Adrenoleukodystrophy
Definition
Adrenoleukodystrophy (ALD) is a progressive condition that affects both the adrenal glands (located atop the kidneys and responsible for the production of adrenalin) and myelin (the substance that insulates the nerves in the brain, spinal cord, and the limbs).
Description
First described in the early 1900s, adrenoleukodys-trophy was originally called Schilder-Addision disease. "Adreno" refers to the adrenal glands, "leuko" is the Greek word for white (myelin is the main component of the white matter in the brain and spinal cord), and "dystrophy" means impaired growth. This disease affects the adrenal glands and the growth of the myelin.
Types of ALD
There are three types of ALD, each with a different severity of symptoms and age of onset of ALD. All varying degrees of severity have been seen within the same family. Therefore, a family who has many mildly affected members could still have a more severely affected member. Some patients do not fall neatly into one of the three categories, and instead fall somewhere in between. Each type is given a different name, although all have mutations (changes in the genetic code) in the same gene and the same type of inheritance.
The most severe form of ALD is called childhood ALD. About 35% of people with ALD have this type. These children usually have normal development in the first few years of life. Symptoms typically begin between four and eight years of age. Very rarely is the onset before the age of three or after the age of 15. In some boys, the first symptom may be seizures. Other children become hyperactive and have behavioral problems that may initially be diagnosed as attention deficit/hyperactivity disorder (ADHD). Early signs may also include poor school performance due to impaired vision that is not correctable by eyeglasses. Although these symptoms may last for a few months, other more severe problems develop. These include increasing problems with schoolwork and deterioration in handwriting and speech. Affected children usually develop clumsiness, difficulty in reading and comprehension of written material, aggressive or uninhibited behavior, and various personality and behavioral changes. Most affected boys have problems with their adrenal glands by the time their first symptoms are noticed.
A milder form of ALD, called adrenomyeloneuropathy (AMN), usually has a symptom onset at the age of 20 or later. Approximately 40–45% of people with ALD have AMN. The first symptoms are typically a progressive stiffness and weakness in the legs. Problems with urination and sexual function may also develop. Symptoms slowly progress over many years. Less than 20% of men with AMN will develop significant brain involvement that leads to cognitive and behavioral problems that are severe and may cause a shortened lifespan. About 70% of men with AMN will have problems with their adrenal glands when other symptoms are initially noticed.
A third type of ALD is called Addison disease and affects about 10% of all of those with ALD. In this condition, people do not have the neurologic symptoms associated with ALD and AMN, but they do have problems resulting from adrenal insufficiency. Symptoms typically begin between two years of age and adulthood. The first symptoms are often vomiting, weakness, or coma. People with Addision disease may or may not have darker skin. Many who are initially diagnosed with Addison disease will later develop symptoms of AMN.
In female carriers of ADL, about 20% will develop mild to moderate progressive stiffness and weakness in the legs and sometimes problems with urination. Rarely do they develop adrenal insufficiency. Symptoms in women generally do not begin before middle age.
Demographics
ALD is found in all ethnic groups. About one in every 100,000 people suffers from ALD. Because the most severe form, called classic ALD, is X-linked, many more males than females are affected. Women are carriers of this X-linked form of the disease and may exhibit no or only mild symptoms. Another form of the disease is called neonatal ALD; this form of ALD is not X-linked and therefore both male and female babies exhibit symptoms. An adult-onset type of the disease is commonly called adrenomyeloneuropathy.
Causes and symptoms
ALD causes problems in the peroxisomes, tiny cellular structures that are involved in breaking down large molecules of fats into smaller ones that can be used by the body. In ALD, the peroxisomes cannot break down a type of fat called very long chain fatty acid (VLCFA). As a result, VLCFAs accumulate throughout the body, particularly in the brain and adrenal glands. This accumulation interferes with the adrenal glands' conversion of cholesterol into steroids, and prompts deterioration of the myelin covering nerve cells within the white matter of the brain, thus interfering with nerve function. Additionally, fats that are usually made from the breakdown products of VLCFAs cannot be produced. Because these fats would usually be utilized in the synthesis of myelin, nerve function is further compromised.
