Leukodystrophy

Leukodystrophy refers to a group of conditions that mainly affect the white matter of the brain and the spinal cord. The white matter is the wiring network of the brain, linking the brain to the spinal cord and the rest of the body.

How leukodystrophies affect myelin#

Myelin is the substance that surrounds and insulates the nerve fibres in the nervous system. The leukodystrophies affect either the production or the breakdown of myelin. When myelin is damaged, messages between the brain and the rest of the body are slowed down or blocked.

Most leukodystrophies are progressive conditions, which means they can get worse over time. As the white matter is damaged, normal brain functions are gradually lost.

Symptoms#

Life expectancy depends on the type of leukodystrophy a person has and whether specific treatments are available to slow or stop its progression.

The white matter plays a large role in motor function (movement), so damage usually leads to problems in this area. Symptoms can vary depending on how quickly the white matter is damaged, which parts of the brain or spinal cord are affected, and how much the peripheral nerves are involved.

The onset of symptoms varies. Symptoms can include subtle or gradual changes to:

• muscle tone
• body movements and walking style
• speech, and the ability to chew and swallow
• eyesight and hearing
• behaviour and mental ability

Types of leukodystrophy#

There are several different types of leukodystrophy.

Adrenoleukodystrophy (ALD)#

This is a common leukodystrophy that usually only affects males, because the gene change is on the X chromosome. The childhood form (childhood cerebral ALD) usually begins before 10 years of age and may progress rapidly.

The adrenal glands may also be affected. The adult form (adrenomyeloneuropathy) affects the spinal cord and the adrenal glands. Females usually have much milder symptoms because they have two X chromosomes. In some people with the same genetic change, only the adrenal gland is affected, leading to Addison’s disease.

Metachromatic leukodystrophy (MLD)#

This leukodystrophy has a range of subtypes, related to the age at which symptoms appear. For example, in the infantile form (late infantile MLD), a loss of motor (movement) and verbal skills may be the first sign. Symptoms typically become progressively worse. In addition to the brain, the peripheral nerves in the arms and legs are usually affected.

Canavan’s disease (spongy degeneration)#

This form of leukodystrophy affects myelin growth and is most commonly seen in babies around three to five months of age. It is typically characterised by poor head control, decreased muscle tone, regression and a markedly enlarged head. Eventually, the decreased muscle tone changes to stiffness. Life expectancy is limited for babies with the neonatal form. There is also a less common, milder form of the disease.

Krabbe disease (globoid leukodystrophy)#

This affects the myelin of the central and peripheral nervous systems. About 90 per cent of people affected are babies, with symptoms usually appearing before six months of age. There is also a rare adult form.

Mitochondrial diseases#

This is a broad group of conditions caused by mitochondria (the energy producers in our cells) not producing enough energy. Many of these conditions can also affect the white matter.

Hypomyelinating leukodystrophies#

These are characterised by abnormal myelin production. They usually begin in childhood and cause problems with muscle tone, movement and eye movement.

How leukodystrophies are inherited#

Genes come in paired sets, with one set inherited from each parent. The leukodystrophies are inherited in one of three ways.

X-linked inheritance#

The affected gene is carried on the X chromosome, which is involved in determining a baby’s sex. Males usually have an X and a Y chromosome, and females usually have two X chromosomes. Because males have only a single copy of the genes on the X chromosome, an altered gene has no second copy to compensate. Males and females are therefore affected differently.

Autosomal recessive inheritance#

The child can only inherit the condition if both parents are carriers of the genetic change. A carrier has inherited one copy of the altered gene and normally shows little to no symptoms; the condition only becomes apparent when an individual inherits two copies. Boys and girls are equally affected. The parents will not have symptoms, but each of their children has a one in four chance of developing leukodystrophy and a one in two chance of being a carrier.

Autosomal dominant inheritance#

One copy of the gene change is enough to cause the condition, and males and females are equally affected. The gene change may be inherited from a parent or may have occurred randomly in the affected individual.

Other causes of white matter disease#

Not every disease that affects white matter is a leukodystrophy. The white matter can be affected by many genetic and non-genetic conditions. Non-genetic causes include reduced blood supply (ischaemia), infection and multiple sclerosis.

Diagnosis#

Diagnosing a specific leukodystrophy is often difficult and may involve a number of specialists, including neurologists, geneticists and metabolic physicians. In around one-third of cases, a named diagnosis may not be possible.

Depending on the type of leukodystrophy, diagnostic methods can include:

• physical examination
• blood tests and urine tests
• MRI scans
• nerve conduction tests
• neurocognitive tests
• genetic tests

Treatment#

Currently, most leukodystrophies cannot be cured. Stem cell therapy and bone marrow transplantation have been tried in some cases, but the benefits depend on the timing, the age of onset and the severity of symptoms. When successful, these therapies may stop the disease from getting worse, but they rarely reverse existing damage. Therapies such as gene therapy and enzyme replacement therapy are under investigation, and improved understanding of leukodystrophies is leading to increased research into specific treatments.

For now, treatment is mainly supportive and may include:

• medications (for example, for seizures or muscle spasticity)
• physical therapy and occupational therapy
• psychological counselling
• family counselling, including genetic counselling

Genetic counselling#

If your child or another family member has been diagnosed with leukodystrophy, or if leukodystrophy runs in your family, it can help to speak to a genetic counsellor. Genetic counsellors are health professionals qualified in both counselling and genetics. As well as providing emotional support, they can help you understand a condition and its cause, how it is inherited, and what a diagnosis means for your health, lifestyle and plans for the future. They are trained to provide information and support that is sensitive to your family circumstances, culture and beliefs.

If a leukodystrophy runs in your family, a genetic counsellor can explain the genetic testing options available to you and other family members. You may choose to see a genetic counsellor if you are planning a family, to find out your risk of passing the condition on to a child, or to arrange prenatal tests.

Key points#

• Leukodystrophy refers to a group of conditions that mainly affect the white matter of the brain and the spinal cord.
• Leukodystrophies cause loss of normal brain functions.
• Symptoms can vary, depending in part on how much the peripheral nerves are affected.
• The onset of symptoms varies and can include subtle or gradual changes to behaviour.

Where to get help#