$Unique_ID{BRK03935} $Pretitle{} $Title{Leukodystrophy} $Subject{Leukodystrophy Refsum's Disease Cerebrotendinous Xanthomatosis Metachromatic Leukodystrophy Globoid Leukodystrophy (Krabbe's Disease) Adrenoleukodystrophy Sudanophilic Leukodystrophy (Schilder's Disease Pelizaeus-Merzbacher Brain Sclerosis Canavan's Disease Alexanders Disease Multiple Sclerosis Gaucher's Disease Tay-Sachs Disease} $Volume{} $Log{} Copyright (C) 1989 National Organization for Rare Disorders, Inc. 676: Leukodystrophy ** IMPORTANT ** It is possible that the main title of the article (Leukodystrophy) is not the name you expected. Please check the SYNONYM listing to find the alternate names and disorder subdivisions covered by this article. Synonyms Disorder Subdivisions: Refsum's Disease Cerebrotendinous Xanthomatosis Metachromatic Leukodystrophy Globoid Leukodystrophy (Krabbe's Disease) Adrenoleukodystrophy Sudanophilic Leukodystrophy (Schilder's Disease Pelizaeus-Merzbacher Brain Sclerosis Canavan's Disease Alexanders Disease Information on the following diseases can be found in the Related Disorders section of this report: Multiple Sclerosis Gaucher's Disease Tay-Sachs Disease General Discussion ** REMINDER ** The information contained in the Rare Disease Database is provided for educational purposes only. It should not be used for diagnostic or treatment purposes. If you wish to obtain more information about this disorder, please contact your personal physician and/or the agencies listed in the "Resources" section of this report. Leukodystrophy is the name given to a group of very rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each of the leukodystrophies will affect one of the chemicals that make up the myelin sheath or white matter of the brain, causing the various types of leukodystrophy. The myelin sheath, which acts as insulation of the nervous system, is composed of different lipids (fatty substances). Thus defects in production and degradation of these lipids can lead to the many ways in which these diseases can manifest themselves. Symptoms Leukodystrophy affects the white matter of the brain or insulation (myelin sheath) of the nervous system made up of the brain, the spinal cord and nerves. The symptoms of the disease tend to get worse as the patient gets older. Most of the leukodystrophies are present at birth though some may appear more slowly over time. The particular chemical defect determines the type of leukodystrophy a person will have. The myelin sheath is made up of a number of fatty substances or lipids that protect and insulate it. When this protection is defective the brain, spinal cord and nerves can be seriously impaired. Leukodystrophy causes the patient to have problems with movement, vision, hearing, feeling and thinking. Infants or children who initially appear healthy will begin to change as they mature. Parents will notice the child's mental abilities are deteriorating, or the way the child walks has changed, or the child's vision is poor. There can also be muscle stiffness or floppiness, paralysis or convulsions. These symptoms may occur slowly or they can happen quickly according to the type of leukodystrophy affecting the child. DISORDER SUBDIVISIONS: Refsum Syndrome is a type of leukodystrophy inherited as a recessive trait. Symptoms may include a degenerative nerve disease, peripheral neuropathy, impaired muscle coordination, walking difficulties (ataxia), a progressive vision disorder (retinitis pigmentosa), and bone and skin changes. This disorder is believed to be due to the absence of phytanic acid hydroxylase in the blood, an enzyme needed for the metabolism of phytanic acid which is found in dairy products, beef, lamb and some seafoods. It is characterized by the accumulation of phytanic acid in the plasma and tissues. (For more information on this disorder please choose "Refsum" as you search term in the Rare Disease Database). Cerebrotendinous Xanthomatosis is a type of Leukodystrophy which is related to the chemical cholestanol in the myelin sheath. It is inherited as an autosomal recessive trait. Cerebrotendinous Xanthomatosis is characterized by deposits of lipid granulomatosis especially in the brain and other tissues. The plasma shows high cholesterol levels but the cholesterol level in the blood is normal. Progressive cerebellar ataxia, (usually beginning after puberty), juvenile cataracts, and spinal cord involvement are symptoms of the disorder. It is possible to detect persons who are carriers of this disorder, as well as a prenatal diagnosis for pregnant women. Metachromatic Leukodystrophy is inherited as an autosomal recessive genetic trait. It affects the brain and spinal cord. The disease is characterized by progressive paralysis and dementia. It occurs in the following forms: Infantile, Juvenile, and Adult onset MLD, and a form of MLD which is due to a deficiency of Cerebroside Sulfatase Activator. MLD usually begins gradually in a child or adult who previously appeared healthy. Some subtle change