The adrenal glands of almost all individuals affected with ALD do not secret a sufficient amount of hormones; this is called adrenal insufficiency. Symptoms include sluggishness, weakness, weight loss, hypoglycemia, nausea, vomiting, darkening of the skin color, and mental changes. Because adrenal insufficiency can cause problems with regulating the balance of sodium and potassium in the body, a person can go into shock and coma, which can be potentially life threatening. As this aspect of ALD is readily treatable, identifying these patients helps prevent these complications.
Diagnosis
When the diagnosis of ALD is suspected, the results of a test called magnetic resonance imaging (MRI) are sometimes abnormal. In this test, pictures of the brain are taken. In people with symptoms of ALD, there are usually detectable changes in the white matter. While an MRI can be helpful in making the diagnosis of ALD, a normal MRI does not exclude the diagnosis and an abnormal MRI does not definitively make the diagnosis of ALD.
A more definitive diagnosis of ALD can be made by measuring the level of the VLCFA in the blood. In nearly all males with ALD, the level of the VLCFA in blood is very high.
When ALD is suspected, testing should also be performed to measure the adrenal function. In 90% of boys with symptoms of ALD and 70% of men with AMN, the adrenal glands are affected.
Approximately 85% of female carriers will have higher than normal levels of VLCFA in their blood. However, 15–20% of female carriers will have normal levels of VLCFA in their blood, which gives a "false negative" result. If a woman wants to be certain about her carrier status, genetic testing to look for a specific mutation in the ALD gene can be performed. Before a woman could have testing to determine her carrier status, a mutation in the ALD gene must have already been found in an affected member of the family.
Treatment team
A number of professionals can provide supportive (though not curative) care for patients with adrenoleuko-dystrophy: neurogeneticists, to help with diagnosis; pediatric or adult neurologists (depending on the type of ALD and age of onset) to monitor and manage the neurological effects; pediatric or adult endocrinologists to manage the adrenal complications; and pediatric or adult urologists to manage bladder complications in both children and adults and sexual problems in adults. In addition, physical therapists, occupational therapists, speech therapists, learning specialists, and behavioral psychologists may be helpful.
Treatment
When the diagnosis of ALD is made, an important first step is to measure the level of adrenal function. If there is adrenal insufficiency, treatment should be given by steroid replacement, which can prove to be lifesaving. Adrenal function should be tested periodically.
Lorenzo's oil
In the early 1990s, a film called Lorenzo's Oil presented a fictionalized account of a real ALD patient, a young boy named Lorenzo, and his family's search to find a cure for him. A possible treatment was found and was named Lorenzo's oil. The Lorenzo's oil therapy worked to reduce the level of VLCFA in the blood. The idea was that if the level of VLCFA could be reduced, perhaps it would cure or help the symptoms. After a number of years of use, Lorenzo's oil unfortunately does not seem to be an effective treatment, at least in those with advanced signs and symptoms. Although it does reduce the level of VLCFA in blood, it does not seem to alter a person's symptoms.
Bone marrow transplant
One promising treatment is bone marrow transplant. However, this is a potentially dangerous procedure that has a 10–20% rate of death. As of early 2001, information is available on a limited number of patients. In the very small number of patients who have had a bone marrow transplant, a few had their condition stabilize and a few even made slight improvements. However, all of these people had the bone marrow transplant at an early stage of their disease. This treatment does have drawbacks, including the fact that there are limited numbers of donors who are a suitable match and a significant risk that complications will develop from the transplant. Early data suggests that bone marrow transplant is most effective when it is performed at an early stage of the disease when neurological abnormalities are mild. Additional long-term studies are necessary to determine the overall success of these procedures.
Other treatments
Research is being done with other treatments such as lovastatin and 4-phenylbutyrate, both of which may help lower VLCFA levels in cells, but more work is necessary to determine their effectiveness. Gene therapy, a possible method of treatment, works by replacing, changing, or supplementing non-working genes. Although different gene therapy methods are being tested on animals, they are not ready for human trials.
Other types of therapy and supportive care are of benefit to both affected boys and their families. Physical therapy can help reduce stiffness and occupational therapy can help make the home more accessible. Support from psychologists and other families who have been or are in a similar situation can be invaluable. Many men with AMN lead successful personal and professional lives and can benefit from vocational counseling and physical and occupational therapy.
