Charcot-Marie-Tooth disease (CMT) is the most common inherited neurological disorder, affecting the peripheral nerves responsible for movement and sensation in the limbs. CMT is not a single condition but a diverse group of disorders caused by mutations in over 130 different genes. These genetic changes can be passed down through families using several distinct inheritance patterns. Understanding the specific pattern is essential for accurate diagnosis and risk assessment.
Charcot-Marie-Tooth Disease is a Group of Disorders
CMT is an inherited peripheral neuropathy, affecting the nerves outside the brain and spinal cord. Peripheral nerves contain an inner wire, the axon, which transmits signals, and an outer insulating layer, the myelin sheath. Different types of CMT are categorized based on which part of the nerve is primarily damaged and the inheritance pattern involved.
The classification system divides CMT into major types, such as CMT Type 1 (CMT1) and CMT Type 2 (CMT2). CMT1 is a demyelinating neuropathy where the myelin sheath is damaged. CMT2 is an axonal neuropathy where the axon itself is affected. This distinction, combined with the inheritance pattern, allows for further subtyping into specific genetic conditions, like CMT1A or CMTX1.
Autosomal Dominant Inheritance
Autosomal dominant inheritance is the most frequent pattern observed in Charcot-Marie-Tooth disease, accounting for the majority of cases. The mutated gene is located on an autosome (non-sex chromosome). Only one copy of the altered gene is needed to cause the disorder, meaning a person only needs to inherit the mutation from one affected parent.
The most common cause of CMT, CMT1A, is transmitted this way. It results from a duplication on chromosome 17 containing the PMP22 gene. This duplication disrupts the myelin sheath structure by causing the production of too much peripheral myelin protein 22. If one parent has an autosomal dominant form of CMT, each child has a 50% chance of inheriting the mutated gene, regardless of their sex.
Recessive X-Linked and De Novo Patterns
Autosomal recessive and X-linked inheritance patterns also cause Charcot-Marie-Tooth disease. Autosomal recessive CMT, typically categorized as CMT Type 4 (CMT4), requires a person to inherit two copies of the mutated gene, one from each parent. The parents are usually unaffected carriers who carry one mutated copy but do not show symptoms of the disease.
If two parents are carriers, there is a 25% chance with each pregnancy that the child will inherit both mutated genes and develop CMT. Recessive forms of CMT are often associated with earlier onset and more severe symptoms than the dominant forms.
X-linked CMT (CMTX), such as CMTX1, is caused by a mutation on the X chromosome, frequently involving the GJB1 gene. This location leads to different inheritance patterns and symptom severity between sexes. Males, who have only one X chromosome, are often more severely affected than females, who have a second healthy copy that can partially compensate. An affected father cannot pass the condition to his sons, but all of his daughters will inherit the altered gene.
A person may also develop CMT due to a de novo mutation, meaning the genetic change is new and was not inherited from either parent. These spontaneous mutations occur in the sperm, egg, or shortly after conception. Although not inherited, this new mutation can still be passed on to the affected individual’s children according to the specific CMT subtype’s inheritance pattern. For example, de novo duplications causing the dominant CMT1A account for over 10% of cases in some families.
Genetic Testing for Specific Diagnosis
Determining the specific subtype of CMT is necessary for accurate medical management and family counseling, given the variety of genetic causes and inheritance patterns. Genetic testing, often performed using a blood or saliva sample, analyzes a person’s DNA to pinpoint the exact gene mutation responsible. Testing may involve single-gene testing, multi-gene panel testing, or whole-exome sequencing, depending on initial clinical findings.
Identifying the mutated gene, such as PMP22, GJB1, or MFN2, confirms the diagnosis and clarifies the mode of inheritance. This clarification is crucial for family planning. For example, a confirmed PMP22 duplication points to an autosomal dominant pattern with a 50% risk to offspring. Test results also help guide patients toward clinical trials and future treatments specific to their genetic subtype.