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Adrenoleukodystrophy

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Adrenoleukodystrophy
SpecialtyEndocrinology Edit this on Wikidata

Adrenoleukodystrophy (ALD) (also known as Addison-Schilder Disease or Siemerling-Creutzfeldt Disease) is a rare, (1 in 20,000 boys) 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 very long-chain fatty acids found in the normal diet. Lack of this protein can give rise to a build-up of very long-chain fatty acids, (VLCFA) in the body which can damage the brain and the adrenal gland.

Patients with X-linked ALD are all male, but about one in five women carrying the disease developing a milder form in adult life, called adrenomyeloneuropathy. There are several different types of the disease which can be inherited' but the most common form is 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.

Symptoms

The clinical presentation is largely dependent on the age of onset of the disease. The classical, severe type is the childhood cerebral form which, as an X-linked disease, affects males. Symptoms normally start between the ages of 4 and 10 and include loss of previously acquired neurologic abilities, seizures, ataxia, Addison's disease, as well as degeneration of visual and auditory function. It has been seen that infants that have been positively diagnosed by the age of 1 year old have usually become very ill by the age of 10 to 12 years of age and die soon after.This severe form of the disease was first described by E. Siemerling and Hans Gerhard Creutzfeldt.[1] A similar form can also occur in adolescents and very rarely in adults. Addison's disease can be an initial symptom of ALD, and many pediatric endocrinologists will measure very long chain free fatty acids in newly diagnosed males with this condition, as a screening test for ALD.

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. ALD also causes uncontrollable rage in some cases.[citation needed]

Diagnosis

The diagnosis is established by clinical findings and the detection of serum very long-chain free fatty acid levels.[2] MRI examination reveals white matter abnormalities, and neuro-imaging findings of this disease are somewhat reminiscent of the findings of multiple sclerosis. Genetic testing for the analysis of the defective gene is available in some centers.

Pathophysiology

X-linked

The most common form of ALD is X-linked. The defective gene is on the X chromosome, location Xq28, and the disease is characterized by excessive accumulation of very long-chain fatty acids (VLCFA), which are fatty acids with chains of 24–30 carbon atoms. The most common is hexacosanoate, with a 26 carbon skeleton. The elevation in (VLCFA) was originally described by Moser et al in 1981.[3] The ALD gene was discovered in 1993, and it coded for a protein that was a member of a family of transporter proteins, not an enzyme. It is unknown how high levels of very long chain fatty acids cause the loss of myelin.

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.[4] 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 they do accumulate 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.

Autosomal

Autosomal adrenoleukodystrophy has been associated with PEX1, PEX5, PEX10, PEX13, and PEX26.[5]

Screening

Neonatal screening may become available in the future, which may permit early diagnosis and treatment.[6]

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.[7] A 2007 report also appraises "Lorenzo's oil".[8] See also the Myelin Project. X-linked adrenoleukodystrophy has a very variable clinical course, even within a single family.[9] It is therefore not possible to determine if Lorenzo's oil is preventing progression of the disease in assymptomatic patients, or if these patients would have remained assymptomatic even without treatment. Current double blind placebo-controlled trials may be able to answer the questions regarding the effectiveness of treatment.

Bone marrow transplantation (BMT) is thought to be able to stop the progression of the disease, but has not been shown to be effective in boys with cerebral X-linked ALD.[citation needed] 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 have some effect in vitro, but not in mice with the animal model of adrenoleukodystrophy.[10] Currently, researchers at The Children's Hospital at the University of Minnesota, Dr. Charnas and Dr. Orchard, are investigating Mucomyst as an adjunct to bone marrow transplant, with some increase in survival time after transplant in 3 patients.[11]

According to a 1986 study, Oleic acid may lower the levels of very long chain free fatty acids in vitro. [12]

Prognosis

Treatment is symptomatic. Progressive neurological degeneration makes the prognosis generally poor. Death occurs within one to ten years of presentation of symptoms. The use of Lorenzo's Oil or of bone marrow transplant are currently under investigation.

Research

Active clinical trials are currently in progress to see if proposed treatments are effective or not:[13]

Lorenzo Odone

Main article: Lorenzo Odone

Lorenzo Michael Murphy Odone (May 29, 1978 – May 30, 2008)[18] was probably the most famous patient with ALD. His parents Augusto and Michaela Odone, frustrated by the limited treatment available,[19] sparked the invention of "Lorenzo's oil", which is still being studied to see if it has 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).

References

  1. ^ Siemerling E, Creutzfeldt HG (1923). "Bronzekrankheit und sklerosierende Encephalomyelitis". Arch. Psychiat. Neurokrankh. 68: 217–44.
  2. ^ Moser HW, Moser AB, Frayer KK; et al. (1981). "Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids". Neurology. 31 (10): 1241–9. PMID 7202134. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Moser HW, Moser AB, Frayer KK; et al. (1981). "Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids". Neurology. 31 (10): 1241–9. PMID 7202134. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Mosser J, Douar AM, Sarde CO; et al. (1993). "Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters". Nature. 361 (6414): 726–30. doi:10.1038/361726a0. PMID 8441467. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Online Mendelian Inheritance in Man (OMIM): ADRENOLEUKODYSTROPHY, AUTOSOMAL NEONATAL FORM - 202370
  6. ^ Moser HW, Raymond GV, Dubey P (2005). "Adrenoleukodystrophy: new approaches to a neurodegenerative disease". JAMA. 294 (24): 3131–4. doi:10.1001/jama.294.24.3131. PMID 16380594. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Moser, HW (2005-07). "Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's Oil". Archives of Neurology. 62 (7): p. 1073–80. doi:10.1001/archneur.62.7.1073. PMID 16009761. {{cite journal}}: |pages= has extra text (help); Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Moser HW, Moser AB, Hollandsworth K, Brereton NH, Raymond GV (2007). ""Lorenzo's oil" therapy for X-linked adrenoleukodystrophy: rationale and current assessment of efficacy". J. Mol. Neurosci. 33 (1): 105–13. doi:10.1007/s12031-007-0041-4. PMID 17901554. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Online Mendelian Inheritance in Man (OMIM): Adrenoleukodystrophy - 300100
  10. ^ Yamada T, Shinnoh N, Taniwaki T; et al. (2000). "Lovastatin does not correct the accumulation of very long-chain fatty acids in tissues of adrenoleukodystrophy protein-deficient mice" (PDF). J. Inherit. Metab. Dis. 23 (6): 607–14. PMID 11032335. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Tolar J, Orchard PJ, Bjoraker KJ, Ziegler RS, Shapiro EG, Charnas L (2007). "N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy". Bone Marrow Transplant. 39 (4): 211–5. doi:10.1038/sj.bmt.1705571. PMID 17290278. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Rizzo WB, Watkins PA, Phillips MW, Cranin D, Campbell B, Avigan J (1986). "Adrenoleukodystrophy: oleic acid lowers fibroblast saturated C22-26 fatty acids". Neurology. 36 (3): 357–61. PMID 3951702. Retrieved 7 October 2008. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ clinicaltrials.gov/
  14. ^ Clinical trial number NCT00545597 at ClinicalTrials.gov
  15. ^ Clinical trial number NCT00004450 at ClinicalTrials.gov
  16. ^ Clinical trial number NCT00004418 at ClinicalTrials.gov
  17. ^ Clinical trial number NCT00383448 at ClinicalTrials.gov
  18. ^ "Boy whose parents made Lorenzo's oil dies at 30". SFGate.com. Retrieved 2008-05-30.
  19. ^ "About Lorenzo, his Parents, and Oumouri". The Myelin Project. Retrieved 2006-06-03.

External links

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