Information on Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is an inheritable genetic disorder that affects the metabolism of long chain fatty acids (Newmark 1). ALD is a member of a group of disorders called the leukodystrophies, which damage the myelin sheath that insulates the nerve fibers in the brain (NIH 1). Dr. Michael Blaw named Adrenoleukodystrophy in 1971 by combining "adreno= referring to the adrenal glands; leuko= referring to the white matter of the brain; and dystrophy= meaning imperfect growth or development" (Collins 1). ALD has been found in people of all different ethnic groups from many countries around the world, so it is not indigenous to any group of people (Collins 1).

Seven recognized forms of Adrenoleukodystrophy exist (Newmark 1). There are three main types of the disease seen in males and some symptoms occasionally appear in female carriers (Boehm 1). Neonatal ALD appears shortly after birth, the childhood cerebral form develops around four to eight years of age, and the adult-onset form usually begins between the ages of 21 and 35 (NIH 1). Neonatal ALD is autosomal recessive instead of X-linked like the other forms of ALD. This means that it can appear in both male and female infants. These infants have the same high levels of very long chain fatty acids that are characteristic of ALD (Richardson 1). Death usually occurs during infancy because the disease progresses so quickly (Newmark 1). The childhood form, occurring only in boys, is the most severe form of ALD. It usually results in total disability after about two years (Boehm 1). The deterioration of the nervous system will leave the patient bedridden. This form is fatal and follows a one to ten year course. About 35% of people with ALD develop the classic childhood form, but 65% are able to avoid it even without therapy (Collins 1). Adrenomyeloneuropathy (AMN) is a milder, adult-onset form of ALD that is the most common form because it affects 50% of ALD patients (Collins 2). AMN usually follows Addison's disease, which develops around seven and a half years of age and is characterized by primary adrenocortical insufficiency (Boehm 1). About 20% of female carriers of ALD develop mild neurological symptoms, like those of AMN, around 35 years of age or older. These women have a milder case of the disease than the affected men (Boehm 1). Although there are several different types of ALD affecting people of different ages, they tend to have similar symptoms.

ALD sufferers are forced to deal with severe, debilitating symptoms. Infants with Neonatal ALD suffer mental retardation as well as impaired psychomotor and neurological development and liver function (Richardson 1). Other symptoms include "facial abnormalities, frequent respiratory infections, seizures, retinal degeneration, hypotonia, heptomegaly, and adrenal dysfunction" (NIH 1).

Children with the childhood form of ALD develop symptoms that originally resemble Attention Deficit Disorder or hyperactivity. They exhibit behavior or learning deficits for months until more serious symptoms develop. These new symptoms may signal the child has ALD to doctors. Seizures may be the first sign for some sufferers. The new symptoms might include "inattention, deterioration in handwriting skills, diminishing school performance, difficulty in understanding speech, difficulty in reading, spatial orientation, comprehension of written material, clumsiness, visual disturbances and diplopia, and aggressive or disinhibited behavior" (Boehm 4). Childhood ALD sufferers sometimes develop crossed eyes, difficulty swallowing, memory loss, coordination problems, and changes in muscle tone (Newmark 2, Collins 1). Even before symptoms become severe, a brain MRI can be extremely abnormal, which helps to diagnose the disease (Boehm 4). As the nervous system deteriorates, patients experience paralysis, hearing loss, visual impairment, deteriorating fine motor control, and possibly eventually a vegetative state. The symptoms of adrenal gland failure are muscular weakness, wasting, decreased appetite, and increased skin pigmentation (Newmark 2).

The manifestations of AMN are progressive over decades. Approximately 70% of patients have impaired adrenocortical function when they first begin to notice symptoms. These men can develop stiffness and weakness in the legs, emotional disturbances, depression and abnormalities of sphincter control (Collins 2, Boehm 4). In a small percentage of AMN patients, brain involvement "leads to serious cognitive and behavioral disturbances that may progress to total disability and death" (Boehm 4).

Symptoms that appear in women carriers of ALD are mild and can include "spastic paraparesis of the lower limbs, moderate sensory loss, ataxia, hypertonia, peripheral neuropathy, and urinary problems (NIH 1). Adrenal function is not usually affected (Collins 2). Symptoms vary with the age of the patient and the time and type of their treatment.

