National Organization for Rare Disorders, Inc.
It is possible that the main title of the report Adrenoleukodystrophy is not the name you expected.
Adrenoleukodystrophy is an X-linked recessive genetic disorder caused by an abnormality in the ABCD1 gene on the X chromosome. This condition affects the white matter of the nervous system and the adrenal cortex. Some affected individuals have adrenal insufficiency, which means that reduced amounts of certain hormones such as adrenaline and cortisol are produced, leading to abnormalities in blood pressure, heart rate, sexual development and reproduction. Some of those affected experience serious neurological problems that can affect mental function and lead to disability and reduced life span. This condition has been categorized into six types based on symptoms and age of onset: childhood cerebral ALD, adolescent cerebral ALD, adrenomyeloneuropathy, adult cerebral ALD, adrenal insufficiency only and ALD that occurs in females.
The childhood cerebral form of ALD usually begins between four and eight years of age and symptoms include attention deficit disorder, progressive loss of intellectual function, and vision, hearing and motor deterioration. Adolescent cerebral ALD begins between 11 and 21 years of age and the symptoms are similar to the childhood cerebral type but the disease progresses more slowly. The adrenomyeloneuropathy type of ALD usually begins in the late twenties and is characterized by difficulty walking, a progressive weakness and stiffness in the legs (paraparesis), a loss in ability to coordinate muscle movements, excessive muscle tone (hypertonia), vision loss, difficulty speaking dysarthria), seizures and adrenal insufficiency. Adult cerebral ALD can begin between the twenties and fifties with symptoms similar to schizophrenia with dementia. Individuals with adrenal insufficiency only do not initially have neurological problems, but symptoms such as those seen in adrenomyeloneuropathy usually develop later. ALD in females usually begins later in life and symptoms can vary greatly from mild to severe, but usually do not include adrenal insufficiency.
ALD is caused by an abnormality in the ABCD1 gene located on the X chromosome. This gene abnormality leads to the production of an abnormal ALDP protein in a part of the cell called the peroxisome, and is responsible for breaking down very long chain fatty acids. The accumulation of very long fatty acids damages the protective covering of nerves (myelin sheath), resulting in neurological problems.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.
ALD is inherited as an X-linked recessive genetic disease. 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 often 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.
ALD is the most common leukodystrophy, accounting for about half of all leukodystrophies. The prevalence is approximately 1/20,000-1/50,000 births and most of those affected are boys. Approximately half of all females who carry the abnormal ABCD1 gene will develop some symptoms of ALD. The condition occurs in all ethnic groups.
Symptoms of the following disorders can be similar to those of adrenoleukodystrophy. Comparisons may be useful for a differential diagnosis:
Addison disease is a rare disorder of the adrenal glands. In the majority of cases the cause is not known. Symptoms may result from chronic and progressive low level function (hypofunction) of the outer layers (cortex) of the adrenal gland resulting in deficiencies of the hormones cortisol and aldosterone. The deficiency of these hormones leads to low levels of sodium and chloride and high levels of potassium (electrolyte imbalance) in the blood. The imbalance of electrolytes causes increased water excretion, low blood pressure (hypotension), and abnormally low levels of water in the body (dehydration). The major symptoms of Addison disease may include fatigue, weakness, loss of appetite (anorexia), frequent urination, gastrointestinal discomfort and changes in skin pigmentation. (For more information on this disorder, choose "Addison" 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).
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" as your search term in the Rare Disease Database).
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.)
The concentration of very long fatty acids (VLFA) in blood plasma is elevated in 99% of males with ALD and in approximately 85% of female carriers of the abnormal ABCD1 gene. Molecular testing for the ABCD1 gene is available and is used primarily to confirm a diagnosis if other testing is not conclusive, to provide genetic counseling to family members and for prenatal diagnosis. Adrenal function tests are abnormal in 90% of boys with ALD who have neurologic symptoms and in approximately 70% of men with adrenomyeloneuropathy.
The abnormal adrenal function is treated with corticosteroid replacement therapy. Bone marrow transplantation has been successful in individuals who are in the early stages of ALD.
Affected individuals can benefit from supportive care from psychologists, educators, physical therapists, urologists, and family and vocational counselors. Genetic counseling is recommended for affected individuals and their family members.
Studies are underway to determine if Lorenzo oil therapy is beneficial in reducing the severity of neurological symptoms in individuals who do not yet have neurological problems. This therapy is not effective in altering the progression of the disease if the brain is already affected.
The Kennedy Krieger Institute and the General Clinical Research Center at Johns Hopkins Hospital are conducting (2006) a large NIH-funded study of Lorenzo's oil therapy in patients with adrenomyeloneuropathy (AMN). The study will involve 120 men and 120 women. Information about this study can be obtained by contacting Ms. Kim Hollandsworth (Hollandsworth@KennedyKrieger.org).
Studies are underway to determine if lovastatin and 4-phenylbutyrate are effective therapies for ALD.
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 web site.
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
For information about clinical trials sponsored by private sources, contact:
Moser HW, Raymond GV, Lu SE, et al. Follow-up of 89 Lorenzo's oil treated asymptomatic adrenoleukodystrophy patients. Arch of Neurol 2005;62:1073-78.
Peters C, Charnas LR, Tan Y. Cerebral x-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 2004;104:881-88.
Aubourg P and Chaussain JL. Adrenoleukodystrophy:the most frequent cause of Addison's disease. Horm Res 2003;59(Suppl 1):104-5.
Bezman L, Moser AB, Raymond GV, et al. Adrenoleukodystrophy: incidence, new mutation rate and results of extended family screening. Ann Neurol 2001;49:512-7.
Shapiro E, Krivit W, Lockman L, et al. Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet 2000;356:713-8.
Moser HW Smith KD, Watkins PA, et al. X-linked adrenoleukodystrophy. In: Scriver CR, Beaudet AL, Valle D, Sly WS, (eds) The Metabolic Basis of Inherited Disease, 8th ed. McGraw-Hill, New York:3257-302.
FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 300100; Last Update:9/28/05.
Moser HW, Moser AB and Steinberg SJ. (Updated 4/15/04). X-Linked Adrenoleukodystrophy. In GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2005. Available at //www.genetests.org. Accesssed 11/05.
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Last Updated: 8/8/2007
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