMT Inheritance Patterns
CMT can be inherited in several ways, depending on the specific gene mutation involved. The most common forms are autosomal dominant, followed by X-linked, and then autosomal recessive, which is the least common in the United States.
Autosomal Dominant Inheritance
In autosomal dominant inheritance, a person develops CMT by inheriting one copy of a mutated gene from an affected parent. If one parent has an autosomal dominant form of CMT, each child has a 50% chance of inheriting the mutated gene and developing the disorder, regardless of sex. Many types of CMT, including CMT1A and most CMT2 types, follow this pattern. CMT1A, the most common form of CMT, is caused by a duplication of the PMP22 gene.
Autosomal Recessive Inheritance
Autosomal recessive inheritance requires a child to inherit two copies of the mutated gene, one from each parent. Both parents are carriers, meaning they each have one mutated gene copy but do not show symptoms because they have one working copy. If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two mutated copies and be affected by CMT. CMT Type 4 (CMT4) is a group of CMT types inherited in this manner.
X-Linked Inheritance
X-linked inheritance occurs when the gene mutation is on the X chromosome. This pattern affects males and females differently because males have one X and one Y chromosome, while females have two X chromosomes. Males inheriting the mutated gene on their single X chromosome experience more severe symptoms than females, whose second, unaffected X chromosome can compensate. Fathers with X-linked CMT cannot pass the condition to their sons, but they pass the mutated X chromosome to all their daughters, who may be affected or carriers. CMTX1, a common X-linked type, is caused by GJB1 gene mutations.
Implications for Families
Understanding a family’s specific CMT inheritance pattern provides practical information. Knowing the mode of inheritance helps assess the likelihood of passing the condition to future children. For example, a person with an autosomal dominant form of CMT knows each child has a 50% chance of inheriting the condition.
This knowledge also aids family planning decisions. Genetic counseling offers guidance on reproductive options, such as preimplantation genetic diagnosis (PGD) with in vitro fertilization (IVF) to select embryos free of the specific genetic mutation. Identifying the inheritance pattern can also help pinpoint other family members who might be affected or carriers, even with mild or no symptoms.
Genetic Testing and Diagnosis
Genetic testing confirms a CMT diagnosis and identifies the specific gene mutation responsible. This testing involves a blood sample, with DNA analyzed to detect known CMT-causing mutations. While over 100 genes are linked to CMT, most identified genetic causes involve mutations in a few genes, such as PMP22, GJB1, MPZ, and MFN2.
Genetic counselors interpret test results and provide personalized guidance to individuals and families. They explain the implications of the identified mutation and its inheritance pattern for the affected individual and their relatives. Genetic testing can also be used for prenatal screening during pregnancy through methods like chorionic villus sampling (CVS) or amniocentesis, allowing families to understand if a developing fetus carries the mutation.