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| GeneReviewsName= X-Linked Adrenoleukodystrophy
| GeneReviewsName= X-Linked Adrenoleukodystrophy
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'''Adrenoleukodystrophy''' (ALD), also called Siemerling-Creutzfeldt Disease or '''Schilder's disease'''<ref name="Andrews">{{cite book |author=James, William D.; Berger, Timothy G.; et al. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |location= |year=2006 |pages= |isbn=0-7216-2921-0 |oclc= |doi= |accessdate=}}</ref>{{Rp|545|date=June 2009}}) is a rare, inherited disorder that leads to progressive brain damage, failure of the [[adrenal gland]]s and eventually death. ALD is a disease in a group of genetic disorders called [[Leukodystrophy|leukodystrophies]]. Adrenoleukodystrophy progressively damages the [[myelin]] sheath, a complex fatty neural tissue that insulates many nerves of the [[central nervous system|central]] and [[peripheral nervous system]]s. Without functional myelin, [[nerve]]s are unable to conduct an [[action potential|impulse]], which leads to increasing [[disability]].
'''Adrenoleukodystrophy''' (ALD), also called Retards Disease or '''Schilder's disease'''<ref name="Andrews">{{cite book |author=James, William D.; Berger, Timothy G.; et al. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |location= |year=2006 |pages= |isbn=0-7216-2921-0 |oclc= |doi= |accessdate=}}</ref>{{Rp|545|date=June 2009}}) is a rare, inherited disorder that leads to progressive brain damage, failure of the [[adrenal gland]]s and eventually death. ALD is a disease in a group of genetic disorders called [[Leukodystrophy|leukodystrophies]]. Adrenoleukodystrophy progressively damages the [[myelin]] sheath, a complex fatty neural tissue that insulates many nerves of the [[central nervous system|central]] and [[peripheral nervous system]]s. Without functional myelin, [[nerve]]s are unable to conduct an [[action potential|impulse]], which leads to increasing [[disability]].


Patients with X-linked ALD have defects in the ATP-binding cassette, sub-family D (ALD), member 1 [[transporter protein]], which is encoded by the ''ABCD1'' gene. The ABCD1 (aka ALDP) protein is indirectly involved in the break down of very long-chain [[fatty acid]]s (VLCFAs) found in the normal diet. Lack of this protein can give rise to an over-accumulation of VLCFAs which can lead to damage to the [[brain]], [[adrenal gland]], and [[peripheral nervous system]].
Patients with X-linked ALD have defects in the ATP-binding cassette, sub-family D (ALD), member 1 [[transporter protein]], which is encoded by the ''ABCD1'' gene. The ABCD1 (aka ALDP) protein is indirectly involved in the break down of very long-chain [[fatty acid]]s (VLCFAs) found in the normal diet. Lack of this protein can give rise to an over-accumulation of VLCFAs which can lead to damage to the [[brain]], [[adrenal gland]], and [[peripheral nervous system]].

Revision as of 12:47, 2 November 2010

Adrenoleukodystrophy
SpecialtyEndocrinology, genetics Edit this on Wikidata

Adrenoleukodystrophy (ALD), also called Retards Disease or Schilder's disease[1]: 545 ) is a rare, inherited disorder that leads to progressive brain damage, failure of the adrenal glands and eventually death. ALD is a disease in a group of genetic disorders called leukodystrophies. Adrenoleukodystrophy progressively damages the myelin sheath, a complex fatty neural tissue that insulates many nerves of the central and peripheral nervous systems. Without functional myelin, nerves are unable to conduct an impulse, which leads to increasing disability.

Patients with X-linked ALD have defects in the ATP-binding cassette, sub-family D (ALD), member 1 transporter protein, which is encoded by the ABCD1 gene. The ABCD1 (aka ALDP) protein is indirectly involved in the break down of very long-chain fatty acids (VLCFAs) found in the normal diet. Lack of this protein can give rise to an over-accumulation of VLCFAs which can lead to damage to the brain, adrenal gland, and peripheral nervous system.

There are several different types of the disease which can be inherited, but the most common form is an X-linked condition. X-linked ALD primarily affects males, but about one in five women with the disease gene develop some symptoms. Adrenomyeloneuropathy is a less-severe form of ALD, with onset of symptoms occurring in adolescence or adulthood. This form does not include cerebral involvement, and should be included in the differential diagnosis of all males with adrenal insufficiency. Although they share a similar name, X-linked ALD and neonatal adrenoleukodystrophy (NALD), a peroxisome biogenesis disorder, are completely different diseases.

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.

