CD-ROM Today 1996 January/CD-ROM Today 1996 January.iso/dp/0343/03430.txt

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$Unique_ID{BRK03430}
$Pretitle{}
$Title{Adrenoleukodystrophy}
$Subject{Adrenoleukodystrophy ALD Addison-Schilder Disease Addison Disease
with Cerebral Sclerosis Adrenomyeloneuropathy AMN Bronze Schilder's Disease
Encephalitis Periaxialis Diffusa Flatau-Schilder Disease Melanodermic
Leukodystrophy Myelinoclastic Diffuse Sclerosis Schilder Disease Schilder
Encephalitis Siewerling-Creutzfeldt Disease Sudanophilic Leukodystrophy Adult
Onset ALD Adrenomyeloneuropathy Childhood Adrenoleukodystrophy Neonatal
Adrenoleukodystrophy Addison Disease Leukodystrophy, Canavan Leukodystrophy,
Metachromatic Zellweger Syndrome}
$Volume{}
$Log{}

Copyright (C) 1985, 1986, 1988, 1989, 1990, 1993 National Organization
for Rare Disorders, Inc.

43:
Adrenoleukodystrophy

** IMPORTANT **
It is possible that the main title of the article (Adrenoleukodystrophy)
is not the name you expected.  Please check the SYNONYMS listing to find the
alternate name and disorder subdivisions covered by this article.

Synonyms

     ALD
     Addison-Schilder Disease
     Addison Disease with Cerebral Sclerosis
     Adrenomyeloneuropathy
     AMN
     Bronze Schilder's Disease
     Encephalitis Periaxialis Diffusa
     Flatau-Schilder Disease
     Melanodermic Leukodystrophy
     Myelinoclastic Diffuse Sclerosis
     Schilder Disease
     Schilder Encephalitis
     Siewerling-Creutzfeldt Disease
     Sudanophilic Leukodystrophy

DISORDER SUBDIVISIONS

     Adult Onset ALD also known as Adrenomyeloneuropathy
     Childhood Adrenoleukodystrophy
     Neonatal Adrenoleukodystrophy

Information on the following diseases can be found in the Related
Disorders section of this report:

     Addison Disease
     Leukodystrophy, Canavan
     Leukodystrophy, Metachromatic
     Zellweger Syndrome

General Discussion

** REMINDER **
The Information contained in the Rare Disease Database is provided for
educational purposes only.  It should not be used for diagnostic or treatment
purposes.  If you wish to obtain more information about this disorder, please
contact your personal physician and/or the agencies listed in the "Resources"
section of this report.


Adrenoleukodystrophy is a rare inherited metabolic disorder characterized
by the loss of the fatty covering (myelin sheath) on nerve fibers within the
brain (cerebral demyelination) and the progressive degeneration of the
adrenal gland (adrenal atrophy).  Adrenoleukodystrophy that is inherited as
an X-linked genetic trait may begin in childhood or adulthood.  However,
Adrenoleukodystrophy that is inherited as an autosomal recessive genetic
trait typically begins during infancy (neonatal period).

Symptoms

Adrenoleukodystrophy is a rare inherited disorder characterized by greatly
increased levels of very long chain fatty acids (VLCFA) in the blood plasma
and tissues of the body.  These fatty acids accumulate in the brain (cerebral
white matter) and the adrenal glands.

A very small percentage of people with elevated VLCFA levels may have
mild symptoms or no symptoms of Adrenoleukodystrophy.  In other people the
disorder may progress very slowly.

Women who have the gene for Childhood or Adult-onset
Adrenoleukodystrophy, but have no symptoms during childhood, may have
elevated levels of VLCFA.  In these women, the symptoms of
Adrenoleukodystrophy may begin around the age of 30 years.  These symptoms
may include:  progressive spastic partial paralysis (paraparesis); an
impaired ability to coordinate muscle movement (ataxia); muscular rigidity
(hypertonia); tingling or burning sensations in the arms and/or legs (mild
peripheral neuropathy); abnormal reflexes of the foot and toes (plantar
extensors); and/or urinary problems.   There are typically no symptoms
associated with adrenal gland malfunction in these women.  Mental and sensory
functions are generally not impaired.  (For more information about these
symptoms, choose "Ataxia" and "Peripheral Neuropathy" as your search terms in
the Rare Disease Database.)

