Leukodystrophy describes a collection of about 15 rare genetic disorders that effect the brain, spinal cord and peripheral nerves. It is characterized by imperfect growth or development of the white matter covering nerve fibers in the brain.
Leukodystrophy comes from the Greek words leuko meaning white (referring to the white matter of the nervous system) and dystrophy meaning imperfect growth or development. The white matter is called the myelin sheath and is an extremely complex substance composed of at least 10, and probably more, chemicals. The myelin sheath protects the axon (a long and single-nerve cell process that acts as a wire to conduct impulses away from the cell body), much the way insulation does to an electric wire.
Each type of leukodystrophy affects one of these chemicals. Leukodystrophies covered in this essay are Alexander's disease, childhood ataxia with central nervous system hypomyelination (CACH), also known as vanishing white matter disease, cerebralautosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebrotendinous xanthomatosis (CTX), metachromatic leukodystrophy, ovarioleukodystrophy syndrome, and Van der Knapp syndrome, also called vacuolating leukodystrophy with subcortical cysts.
Leukodystrophies covered as separate entries in this encyclopedia are adrenoleukodystrophy (ALD)/adrenomyeloneuropathy (AMN), Aicardi-Goutieres syndrome, canavan disease (spongy degeneration), Krabbe disease (globoid cell leukodystrophy), neonatal adrenoleukodystrophy, Pelizaeus-Merzbacher disease (X-linked spastic paraplegia), Refsum disease, and Zellweger syndrome.
Genes are the blueprint for the human body that directs the development of cells and tissue. Mutations in
All of the leukodystrophies discussed in this article have an autosomal recessive pattern of inheritance that affects males and females. People with only one abnormal gene are carriers but since the gene is recessive, they do not have the disorder. Their children will be carriers of the disorder but not show symptoms of the disease. Both parents must have one of the abnormal genes for a child to have symptoms of an autosomal recessive leukodystrophy. When both parents have the abnormal gene, there is a 25% chance each child will inherit both abnormal genes and have the disease. There is a 50% chance each child will inherit one abnormal gene and become a carrier of the disorder but not have the disease itself. There is a 25% chance each child will inherit neither abnormal gene and not have the disease nor be a carrier.
All of the leukodystrophies discussed here appear to affect all racial and ethnic groups and all geographic populations. However, metachromatic leukodystrophy has been found in a higher frequency in highly inbred groups, such as the Habbanite Jewish population. Van der Knapp syndrome has a high prevalence among Turkish and Asian-Indian people.
Signs and symptoms
The most common signs seen in most leukodystrophies include gradual changes in an infant or child who previously appeared healthy. These changes may appear in body tone, movements, gait, speech, the ability to eat, hearing, vision, behavior, and memory. Specific signs and symptoms for individual leukodystrophies include:
- Metachromatic, with the most common and most severe form occurring between the ages of six months and two years with symptoms such as irritability, decreased muscle tone, muscle wasting, and difficulty learning to walk and talk. Onset symptoms in older children and adults include deterioration of intellectual performance, and behavioral or psychiatric problems. Blindness, seizures, and paralysis occur as the disease progresses.
- Alexander's disease, which usually begins in infancy (six to 24 months of age) and affects mostly males. Initial signs are physical and mental retardation and as the disease progresses, enlargement of the brain and head, spasticity, and seizures. In children and adults, symptoms are the same but occur less frequently and progress more slowly.
- CACH is usually diagnosed in infancy and initial symptoms include motor and speech difficulties that progressively worsen. Later symptoms include difficulty swallowing, seizures, and coma.
- CADASIL can be diagnosed in children and adults but usually shows up at around age 45. The initial symptom is usually migraine headaches, followed in about 10 years by ischemic attacks and small strokes followed by mood disturbances and dementia. Epilepsy sometimes occurs.
- CTX may present initial symptoms of cataracts, mild mental retardation, fatty tumors (called xanthomas) in tendons, especially the Achilles tendon or heel cord. Later symptoms include seizures, emotional or psychiatric disturbances, and impaired motion or muscle movement.
- Ovarioleukodystrophy syndrome usually has onset symptoms of walking difficulties and/or mental retardation.
- Van der Knapp syndrome can have onset at or shortly after birth with the symptom of an extremely enlarged head. But onset usually occurs between ages four and five with initial symptoms of cerebella ataxia followed by spasticity. Later symptoms include mental slowing and learning problems and sometimes epileptic seizures and severe walking impairment.
Leukodystrophies are occasionally misdiagnosed as muscular dystrophy, since they all are neurological disorders involving white matter. Genetic testing is usually in order for all leukodystrophies except Alexander's disease and Van der Knapp syndrome for which the specific genetic abnormalities are unknown. A nerve conduction velocity (NCV) test is sometimes used to evaluate nerve damage in people with metachromatic leukodystrophy. The NCV test sends small electrical shocks through one end of a nerve. The time it takes to travel to the other end of the nerve is measured to help determine the severity of nerve damage. Diagnosis of CTX is made by measuring the levels of bile alcohol in the blood or urine, or of cholestanol in the blood. Cholestanol is similar chemically to cholesterol but can be distinguished from it by special chemical tests. MLD and Van der Knapp syndrome diagnosis are usually made by a brain imaging scan called magnetic resonance imaging (MRI). A series of biochemical tests is sometimes used to diagnose MLD.
Treatment and management
With the exception of CTX, none of the leukodystrophies covered here are treatable. In some of the disorders, specific symptoms can be treated. For example some infections associated with MLD, such as pneumonia, can be treated with antibiotics. In ovarioleukodystrophy syndrome, ovarian insufficiency can be treated with hormone replacement therapy. But there are no treatments available for most of the conditions associated with leukodystrophies, such as mental retardation, dementia, deterioration of speech, vision, and mobility, and degeneration of myelin (white matter). In CTX, administration of certain bile acids, especially chenododeoxycholic acid, can prevent further progression of the disorder and in some cases may bring improvement.
The prognosis varies between leukodystrophy types but overall, most people with leukodystrophy can expect a shortened life span. Infants with Alexander's disease generally do not live past the age of five or six. Infants with metachromatic leukodystrophy (MLD) usually do not live past age 10. In children and adults, Alexander's disease and MLD progress more slowly but life expectancy is still shortened. Life expectancy with CACH is also shortened, with few people living beyond age 40 years. CADASIL progresses slowly but death occurs on average about 21–22 years after onset of symptoms. Life expectancy is closer to normal with CTX provided it is diagnosed and treated early. Ovarioleukodystrophy is a relatively newly identified disorder and there is not enough information available to make a prognosis of life expectancy, other than to say it is probably reduced. The average life expectancy is also unknown for Van der Knapp syndrome; several patients have died in their 20s but others are still alive in their 40s.
A number of government agencies and private foundations are currently funding research into many of the leukodystrophies, including identifying the cause of individual disorders, developing therapies to prevent disease progression, and to prevent onset of disease. However, little research is being done on therapies to repair damage already done by the disorders, or of restoring functions lost because of the disorders, according to The Myelin Project, a private research foundation.
Scheltens, P. White Matter Disease. Basel, Switzerland: S. Karger Publishing AG, 1999.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. <http://www.ulf.org>.
The Myelin Project. <http://www.myelin.org>.
Delayed Myelin. Myelin Associated Infant-Childhood Development Disorders. <http://www.delayedmyelin.homestead.com>.
Ken R. Wells