Adrenoleukodystrophy

From Wikipedia, the free encyclopedia

 This article may require cleanup to meet Wikipedia's quality standards.
Please improve this article if you can. (September 2006)
Adrenoleukodystrophy
Classification and external resources
ICD-10 E71.3
ICD-9 330.0, 277.86
OMIM 300100 202370
DiseasesDB 292
MeSH D000326

Adrenoleukodystrophy (ALD) (also known as Addison-Schilder Disease or Sudanophilic Leukodystrophy) is a rare inherited disorder that leads to progressive brain damage, failure of the adrenal glands and eventually death. ALD is one disease in a group of inherited disorders called leukodystrophies. Adrenoleukodystrophy progressively damages the 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.

An essential protein, called a transporter protein, is missing in sufferers. This protein is needed to carry an enzyme which is used to break down long-chain fatty acids found in the normal diet. Lack of this protein can give rise to a build-up of long-chain fatty acids in the body which can damage the brain and the adrenal gland.

The victims of ALD are nearly always male, with about one in five women carrying the disease developing a milder form in adult life. There are several different types of the disease which can be inherited in two different ways. It is more commonly inherited as an X-linked condition.

Although this disorder affects the growth and/or development of myelin, leukodystrophies are different from demyelinating disorders such as multiple sclerosis where myelin is formed normally but is lost by immunologic dysfunction or for other reasons.

Contents

[edit] 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 most likely strikes males and which normally occurs between the ages of 4 and 10 and is characterized by failure to develop, seizures, ataxia, adrenal insufficiency, as well as degeneration of visual and auditory function. This form can also occur in adolescents and very rarely in 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 forms of the disease also exist but they are extremely rare. (These tend to affect both males and females and be inherited in an autosomal recessive manner.) Some patients may present with sole findings of adrenal insufficiency (Addison's disease). ALD also causes uncontrollable rage in some cases.

[edit] 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.

[edit] Pathophysiology

[edit] X-linked

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) — fatty acids chains with 24–30 carbon atoms (particularly hexacosanoate, C26) in length. This was originally described by Moser et al in 1981.[1] 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 unknown how the transporter affects the function of the fatty acid enzyme and, for that matter, how high levels of very long chain fatty acids cause the loss of myelin on nerve fibres.

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 β-oxidation.[2] A dysfunctional gene leads to the accumulation of very long chain fatty acids (VLCFA).

The precise mechanisms through which high VLCFA concentrations cause the disease were still unknown as of 2005, 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.

[edit] Autosomal

Autosomal adrenoleukodystrophy has been associated with PEX1, PEX5, PEX10, PEX13, and PEX26.[3]

[edit] Screening

Neonatal screening is likely to become available which may permit proactive monitoring and treatment.[4]

[edit] Treatment

While there is currently no cure for the disease, some dietary treatments, for example, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate (Lorenzo's oil) in combination with a diet low in VLCFA, have been used with limited success, especially before disease symptoms appear. A 2005 study shows positive long-term results with this approach.[5] A 2007 report also appraises "Lorenzo's oil".[6] See also the Myelin Project.

Bone marrow transplantation (BMT) is the only known treatment that can stop the progression of the disease, and is the preferred first-line treatment for boys with cerebral X-linked ALD. However, BMT carries a risk of mortality and morbidity and is not recommended for patients whose symptoms are already severe. Lovastatin is an anti-cholesterol drug that appears to help, but researchers are unsure as to the mechanism of action.

[edit] Prognosis

There is no current cure for ALD and any treatment is purely symptomatic. Progressive neurological degeneration makes the prognosis generally poor. Death occurs within one to ten years of presentation of symptoms.

[edit] Research

Active clinical trials:[7]

[edit] Lorenzo Odone

Lorenzo Michael Murphy Odone (May 29, 1978 – May 30, 2008)[12] was probably the most famous patient with ALD. His parents Augusto and Michaela Odone, frustrated by the limited treatment available,[13] sparked the invention of "Lorenzo's oil", which is the first agent to have shown therapeutic benefit in halting the destruction of the myelin sheathing of nerves caused by this disease. The quest for a treatment for Lorenzo was depicted in the 1992 film Lorenzo's Oil, and was the subject of the Phil Collins song "Lorenzo" (on his 1996 album Dance Into The Light).

[edit] References

  1. ^ Moser HW, Moser AB, Frayer KK, Chen W, Schulman JD, O'Neill BP, Kishimoto Y. Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. Neurology 1981;31:1241-9. PMID 7202134.
  2. ^ Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, Poustka AM, Mandel JL, Aubourg P. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 1993;361:726-30. PMID 8441467.
  3. ^ OMIM - ADRENOLEUKODYSTROPHY, AUTOSOMAL NEONATAL FORM. Retrieved on 2008-03-23.
  4. ^ PMID 16380594
  5. ^ Moser, HW; Raymond GV, Lu S-E, Muenz LR, Moser AB, Xu J, Jones RO, Loes DJ, Melhem ER, Dubey P, Bezman L, Brereton NH, Odone A (2005-07). "Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's Oil.". Archives of Neurology 62 (7): p. 1073-80. PMID 16009761. 
  6. ^ Moser, HW; Moser AB, Hollandsworth K, Brereton NH, Raymond GV (2007-09). ""Lorenzo's oil" therapy for X-linked adrenoleukodystrophy: rationale and current assessment of efficacy.". Journal of Molecular Neuroscience 33 (1): p. 105-13. PMID 17901554. 
  7. ^ clinicaltrials.gov/
  8. ^ ClinicalTrials.gov NCT00545597
  9. ^ ClinicalTrials.gov NCT00004450
  10. ^ ClinicalTrials.gov NCT00004418
  11. ^ ClinicalTrials.gov NCT00383448
  12. ^ Boy whose parents made Lorenzo's oil dies at 30. SFGate.com. Retrieved on 2008-05-30.
  13. ^ About Lorenzo, his Parents, and Oumouri. The Myelin Project. Retrieved on 2006-06-03.

[edit] External links

v • d • e
Lipid metabolism disorders / Inborn error of lipid metabolism - dyslipidemia (E78 and E71.3, 272)
Hyperlipidemia
Hypolipoproteinemia
Lipodystrophy
Fatty acid metabolism deficiency
Cholesterol synthesis
Other
v • d • e
Peroxisomal disorders
Zellweger spectrum
Other