The most common form of Adrenoleukodystrophy is the childhood form that
affects only males.  Females may be carriers of the Childhood
Adrenoleukodystrophy gene but are usually without symptoms.  Symptoms often
first appear in boys between the ages of 4 and 8 years and may include:
behavioral changes such as poor memory; increasingly poor school work; loss
of emotional control; and/or dementia.  Other symptoms may include:  a jerky
uncoordinated walk (ataxia); exaggerated reflex responses (hyperreflexia);
muscle weakness on one side of the body (hemiparesis); difficulties with
speech; hearing loss; and/or visual problems.  A decrease in visual
perception and the inability to recognize familiar objects or surroundings
may also occur in children with Adrenoleukodystrophy (visual agnosia).

The symptoms of decreased adrenal gland function associated with
Adrenoleukodystrophy usually appear after the neurological symptoms of the
disorder.  Adrenocortical (outer layers of the adrenal gland) symptoms may
include:  low blood pressure (hypotension); generalized weakness; fatigue;
excessive loss of water from body tissues (dehydration); weight loss; an
abnormally small heart (microcardia); an increase of color (pigmentation) in
the skin; and/or a decrease in the secretion of adrenal hormones in response
to adrenocorticotropic hormone (ACTH) that is produced in the pituitary
gland.

More advanced neurologic symptoms of Adrenoleukodystrophy may include a
progressive degeneration of the nerves of the eyes (optic atrophy) and loss
of the fatty covering that surrounds nerve fibers in the brain
(demyelination).  Magnetic resonance imaging (MRI) may show lesions of the
white matter of the lower and middle back portions of the brain (posterior
occipital and parietal lobe).  In the adrenal cortex, abnormally enlarged
cells can be found in the inner and the thick middle layers.

Adolescent or Adult-Onset Adrenoleukodystrophy, also called
Adrenomyeloneuropathy, affects the spinal cord.  This form of the disorder
affects only males although females may be carriers of the gene.  Symptoms
usually begin between the ages of 21 and 35 years and may include progressive
leg stiffness, partial spastic paralysis (paraparesis) of the legs and/or an
impaired ability to coordinate muscle movement (ataxia).  Sensory changes
suggest that spinal cord nerve fibers and peripheral nerves have become
damaged.  Peripheral nerves comprise those nerves not in the spinal cord or
brain.  There may also be a decrease in the function of the adrenal cortex
and/or testes.  If neurological symptoms are absent, Adrenoleukodystrophy
should be suspected in males who have decreased adrenal function with a
family history of Addison's disease.  Adult-Onset Adrenoleukodystrophy
typically progresses more slowly than the childhood form of the disorder.
However, it can ultimately result in deterioration of brain function.  (For
more information, choose "Addison" and "Ataxia" as your search term in the
Rare Disease Database.)

Neonatal Adrenoleukodystrophy is inherited as an autosomal recessive
genetic trait.  Both males and females are affected by this form of the
disorder.  The abnormalities of the brain and adrenal glands caused by
Neonatal Adrenoleukodystrophy appear to be different from those caused by
other types of Adrenoleukodystrophies.  This can be demonstrated with
microscopic tissue examination (pathological testing).  The first symptoms of
Neonatal Adrenoleukodystrophy begin when the child is born or shortly after.
These symptoms may include:  mental retardation; facial abnormalities;
seizures; multiple developmental abnormalities of the brain (polymicrogyria);
degeneration of the retina of the eyes; generalized muscle weakness
(hypotonia); an enlarged liver (hepatomegaly); and/or abnormally low levels
of adrenal hormones (adrenal insufficiency).

In Neonatal Adrenoleukodystrophy there is destruction of the covering of
the nerve cells in the white matter of the brain.  There may also be nerve
demyelination in the gray matter deep within the spinal cord.  Specialized
microscopic bodies that participate in metabolism of fats in the liver
(hepatic perxisomes) may be absent or decreased in number.  The concentration
of pipecolic acid in the blood may be increased.  Neonatal
Adrenoleukodystrophy tends to progress rapidly.  People who have only one of
the pair of characteristic genes for Neonatal Adrenoleukodystrophy typically
have no neurological or adrenal symptoms.

