Adrenoleukodystrophy
Encyclopedia
Adrenoleukodystrophy 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 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 y-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
, 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
. 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.
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:
Lack of brain-to-body coordination
Loss of control and temper in outbreaks (random abrupt berserk behavior)
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.
Neonatal screening may become available in the future, which may permit early diagnosis and treatment.
of X-ALD is at least 1 in 20,000 male births. 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.
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. The precise mechanisms through which high VLCFA concentrations in affected organs cause the disease is still unknown.
(ZS), and infantile Refsum disease
(IRD). NALD is most frequently caused by mutations in the PEX1, PEX5, PEX10, PEX13, and PEX26 genes.
) 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. A 2007 report also appraises "Lorenzo's oil". See also the Myelin Project
. X-linked adrenoleukodystrophy has a very variable clinical course, even within a single family. 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. 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.
Lovastatin
is an anti-cholesterol drug that appears to have some effect in vitro, but not in mice with the animal model
of adrenoleukodystrophy. A clinical study of lovastatin showed encouraging biochemical changes, but no objective clinical improvement. 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.
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.
According to a 1986 study, Oleic acid
may lower the levels of saturated VLCFAs in vitro.
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.
Prenatal diagnosis of X-ALD is also available. It is done by evaluating cells from chronic villus sampling or amniocentesis.
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.
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.
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.
is currently under investigation.
, frustrated by the limited treatment available, 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).
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s and eventually death. ALD is a disease in a group of genetic disorders called leukodystrophies
Leukodystrophy
Leukodystrophy refers to a group of disorders characterized by dysfunction of the white matter of the brain. The leukodystrophies are caused by imperfect growth or development of the myelin sheath, the fatty covering that acts as an insulator around nerve fibers...
, whose chief feature is damage to myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
. In adrenoleukodystrophy, over-accumulation of VLCFAs
Very long chain fatty acid
A very long chain fatty acid is a fatty acid with aliphatic tails longer than 22 carbons.Unlike most fatty acids, VLCFAs are too long to be metabolized in the mitochondria, and must be metabolized in peroxisomes....
leads to damage to the brain
Brain damage
"Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...
, adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
, and peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
.
on the age of onset of the disease. The classical, severe type is the childhood cerebral form which, as an y-linked disease, affects males. Symptoms normally start between the ages of 4 and 10 and include loss of previously acquired neurologic abilities, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, Addison's disease
Addison's disease
Addison’s disease is a rare, chronic endocrine disorder in which the adrenal glands do not produce sufficient steroid hormones...
, 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
Ernst Siemerling
Ernst Siemerling was a German neurologist and psychiatrist born in Müssow near Greifswald.In 1882 he obtained his medical doctorate from the University of Marburg...
and Hans Gerhard Creutzfeldt
Hans Gerhard Creutzfeldt
Hans Gerhard Creutzfeldt was a German neuropathologist, who first described the Creutzfeldt-Jakob disease. He was born in Harburg upon Elbe and died in Munich.-Biography:...
. 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
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
dysfunction is more prominent and is therefore called adrenomyeloneuropathy
Adrenomyeloneuropathy
Adrenomyeloneuropathy is a rare inherited disorder. It is a milder form of X-linked adrenoleukodystrophy . In adrenoleukodystrophy, young children generally exhibit cerebral dysfunction, with rapid progression to dementia and quadriparesis. Adrenomyeloneuropathy progresses more slowly, with...
, 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.
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
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
.
Childhood cerebral type:
- Changes in muscle tone, especially muscle spasms and spasticity
- Crossed eyes
- Decreased understanding of verbal communication
- Deterioration of handwriting
- Difficulty at school
- Difficulty understanding spoken material
- Hearing loss
- Hyperactivity
- Worsening nervous system deterioration
Lack of brain-to-body coordination
Loss of control and temper in outbreaks (random abrupt berserk behavior)
- Coma
- Decreased fine motor control
- Paralysis
- Seizures
- Swallowing difficulties
- Visual Impairment (Blindness)
Diagnosis
The diagnosis is established by clinical findings and the detection of serumBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
very long-chain free fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
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
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is available in some centers.
Neonatal screening may become available in the future, which may permit early diagnosis and treatment.
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 incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of X-ALD is at least 1 in 20,000 male births. The ABCD1
ABCD1
ABCD1 is a protein that transfers fatty acids into peroxisomes.The protein encoded by this gene is a member of the superfamily of ATP-binding cassette transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct...
("ATP-binding cassette, subfamily D, member 1") gene was discovered in 1993 and codes for a peroxisome
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
membrane protein necessary for the β-oxidation
Beta oxidation
Beta oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA, the entry molecule for the Citric Acid cycle....
of VLCFAs.
X-ALD is characterized by excessive accumulation of very long-chain fatty acids (VLCFA), which are fatty acids with chains of 25–30 carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
atoms. The most common is hexacosanoate, with a 26 carbon skeleton. The elevation in (VLCFA) was originally described by Moser et al. in 1981. The precise mechanisms through which high VLCFA concentrations in affected organs cause the disease is still unknown.
Cause
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 a 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.Autosomal
Neonatal adrenoleukodystrophy (NALD) is one of three autosomal recessive disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). The other two disorders are Zellweger syndromeZellweger syndrome
Zellweger syndrome, also called cerebrohepatorenal syndrome is a rare, congenital disorder, characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called leukodystrophies...
