Adrenoleukodystrophy 52952 225822770 2008-07-15T15:51:24Z Nursing101 7480655 /* Diagnosis */ deleted a sentence and put it in symptoms {{Cleanup|date=September 2006}} {{Infobox_Disease | Name = Adrenoleukodystrophy | Image = | Caption = | DiseasesDB = 292 | ICD10 = {{ICD10|E|71|3|e|70}} | ICD9 = {{ICD9|330.0}}, {{ICD9|277.86}} | ICDO = | OMIM = 300100 | OMIM_mult = {{OMIM2|202370}} | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | MeshID = D000326 }} '''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 gland]]s 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 nervous system|central]] and [[peripheral nervous system]]s. Without myelin, [[nerve]]s 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 acid]]s 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. The victims of ALD are nearly always male, with 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 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. ==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, [[seizure]]s, [[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 yr old have usually become very ill by the age of 10 to 12 yrs of age and die soon after.This severe form of the disease was first described by E. Siemerling and [[Hans Gerhard Creutzfeldt]].<ref>Siemerling E and Creutzfeldt, HG. Bronzekrankheit und sklerosierende Encephalomyelitis. 'Arch. Psychiat. Neurokrankh.' 68:217-244, 1923</ref> A similar form can also occur in [[adolescent]]s and very rarely in adults. [[Addisons disease]] can be an initial symptom of ALD, and many [[pediatric endocrinologist]]s 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]] (Addisons disease). ALD also causes uncontrollable rage in some cases.{{Fact|date=July 2008}} ==Diagnosis== The diagnosis is established by clinical findings and the detection of [[blood plasma|serum]] very long-chain free [[fatty acid]] levels. [[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 is characterized by excessive accumulation of very long-chain [[fatty acids]] (VLCFA) &mdash; fatty acids chains with 24&ndash;30 [[carbon]] atoms (particularly hexacosanoate, C26) in length. This was originally described by Moser ''et al'' in 1981.<ref>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.</ref> 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 [[peroxisome]]s, the cellular [[organelle]]s where the fatty acids undergo [[beta oxidation|β-oxidation]].<ref>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 (journal)|Nature]] 1993;361:726-30. PMID 8441467.</ref> 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. ===Autosomal=== Autosomal adrenoleukodystrophy has been associated with [[PEX1]], [[PEX5]], [[PEX10]], [[PEX13]], and [[PEX26]].<ref name="titleOMIM - ADRENOLEUKODYSTROPHY, AUTOSOMAL NEONATAL FORM">{{cite web |url=http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=202370 |title=OMIM - ADRENOLEUKODYSTROPHY, AUTOSOMAL NEONATAL FORM |accessdate=2008-03-23 |format= |work=}}</ref> ==Screening== Neonatal screening is likely to become available which may permit proactive monitoring and treatment.<ref>PMID 16380594</ref> ==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.<ref>{{cite journal|last=Moser|first=HW|coauthors=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|date=2005-07|title=Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's Oil.|journal=Archives of Neurology|volume=62|issue=7|pages=p. 1073–80|pmid=16009761|doi=10.1001/archneur.62.7.1073}}</ref> A 2007 report also appraises "Lorenzo's oil".<ref name="Moser2007-09">{{cite journal|last=Moser|first= HW|coauthors=Moser AB, Hollandsworth K, Brereton NH, Raymond GV|date=2007-09|title="Lorenzo's oil" therapy for X-linked adrenoleukodystrophy: rationale and current assessment of efficacy.|journal=Journal of Molecular Neuroscience|volume=33|issue=1|pages=p. 105–13|pmid=17901554|doi=10.1007/s12031-007-0041-4}}</ref> See also [[the Myelin Project]]. X-linked adrenoleukodystrophy has a very variable clinical course, even within a single family.