Causes

Adrenoleukodystrophy may be inherited as an X-linked or autosomal recessive
genetic trait.

Human traits, including the classic genetic diseases, are the product of
the interaction of two genes, one received from the father and one from the
mother.

X-linked recessive disorders are conditions which are coded on the X
chromosome.  Females have two X chromosomes, but males have one X chromosome
and one Y chromosome.  Therefore, in females, disease traits on the X
chromosome can be masked by the normal gene on the other X chromosome.  Since
males only have one X chromosome, if they inherit a gene for a disease
present on the X, it will be expressed.  Men with X-linked disorders transmit
the gene to all their daughters, who are carriers, but never to their sons.
Women who are carriers of an X-linked disorder have a fifty percent risk of
transmitting the carrier condition to their daughters, and a fifty percent
risk of transmitting the disease to their sons.

In recessive disorders, the condition does not appear unless a person
inherits the same defective gene for the same trait from each parent.  If one
receives one normal gene and one gene for the disease, the person will be a
carrier for the disease, but usually will not show symptoms.  The risk of
transmitting the disease to the children of a couple, both of whom are
carriers for a recessive disorder, is twenty-five percent.  Fifty percent of
their children will be carriers, but healthy as described above.  Twenty-five
percent of their children will receive both normal genes, one from each
parent, and will be genetically normal.

The symptoms of Adrenoleukodystrophy may develop due to abnormal or
absent peroxisomes (microbodies that participate in the metabolism of fats)
in the liver.  This causes a disturbance of fatty acid metabolism and results
in the abnormal accumulation of very long chain fatty acids (VLCFAs).  The
excess amounts of saturated and unsaturated fatty acids are distributed
throughout the tissues of the entire body, but tend to accumulate more in the
white matter of the brain and in the adrenal cortex.  The exact enzyme
deficiency that prevents the breakdown of VLCFAs in Adrenoleukodystrophy is
not known.

Affected Population

All forms of Adrenoleukodystrophy are rare in the United States.  Childhood
Adrenoleukodystrophy usually begins before age 10 (generally around age 7
years) and affects only males.  Females may be carriers of Childhood
Adrenoleukodystrophy but generally have no symptoms of this disorder.

The onset of Adult Adrenoleukodystrophy is usually between the ages of 21
and 35 years.  This form of the disorder also affects males only.  Female
heterozygotes for Adrenoleukodystrophy rarely experience symptoms.  If
symptoms do occur in these females, it is typically after the age of 30
years.

The symptoms of Neonatal Adrenoleukodystrophy begin in the newborn child.
This form of the disorder affects males and females in equal numbers.

Related Disorders

Symptoms of the following disorders can be similar to those of
Adrenoleukodystrophy.  Comparisons may be useful for a differential
diagnosis:

Addison's Disease is a rare disorder of the adrenal glands.  In the
majority of cases the cause is not known.  Symptoms may result from chronic
and progressive low level function (hypofunction) of the outer layers
(cortex) of the adrenal gland resulting in deficiencies of the hormones
cortisol and aldosterone.  The deficiency of these hormones leads to low
levels of sodium and chloride and high levels of potassium (electrolyte
imbalance) in the blood.  The imbalance of electrolytes causes increased
water excretion, low blood pressure (hypotension), and abnormally low levels
of water in the body (dehydration).  The major symptoms of Addison's Disease
may include fatigue, weakness, loss of appetite (anorexia), frequent
urination, gastrointestinal discomfort, and changes in skin pigmentation.
The symptoms of Addison's Disease often affect people with
Adrenoleukodystrophy.  (For more information on this disorder, choose
"Addison" as your search term in the Rare Disease Database).

Canavan's Leukodystrophy is another type of Leukodystrophy that affects
the central nervous system.  A chemical imbalance in the brain causes the
progressive degeneration of nerves within the brain and spinal cord.  This
results in progressive mental deterioration accompanied by increased muscle
tone (hypertonia), poor head control, an enlargement of the brain
(megalocephaly), and blindness.  Symptoms typically begin in infancy.  Early
symptoms of Canavan's Leukodystrophy may include general lack of interest in
daily living (apathy), muscle weakness and floppiness (hypotonia), and the
loss of previously acquired mental and motor skills.  As the disease
progresses, there may be spastic muscle contractions of the arms and legs and
a lack of muscle strength in the neck.  The brain may swell (megalocephaly)
resulting in the failure of the bones in the skull to fuse normally and
paralysis may occur.  The infant may be more susceptible to respiratory tract
infections due to the progressive loss of muscle strength in the chest.  (For
more information on this disorder, choose "Canavan's Leukodystrophy" as your
search term in the Rare Disease Database).

