Adrenoleukodystrophy (ALD). SYNONYMS. DIFFERENT FORMS. NATURE OF ALD. GENE LOCATION. SYMPTOMS. Maryann Reis. Synonyms for ALD. Flatau-Schilder’s Disease Melanodermic Leukodystophy Myelinoclastic Diffuse Sclerosis Schilder Disease Schilder Encephalitis Slewering-Creutzfeldt Disease
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NATURE OF ALD
Synonyms for ALD
Nature of ALD
People with ALD accumulate high levels of saturated, very long chain fatty acids in their brain and adrenal cortex because the fatty acids are not broken down by an enzyme in the normal manner.
Adrenoleukodystrophy (ALD) is a rare, genetic disorder characterized by the breakdown or loss of the myelin sheath surrounding nerve cells in the brain and progressive disfunction of the adrenal gland.
The name adrenoleukodystrophy was introduced by Michael Blaw in 1970, and is defined as a serious progressive, genetic disorder, which affects the adrenal glands and the white matter of the nervous system. It was first recognized in 1923 and has been known as Schilder's disease and sudanophilic leukodystrophy. Blaw coined the name adrenoleukodystrophy; adreno refers to the adrenal glands; leuko refers to the white matter of the brain, and dystrophy means imperfect growth or development.
The first report of a patient with X-chromosomal linked adrenoleukodystrophy (X-ALD) was published in the medical literature in 1923.
Symptoms of ALD
Different Forms of X-linked ALD
X-ALD is found in about 1 in 21.000 new born males and approximately 1 in 14.000 new born females are carrier for this disease.
The overall frequency for X-ALD is about 1 in 17.000 life births.
-ALD is an X-linked disorder, which means it affects only males and is transmitted by a female carrier. Such disorders are referred to as "X-linked" since the genetic abnormality involves the X-chromosome.
X-ALD is a peroxisomal storage disease whereby abnormal function of peroxisomes leads to the accumulation of very long-chain fatty acids (VLCFA) in tissues of the body, especially the brain and the adrenal glands.
This gene is located on the X-chromosome (it’s official name is the ABCD1 gene).
GTG GAG CTG GCC CTG CTA CAG CGC TCC TAC CAG GAC (901)
V E L A L L Q R S Y Q D 312
CTG GCC TCG CAG ATC AAC CTC ATC CTT CTG GAA CGC CTG
L A S Q I N L I L L E R L 325
TGG TAT GTT ATG CTG GAG CAG TTC CTC ATG AAG TAT GTG
W Y V M L E Q F L M K Y V 338
TGG AGC GCC TCG GGC CTG CTC ATG GTG GCT GTC CCC ATC
W S A S G L L M V A V P I 351
ATC ACT GCC ACT GGC TAC TCA GAG TCA G(1081)
I T A T G Y S E S D 361
Mutations/Variations in the Gene
Allelic variants are given a 10 digit number: the 6-digit number of the parent locus followed by a decimal point and a unique 4-digit variant number.
Note that for most gene loci, only selected mutations are included as specific subentries. Criteria for inclusion include the first mutation to be discovered, high population frequency, distinctive phenotype, historic significance, unusual mechanism of mutation, unusual pathogenetic mechanism, and distinctive inheritance (e.g., dominant with some mutations, recessive with other mutations in the same gene).
Most of the allelic variants represent disease-producing mutations. A few polymorphisms are included, many of which show a positive statistical correlation with particular common disorders.
Oligodendrocytes (red), the myelin-producing cells of the brain, shown here in tissue culture in association with astrocytes (green).
Total number of mutations
Nucleotide substitutions (missense / nonsense)
Nucleotide substitutions (regulatory)
Nucleotide substitutions (splicing)
Gross insertions & duplications
Complex rearrangements (including inversions)
15 of the 25 Mutations
There are currently two different techniques for getting disease-free stem cells into an ALD patient: a bone marrow transplant (BMT) or an umbilical cord blood transplant (UCBT). Both bone marrow and umbilical cord blood are rich in stem cells. By transplanting healthy donor stem cells into an ALD patient, ALD progression may be halted and in some cases reversed. There are many similarities between bone marrow transplants and umbilical cord blood transplants. The goal of both types of transplants is to get healthy stem cells which produce a functioning ALD protein which is lacking in an ALD patient.
Other treatment includes:
The picture above shows the makeup of oleic and erucic acids and how they combine to make "Lorenzo's Oil."
There are two distinct advantages to gene therapy within the context of treating ALD.
1. The chemotherapy and/or radiation that is required to allow the donor cells to engraft, or become accepted by the host would no longer be such a dangerous issue. The cells that are transplanted into the patient after gene correction are autologous, in other words, they come from the patient himself. Therefore, all issues related to the discordance between host and donor tissues, and the subsequent medical complications that ensue, would be significantly lessened.
2. Many ALD individuals are not eligible for a BMT or UCBT due to lack of a suitable donor. Due to the autologous nature of the treatment, each person serves as his own donor and recipient. Matching donors and recipients will no longer be an issue.
The goal of successful gene therapy would yield the positive results of BMT with significantly decreased morbidity and mortality. In addition, no patient would be turned away due to lack of a match. In summary, a safer treatment that could be offered to a much larger group of patients.
Other Projected Ideas
Other Possible Therapies: 4 Phenylbuterate – A Case in Point
4 Phenylbuterate is a drug that is currently used for a variety of disorders, and has shown some promise as far as treating ALD. Dr. Hugo Moser is currently proposing a clinical trial. However, because he must apply for funding in the form of a grant, which must be submitted, reviewed, etc., these trials will not take place in the immediate future. If Dr. Moser had ready access to funding, he need only apply for an IRB, a minor task, and the trial could proceed. Thus it is important for The Stop ALD Foundation to have an infrastructure in place that can properly and efficiently evaluate these types of proposals, take the necessary action, and provide the necessary resources -- whatever they may be.
National Institution of Neurological Disorder and stroke (NINDS) supports research on genetic disorders. The aim of this research is to find ways to prevent, treat, and cure diseases.
Much research is being done in different areas. People are working on ways of remyelinating nerves (The Myelin Project, founded by Augusto and the late Michaela Odone (the parents of Lorenzo Odone, for whom Lorenzo's Oil is named)). As well, research is being conducted into various gene therapies, but those are years away from humantrials.
More recently, all the transporters related to ALD protein have been found in the yeast Saccharomyces cerevisiae, and a mouse model for the human disease has been developed. These and other molecular biology approaches should further our understanding of ALD and hasten our progress towards effective therapies.