Definition
Channelopathies are inherited diseases caused by defects in cell proteins called ion channels.
Channelopathies include a wide range of neurologic diseases, including periodic paralysis, congenital myasthenic syndromes, malignant hypothermia, a form of Charcot-Marie-Tooth disease, and several other disorders. Cystic fibrosis and long Q-T syndrome, which are not neurological diseases, are also types of channelopathy.
Description
Cells of the body, including nerve and muscle cells, are surrounded by thin coverings called membranes. Embedded in these membranes are a large and varied set of proteins that control the movement of materials across the membrane, in and out of the cell. One major type of material that crosses through such proteins are called ions, and the proteins that transport them are called ion channels.
Ions perform many different functions in cells. In neurons (nerve cells), they help transmit the electrical messages that allow neurons to communicate with each other, and with muscle cells. In muscle cells, they allow the muscle to contract. When the ion channels are defective, these activities may be disrupted.
Inheritance
The proteins responsible for channelopathies are made by genes, and defects in genes are the cause for the diseases. Genes are inherited from both parents. If two defective copies of a gene are needed in order for a person to develop the disease, this is known as a recessive inheritance pattern. Two parents, each of whom carry one defective copy, have a 25% chance with each pregnancy of having a child with the disease.
If only one defective copy of the gene is needed in order to develop the disease, this is known as a dominant inheritance pattern. A single parent who carries the disease gene (and likely has the disease as well) has a 50% chance with each pregnancy of having a child with the disease.
Types of Channelopathies
Periodic paralysis
A person with periodic paralysis experiences sudden onset of weakness, which gradually subsides, only to return again later. Two forms of periodic paralysis exist, termed "hyperkalemic," referring to the excessively high levels of potassium in the blood which can trigger attacks, and "hypokalemic," in which excessively low levels of potassium are the culprit. Each is caused by different genetic mutations of a potassium ion channel, and both exhibit the dominant inheritance pattern. Onset is usually in childhood for the hyperkalemic form, and childhood to adulthood for the hypokalemic form. Dietary restrictions can reduce the frequency of attacks of both forms, with a high-carbohydrate, low-potassium diet for the hyperkalemic form, and a low-carbohydrate, high-potassium diet for the hypokalemic form.
Congenital myasthenic syndromes
Congenital myasthenic syndromes are a group of related disorders caused by inherited defects in the acetylcholine receptor. This protein sits on the surface of muscle cells; when a nearby neuron releases the chemical acetylcholine, it binds to the receptor, causing the muscle to contract. Defects cause myasthenia ("muscle weakness") and fatigue, and may be life-threatening in some individuals. Most forms display the recessive inheritance pattern. Onset is in infancy. Treatment usually includes the drug mestinon, which blocks the breakdown of the acetylcholine after it is released, prolonging its action, and another drug, called 3, 4-DAP, which increases the amount of acetylcholine released.
Malignant hyperthermia
Malignant hyperthermia is caused by mutations in the gene for a membrane protein inside the muscle cell, called the ryanodine receptor, which controls calcium ion movement within the muscle. Another form is due to mutation in a different muscle protein controlling calcium. Malignant hyperthermia is usually triggered by exposure to certain kinds of anesthetics or muscle relaxants. It causes a dangerous increase in the rate of activity within the muscle, and a sharp rise in temperature, leading to a cascade of crises which may include severe damage to muscle cells, heart malfunction, swelling of tissues including the brain, and death. It is treated with dantrolene, an anti-spasticity medication that blocks calcium ion movement in the muscle. Awareness of the condition has led to better screening for it among anesthesia patients and a significant reduction in mortality.
X-linked Charcot-Marie-Tooth disease
X-linked Charcot-Marie-Tooth disease (CMTX) is caused by a defect in connexin 32. This protein forms connections between adjacent cells, allowing ions to flow between them. The cells affected are those that surround neurons and provide their electrical insulation. Outside the brain and spinal cord (together called the central nervous system, or CNS), this job is performed by Schwann cells. Inside the CNS, the insulating cells are called oligodendrocytes. Like other forms of CMT, CMTX causes slowly progressing muscle weakness in the distal muscles (those furthest away from the body center), including the hands and feet. There may also be decreased sensation in the extremities. CMTX is inherited on the X chromosome, of which males have one and females have two. For this reason, CMTX usually affects males more severely than females because they have only one X chromosome, and therefore lack a second normal copy of the gene.
Resources
WEBSITES
Muscular Dystrophy Association. www.mdausa.org.
Charcot-Marie-Tooth Association. www.cmta.org.
Richard Robinson
