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$Unique_ID{BRK03935}
$Pretitle{}
$Title{Leukodystrophy}
$Subject{Leukodystrophy Refsum's Disease Cerebrotendinous Xanthomatosis
Metachromatic Leukodystrophy Globoid Leukodystrophy (Krabbe's Disease)
Adrenoleukodystrophy Sudanophilic Leukodystrophy (Schilder's Disease
Pelizaeus-Merzbacher Brain Sclerosis Canavan's Disease Alexanders Disease
Multiple Sclerosis Gaucher's Disease Tay-Sachs Disease}
$Volume{}
$Log{}

Copyright (C) 1989 National Organization for Rare Disorders, Inc.

676:
Leukodystrophy

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

Synonyms

Disorder Subdivisions:

     Refsum's Disease
     Cerebrotendinous Xanthomatosis
     Metachromatic Leukodystrophy
     Globoid Leukodystrophy (Krabbe's Disease)
     Adrenoleukodystrophy
     Sudanophilic Leukodystrophy (Schilder's Disease
     Pelizaeus-Merzbacher Brain Sclerosis
     Canavan's Disease
     Alexanders Disease

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

     Multiple Sclerosis
     Gaucher's Disease
     Tay-Sachs Disease

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.

Leukodystrophy is the name given to a group of very rare, progressive,
metabolic, genetic diseases that affect the brain, spinal cord and often the
peripheral nerves.  Each of the leukodystrophies will affect one of the
chemicals that make up the myelin sheath or white matter of the brain,
causing the various types of leukodystrophy.  The myelin sheath, which acts
as insulation of the nervous system, is composed of different lipids (fatty
substances).  Thus defects in production and degradation of these lipids can
lead to the many ways in which these diseases can manifest themselves.

Symptoms

Leukodystrophy affects the white matter of the brain or insulation (myelin
sheath) of the nervous system made up of the brain, the spinal cord and
nerves.  The symptoms of the disease tend to get worse as the patient gets
older.  Most of the leukodystrophies are present at birth though some may
appear more slowly over time.  The particular chemical defect determines the
type of leukodystrophy a person will have.

The myelin sheath is made up of a number of fatty substances or lipids
that protect and insulate it.  When this protection is defective the brain,
spinal cord and nerves can be seriously impaired.  Leukodystrophy causes the
patient to have problems with movement, vision, hearing, feeling and
thinking.

Infants or children who initially appear healthy will begin to change as
they mature.  Parents will notice the child's mental abilities are
deteriorating, or the way the child walks has changed, or the child's vision
is poor.  There can also be muscle stiffness or floppiness, paralysis or
convulsions.  These symptoms may occur slowly or they can happen quickly
according to the type of leukodystrophy affecting the child.

DISORDER SUBDIVISIONS:

Refsum Syndrome is a type of leukodystrophy inherited as a recessive
trait.  Symptoms may include a degenerative nerve disease, peripheral
neuropathy, impaired muscle coordination, walking difficulties (ataxia), a
progressive vision disorder (retinitis pigmentosa), and bone and skin
changes.  This disorder is believed to be due to the absence of phytanic acid
hydroxylase in the blood, an enzyme needed for the metabolism of phytanic
acid which is found in dairy products, beef, lamb and some seafoods.  It is
characterized by the accumulation of phytanic acid in the plasma and tissues.
(For more information on this disorder please choose "Refsum" as you search
term in the Rare Disease Database).

Cerebrotendinous Xanthomatosis is a type of Leukodystrophy which is
related to the chemical cholestanol in the myelin sheath.  It is inherited as
an autosomal recessive trait.  Cerebrotendinous Xanthomatosis is
characterized by deposits of lipid granulomatosis especially in the brain and
other tissues.  The plasma shows high cholesterol levels but the cholesterol
level in the blood is normal.  Progressive cerebellar ataxia, (usually
beginning after puberty), juvenile cataracts, and spinal cord involvement are
symptoms of the disorder.  It is possible to detect persons who are carriers
of this disorder, as well as a prenatal diagnosis for pregnant women.

