Leukodystrophy Health Article

Definition

Leukodystrophy refers to a group of rare genetic disorders affecting the central and peripheral nervous systems. They are neurodegenerative diseases characterized by abnormalities in myelin, the fatty substance that surrounds, insulates, and facilitates the function of nerve cells.

Description

Leukodystrophy derives from two Greek words; "leuko" means white, referring to the white matter (myelin) of the nervous system, and "dystrophy" means abnormal growth or development. Myelin insulates, or sheaths, nerve cells, helping them to transmit electrical nerve signals. It is a complex substance composed of a number of fat and protein molecules. Without myelin, nerve cells cease to function and eventually die. It also covers the spinal cord and the long nerve cell projections, known as axons, which innervate all of the peripheral tissues.

More than 15 different types of leukodystrophy have been described, the most common of which will be discussed here. They are all caused by either an abnormality in one of the protein components of myelin, or by a defective or missing enzyme that assists in the production or normal degradation of myelin. As such, leukodystrophies are often referred to as demyelinating or dysmyelinating diseases, as well as leukoencepalopathies.

Based on the part of the nervous system that is most affected, leukodystrophies may be categorized as central (brain and spinal cord), peripheral, or combined. The neurologic symptoms vary widely, both within and between the different types. All types of leukodystrophy are genetic (present at conception), progressive, and never spontaneously resolve. None of the leukodystrophies can be cured, and effective treatments are limited.

Demographics

Most of the individual leukodystrophies are rare. The most common type is Canavan disease, with an incidence of about one in 8,000, followed by X-linked adrenoleukodystrophy (XL-ALD), which occurs in one in 40,000 male births. Some types of leukodystrophy are more common in certain ethnic groups, such as Canavan disease in Ashkenazi Jews, or globoid cell leukodystrophy (GLD) and metachromatic leukodystrophy (MLD) in Scandinavians.

As indicated, all types of leukodystrophy are genetic, with several patterns of inheritance represented. Genes reside on the chromosomes in the nucleus of each cell; a normal complement is 46 chromosomes arranged in 23 pairs. The first 22 pairs are the autosomes, and the last pair, designated X and Y, are the sex chromosomes. Males have one X and one Y, while females have two X chromosomes. One of each chromosome/gene pair is contributed by each parent at conception.

Autosomal recessive inheritance refers to a disorder that only occurs if both copies of a gene pair are defective. An affected individual is typically born to unaffected parents, who each silently carry one copy of the disease gene. Each time parents who both carry the same recessive gene conceive a pregnancy, there is a 25% chance they will both transmit the disease gene and have an affected child.

Autosomal dominant inheritance requires that only one copy of a gene pair be defective in order to develop the disorder. Each offspring of a parent with an autosomal dominant disorder has a 50% risk of inheriting the gene. In some conditions (e.g., Alexander disease), most cases are due to a new mutation of the gene in a sperm or egg (unaffected parent).

A male who inherits the gene for an X-linked recessive disorder develops the condition because he has no normal gene on a second X chromosome to compensate for it. Female carriers of an X-linked recessive disorder are usually unaffected, but not always. If they do develop signs/symptoms, they tend to have later onset and milder symptoms. A woman who carries an X-linked recessive gene faces one of four possible outcomes with each pregnancy: affected male, unaffected male, carrier female, and noncarrier female. If an affected male has children, all of his daughters will be carriers, but none of his sons will be affected.