<ref>Adrenoleukodystrophy (OMIN) [http://wwwncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300100]</ref> 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 remain 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 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.{{Fact|date=July 2008}} 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 have some effect ''in vitro'', but not in mice with the [[animal model]] of adrenoleukodystrophy.<ref>Lovaststin does not correct the accumulation of very long-chain free fatty acids in tissues of adrenoleukodystrophy protein deficient mice. PMID 11032335 |year=2000 </ref> 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 suvival time after transplant in 3 patients.<ref>|year=2007 |title=N-acetyl-cysteine improves outcome of advanced adrenoleukodystrophy. PMID 17290278</ref> ==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 inprogress to see if proposed treatments are effective or not:<ref>[http://clinicaltrials.gov/ct/search?term=Adrenomyeloneuropathy&submit=Search clinicaltrials.gov/]</ref> * Glyceryl Trioleate ([[Lorenzo's oil]])<ref>{{ClinicalTrialsGov|NCT00545597}}</ref> * [[Interferon|Beta Interferon]] and [[Thalidomide]]<ref>{{ClinicalTrialsGov|NCT00004450}}</ref> * Combination of [[Glyceryl Trierucate]] and Glyceryl Trioleate (Lorenzo's Oil)<ref>{{ClinicalTrialsGov|NCT00004418}}</ref> * [[Hematopoietic stem cell]] transplantation<ref>{{ClinicalTrialsGov|NCT00383448}}</ref> ==Lorenzo Odone== {{main|Lorenzo Odone}} Lorenzo Michael Murphy Odone ([[May 29]], [[1978]] &ndash; [[May 30]], [[2008]])<ref> {{cite web|title=Boy whose parents made Lorenzo's oil dies at 30 | work=SFGate.com | url=http://www.sfgate.com/cgi-bin/article.cgi?f=/n/a/2008/05/30/national/a165519D26.DTL&tsp=1 | accessdate=2008-05-30 }}</ref> was probably the most famous patient with ALD. His parents [[Augusto and Michaela Odone]], frustrated by the limited treatment available,<ref>{{cite web | title=About Lorenzo, his Parents, and Oumouri | work=The Myelin Project | url=http://www.myelin.org/aboutlorenzo.htm | accessdate=2006-06-03}}</ref> 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 (film)|Lorenzo's Oil]]'', and was the subject of the [[Phil Collins]] song "Lorenzo" (on his 1996 album ''[[Dance into the Light#Track listing|Dance Into The Light]]''). ==References== <!-- this 'empty' section displays references defined elsewhere --> {{reflist}} ==External links== *{{DMOZ|Health/Conditions_and_Diseases/Neurological_Disorders/Demyelinating_Diseases/Leukodystrophy/Adrenoleukodystrophy/}} * {{NINDS|adrenoleukodystrophy}} * [http://rad.usuhs.edu/medpix/master.php3?mode=topic_images&recnum=1494&quiz=#top Images of ALD] at [[Uniformed Services University of the Health Sciences|USUHS]] * [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.226 Adrenoleukodystrophy] at [[National Center for Biotechnology Information]] * [http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.htm&r=1&f=G&l=50&d=PTXT&p=1&S1=5331009.PN.&OS=pn/5331009&RS=PN/5331009/ US Patent 5,331,009] &mdash; Patent to Croda International Plc on treating ALD with special oil composition inspired by Augusto Odone * http://www.aldlife.org *[http://www.rareshare.org/communities/adrenoleukodystrophy Adrenoleukodystrophy Community on RareShare] {{Lipidemias}} {{Peroxisomal disorders}} [[Category:Genetic disorders]] [[Category:Leukodystrophies]] [[Category:Endocrinology]] [[Category:Neurology]] [[de:Adrenoleukodystrophie]] [[es:Adrenoleucodistrofia]] [[fr:Adrénoleucodystrophie liée à l'X]] [[hr:Adrenoleukodistrofija]] [[it:Adrenoleucodistrofia]] [[he:ALD]] [[ja:副腎白質ジストロフィー]] [[pl:Adrenoleukodystrofia]] [[pt:Adrenoleucodistrofia]] [[fi:ALD]] [[sv:Adrenoleukodystrofi]] [[tr:Adrenolökodistrofi]]