Metachromatic Leukodystrophy is inherited as an autosomal recessive
genetic trait.  It affects the brain and spinal cord.  The disease is
characterized by progressive paralysis and dementia.  It occurs in the
following forms:  Infantile, Juvenile, and Adult onset MLD, and a form of MLD
which is due to a deficiency of Cerebroside Sulfatase Activator.  MLD usually
begins gradually in a child or adult who previously appeared healthy.  Some
subtle change in the patient's thought processes, memory, behavior, or
walking pattern is noticeable.  Sometimes a disturbance in vision, or less
commonly in hearing, or numbness in parts of the body may be the first
symptoms.  (For more information on this disorder choose "Metachromatic" as
your search term in the Rare Disease Database).

Krabbe's Leukodystrophy is a rare genetic lipid storage disorder caused
by a deficiency of the enzyme galactoside beta-galactosidase (galactosyl-
ceramidase).  This causes the myelin sheath surrounding nerves in the brain
to degenerate (demyelination).  Characteristic globoid cells appear in
affected areas of the brain.  It is characterized by progressive neurological
dysfunction such as mental retardation, paralysis, blindness, deafness and
pseudobulbar palsy.  Symptoms of Krabbe's usually first occur between three
and five months of age.  A later-onset form occurs at eighteen months of age
or later.  (For more information on this disorder choose "Krabbe's" as your
search term in the Rare Disease Database).

Adrenoleukodystrophy (ALD) can be inherited in two ways:  x-linked or
autosomal recessive.  Both are characterized by destruction of the lipid
sheaths surrounding the nerves in the brain.  All types of ALD are
characterized by an accumulation of very long chain fatty acids, which is a
type of fat molecule that accumulates in the body's tissues, especially in
the adrenal gland and the white matter of the brain.  There are three
different types of Adrenoleukodystrophy, each distinguished by the time of
onset and by the features that are present.

Childhood ALD affects only males between the ages of four and eight
years.  There are behavioral changes, signs of decreased adrenal gland
function and neurological symptoms.

Adolescent or adult onset ALD affects only males and first appears around
the age of twenty one.  It includes progressive leg stiffness, paralysis of
the legs and gait abnormalities (ataxia).

Neonatal ALD begins at birth and affects both males and females.  It is
characterized by seizures, decreased muscle tone, mental retardation, vision
problems, enlargement of the liver and adrenal insufficiency.  It affects
both the white and grey matter of the brain.  (For more information on this
disorder choose "ALD" as your search term in the Rare Disease Database).

Schilder's Disease is an infantile form of leukodystrophy.  It is similar
to Neonatal ALD in that the chemical missing from the myelin sheath is also a
very long chain fatty acid.  It is inherited as an autosomal recessive
disease and affects males and females equally.

Pelizaeus-Merzbacher Brain Sclerosis usually appears in early infancy,
although there is also a type that occurs later in childhood.  The child
fails to develop normal head control and grows very slowly.  There is lack of
eye control and involuntary motor movements.  Later, there may be tremors,
grimacing, weakness, unsteady gait, and muscle contractures.  In cases of
later onset, speech deteriorates, arms and legs become spastic and mental
retardation occurs.  (For more information choose "Peliazeus" as your search
term in the Rare Disease Database).

Canavan's Leukodystrophy occurs in early infancy with the development of
microscopic fluid filled spaces in the white matter of the brain.  The first
symptoms are loss of muscle control.  Floppiness and weakness occur in the
muscles supporting the head.  There are feeding problems, mental retardation,
and apathy.  The head becomes enlarged as the brain swells, and the bones of
the skull do not fuse normally.  This very rare form of leukodystrophy most
frequently affects male and female infants of Eastern European Jewish
ancestry.  (For more information on this disorder choose "Canavan's" as your
search term in the Rare Disease Database).

Alexander's Disease is the rarest of the leukodystrophies.  The
destruction of the white matter in the brain is accompanied by the formation
of fibrous, deposits known as Rosenthal fibers.  Onset occurs in infancy,
affecting mostly males and resulting in mental and physical retardation.  As
in Canavan's Leukodystrophy there is progressive enlargement of the brain and
head, spasticity of the limbs, and in some cases seizures.  It is inherited
as an autosomal recessive genetic trait.  The exact myelin chemical which
causes the disorder is unknown.  (For more information choose "Alexander's"
as your search term in The Rare Disease Database).

Causes

Leukodystrophy is caused by a breakdown in the chemicals that make up the
myelin sheath in the nervous system or white matter in the brain.
Leukodystrophy in infants and children can occur because of either autosomal
recessive or X-linked genetic traits.

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.