Prenatal diagnosis
Prenatal testing to determine whether an unborn child is affected is possible if a specific ALD mutation has been identified in a family. This testing can be performed at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS), which involves removing a tiny piece of the placenta and examining the cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the fetus and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it. Couples interested in these options should have genetic counseling to carefully explore all of the benefits and limitations of these procedures.
An experimental procedure, called preimplantation diagnosis, allows a couple to have a child that is unaffected with the genetic condition. This procedure is only possible for those families in which a mutation in the ALD gene has been identified.
Clinical Trials
A number of clinical trials are underway, including testing the efficacy of Lorenzo's oil (combination glyceryl trierucate and glyceryl trioleate), oral bile acid therapy with cholic acid, chenodeoxycholic acid, and ursodeoxycholic acid, and bone marrow or umbilical cord blood transplantation.
Prognosis
The prognosis for people with ALD is highly variable. Those diagnosed with childhood ALD usually have a very rapid course. Symptoms typically progress very fast and these children usually become completely incapacitated and die within three to five years of the onset of symptoms.
The symptoms of AMN progress slowly over decades. Most affected individuals have a normal lifespan.
Resources
PERIODICALS
Laan, L. A. E. M., et al. "Childhood-onset Cerebral X-linked Adrenoleukodystrophy." The Lancet 356 (November 4, 2000): 1608–1609.
Moser, H. W., L. Bezman, S. E. Lu, and G. V. Raymond. "Therapy of X-linked Adrenoleukodystrophy: Prognosis Based Upon Age and MRI Abnormality and Plans for Placebo-controlled Trials." Journal of Inherited Metabolic Disease 23 (2000): 273–277.
Moser, H. W. "Treatment of X-linked Adrenoleukodystrophy with Lorenzo's Oil." Journal of Neurology, Neurosurgery and Psychiatry 67, no. 3 (September 1999): 279–280.
Shapiro, E., et al. "Long-term Effect of Bone Marrow Transplantation for Childhood-onset Cerebral X-linked Adrenoleukodystrophy." The Lancet 356, no. 9231 (August 26, 2000): 713–718.
Suzuki, Y., et al. "Bone Marrow Transplantation for the Treatment of X-linked Adrenoleukodystrophy." Journal of Inherited Metabolic Disease 23, no. 5 (July 2000): 453–458.
Unterrainer, G., B. Molzer, S. Forss-Petter, and J. Berger. "Co-expression of Mutated and Normal Adrenoleukodystrophy Protein Reduces Protein Function: Implications for Gene Therapy of X-linked Adrenoleukodystrophy." Human Molecular Genetics 9, no. 18 (2000): 2609–2616.
Van Geel, B. M., et al, on behalf of the Dutch X-ALD/AMN Study Group. "Progression of Abnormalities in Adrenomyeloneuropathy and Neurologically Asymptomatic X-linked Adrenoleukodystrophy Despite Treatment with 'Lorenzo's Oil.'" Journal of Neurology, Neurosurgery and Psychiatry 67, no. 3 (September 1999): 290–299.
Verrips, A., M. A. A. P. Willemsen, E. Rubio-Gozalbo, J. De Jong, and J. A. M. Smeitink. "Simvastatin and Plasma Very Long Chain Fatty Acids in X-linked Adrenoleukodystrophy." Annals of Neurology 47, no. 4 (April 2000): 552–553.
ORGANIZATIONS
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. (May 9, 2004.) <http://www.rarediseases.org>.
United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483; Fax: (815) 895-2432. (May 9, 2004.) <http://www.ulf.org>.
WEBSITES
"Entry 300100: Adrenoleukodystrophy, (ALD)." OMIM—Online Mendelian Inheritance in Man. (May 9, 2004.) <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300100>.
Moser, Hugo W., Anne B. Moser, and Corinne D. Boehm. "X-linked Adrenoleukodystrophy." March 9, 1999 (May 9, 2004). University of Washington, Seattle. GeneClinics. <http://www.geneclinics.org/profiles/x-ald/>.