in the patient's thought processes, memory, behavior, or walking pattern is noticeable. Sometimes a disturbance in vision, or less commonly in hearing, or numbness in parts of the body may be the first symptoms. (For more information on this disorder choose "Metachromatic" as your search term in the Rare Disease Database). Krabbe's Leukodystrophy is a rare genetic lipid storage disorder caused by a deficiency of the enzyme galactoside beta-galactosidase (galactosyl- ceramidase). This causes the myelin sheath surrounding nerves in the brain to degenerate (demyelination). Characteristic globoid cells appear in affected areas of the brain. It is characterized by progressive neurological dysfunction such as mental retardation, paralysis, blindness, deafness and pseudobulbar palsy. Symptoms of Krabbe's usually first occur between three and five months of age. A later-onset form occurs at eighteen months of age or later. (For more information on this disorder choose "Krabbe's" as your search term in the Rare Disease Database). Adrenoleukodystrophy (ALD) can be inherited in two ways: x-linked or autosomal recessive. Both are characterized by destruction of the lipid sheaths surrounding the nerves in the brain. All types of ALD are characterized by an accumulation of very long chain fatty acids, which is a type of fat molecule that accumulates in the body's tissues, especially in the adrenal gland and the white matter of the brain. There are three different types of Adrenoleukodystrophy, each distinguished by the time of onset and by the features that are present. Childhood ALD affects only males between the ages of four and eight years. There are behavioral changes, signs of decreased adrenal gland function and neurological symptoms. Adolescent or adult onset ALD affects only males and first appears around the age of twenty one. It includes progressive leg stiffness, paralysis of the legs and gait abnormalities (ataxia). Neonatal ALD begins at birth and affects both males and females. It is characterized by seizures, decreased muscle tone, mental retardation, vision problems, enlargement of the liver and adrenal insufficiency. It affects both the white and grey matter of the brain. (For more information on this disorder choose "ALD" as your search term in the Rare Disease Database). Schilder's Disease is an infantile form of leukodystrophy. It is similar to Neonatal ALD in that the chemical missing from the myelin sheath is also a very long chain fatty acid. It is inherited as an autosomal recessive disease and affects males and females equally. Pelizaeus-Merzbacher Brain Sclerosis usually appears in early infancy, although there is also a type that occurs later in childhood. The child fails to develop normal head control and grows very slowly. There is lack of eye control and involuntary motor movements. Later, there may be tremors, grimacing, weakness, unsteady gait, and muscle contractures. In cases of later onset, speech deteriorates, arms and legs become spastic and mental retardation occurs. (For more information choose "Peliazeus" as your search term in the Rare Disease Database). Canavan's Leukodystrophy occurs in early infancy with the development of microscopic fluid filled spaces in the white matter of the brain. The first symptoms are loss of muscle control. Floppiness and weakness occur in the muscles supporting the head. There are feeding problems, mental retardation, and apathy. The head becomes enlarged as the brain swells, and the bones of the skull do not fuse normally. This very rare form of leukodystrophy most frequently affects male and female infants of Eastern European Jewish ancestry. (For more information on this disorder choose "Canavan's" as your search term in the Rare Disease Database). Alexander's Disease is the rarest of the leukodystrophies. The destruction of the white matter in the brain is accompanied by the formation of fibrous, deposits known as Rosenthal fibers. Onset occurs in infancy, affecting mostly males and resulting in mental and physical retardation. As in Canavan's Leukodystrophy there is progressive enlargement of the brain and head, spasticity of the limbs, and in some cases seizures. It is inherited as an autosomal recessive genetic trait. The exact myelin chemical which causes the disorder is unknown. (For more information choose "Alexander's" as your search term in The Rare Disease Database). Causes Leukodystrophy is caused by a breakdown in the chemicals that make up the myelin sheath in the nervous system or white matter in the brain. Leukodystrophy in infants and children can occur because of either autosomal recessive or X-linked genetic traits. