SNP Shot: Genomic Insights

Charcot-Marie-Tooth disease (CMT) is a group of inherited disorders, also known as hereditary sensory and motor neuropathies, that affect the peripheral nerves. These nerves are responsible for connecting the brain and spinal cord to muscles and sensory cells, which allow us to feel touch, pain, heat, and sound. Over time, damage to these peripheral nerves can lead to changes or loss of sensation and muscle wasting (atrophy) in the feet, legs, and hands.

While CMT typically becomes noticeable during adolescence or early adulthood, it can start at any age. The severity and age of onset of CMT symptoms can vary greatly, even among family members. Some individuals may never realize they have the condition due to very mild symptoms, while most experience a moderate level of physical disability. In rare cases, individuals may experience severe weakness or other complications that can be life-threatening. However, for most people with CMT, life expectancy is not affected.

The earliest signs of CMT often involve muscle atrophy in the feet. This can lead to foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). Individuals may find it difficult to flex their foot or walk on their heel, resulting in a high-stepping walk (steppage gait) and an increased risk of ankle injuries and tripping. As the disease progresses, the muscles in the lower legs usually weaken, although leg and foot problems rarely necessitate the use of a wheelchair.

Weakness in the hands can also develop, making everyday tasks like writing, buttoning clothes, and turning doorknobs challenging. People with CMT typically experience reduced sensitivity to touch, heat, and cold in their feet and lower legs, and may occasionally feel aching or burning sensations. In rare instances, affected individuals may experience vision loss or gradual hearing loss, sometimes leading to deafness.

There are several types of CMT, distinguished by how they affect nerve cells and their inheritance patterns. Type 1 (CMT1) involves abnormalities in myelin, the protective fatty substance surrounding nerve cells that helps transmit nerve impulses. These abnormalities slow down nerve impulse transmission and can impair the health of the nerve fiber itself. Type 2 (CMT2) involves abnormalities in the axon, the fiber extending from the nerve cell body to muscles or sensory organs. These axon abnormalities weaken the nerve impulse. Individuals with CMT2 may develop amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, muscle loss, and difficulty controlling movement. In forms of CMT classified as intermediate type, nerve impulses are both slowed and weakened, likely due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished by its inheritance pattern; it can affect either the axons or myelin. Type X CMT (CMTX) is caused by gene mutations on the X chromosome, one of the two sex chromosomes. Within each CMT type are subtypes (e.g., CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1), each indicating a different genetic cause.

Sometimes, older names are used to refer to specific forms of CMT. For instance, Roussy-Levy syndrome is a form of CMT1 with the added symptom of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe form of CMT that begins in early childhood; it's also sometimes called type 3 (CMT3). Depending on the specific gene affected, this severe, early-onset form may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.

Inheritance:

The way CMT is inherited varies depending on the specific type. CMT1, most cases of CMT2, and most intermediate forms follow an autosomal dominant inheritance pattern. This means that only one copy of the mutated gene in each cell is enough to cause the disorder. In most cases, an affected person has one parent who also has the disorder. Each child of an affected parent has a 50% chance of inheriting CMT. CMT4, some CMT2 subtypes, and some intermediate forms are inherited in an autosomal recessive pattern. This requires both copies of the gene in each cell to have mutations. Typically, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs or symptoms of the condition themselves. Children are only affected if both parents pass down a mutated gene. CMTX is inherited in an X-linked dominant pattern. An X-linked condition means the mutated gene is located on the X chromosome. Dominant inheritance means only one copy of the altered gene is needed to cause the condition. In most cases, affected males, who have the mutation on their only X chromosome, experience more severe symptoms than affected females, who have the mutation on one of their two X chromosomes. A key feature of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. All daughters of affected men will inherit one altered X chromosome but may only have mild symptoms. Some cases of autosomal dominant or X-linked CMT arise from a new mutation, occurring in people with no family history of the disorder.