Signs and 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, and 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 and die soon after. This severe form of the disease was first described by Ernst Siemerling and Hans Gerhard Creutzfeldt.[2] 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, one primarily strikes young men, the spinal cord dysfunction is more prominent and is therefore called adrenomyeloneuropathy, or "AMN." The patients usually present with weakness and numbness of the limbs. Most victims of this form are also males, although some female carriers exhibit symptoms of AMN.[3]

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.[citation needed]

Diagnosis

The diagnosis is established by clinical findings and the detection of serum very long-chain free fatty acid levels.[4] 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.

Neonatal screening may become available in the future, which may permit early diagnosis and treatment.[5]

Genetics

X-linked

X-linked ALD (X-ALD) is the most common form of ALD. In X-ALD, the defective ABCD1 gene resides on the X chromosome (Xq28). The incidence of X-ALD is at least 1 in 20,000 male births.[6] The ABCD1 ("ATP-binding cassette, subfamily D, member 1") gene was discovered in 1993 and codes for a peroxisome membrane protein necessary for the β-oxidation of VLCFAs.[7]

X-ALD is characterized by excessive accumulation of very long-chain fatty acids (VLCFA), which are fatty acids with chains of 25–30 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.[8] The precise mechanisms through which high VLCFA concentrations in affected organs cause the disease is still unknown.

Autosomal

Neonatal adrenoleukodystrophy (NALD) is one of three autosomal dominant disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD).[9] The other two disorders are Zellweger syndrome (ZS), and infantile Refsum disease (IRD).[10][11] NALD is most frequently caused by mutations in the PEX1, PEX5, PEX10, PEX13, and PEX26 genes.[12]

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 VLCSFA (very long chain saturated fatty acids), have been used with limited success, especially before disease symptoms appear. A 2005 study shows positive long-term results with this approach.[13] A 2007 report also appraises "Lorenzo's oil".[14] See also the Myelin Project. X-linked adrenoleukodystrophy has a very variable clinical course, even within a single family.[15] It is therefore not possible to determine if Lorenzo's oil is preventing progression of the disease in asymptomatic patients, or if these patients would have remained asymptomatic even without treatment. Current double blind placebo-controlled trials may be able to answer the questions regarding the effectiveness of treatment.

Hematopoietic stem cell transplantation (HSCT, including bone marrow transplant) is thought to be able to stop the progression of the X-ALD disease in asymptomatic or mildly symptomatic boys who have a Loes score lower than 9 (an MRI measure of the severity of the disease), though outcomes are markedly poorer in symptomatic boys [16]. HSCT carries a risk of mortality and morbidity and is not recommended for patients whose symptoms are already severe. Umbilical cord blood stem cell transplant may provide an alternative for patients who do not have a matched related stem cell donor. Preliminary studies suggest that the outcome of cord blood stem cell transplant for X-ALD is particularly good in very young, presymptomatic patients [17].

Lovastatin is an anti-cholesterol drug that appears to have some effect in vitro, but not in mice with the animal model of adrenoleukodystrophy.[18] A clinical study of lovastatin showed encouraging biochemical changes, but no objective clinical improvement.[19] In a randomized, double-blind, placebo-controlled crossover trial, researchers found no effect of lovastatin on tissue levels of very long chain free fatty acids, and they recommended that it not be used in X-ALD.[20]

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.[21]

According to a 1986 study, Oleic acid may lower the levels of saturated VLCFAs in vitro.[22]

Research directions

Active clinical trials are currently in progress to determine if the proposed treatments are effective:[23]

Experimental Therapies

In November 2009, Science published a report on a pilot study of two patients receiving gene therapy combined with blood-stem-cell therapy, and stating that the combination "may be a useful tool for treating" X-linked ALD.[28]

Presently, a boy with X-linked ALD (X-ALD) is undergoing gene therapy treatments in France. Professor Patrick Aubourg and Doctor Nathalie Cartier-Lacave are treating him with stem cells which have been altered by the introduction of replication-defective HIV-1–derived lentiviral vectors. They have also successfully treated other children in this way. Says Nathalie Cartier-Lacave, “We have completely stabilised the evolution of this disease. These children are well, they go to school, they have a social life, a normal family life, and there’s no reason to think that this stabilisation isn’t permanent.” The technique was developed in the Faculty of Pharmacy in Paris. First, peripheral blood mononuclear cells (PBMCs) were obtained from the X-ALD patients previously injected with granulocyte colony-stimulating factor. CD34+ cells (i.e. expressing the CD34 cell surface protein) were isolated from these PBMC cell population and then pre-activated ex vivo (outside the body) with a mixture of cytokines. Afterwards, a normal copy of the ABCD1 gene was introduced into these cells using lentiviral vectors. In parallel, patients were treated with cyclophosphamide and busulfan so that their hematopoietic stem cells (HSCs) containing the ABCD1 mutation were greatly diminished. The patients were then infused with their own CD34+ cells engineered to contain normal copies of the ABCD1 gene. These engineered CD34+ can differentiate into a vast number of different blood cell types. Most importantly, they turned into microglial cells that corrected the deficiencies in the brain responsible for X-ALD. If further research confirms these results, this could become standard treatment in the future – replacing heterologous bone marrow transplants which are risky, invasive, and which require a compatible donor to be effective.[29]

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, bone marrow transplant, and gene therapy is currently under investigation.