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If a person receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will show no symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is twenty-five percent. Fifty percent of their children will be carriers, but healthy as described above. Twenty-five percent of their children will receive both normal genes, one from each parent, and will be genetically normal. X-linked recessive disorders are conditions which are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a fifty percent risk of transmitting the carrier condition to their daughters, and a fifty percent risk of transmitting the disease to their sons. Leukodystrophy that occurs in adults is caused by autosomal dominant genetic traits. In autosomal dominant disorders, a single abnormal gene, contributed by either parent, "overrides" the normal gene contributed by the other parent causing disease. Individuals with one affected parent have a 50% change of inheriting the disorder. Males and females are affected in equal numbers. (For more detailed information about the genetic transmission of all forms of Leukodystrophy, choose "Leukodystrophy" as you search term in the Rare Disease Database). Affected Population The Leukodystrophies can affect either adults or children. However it is more common in children. It can also affect males and females equally but in some types it affects only males. Some types of Leukodystrophy tend to affect persons of Eastern European Jewish ancestry, and other types affect persons of all heritages. Related Disorders Symptoms of the following disorders can be similar to those of Leukodystrophy. Comparisons may be useful for a differential diagnosis: Multiple Sclerosis 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's Disease is a genetic disease of lipid metabolism caused by the failure to produce the enzyme glucocerebrosidase. It is the most common of the lipid storage diseases. There are three types of Gaucher's disease. All three are characterized by the presence of lipid-laden (Gaucher) cells in the bone marrow and other organs such as the spleen and liver. (For more information on this disorder, choose "Gaucher" as your search term in the Rare Disease Database). Tay-Sachs Disease is a genetic disorder that causes the progressive destruction of the central nervous system in children. It is generally found among children of Eastern European Jewish heritage. Children with Tay-Sachs appear normal at birth and seem to develop normally until the age of about six months when they begin to deteriorate. There is general weakness, loss of vision, feeding difficulties and absence of normal development. The disease is progressive. (For more information on this disorder, choose "Tay- Sachs" as your search term in the Rare Disease Database). Therapies: Standard Treatment of most leukodystrophies is symptomatic and supportive. There are treatments for Refsum's Disease and Cerebrotendinous Xanthomatosis. The treatment for Refsum's consists of a diet which restricts the intake of foods containing phytanic acid. Therapy for Cerebrotendinous Xanthomatosis is with chenodeoxycholic acid. Genetic counseling will be of benefit for patients and their families. Therapies: Investigational Researchers are studying ways to control metabolism of long chain fatty acids with the hope of developing treatments for several forms of leukodystrophy. Additionally, geneticists are trying to identify the genes that cause certain types of leukodystrophy in order to understand the biochemical defects that cause these disorders. For more information about clinical and genetic research projects contact the United Leukodystrophy Foundation which is listed in the resources section of this report. This disease entry is based upon medical information available through August 1989. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder. Resources For more information on Leukodystrophy, please contact: National Organization for Rare Disorders (NORD) P.O. Box 8923 New Fairfield, CT 06812-1783 (203) 746-6518 United Leukodystrophy Foundation 2304 Highland Drive Sycamore, IL 60178 (815) 895-3211 (800) 728-5483 NIH/National Institute of Neurological Disorders & Stroke (NINDS) 9000 Rockville Pike Bethesda, MD 20892 (301) 496-5751 (800) 352-9424 National Tay-Sachs and Allied Diseases Association, Inc. 2001 Beacon St, Rm. 304 Brookline, MA 02164 (617) 277-4463 or 277-3965 Adrenoleukodystrophy (ALD) Project Hugo M. Moser, M.D. John F. Kennedy Institute 707 North Broadway Baltimore, MD 21205 (301) 522-5405 International Tremor Foundation 360 W. Superior St. Chicago, IL 60610 (312) 664-2344 Association Europeenne contre les Leucodystrophies 7 Rue Pasteur 54000 NANCY France Tay-Sachs and Allied Diseases Association 17 Sydney Road Barkingside, Ilford, Essex, England 01-550-8989 For Genetic Information and genetic counseling referrals, please contact: March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue White Plains, NY 10605 (914) 428-7100 Alliance of Genetic Support Groups 35 Wisconsin Circle, Suite 440 Chevy Chase, MD 20815 (800) 336-GENE (301) 652-5553 References MENDELIAN INHERITANCE IN MAN, 8th ed.: Victor A. McKusick; Johns Hopkins University Press, 1986. Pp. 205, 573. THE METABOLIC BASIS OF INHERITED DISEASE, 5th Ed.: John B. Stanbury, et al., eds.; McGraw Hill, 1983. Pp.857-905.