Adrenoleukodystrophy

=toc Adrenoleukodystrophy = by Austin

What is Adrenoleukodystrophy?
Adrenoleukodstryophy, commonly referred to as ALD, is an extremely rare, inherited, metabolic and neurologic disorder. Beside its common acronym name ALD, it is also called Addison-Schilder Disease, Siemerling-Creutzfeldt Disease, and Schilder's disease. ALD is a part of the group of inherited diseases called leukodystrophies. It affects about 1 in every 17,900 boys worldwide, which is 0.00006%. Symptoms in boys generally occur between the ages of 4 and 10.

With ALD, the myelin sheath tissue is completely damaged and lost. Myelin is a comlex neutral fatty tissue that forms the myelin sheath layer. The layers of myelin insulates multiple nerves of the peripheral and central nervous systems. Without myelin, nerves develop the inability to properly conduct impulses. As the myelin continues to be destroyed, disabilites increase. The lack of myelin causes demyelineation, which destroys nerves cells in the human brain. ALD eventually progresses in permanent brain damage and addrenal gland failure, which ultimately brings about death.

[[image:better.png width="135" height="92" align="left"]]A Closer Look...
With adrenoleukodstryophy, the transporter protein, which is an essential amino acid, is missing. The transporter protein is needed in the human body to break down very long-chain fatty acids (VLCFA) found in a normal diet generally contain 25-30 carbon atoms. With ALD, one accumulates very high levels of saturated (VLCFA) in the brain and adrenal cortex because the body does not have the necessary essential proteins to break down the (VLCFA). Between the inability to prevent the build-up of the (VLCFA) and the spread of demyelineation, the human body deterioartes.

Types of Adrenoleukodystrophy
There are different subsets of ALD that affect its patients. The most common type of ALD is X-linked. This type of ALD is inherited through genetics and is related to the X-chromosome. Autosomal ALD and adrenomyeloneuropathy are different types of Adrenoleukodystrophy.

X-Linked [[image:http://www.x-ald.nl/carrier400.jpg width="405" height="234" align="right"]]
X-Linked Adrenoleukodystrophy is the most common form found in 1 of every 42,000 male births. The name X-linked is a reference to the defective gene being on the X chromosome, specifically located at the Xq28 chromosome. The disease is classified by the continual growth of (VLCFA). Although the fatty acids can be 25-30 carbon atoms long, the most common type found with the X-Linked ALD has a 26 carbon skeleton. Women are the carriers for the disease since they have two X-chromosomes. Because men have only X-chromosome, they lack the ability to protect against the effect of the extra X-chromosome.

Below are listed the different types X-ALD:


 * 1) Childhood Cerebral ALD: This type of ALD is typically one of the more common forms of X-linked ALD. It accounts for nearly 30% of all patients, generally between ages 2 and 10. Development is nearly normal up to the point of onset. Once onset begins, symptoms may include impaired hearing and vision, behavioral disturbance, and school difficulties. Deterioration begins almost immediately and occurs rapidly. The usual time period between initial symptoms and a bedridden state or death 2 years.
 * 2) Adolescent Cerebral ALD: A much smaller percentage of patients with X-linked ALD will begin between the ages of 11 and 21. Symptoms may appear closely to the those of Childhood Cerebral ALD, but progression of the Adolescent Cerebral ALD may be slower. Additional symptoms may include poor coordination, seizures, slurred speech, migraines, hyperactivity, or dementia.
 * 3) Adrenomyeloneuropathy: Referred to as AMN, Adrenomyeloneuropathy is typically the most common form of the disease, occurring in nearly 40% of all X-ALD patients. Symptoms generally begin to arise in the twenties and can include weakness, weight loss, stiffness, urinary disturbance, cognitive defects, depression, impotence, and difficulty with mobility. The disease spreads extremely slowly, and between 5 to 15 years, a wheelchair or walking cane will be needed.
 * 4) Adult cerebral ALD: This type of ALD is relatively rare, considering that it accounts for only 3% of ALD cases. Age onset may vary anywhere from the twenties to the fifties. Dementia and schizophrenia are common symptoms. Since progression is rather rapid, a vegetative state is reached in only 4 years.
 * 5) Symptomatic Heterozygotes: Women who carry an abnormal copy of a gene for ALD on the X-chromosome also carry a good copy of the gene. However, some women who carry one good and one bad copy of the X-ALD gene, which are the heterozygote, show symptoms of ALD which may range from very mild to very severe. Symptoms for women who are carriers include weakness, ataxia, peripheral neuropathy, urinary problems, and stiffness.