(ZS), and infantile Refsum disease
Infantile Refsum disease
Infantile Refsum disease , also called infantile phytanic acid storage disease, is a rare autosomal recessive congenital peroxisomal biogenesis disorder within the Zellweger spectrum. These are disorders of the peroxisomes that are clinically similar to Zellweger syndrome and associated with...
(IRD). NALD is most frequently caused by mutations in the PEX1, PEX5, PEX10, PEX13, and PEX26 genes.
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 oilLorenzo's oil
Lorenzo's oil is a 4:1 mixture of glycerol trioleate and glycerol trierucate , prepared from olive oil and rapeseed 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. A 2007 report also appraises "Lorenzo's oil". See also the Myelin Project
The Myelin Project
The Myelin Project is an international scientific research organization aimed at accelerating clinical and translational research focused on myelin repair and to regenerate the nerve's myelin sheath, — a process called remyelination — destroyed in a host of diseases such as multiple...
. X-linked adrenoleukodystrophy has a very variable clinical course, even within a single family. 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
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
-controlled trials may be able to answer the questions regarding the effectiveness of treatment.
Hematopoietic stem cell transplantation (HSCT, including bone marrow transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
) 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. HSCT carries a risk of mortality
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
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.
Lovastatin
Lovastatin
Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...
is an anti-cholesterol drug that appears to have some effect in vitro, but not in mice with the animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
of adrenoleukodystrophy. A clinical study of lovastatin showed encouraging biochemical changes, but no objective clinical improvement. 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.
Currently, researchers at The Children's Hospital at the University of Minnesota, Dr. Charnas and Dr. Orchard, are investigating Mucomyst as an adjunct
Adjunct
Adjunct may refer to:* Adjunct , words used as modifiers* Adjunct professor, a professor who does not hold a permanent position at a particular academic institution* Adjuncts, sources of sugar used in brewing...
to bone marrow transplant, with some increase in survival time after transplant in 3 patients.
According to a 1986 study, Oleic acid
Oleic acid
Oleic acid is a monounsaturated omega-9 fatty acid found in various animal and vegetable fats. It has the formula CH37CH=CH7COOH. It is an odorless, colourless oil, although commercial samples may be yellowish. The trans isomer of oleic acid is called elaidic acid...
may lower the levels of saturated VLCFAs in vitro.
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.
Prevention
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.
Research
Active clinical trials are currently in progress to determine if the proposed treatments are effective:- Glyceryl Trioleate (Lorenzo's oilLorenzo's oilLorenzo's oil is a 4:1 mixture of glycerol trioleate and glycerol trierucate , prepared from olive oil and rapeseed oil....
) for Adrenomyelneuropathy. - Beta InterferonInterferonInterferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
and ThalidomideThalidomideThalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
This study is closed. - Combination of Glyceryl TrierucateErucic acidErucic acid is a monounsaturated omega-9 fatty acid, denoted 22:1 ω-9. It has the formula CH37CH=CH11COOH. It is prevalent in rapeseed, wallflower seed, and mustard seed, making up 40-50% of their oils...
and Glyceryl Trioleate (Lorenzo's Oil) in asymptomatic patients. - Hematopoietic stem cell transplantation
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.
Experimental Therapies
In November 2009, ScienceScience (journal)
Science is the academic journal of the American Association for the Advancement of Science and is one of the world's top scientific journals....
published a report on a pilot study of two patients receiving gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
combined with blood-stem-cell therapy, and stating that the combination "may be a useful tool for treating" X-linked ALD.
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
Granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 ....
. CD34+ cells (i.e. expressing the CD34
CD34
CD34 molecule is a cluster of differentiation molecule present on certain cells within the human body. It is a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of stem cells to bone marrow extracellular matrix or directly to stromal cells...
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
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
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.
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 therapyGene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
is currently under investigation.
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 OdoneAugusto and Michaela Odone
Augusto Daniel Odone and Michaela Teresa Murphy Odone are the parents of Lorenzo Odone , a child afflicted with the illness adrenoleukodystrophy...
, frustrated by the limited treatment available, sparked the invention of "Lorenzo's oil
Lorenzo's oil
Lorenzo's oil is a 4:1 mixture of glycerol trioleate and glycerol trierucate , prepared from olive oil and rapeseed 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
Phil Collins
Philip David Charles "Phil" Collins, LVO is an English singer-songwriter, drummer, pianist and actor best known as a drummer and vocalist for British progressive rock group Genesis and as a solo artist....
song "Lorenzo" (on his 1996 album Dance Into The Light).
External links
- GeneReviews/NCBI/NIH/UW entry on Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum
- OMIM entries on Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum
- European Leukodystrophy Foundation
- March of Dimes Foundation
- United Leukodystrophy Foundation
- Images of ALD at USUHSUniformed Services University of the Health SciencesThe Uniformed Services University of the Health Sciences is a health science university run by the U.S. federal government. The primary mission of the school is to prepare graduates for service to the U.S. at home and abroad in the medical corps....
- Adrenoleukodystrophy at National Center for Biotechnology InformationNational Center for Biotechnology InformationThe National Center for Biotechnology Information is part of the United States National Library of Medicine , a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper...
- Information from ALDlife.org