| Adrenoleukodystrophy | |
|---|---|
| Classification and external resources | |
T2 weighted axial scan at the level of the caudate heads demonstrates marked loss of posterior white matter, with reduced volume and increased signal intensity. The anterior white matter is spared. Features are consistent with X-linked adrenoleukodystrophy. |
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| ICD-10 | E71.3 |
| ICD-9 | 330.0, 277.86 |
| OMIM | 300100 202370 |
| DiseasesDB | 292 |
| MeSH | D000326 |
| GeneReviews | X-Linked Adrenoleukodystrophy |
Adrenoleukodystrophy (ALD, also called Siemerling-Creutzfeldt Disease or Addison-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, whose chief feature is damage to myelin. In adrenoleukodystrophy, over-accumulation of VLCFAs leads to damage to the brain, adrenal gland, and peripheral nervous system 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 that 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.
Childhood cerebral type is characterized by:
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The diagnosis is established by clinical findings and the detection of serum very long-chain free fatty acid levels.[5] 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.[6]
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.[7] 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.[8]
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.[9] The precise mechanisms through which high VLCFA concentrations in affected organs cause the disease is still unknown.
Slowly by stripping the myelin sheath (a protective sheath on your nerves in your brain) the affected person would slowly begin to lose body function and eventually will not be able to talk. There is an over load of long chain fatty acids that ones body cannot dispose of. This does not follow the basic unit of life. (Everything one takes in must be able to be disposed of as waste) This over load of fatty acids will build up in your brain and that is what strips the Myelin Sheath.
Neonatal adrenoleukodystrophy (NALD) is one of three autosomal recessive disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD).[10] The other two disorders are Zellweger syndrome (ZS), and infantile Refsum disease (IRD).[11][12] NALD is most frequently caused by mutations in the PEX1, PEX5, PEX10, PEX13, and PEX26 genes.[13]
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.[14] A 2007 report also appraises "Lorenzo's oil".[15] See also the Myelin Project. X-linked adrenoleukodystrophy has a very variable clinical course, even within a single family.[16] 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.[17] 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.[18]
Lovastatin is an anti-cholesterol drug that appears to have some effect in vitro, but not in mice with the animal model of adrenoleukodystrophy.[19] A clinical study of lovastatin showed encouraging biochemical changes, but no objective clinical improvement.[20] 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.[21]
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.[22]
According to a 1986 study, Oleic acid may lower the levels of saturated VLCFAs in vitro.[23]
Adrenal function must be tested periodically in all patients with ALD. Treatment with adrenal hormones can be lifesaving. Symptomatic and supportive treatments for ALD include physical therapy, psychological support, and special education. Recent evidence suggests that a mixture of oleic acid and erucic acid, known as "Lorenzo's Oil," administered to boys with X-ALD can reduce or delay the appearance of symptoms. Bone marrow transplants can provide long-term benefit to boys who have early evidence of X-ALD, but the procedure carries risk of mortality and morbidity and is not recommended for those whose symptoms are already severe or who have the adult-onset or neonatal forms. Oral administration of docosahexanoic (DHA) may help infants and children with neonatal ALD.[24]
Although there is no guaranteed method for preventing X-ALD, health care providers can recommend genetic counseling for prospective parents with a family history of X-ALD. Female carriers can be diagnosed 85% of the time based on blood very long chain fatty acid (VLCFA) levels and genetic testing performed by specialized laboratories.
Prenatal diagnosis of X-ALD is also available. It is done by evaluating cells from chronic villus sampling or amniocentesis.[25]
Active clinical trials are currently in progress to determine if the proposed treatments are effective:[26]
The National Institute of Neurological Disorders and Stroke (NINDS), supports the research on genetic disorders such as ALD. The goal of this research is to find ways to prevent, treat and cure these disorders. Intensive basic research has proposed two new approaches; 4-phenylbutyrate and lovastatin. These two new approaches could potentially lower levels of VLCFA in the brain, the therapeutic trials for both agents are planned.[31]
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.[32]
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.[33]
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 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,[34] 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).
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