In recessive disorders, the condition does not appear unless a person
inherits the same defective gene for the same trait from each parent.  If a
person receives one normal gene and one gene for the disease, the person will
be a carrier for the disease, but usually will show no 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.

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.

Leukodystrophy that occurs in adults is caused by autosomal dominant
genetic traits.  In autosomal dominant disorders, a single abnormal gene,
contributed by either parent, "overrides" the normal gene contributed by the
other parent causing disease.  Individuals with one affected parent have a
50% change of inheriting the disorder.  Males and females are affected in
equal numbers.  (For more detailed information about the genetic transmission
of all forms of Leukodystrophy, choose "Leukodystrophy" as you search term in
the Rare Disease Database).

Affected Population

The Leukodystrophies can affect either adults or children.  However it is
more common in children.  It can also affect males and females equally but in
some types it affects only males.  Some types of Leukodystrophy tend to
affect persons of Eastern European Jewish ancestry, and other types affect
persons of all heritages.

Related Disorders

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

Multiple Sclerosis is a chronic disease affecting the myelin sheath of
the brain and spinal cord (central nervous system).  It may be progressive,
relapsing and remitting, or stable.  MS consists of small lesions called
plaques that form randomly throughout the brain and spinal cord.  These
plaques on the myelin sheath prevent proper transmission of nervous system
signals.  Symptoms may include visual and speech problems, numbness, walking
difficulty and loss of bladder or bowel control.  MS affects adults, and its
cause is unknown.  (For more information on this disorder, choose "MS" as
your search term in the Rare Disease Database).

Gaucher's Disease is a genetic disease of lipid metabolism caused by the
failure to produce the enzyme glucocerebrosidase.  It is the most common of
the lipid storage diseases.  There are three types of Gaucher's disease.  All
three are characterized by the presence of lipid-laden (Gaucher) cells in the
bone marrow and other organs such as the spleen and liver.  (For more
information on this disorder, choose "Gaucher" as your search term in the
Rare Disease Database).

Tay-Sachs Disease is a genetic disorder that causes the progressive
destruction of the central nervous system in children.  It is generally found
among children of Eastern European Jewish heritage.  Children with Tay-Sachs
appear normal at birth and seem to develop normally until the age of about
six months when they begin to deteriorate.  There is general weakness, loss
of vision, feeding difficulties and absence of normal development.  The
disease is progressive.  (For more information on this disorder, choose "Tay-
Sachs" as your search term in the Rare Disease Database).

Therapies:  Standard

Treatment of most leukodystrophies is symptomatic and supportive.  There are
treatments for Refsum's Disease and Cerebrotendinous Xanthomatosis.  The
treatment for Refsum's consists of a diet which restricts the intake of foods
containing phytanic acid.  Therapy for Cerebrotendinous Xanthomatosis is with
chenodeoxycholic acid.  Genetic counseling will be of benefit for patients
and their families.

Therapies:  Investigational

Researchers are studying ways to control metabolism of long chain fatty acids
with the hope of developing treatments for several forms of leukodystrophy.
Additionally, geneticists are trying to identify the genes that cause certain
types of leukodystrophy in order to understand the biochemical defects that
cause these disorders.  For more information about clinical and genetic
research projects contact the United Leukodystrophy Foundation which is
listed in the resources section of this report.

This disease entry is based upon medical information available through
August 1989.  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 Leukodystrophy, please contact:

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

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

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

     National Tay-Sachs and Allied Diseases Association, Inc.
     2001 Beacon St, Rm. 304
     Brookline, MA  02164
     [phone] or 277-3965

     Adrenoleukodystrophy (ALD) Project
     Hugo M. Moser, M.D.
     John F. Kennedy Institute
     707 North Broadway
     Baltimore, MD 21205
     [phone]

     International Tremor Foundation
     360 W. Superior St.
     Chicago, IL  60610
     [phone]

     Association Europeenne contre les Leucodystrophies
     7 Rue Pasteur
     54000 NANCY
     France

     Tay-Sachs and Allied Diseases Association
     17 Sydney Road
     Barkingside, Ilford, Essex, England 01-550-8989

For Genetic Information and genetic counseling referrals, please contact:

     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, 8th ed.:  Victor A. McKusick; Johns Hopkins
University Press, 1986.  Pp. 205, 573.

THE METABOLIC BASIS OF INHERITED DISEASE, 5th Ed.:  John B. Stanbury, et
al., eds.;  McGraw Hill, 1983.  Pp.857-905.