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Leukodystrophy
NORD is very grateful to Hugo Moser, MD, deceased, former Director of the Neurogenetics Research Center at the Kennedy Krieger Institute and University Professor of Neurology and Pediatrics at Johns Hopkins University, for assistance in the preparation of this report.
Synonyms of Leukodystrophy
- No synonyms found.
Disorder Subdivisions
- Alexander Disease
- Canavan Disease
- Cerebrotendinous Xanthomatosis
- Childhood Ataxia and Cerebral Hypomyelination (CACH)
- Krabbe Disease
- Megalencephaly with Subcortical Cysts
- Metachromatic Leukodystrophy
- Multiple Sulfatase Deficiency
- Other Leukodystrophies
- Pelizaeus-Merzbacher Disease
- Refsum Disease
- X-linked Adrenoleukodystrophy
- Zellweger Syndrome Spectrum Disorders
General Discussion
Leukodystrophies are a group of very rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development of one of at least 10 different chemicals that make up the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can't function normally without it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems.
Symptoms
Symptoms of some types of leukodystrophy begin shortly after birth, but others develop later in childhood or even in adulthood. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. Leukodystrophy can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. Leukodystrophies are progressive diseases meaning that the symptoms of the disease tend to get worse over time.
Disorder Subdivisions:
X-linked adrenoleukodystrophy (ALD) is the most common leukodystrophy and affects the myelin sheath and adrenal cortex of the brain. X-linked ALD is a progressive disease characterized by an accumulation of very long chain fatty acids that cause tissue damage. There are three types of X-linked adrenoleukodystrophy, each distinguished by the age of onset and by the features that are present. These three types have been termed the childhood cerebral form, adrenomyeloneuropathy and "Addison disease only". (For more information about this disease, choose "ALD" as your search term in Rare Disease Database.)
Alexander Disease is an extremely rare, progressive, leukodystrophy that usually becomes apparent during infancy or early childhood but juvenile and adult onset forms have also been reported. Alexander disease is characterized by degenerative changes of the white matter of the brain caused by a lack of normal amounts of myelin. The disorder is also associated with the formation of abnormal, fibrous deposits known as "Rosenthal fibers" throughout certain regions of the brain and spinal cord.
(For more information choose "Alexander" as your search term in The Rare Disease Database).
Canavan disease is a rare inherited neurological disorder characterized by spongy degeneration of the brain and spinal cord (central nervous system). Physical symptoms that appear in early infancy may include progressive mental decline accompanied by the loss of muscle tone, poor head control, an abnormally large head (macrocephaly), and/ or irritability. Physical symptoms appear in early infancy and usually progress rapidly. Canavan disease is caused by an abnormality in the ASPA gene that leads to a deficiency of the enzyme aspartoacylase. Canavan disease is inherited as an autosomal recessive genetic disorder. (For more information about this condition, choose "Canavan" as your search term in the Rare Disease Database).
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive leukodystrophy caused by a deficiency of the sterol 27-hydroxylase enzyme that is responsible for converting certain forms of cholesterol and cholestanol into bile acids. CTX is characterized by deposits of lipid in the brain, tendons, lens of the eye and arteries. The range and severity of CTX is variable but early symptoms can include delayed motor milestones in infancy and cataracts and later symptoms may involve weakness in arms and legs, and a loss of coordinated muscle movement (ataxia).
Krabbe disease, also known as globoid cell leukodystrophy, is an autosomal recessive lipid storage disorder caused by a deficiency of the enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids galactosylceremide and psychosine. Failure to break down these sphingolipids results in degeneration of the myelin sheath surrounding nerves in the brain (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction such as mental retardation, paralysis, blindness, deafness and paralysis of certain facial muscles (pseudobulbar palsy). (For more information on this disorder choose "Krabbe's" as your search term in the Rare Disease Database).
Metachromatic leukodystrophy is an autosomal recessive leukodystrophy characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). Myelin is lost from areas of the central nervous system due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. Infantile, juvenile, and adult onset forms of metachromatic leukodystrophy have been distinguished. (For more information on this disorder choose "metachromatic" as your search term in the Rare Disease Database).
Pelizaeus-Merzbacher disease, also known as X-linked spastic paraplegia, is a rare inherited disorder affecting the central nervous system that is associated with a lack of myelin sheath. Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, and/or brain stem. Symptoms may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, loss of motor abilities, and the progressive deterioration of intellectual function. The symptoms of Pelizaeus-Merzbacher disease are usually slowly progressive. Several forms of the disorder have been identified, including classical X-linked Pelizaeus-Merzbacher disease; acute infantile (or connatal) Pelizaeus-Merzbacher disease; and autosomal dominant, adult-onset (or late-onset) Pelizaeus-Merzbacher disease. (For more information choose "Peliazeus" as your search term in the Rare Disease Database).
Refsum disease is an autosomal recessive leukodystrophy in which the myelin sheath fails to grow. The disorder is caused by the accumulation of a particular fatty acid (phytanic acid) in blood plasma and tissues due to the presence of an abnormal gene. This condition is characterized by progressive loss of vision (retinitis pigmentosa); degenerative nerve disease (peripheral neuropathy); failure of muscle coordination (ataxia); and dry, rough, scaly skin (ichthyosis). Treatment with a diet low in foods that contain phytanic acid can be beneficial. (For more information on this disorder please choose "Refsum" as you search term in the Rare Disease Database).