Lorenzo Odone

Main article: Lorenzo Odone

Lorenzo Michael Murphy Odone (May 29, 1978 – May 30, 2008) was probably the most famous patient with ALD. His parents Augusto and Michaela Odone, frustrated by the limited treatment available,[30] sparked the invention of "Lorenzo's oil", which is still being studied to see if it can prevent or delay the onset of 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. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. {{cite book}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  2. ^ Siemerling E, Creutzfeldt HG (1923). "Bronzekrankheit und sklerosierende Encephalomyelitis". Arch. Psychiat. Neurokrankh. 68: 217–44. doi:10.1007/BF01835678.
  3. ^ O'Brien TJ, Gates PG, Byrne E (1996). "Symptomatic female heterozygotes for adrenoleukodystrophy: A report of two unrelated cases and review of the literature". Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. 3 (2): 166–70. PMID 18638861. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ 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)
  5. ^ 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)
  6. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16949688, please use {{cite journal}} with |pmid=16949688 instead.
  7. ^ 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)
  8. ^ 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)
  9. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17055079, please use {{cite journal}} with |pmid=17055079 instead.
  10. ^ GeneReviews: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum
  11. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17041890, please use {{cite journal}} with |pmid= 17041890 instead.
  12. ^ Template:Cite OMIM
  13. ^ 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)
  14. ^ 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)
  15. ^ Online Mendelian Inheritance in Man (OMIM): Adrenoleukodystrophy - 300100
  16. ^ Peters C, Charnas LR, Tan Y, Ziegler RS, Shapiro EG, DeFor T, Grewal SS, Orchard PJ, Abel SL, Goldman AI, Ramsay NK, Dusenbery KE, Loes DJ, Lockman LA, Kato S, Aubourg PR, Moser HW, Krivit W (2004). "Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999". Blood. 104 (3): 881–8. doi:10.1182/blood-2003-10-3402. PMID 15073029.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Beam D, Poe MD, Provenzale JM, Szabolcs P, Martin PL, Prasad V, Parikh S, Driscoll T, Mukundan S, Kurtzberg J, Escolar ML (2007). "Outcomes of unrelated umbilical cord blood transplantation for X-linked adrenoleukodystrophy". Biol Blood Marrow Transplant. 13 (6): 665–74. doi:10.1016/j.bbmt.2007.01.082. PMID 17531776.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ 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. doi:10.1023/A:1005634130286. PMID 11032335. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Pai GS, Khan M, Barbosa E, Key LL, Craver JR, Curé JK, Betros R, Singh I (2000). "Lovastatin therapy for X-linked adrenoleukodystrophy: clinical and biochemical observations on 12 patients". Molecular Genetics and Metabolism. 69 (4): 312–22. doi:10.1006/mgme.2000.2977. PMID 10870849. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ Engelen M, Ofman R, Dijkgraaf MG; et al. (2010). "Lovastatin in X-linked adrenoleukodystrophy". The New England Journal of Medicine. 362 (3): 276–7. doi:10.1056/NEJMc0907735. PMID 20089986. {{cite journal}}: |access-date= requires |url= (help); Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)Lovaststin should not be prescribed as therapy to lower levels of very-long-chain fatty acids in patients with X-ALD.
  21. ^ 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)
  22. ^ 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. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  23. ^ clinicaltrials.gov/
  24. ^ "A Phase III Trial of Lorenzo's Oil in Adrenomyeloneuropathy". Retrieved 2009-06-06.
  25. ^ Clinical trial number NCT00004450 at ClinicalTrials.gov
  26. ^ "Study of Glyceryl Trierucate and glyceryl trioleate (Lorenzo's Oil) therapy in male children with adrenoleukodystrophy". Retrieved 2009-06-06.
  27. ^ "HSCT for High Risk Inherited Inborn Errors". Retrieved 2009-06-06.
  28. ^ "Gene Therapy Technique Slows Brain Disease ALD Featured In Movie 'Lorenzo's Oil'" at Science News site
  29. ^ "Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy" at Science Mag site
  30. ^ "About Lorenzo, his Parents, and Oumouri". The Myelin Project. Archived from the original on 2006-04-27. Retrieved 2006-06-03.
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