Autosomal
Autosomal adrenoleukodystrophy is a result of the following: PEX1 (Peroxisome Biogenesis Factor 1), PEX5 (Peroxisomal Targeting Signal 1 Receptor), PEX10 (Peroxisome Biogenesis Factor 10), PEX13 (Peroxisomal Membrane Protein), and PEX26 (Peroxisome Assembly Protein 26).

Adrenomyeloneuropathy (Continued)
Adrenomyeloneuropathy (AMN) is a milder form of X-linked ALD. The abnormal gene that causes the disorder is placed on the long arm of the X-chromosome, which cuases a sex-linked expression patter. Male carriers of mutations in the gene (hemizygous) will always be affected. They have a 50% chance of developing X-ALD in childhood and a 50% chance developing AMN as adolescents or adults. Approximately 1 in 21,000 males are diagnosed with the disease.

AMN is a result of the defective β-oxidation of fatty acids in peroxisomes. These lead to highly elevated concentrations of (VLCFA). They also lead to an accumulation of cholesterol esters of gangliosides and the fatty acids in cell membranes in the adrenal cortex and brain. This accumulation results in the progression of neurological dysfunction and a primary adrenal insufficiency balance.

Symptoms
Symptoms for ALD vary among the different types of the disorder. General ALD symptoms may include:
 * Loss of neurologic abilities
 * Seizures
 * Addison's Disease
 * Ataxia
 * Poor speech
 * Fatigue
 * Intermittent vomiting
 * Increased skin pigmentation
 * Degeneration of auditory and visual senses
 * Spinal cord dysfuction
 * Weakness of limbs
 * Defecation
 * Uncontrollable rage
 * Adrenal insufficiency

Treatment
Currently, there is no scientific treatment for the disease. There are a few dietary remedies patients may use, but there is limited success recorded. For example, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate (Lorenzo's Oil) with a diet low in VLCSFA (very long chain of saturated fatty acids) has been produced and tested. However, it is impossible to determine if Lorenzo's Oil has absolute potential to prevent spread of the disease because X-ALD has a continaully changing clinical course. Another method of possible treatments is hematopoietic stem cell transplantation (HSCT). This transplantation includes bone marrow transplant. HSCT has the risk of morbidity and mortality; thus it is not recommended for severe symptoms. Lovastatin, an anti-cholesterol drug, appears to have effect in vitro. However, the drug did not work on the animal model of ALD. Lovastatin is generally frowned upon by most scientists, especially for the treatment of X-linked ALD. Adrenal hormones, sympotamatic, and supportive treatments are other options for reducing ALD.

// Lorenzo's Oil //
//Lorenzo's Oil// is a 1992 film based on the true story of Augusto and Michaela Odone, two parents struggling to find a cure for their son Lorenzo's adrenoleukodystrophy. Lorenzo Odone was 5 years old when he was first diagnosed with the disease. Since the disease was barely known, a treatment had not yet been discovered. Upset with the lack of knowledge and assistance, the parents began to research myelin and ALD itself. Eventually, they invented the mixture Lorenzo's Oil. One day after his 30th birthday on May 30, 2008, Lorenzo Odone died after developing aspiration pneumonia. Lorenzo had lived 20 years longer than the doctors had predicted when he was just a child. To date, he is the oldest survivor of ALD.

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