SYNONYMS

NATURE
OF ALD
DIFFERENT
FORMS
SYMPTOMS
GENE
LOCATION
AMN
Addison Disease with Cerebral
Sclerosis
Addison-Schilder Disease
Adrenomyeloneuropathy
Adult Onset ALD
Bronze Schilders Disease
Encephalitis Periaxilais Diffusa
Flatau-Schilders Disease
Melanodermic Leukodystophy
Myelinoclastic Diffuse
Sclerosis
Schilder Disease
Schilder Encephalitis
Slewering-Creutzfeldt Disease
Sudanophilic
Leukodystrophy,ADL
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.

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.

The first report of a
patient with X-
chromosomal linked
adrenoleukodystrop
hy (X-ALD) was
published in the
medical literature in
1923.

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.

There are several forms of ALD. Onset of the classic childhood form, which
is the most severe and affects only boys, may occur between ages 4 and 10.
Features of this form may include visual loss, learning disabilities, seizures,
dysarthria (poorly articulated speech), dysphagia (difficulty swallowing),
deafness, disturbances of gait and coordination, fatigue, intermittent vomiting,
melanoderma (increased skin pigmentation), and progressive dementia.

The most common symptoms are usually
behavioral changes such as abnormal
withdrawal or aggression, poor memory, and
poor school performance. In the milder adult-
onset form, which typically begins between
ages 21 and 35, symptoms may include leg
stiffness, progressive spastic paraparesis
(stiffness, weakness and/or paralysis) of the
lower extremities, and ataxia. Although adult-
onset ALD progresses more slowly than the
classic childhood form, it can also result in
deterioration of brain function.

Another form of ALD is occasionally seen in
women who are carriers of the disorder.
Symptoms are mild and may include spastic
paraparesis of the lower limbs, ataxia,
hypertonia (excessive muscle tone), mild
peripheral neuropathy, and urinary problems.
Neonatal ALD affects both male and female
newborns. Symptoms may include mental
retardation, facial abnormalities, seizures, retinal
degeneration, hypotonia (low muscle tone),
heptomegaly (enlarged liver), and adrenal
dysfunction. This form is usually quickly
progressive.

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.

asymptomatic
mild myelopathy
moderate to severe
myeloneuropathy
cerebral involvement
clinically evident
adrenocortical insufficiency

asymptomatic or
presymptomatic
childhood cerebral ALD
adolescent cerebral ALD
adult cerebral ALD
adrenomyeloneuropathy
Addison-only phenotype


-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 (its official name is
the ABCD1 gene).

Chromosome Xq28; Recessive

GENE SEQUENCE
MUTATIONS
exon 2
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
ALLELIC VARIANTS
Selected examples
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).

Mutation type
Total number of
mutations
Nucleotide substitutions (missense / nonsense)

151
Nucleotide substitutions (splicing)

12
Nucleotide substitutions (regulatory)
0
Small deletions

38
Small insertions

14
Small indels

4
Gross deletions

12
Gross insertions & duplications
0
Complex rearrangements (including inversions)

1
Repeat variations
0
TOTAL
232
0001:ADRENOLEUKODYSTROPHY
Mutation : ABCD1, GLU291LYS
0002 : ADRENOLEUKODYSTROPHY
Mutation : ABCD1, PRO484ARG
0003 : ADRENOLEUKODYSTROPHY
Mutation : ABCD1, IVS6AS, A-G, -2,
FS546TER
0004 : ADRENOLEUKODYSTROPHY
Mutation : ABCD1, IVS8AS, G-A, -10, 8-
BP INS, FS638TER
0005 : ADRENOMYELONEUROPATHY
Mutation : ABCD1, ARG389GLY
0006 : ADRENOLEUKODYSTROPHY
Mutation : ABCD1, ASN148SER
0011 :
ADRENOMYELONEUROPATHY
Mutation : ABCD1, ARG464TER
0012 :
ADRENOLEUKODYSTROPHY
Mutation : ABCD1, 2-BP DEL, FS,
TER
0013 :
ADRENOLEUKODYSTROPHY
Mutation : ABCD1, GLU477TER
0014 :
ADRENOLEUKODYSTROPHY
Mutation : ABCD1, SER515PHE
0015 :
ADRENOLEUKODYSTROPHY
Mutation : ABCD1, 1-BP DEL,
1937C, FS557TER
0007 :
ADRENOLEUKODYSTROPHY
Mutation : ABCD1, TYR174ASP
0008 :
ADRENOLEUKODYSTROPHY
Mutation : ABCD1, GLY266ARG
0009 :
ADRENOLEUKODYSTROPHY
Mutation : ABCD1, ARG401GLN
0010 :
ADRENOLEUKODYSTROPHY
Mutation : ABCD1, ARG418TRP

Proteins
(According to SWISS-PROT and/or MIPS)
ALD_HUMAN
Size: 745 amino acids; 82908 Da
Function: PROBABLE TRANSPORTER. THE
NUCLEOTIDE-BINDING FOLD ACTS AS AN ATP-
BINDING SUBUNIT WITH
ATPASE ACTIVITY.

Subunit: CAN FORM HOMO- AND HETERODIMERS
WITH ABCD2/ALDR AND ABCD3/PMP70.
DIMERIZATION IS NECESSARY
TO FORM AN ACTIVE TRANSPORTER.

Subcellular location: Integral membrane protein.
Peroxisomal.

Similarity: BELONGS TO THE ABC TRANSPORTER
FAMILY. ALD SUBFAMILY.

MIPS Pedant Viewer: 34833

REFSEQ proteins: NP_000024.2
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.

Physical therapy
Psychological support
Special education
The picture above shows the
makeup of oleic and erucic
acids and how they combine
to make "Lorenzo's Oil."
Other treatment includes:
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.

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.

Other Possible Therapies: 4 Phenylbuterate A Case in Point

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 human trials.
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.