What is Leukodystrophy?
‘Leukodystrophy’ and the related term ‘Leukoencephalopathy’ refer to a group of over 40 identified (plus more unidentified) conditions (mostly serious) that affect the myelin, or white matter, of the brain and spinal cord, which in turn, impacts the ability of the nervous system to send its signals throughout the body. Although there may be periods of stability, the condition doesn’t go into ‘remission’ as may be seen in some other neurological conditions, and over time, complications might occur and/or the condition typically worsens.
Leukodystrophies are neurological, degenerative disorders, and most are genetic. This means that a person’s condition is caused by a change to one of the genes that are involved in the development of myelin, leading to deterioration in many of the body’s neurological functions.
While most leukodystrophies occur in childhood (varying stages from birth, infancy, juvenile), there are also persons who carry a leukodystrophy gene who are healthy as children or young adults, but who might develop a leukodystrophy later in adult life.
Because there are so many different types of leukodystophy, there is no specific age for onset and the pattern of symptoms of each type of leukodystrophy can be very different - there may even be some variation between different people with the same condition, however all types of leukodystrophy are described as progressive. A child who has been fit and well may gradually show signs of a loss of hearing and/or vision, as well as changes in body tone, movement, gait, balance, speech, ability to eat, behaviour, memory or thought processes.
People with leukodystrophy often experience long delays before receiving a correct diagnosis. This is partly because the symptoms can be quite vague and associated with many different disorders. Sometimes, specific diagnosis of rare types of leukodystrophy are elusive.
In children, initial delays in development may be put down to normal ranges in achieving milestones. As leukodystrophies are rare, it is routine medical practice to rule out more common and treatable causes before testing for rarer conditions, but this can further delay the correct diagnosis of a rare condition. There are many different tests that can be undertaken; MRI (Magnetic Resonance Imaging), blood tests, urine tests and specific genetic tests are most commonly ordered. Some of these tests are very specialised and may need to be sent to experts/advanced testing facilities interstate or overseas.
As mentioned earlier, the term ‘leukodystrophy’ covers a range of conditions; some of these may be diagnosed on a single blood test, while others may still remain ‘unclassified’ (ie no specific cause found) even after many tests over a long period of time. A family history is an important part of the medical assessment to search for clues about possible inheritance of the condition.
The nerves in the human body are composed of two parts. The innermost section is called the axon and is directly responsible for conveying nerve impulses from the brain. Surrounding the axon, rather like insulation around an electrical cord, is the myelin sheath, or ‘white matter‘. The sheath is made up of a variety of chemicals. Its protective covering is vital to the health and function of the nerve axon within.
In leukodystrophies, a mutation in one of the patient’s genes affects the development of one of the multiple chemicals (there are at least 10) that make up the myelin sheath, preventing or inhibiting its development. Without this natural protection, the nerve axons are unable to function correctly. Each form of leukodystrophy affects a different element of the myelin sheath, causing a range of symptoms and affecting different parts of the nervous system, such as the spinal cord and the brain.
Leukodystrophies differ from other diseases of the myelin sheath, such as Multiple Sclerosis, because, rather than following an ‘up and down’ course, leukodystrophies are progressive – that is, the condition continues to get worse throughout the life of the sufferer.
Is there a cure?
Developments in genetic and other therapies provide hope for the future, but currently there is no cure. Depending upon the leukodystrophy, sometimes there are things that can be done to manage the condition, and the fact that there is no cure does not always mean there is no hope.
For some people where particular leukodystrophies such as Adrenoleukodystrophy (ALD) or some types of Metachromatic Leukodystrophy (MLD) are diagnosed prior to the appearance or onset of symptoms, (such as when screening occurs following the diagnosis of leukodystrophy in another family member) bone marrow/cord blood transplants may (depending upon the case) be an option. These procedures are also extremely risky, however, and are not suitable for all individuals or conditions. See Research (below) for more on treatments.
