Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a degenerative disorder of the fatty white sheath covering nerve fibers, known as myelin. A type of leukodystrophy, the victims of ALD are typically male, usually ages 5 to 10, as the disease is usually inherited in a sex-linked manner on the X chromosome. Leukodystrophies are disorders that affect the growth and/or development of myelin, a complex fatty neural tissue that insulates many nerves of the central and peripheral nervous systems. Without myelin, nerves are unable to conduct an impulse, leading to increasing disability as myelin destruction increases and intensifies. Leukodystrophies are different from demyelinating disorders such as multiple sclerosis, in which myelin is formed normally, but is lost by immunologic dysfunction or for other reasons.

Symptoms
The clinical presentation is largely dependent on the age of onset of the disease. The most severe type is the childhood cerebral form, which normally occurs in males between the ages of 5 and 10 and is characterized by failure to develop, seizures, ataxia, adrenal insufficiency and degeneration of visual and auditory function. This form can also occur in adolescents and, very rarely, adults.

In another form of ALD, which primarily strikes young men, the spinal cord dysfunction is more prominent and therefore is called adrenomyeloneuropathy or "AMN." The patients usually present with weakness and numbness of the limbs and urination or defecation problems. Most victims of this form are also males, although some female carriers exhibit symptoms similar to AMN.

Adult and neonatal (which tend to affect both males and females and be inherited in an autosomal recessive manner) forms of the disease also exist but they are extremely rare. Some patients may present with sole findings of adrenal insufficiency (Addison's disease).

Diagnosis
The diagnosis is established by clinical findings and the detection of serum long chain fatty acid levels. MRI examination reveals white matter abnormalities, and neuroimaging findings of this disease are quite reminiscent of the findings of multiple sclerosis. Genetic testing for the analysis of the defective gene is available in some centers.

Pathophysiology
The most common form of ALD is X-linked (the defective gene is on the X chromosome, location Xq28), and is characterized by excessive accumulation of very long chain fatty acids (VLCFA) &mdash; fatty acids chains with 24–30 carbon atoms (particularly hexacosanoate, C26) in length (normally less than 20). This was originally described by Moser et al in 1981. So, when the ALD gene was discovered in 1993, it was a surprise that the corresponding protein was in fact a member of a family of transporter proteins, not an enzyme. It is still a mystery as to how the transporter affects the function the fatty acid enzyme and, for that matter, how high levels of very long chain fatty acids cause the loss of myelin on nerve fibers.

The gene (ABCD1 or "ATP-binding cassette, subfamily D, member 1") codes for a protein that transfers fatty acids into peroxisomes, the cellular organelles where the fatty acids undergo &beta;-oxidation (Mosser et al 1993). A dysfunctional gene leads to the accumulation of long-chain fatty acids.

The precise mechanisms through which high VLCFA concentrations cause the disease are still (2005) unknown, but accumulation is severe in the organs affected.

The prevalence of X-linked adrenoleukodystrophy is approximately 1 in 20,000 individuals. This condition occurs with a similar frequency in all populations.

Treatment
While there is no cure for the disease, some dietary treatments, for example, Lorenzo's oil in combination with a diet low in VLCFA, have been used with limited success, especially before disease symptoms appear. A recent study by Moser et al (2005) shows positive long-term results with this approach.

Bone marrow transplantation has been proven to help ALD who are either presymptomatic or exhibiting mild symptoms early in the course of the disease. Bone marrow transplantation is not recommended for those suffering from AMD or very advanced onset ALD.

Famous patients
Lorenzo Odone is probably the most famous patient with ALD. With the limited research available, his parents Augusto and Michaela Odone sparked the invention of Lorenzo's oil, which is the first agent to have shown therapeutic benefit in ALD. The quest for a treatment for Lorenzo was depicted in the film Lorenzo's Oil, and is the subject of the Phil Collins song Lorenzo (on his 1996 album Dance Into the Light).