Adrenoleukodystrophy progresses faster in younger patients and is inevitably fatal. Neonatal ALD can be expressed through hard to control seizures and a very short lifespan or be milder and allow the patient to survive to their mid-teens (Richardson 1). The rate of progression in the childhood form is variable and might be "rapid with total disability in six months to two years" or allow the child to live for ten years (Boehm 4). Early in the disease, children experience hyperactivity, trouble at school, and possibly seizures. However, once the disease progresses, the symptoms become more advanced and involve further damage to the white matter of the brain, changes in muscle tone, contracture deformities, and coma (Newmark 1).

Adrenoleukodystrophy "affects the adrenal gland and the white matter of the nervous system" (Collins 1). More than 99% of males with X-ALD have an elevated concentration of very long chain fatty acids (VLCFA) in their blood (Boehm 1). VLCFA accumulate in the tissues because of the abnormal peroxisomes in the body. The VLCFA gather especially in the tissues of the brain and the adrenal glands, causing problems in those areas. The acids destroy the myelin sheath that surrounds the nerves and causes neuroligic problems. The malfunction in the adrenal gland causes Addison's Disease. VLCFA accumulate from food and are also derived from production inside the body. Since ALD patients are unable to break down VLCFA, they accumulate in the body. These people are missing a protein required for VLCFA to be broken down in the peroxisome. The protein (ALD protein, or ALDP) is missing because of mutations in the gene that codes for it to be produced (Collins 1).

Adrenoleukodystrophy is transmitted as an X-linked recessive trait. Neonatal ALD is autosomal recessive so it passes on to both males and females. (Newmark 1). The gene for ALD is located on the X-chromosome (Collins 1). In the neonatal form, there is a defect at chromosome 7q21-q22 (Newmark 2). ABCD1 is the only gene associated with ALD and it has over 400 different mutations (Boehm 3). Since ALD is X-linked, it only affects males and is passed along by female carriers. Males are affected because they only have one X chromosome which is inherited from their mother while females have an X from their mother and an X from their father. If the X chromosome inherited by a male has the disease, it will appear in the male because there is no other X chromosome to protect the male from the symptoms of ALD. However, since ALD is recessive, a female would have to have two X-chromosomes with the disease to acquire it. The normal X gene does not allow the affected X chromosome to be revealed. A female carrier has a 50% chance of passing on the ABCD1 gene each time she has a child. A woman carrier of ALD has a one in four possibility of having each: a normal male, a normal female, a carrier female, or an affected male in each pregnancy (Collins 1). If a man with ALD has children, he will transmit the ABCD1 mutation to all of his daughters and none of his sons (Boehm 8).

ALD appears in somewhere between one in 20,000 to one in 50,000 people and is represented in all races (Newmark 1). The estimated minimum frequency of hemizygotes in the United States is one in 21,000 while the projected minimum frequency of hemizygotes plus heterozygotes is one in 16,800 (Boehm 5). The estimated frequency of Childhood Cerebral ALD is 31-35% among all ALD patients while Adolescent Cerebral ALD has a frequency of 4-7%. Adrenomyeloneuropathy is most common with a frequency of 40-49% (Manea 1).While treatment is sometimes able to prolong the life of ALD sufferers, the disease is always fatal.

There are a variety of tests that can be done to determine the probability of a child being born with ALD. Genetic counseling can help prevent adrenoleukodystrophy in a family that has a history of the disease. A very long fatty acid assay and a DNA probe study can be used to diagnose the carrier state in females 85 % of the time (Newmark 1). If the plasma concentration of VLCFA is abnormal, the female is a carrier. (Boehm 8). A newly created DNA-based blood test allows for more accurate identification of carriers (Collins 2). Some people choose not to be tested to determine their carrier status because they are afraid that they will not be able to obtain or keep medical insurance coverage if they are carriers (Boehm 8). Prenatal testing is done for women who are known to be carriers. First, the sex of the child is determined by karyotyping cells obtained from chorionic villus sampling or from amniocentesis. If the karyotype is 46, XY, then "DNA from fetal cells can be analyzed for the known disease-causing mutation" (Boehm 9). Carrier detection permits the couple to decide if they want to take the one in four chance that their child will have ALD and prenatal testing allows parents to prepare for raising a child with the disease.

Although there are no cures for adrenoleukodystrophy, a variety of treatments are in effect. Treatment for ALD is often referred to as "symptomatic and supportive" (NIH 1). A diet containing low amounts of VLCFA and Lorenzo's oil helps to lower the long chain fatty acid levels in some people (Newmark 2). Physical therapy, psychological support, and special education have proved helpful in several patients (NIH 1). The steroid hormone deficiency and adrenal dysfunction in ALD patients can be treated with corticosteroids (Newmark 1).