Metachromatic Leukodystrophy (MLD) is a rare inherited form of
Leukodystrophy in which fat-like substances known as sulfatides accumulate in
the tissues of the nervous system and other organs.  This disorder is
characterized by the loss of the covering on nerve fibers (myelin sheath).
This may result in blindness, convulsions, muscle rigidity (hypertonia)
and/or motor disturbances that may lead to paralysis and dementia.  There is
an infantile, juvenile and adult form of Metachromatic Leukodystrophy.
Infantile Metachromatic Leukodystrophy is generally detected in the 2nd year
of life, typically before 30 months of age.  The juvenile form of this
disorder has an onset between the ages of 4 and 10 years.  Adult
Metachromatic Leukodystrophy usually begins after 16 years of age.  (For more
information on this disorder, choose "Leukodystrophy, Metachromatic" as your
search term in the Rare Disease Database).

Zellweger Syndrome is a rare hereditary disorder characterized by
decreased or missing peroxisomes (microbodies that participate in the
metabolism of fats) in the liver, kidney and brain.   The major symptoms may
include:  abnormalities of the face, eyes and nervous system; enlargement of
the liver (hepatomegaly); and/or unusual problems in development before
birth.  Newborns with Zellweger Syndrome have a typical flat face with a high
forehead, widely spread eyes (hypertelorism), and a small fold of skin over
the inner corner of both eyes (epicanthal folds).  Other symptoms may
include:  profound muscle weakness (hypotonia);  feeding difficulties;
seizures; cardiac defects; enlargement of the liver (hepatomegaly);  and/or
vision abnormalities such as cataracts.  (For more information on this
disorder, choose "Zellweger" as your search term in the Rare Disease
Database.)

Therapies:  Standard

Computerized tomography (CT scan) and/or magnetic resonance imaging (MRI)
will show changes in the brain of people with Adrenoleukodystrophy.
Laboratory tests that check for the presence of very long chain fatty acids
(VLCFAs) offer the most important diagnostic procedure for this disorder.
Female carriers and newborn infants at high risk for Adrenoleukodystrophy may
be detected by measuring the level of very long chain fatty acids in their
blood.  Another test measures the level of VLCFAs in connective tissues cells
that have been removed from the patient and grown in the laboratory
(fibroblast cultures).

Adrenoleukodystrophy may be diagnosed in the developing fetus before
birth.  A small amount of fluid that surrounds the fetus in the uterus is
removed (amniocentesis) by a physician and then the aminocytes (cellular
portion of the fluid) are grown and studied in the laboratory for the level
of VLCFAs.  Diagnosis of Adrenoleukodystrophy may also be made by removing a
tissue sample from the placenta (chorion villus).  These cells are grown in
the laboratory and examined for abnormally high levels of VLCFAs.

Adrenal steroids are given to treat the symptoms of Adrenoleukodystrophy
that are caused by adrenocortical (generally the same drugs prescribed for
Addison's Disease).  Treatment for neurological symptoms associated with
Adrenoleukodystrophy is symptomatic and supportive.  Seizures usually respond
well to anticonvulsants.  The severe discomfort of muscle spasticity has been
managed with some success with the drug baclofen.

The coordination of services such as physical therapy, psychological
support and visiting nurse services are often required to help the patient
and the family cope with the effects of Childhood Adrenoleukodystrophy.

Genetic counseling for families of people with Adrenoleukodystrophy is
suggested.

Therapies:  Investigational

The gene that causes ALD has been located and scientists may be able to
determine the exact cause of the symptoms which will hopefully lead to
development of new treatments for this disease.