Management of Leukodystrophies
Treatment for leukodystrophy and leukoencephalopathy is generally aimed at providing comfort and management of symptoms. Life expectancy varies enormously – while for some people the condition progresses over months or a few years, particularly when symptoms appear in infancy or early childhood, for others, depending upon the leukodystrophy, they may have many years of productive life ahead, with varying levels of impact from symptoms.
Depending upon the case, supports can come from from physicians, nurses, physiotherapists, occupational therapists, nutritionists, educators, psychologists, allied heath & disability services, family, friends, volunteers and other leukodystrophy-aware persons. This support can also include family counselling, respite care, and advice on matters such as medications and social security entitlements.
As leukodystrophies are genetically determined, they are not contagious.
Some leukodystrophies are inherited from the parent/s, even though there may have been no sign of the condition for several generations, while others occur for the first time in the affected person. Genetic conditions can be passed on to future generations. For this reason, once a diagnosis of a genetic condition has been made, doctors and genetic counsellors will discuss the issues that may face other family members, including those who have no symptoms.
This can be a complex and sensitive area – different forms of leukodystrophy have different ‘patterns of inheritance’ and the information provided needs to be relevant to each individual and family situation. While some family members may be reassured that they are unaffected by the genetic condition, others may be faced with important decisions about their own health or future family planning. For this reason, contact with a genetic health service is appropriate.
Inheritance of a leukodystrophy can be either ‘autosomal recessive’ or ‘X-linked’.
Autosomal recessive disorders affect both boys and girls and require both parents to be carriers (heterozygotes). The carriers themselves have no disability. However, should two carriers have children together, on average there is a 25% chance of their child having the illness and a 50% chance of the child being a carrier.
The X-linked (sex-linked) disorders are carried on the X chromosome, with only the mother being the carrier. On average, half of the daughters of a woman who is a carrier will also be carriers, while the other half will not carry the gene. On average, one-half of the woman’s sons will have the illness and the other half will not. If an affected man has children, then none of his sons will carry the disorder, but all of his daughters will be carriers.
Active research into the leukodystrophies is happening worldwide (including Australia). New and experimental therapies are constantly being tested and tried to overcome the effects of the various causes of leukodystrophy and to either reduce the symptoms, slow the progression, or halt the progress of the disease altogether. Some of the leukodystrophies respond to relatively simple therapies. For example, Cerebrotendinous Xanthomatosis - patients can be helped by taking a simple oral medication. The fat which accumulates in the blood of patients with Refsum’s disease (phytanic acid), for example, can be cleared by the implementation of a diet which restricts the intake of this fat in the diet. This can be beneficial for muscle strength and nerve function, and can arrest the deterioration of vision and hearing. International clinical trials on the effects of Lorenzo’s Oil therapy on Adrenoleukodystrophy are still in progress. The studies mostly involve patients who carry the abnormal gene but have not yet developed the disease. It has already been established that this treatment can reduce the levels of the very long chain fats in the blood (these substances accumulate in the tissues and blood of patients and are believed to contribute to the disease), but as yet it is not known whether damage to the brain can be prevented.
Another form of therapy which is showing promise is the partial replacement of the inactive protein with active protein. This can be achieved by bone marrow/cord blood transplantation. Cells derived from the transplant, which contain normal active protein, are able to handle the substance which the patient’s body is unable to cope with. This form of therapy has already been used to treat some of the leukodystrophies, such as Adrenoleukodystrophy or Metachromatic Leukodystrophy. However, matched donors must be available and the procedure carries a risk, and there is still a question as to the extent to which the new cells can enter the brain – the organ most affected by leukodystrophy. Also, it is preferable that the procedure be used before possible irreversible damage to the brain occurs. An alternative approach is enzyme replacement therapy, in which the patient is administered the active protein obtained from some other source.
Perhaps the most exciting development is the replacement of the gene itself. In March 1996, in New Zealand, the world’s first human gene therapy trials for a neurological disease were carried out on two children with Canavan disease. Further trials involving more children have since been conducted.
Research at various stages and covering many different leukodystrophies is taking place globally and every year, further progress is made.
Neuron with normal myelin sheath
Neuron with damaged myelin sheath