Zellweger syndrome spectrum disorders, also known as peroxisomal biogenesis disorders, are characterized by a deficiency or absence of peroxisomes in the cells of the liver, kidneys, and brain. Peroxisomes are very small, membrane-bound structures within the cytoplasm of cells that function as part of the body's waste disposal system. In the absence of the enzymes normally found in peroxisomes, waste products, especially very long chain fatty acids (VLCFA), accumulate in the cells of the affected organ. The accumulation of these waste products has profound affects on the development of the fetus.
Multiple sulfatase deficiency is a very rare leukodystrophy in which all of the known sulfatase enzymes (thought to be seven in number) are deficient or inoperative. Major symptoms include mildly coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton may occur, such as curvature of the spine (lumbar kyphosis) and the breast bone. The skin is usually dry and scaly (ichthyosis). Before symptoms are noticeable, children with this disorder usually develop more slowly than normal. They may not learn to walk or speak as quickly as other children.
Childhood ataxia with cerebral hypomyelination, also known as vanishing white matter disease, is a rare autosomal recessive leukodystrophy that is characterized by progressive deterioration in motor function and speech during the first five years of life. Symptoms may include involuntary muscle contractions, drowsiness, abnormal development of ovaries, loss of muscle coordination, vision abnormalities, seizures and developmental disabilities. Infection or head trauma may trigger a rapid decline.
Megalencephaly with subcortical cysts, also known as van der Knaap syndrome, is an autosomal recessive leukodystrophy that can present between birth and ten years of age. Symptoms can include seizures, lack of coordinated muscle movement, an abnormally large head, muscle spasms, developmental disabilities and mental decline.
Causes
Leukodystrophies are genetic disorders caused by specific gene abnormalities that lead to abnormal development of one of at least 10 different chemicals that make up the myelin sheath in the nervous system or white matter in the brain. Each type of leukodystrophy follows a particular pattern of inheritance such as autosomal recessive, X-linked recessive or dominant pattern of inheritance. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off". A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
Affected Populations
The leukodystrophies can affect either adults or children, but are more common in children. Some types of leukodystrophy affect males and females equally but other types predominantly affect males.
Related Disorders
Symptoms of the following disorders can be similar to those of leukodystrophy. Comparisons may be useful for a differential diagnosis:
Multiple sclerosis (MS) is a chronic disease affecting the myelin sheath of the brain and spinal cord (central nervous system). It may be progressive, relapsing and remitting, or stable. MS consists of small lesions called plaques that form randomly throughout the brain and spinal cord. These plaques on the myelin sheath prevent proper transmission of nervous system signals. Symptoms may include visual and speech problems, numbness, walking difficulty and loss of bladder or bowel control. MS affects adults, and its cause is unknown. (For more information on this disorder, choose "MS" as your search term in the Rare Disease Database.)
Gaucher disease is an autosomal recessive lysosomal storage disorder caused by the failure to produce the enzyme glucocerebrosidase. The symptoms and physical findings associated with Gaucher disease vary greatly from case to case. Some individuals will develop few or no symptoms (asymptomatic); others may have serious complications. Common symptoms associated with Gaucher disease include an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of circulating red blood cells (anemia), low levels of platelets (thrombocytopenia), and skeletal abnormalities. Three separate forms of Gaucher disease have been identified and are distinguished by the absence of, or the presence and extent of, neurological complications. (For more information on this disorder, choose "Gaucher" as your search term in the Rare Disease Database.)
Tay-Sachs disease is a rare autosomal recessive genetic disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. Symptoms of Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes, gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). The classical form of Tay-Sachs disease occurs during infancy; an adult form (late-onset Tay-Sachs disease) may occur anytime from adolescence to the mid 30s. (For more information on this disorder, choose "Tay- Sachs" as your search term in the Rare Disease Database.)
Standard Therapies
Treatment of most leukodystrophies is symptomatic and supportive. Please review the NORD report on the specific type of leukodystrophy for information about successful therapies. Genetic counseling is beneficial for affected individuals and their families.
Investigational Therapies
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
Patients are being recruited (2005) for a study aimed at increasing the understanding of leukodystrophies of unknown cause. For information about this study, which is being sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH, contact the NIH Patient Recruitment Office (see above) or visit the www.clinicaltrials.gov web site.
Organizations related to Leukodystrophy
References
TEXTBOOKS
van Passel-Clark L and Pearl PL. Leukodystrophy (Canavan Disease). In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:550-551.
van Passel-Clark L and Pearl PL. Leukodystrophy (KrabbeDisease). In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:551-552.
Rosser T and Pearl Pl. Metachromatic Leukodystrophy. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:552-553.
Brenner M, Johnson AB, Goldman JE, and Messing A. Alexander Disease. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:510-511.
Moser HW. X-Linked Adrenoleukodystrophy. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:430.
van Passel-Clark L and Pearl PL. Pelizaeus-Merzbacher Disease. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:578-579.
Burns RS. Ataxia, Refsum Disease. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:604-605.
McGuinness MC and Smith KD. Peroxisomal Biogenesis Disorders. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:486-487.
Mancini GMS and Diggelen OP. Multiple Sulfatase Deficiency. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:484.
FROM THE INTERNET
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