Hugo W. Moser, M.D., at the Kennedy Institute in Baltimore, MD, has been
treating Adrenoleukodystrophy experimentally with Glycerol Trioleate combined
with dietary VLCFA restriction.  Dr. Moser is also studying Lorenzo's oil
(erucic acid) together with triolein oil as a possible treatment for patients
with rapidly progressive Childhood Adrenoleukodystrophy.  More research is
needed to determine the long-term safety and effectiveness of these
substances.  For more information about these experimental treatments,
physicians can contact:

     Hugo W. Moser, M.D.
     Kennedy Institute
     707 North Broadway
     Baltimore, MD 21205
     [phone]

Bone marrow transplantation is being tested as a treatment for Childhood
Adrenoleukodystrophy.  Bone marrow transplantation is not recommended for
patients with relatively advanced neurological symptoms.  More research is
necessary to determine safety and effectiveness of this procedure.

This disease entry is based upon medical information available through
March 1993.  Since NORD's resources are limited, it is not possible to keep
every entry in the Rare Disease Database completely current and accurate.
Please check with the agencies listed in the Resources section for the most
current information about this disorder.

Resources

For more information on Adrenoleukodystrophy, please contact:

     National Organization for Rare Disorders (NORD)
     P.O. Box 8923
     New Fairfield, CT  06812-1783
     [phone]

     The National Adrenal Diseases Foundation, Inc.
     505 Northern Blvd., Suite 200
     Great Neck, NY  11021
     [phone]

     United Leukodystrophy Foundation
     2304 Highland Drive
     Sycamore, IL 60178
     [phone]
     [phone]

     ALD Project
     Dr. Hugo W. Moser
     John F. Kennedy Institute
     707 North Broadway
     Baltimore, MD  21205
     [phone]

     NIH/National Institute of Neurological Disorders & Stroke (NINDS)
     9000 Rockville Pike
     Bethesda, MD  20892
     [phone]
     [phone]

     Association Europeenne contre les Leucodystrophies
     7 Rue Pasteur
     54000 NANCY
     France

     Research Trust for Metabolic Diseases in Children
     Golden Gates Lodge, Weston Road
     Crewe CW1 1XN, England
     Telephone: [phone]

For Genetic Information and Genetic Counseling Referrals:

     March of Dimes Birth Defects Foundation
     1275 Mamaroneck Avenue
     White Plains, NY 10605
     [phone]

     Alliance of Genetic Support Groups
     35 Wisconsin Circle, Suite 440
     Chevy Chase, MD  20815
     (800) 336-GENE
     [phone]

References

MENDELIAN INHERITANCE IN MAN, 10th Ed.:  Victor A. McKusick, Editor:  Johns
Hopkins University Press, 1992.  Pp. 1199, 1769-1772.

THE METABOLIC BASIS OF INHERITED DISEASE, 6th Ed.:  Charles R. Scriver, et
al., Editors; McGraw Hill, 1989.  Pp. 1494-1527.

BIRTH DEFECTS ENCYCLOPEDIA, Mary Louise Buyse, M.D., Editor-In-Chief;
Blackwell Scientific Publications, 1990.  Pp. 61-62.

PRINCIPLES OF NEUROLOGY, 4th Ed.; Raymond D. Adams, M.D. and Maurice
Victor, M.D., Editors; McGraw-Hill Information Services Company, 1989.  Pp.
811-812.

ADRENOLEUKODYSTROPHY:  EXTRACTS FROM "ADRENOLEUKODYSTROPHY IN CHILDREN
AND ADULTS - DIAGNOSIS AND GENETIC COUNSELLING":  Hugo W. Moser;  Newsletter
of Research Trust for Metabolic Diseases in Children (1986).  Pp. 5-7.

ADRENOLEUKODYSTROPHY:  SURVEY OF 303 CASES:  BIOCHEMISTRY, DIAGNOSIS, AND
THERAPY:  Hugo W. Moser, et. al.;  Annals of Neurology (December 1984:  issue
16,6).  Pp. 628-641.

PERIOXISOMAL DISORDERS.  Hugo W. Moser; Biochem Cell Biol (July 1991;
issue 69(7)).  Pp. 463-474.

CLINICAL ASPECTS OF ADRENOLEUKODYSTROPHY AND ADRENOMYELONEUROPATHY.  Hugo
W. Moser; Dev Neurosci (1991; issue 13(4-5)).  Pp. 254-261.