Research continues as experimental tests are done with Lorenzo's Oil and bone marrow transplant (Collins 2). Bone marrow transplant results work best in patients with an IQ above 80 (Boehm 6). Lovastatin and 4 phenylbutyrate are now being studied to determine if they might be beneficial. Gene therapy is being investigated in ALD animals, but is not ready to be tested on humans (Collins 2). Researchers are also investigating a promising new treatment from stem cells. These cells could eventually be put into the body and cause it to make myelin and restore patients to normal health (Stith 2).

The treatment called Lorenzo's oil was made famous by the Hollywood movie of the same name. The oil therapy does not have much affect on patients who already have symptoms and neurological impairment. There are studies being done to determine if Lorenzo's oil actually "reduces the frequency and severity of subsequent neurologic disease" in people who are neurologically uninvolved (Boehm 6). A researcher, Dr. Moser, thinks that Lorenzo's oil does not help children with ALD that have symptoms because the erucic acid does not enter the brain, which is where the VLCFA are built up. He believes Lorenzo survived because of the "intense effort" of him and his parents (Stith 1). Lorenzo's oil does seem to have the ability to reduce the onset of ALD if the oil is given long before symptoms appear. However, this fact is hard to prove because the clinical trials have no control groups. Dr. Moser estimates that about 30-40% of the patients in his experiment should have developed symptoms but the oil may have reduced that number to about 10%. A more recent study in 2002 showed that Lorenzo's oil reduced the development of ALD symptoms by two-thirds. The oil's ability to lower the amount of VLCFA in asymptomatic boys helped reduce the risk that they would develop ALD. For example, "an asymptomatic ALD boy who succeeds in bringing down his plasma VLCFA levels from 0.8 micrograms per milliliter to 0.2 can expect a 93% drop in his risk of developing ALD symptoms" (Stith 1). However, some boys will still develop ALD even while taking the oil. Another disadvantage of Lorenzo's oil is that it is only made in Europe because it has not been approved by the Federal Drug Administration as a drug in the United States yet. This makes the oil expensive at $56 for a 500mL bottle and hard to obtain. Lorenzo's oil is only available to patients taking part in Dr. Moser's clinical trial (The Myelin Project Headquarters 1).

While adrenoleukodystrophy is a rare genetic disease that does not receive much attention and funding, research is continually being conducted to help people with the disorder. The debilitating symptoms of ALD can sometimes be prevented if Lorenzo's oil is administered early enough. Eventually, the work of researchers and The Myelin Project might help ALD suffers to live normal lives by reducing the amount of VLCFA in their blood and rebuilding the myelin sheath surrounding the nerves of the brain.

Boehm, Corinne D. X-Linked Adrenoleukodystrophy. 15 April 2004. Gene Reviews. 5 Feb 2005. http://www.geneclinics.org/profiles/x-ald/index.html

Collins, Debra. Introduction to Leukodystrophy. 4 Sept 2004. United Leukodystrophy Foundation. 5 Feb 2005. http://www.ulf.org/ulf/intro/#Inf3

Manea, Silvia. Adrenoleukodystrophy. 30 March 2000. Medline Current Contents. 11 Feb 2005. http://malattierare.pediatria.unipd.it/pubblicaMR/ mr_dx_ing.asp?mr=10

National Institutes of Health. Adrenoleukodystrophy. 11 March 1999. HeathLink. 5 Feb 2005. http://healthlink.mcw.edu/article/921176192.html

Newmark, Chayim Y. Adrenoleukodystrophy. 1 March 2002. ADAM, Inc. 5 Feb 2005. http://health.yahoo.com/ency/adam/001182/0

Richardson, Cheryl. Neonatal Adrenoleukodystrophy (ALD). 2002. Richardson Enterprises. 11 Feb 2005. http://www.epeconline.com/NeonatalAdrenoleukodystro phy.html

Stith, Bradley. The use of the movie "Lorenzo's Oil" as a Teaching Tool. 6 August 1997. University of Colorado. 5 Feb 2005. http://carbon.cudenver.edu/~bstith/loren.htm

The Myelin Project Headquarters. Information About Lorenzo's Oil. 2005 The Myelin Project. 11 Feb 2005. http://www.myelin.org/aboutoil.htm