More about
leukodystrophies
Definition
“Leukodystrophy” comes from the Greek leukos, meaning “white,”
dys (“disorder”) and trophe (“food”).
The term leukodystrophy refers to a group of genetic diseases affecting the
myelin of the central nervous system.
Myelin
is a white substance in the brain and spinal cord that covers our nerves in the
same way that insulation surrounds electric wires. It is this substance that
allows nerve impulses to be correctly carried through the nerves.
In leukodystrophies, the myelin has problems forming or maintaining itself
properly and sometimes even the opposite problem of being too thick. The result
is a poor transmission of the nerve impulse, with all the consequences that can
have in the body. Motor functions (shaking, stiffness, balance), vital functions
(breathing, swallowing) as well as the senses (sight, hearing, smell, taste and
touch) can all be affected to varying degrees as the disease progresses.
These symptoms may occur at any age and may manifest themselves differently
according to the location of the affected myelin, the progression of the disease
and the type of leukodystrophy.
How the disease works
Each genetic anomaly causes a modification of the myelin sheath.
In all cases, these modifications disturb the way in which the myelin functions
and the nerve impulses are not transmitted normally. For example, if the area of
the brain that controls image processing is affected the result can be partial
or total blindness, whereas the eyes are completely unaffected. It is the
transmission of the nerve impulse from one part of the body to another that is
disturbed. As a result, the motor, sensory and intellectual functions may be
affected to varying degrees.
Manifestations of the disease
Clinical manifestations appear differently, according to the
type of leukodystrophy.
Most of the time, neurological manifestations may occur at any
age and are usually progressive.
-
Balance/equilibrium problems.
-
Shaking (ataxia) • Problems with motor abilities (walking,
running)
-
Problems with intellectual abilities (comprehension, memory,
behaviour)
-
Sensory problems (sight, hearing, etc.)
In the absence of treatment, all these symptoms will worsen more
or less quickly, leading to total paralysis, blindness, deafness and the
inability to speak and feed oneself normally. The progression of
leukodystrophies is variable from one type to another, however. Usually, the
earlier that the disease manifests itself, the quicker its progression is.
Means of transmission
Leukodystrophies have two means of
transmission, which depend on the type of leukodystrophy. The first means of
transmission is related to gender (the X chromosome is affected). Boys have a
50% chance of being sick and carrying the defective chromosome. Girls cannot be
sick, but they nonetheless have a 50% chance of carrying the defective
chromosome. The other means of transmission is called autosomal recessive.
“Autosomal” means that it is not related to the gender chromosome and
“recessive” comes from the fact that both parents must be carriers of the same
defective gene in order for the disease to be transmitted. This fact means that
transmission is not related to the X chromosome and affects both boys and girls
Sex linked transmission
.
In the above diagram, we can see that the girl on the far left
will be a healthy carrier, since the healthy X chromosome will compensate for
the defective one received from the mother. The boy on the left, however, does
not have a healthy X chromosome to make up for the defective one. As a result,
he will be affected with the disease.
Among leukodystrophies whose transmission is related to gender,
there are adrenoleukodystrophy, adrenomyeloneuropathy and Pelizaeus-Merzbacher
disease.
Autosomal
recessive transmission
In this means of transmission, both parents must be healthy
carriers of the same defective gene. They therefore have a 50% chance that their
children will also be healthy carriers and thus susceptible of transmitting this
same defective chromosome to their own children, as well. One out of four
children of carrier parents will be stricken with the disease and another one
out of four will be free of the defective gene altogether. This type of genetic
transmission is found in metachromatic leukodystrophy, Krabbe’s disease,
Canavan’s disease, CACH syndrome, leukodystrophy with macrocephaly and cysts and
Aicardi-Goutières syndrome.
Known types of leukodystrophies
So far, there are over a dozen types of
leukodystrophies whose behaviours are more or less known. Currently, about
30% of diagnosed leukodystrophies are of an unknown type.
|
Type of leukodystrophy |
Myelin component affected |
Transmission |
Gene identified? |
Prenatal diagnosis? |
Therapy |
|
Metachromatic Leukodystrophy |
Sulfatide |
Autosomal recessive |
Yes |
Yes |
Bone marrow transplant
(juvenile type) |
|
Krabbe’s
Disease |
Galacto-cerebroside |
Autosomal recessive |
Yes |
Yes |
Bone marrow transplant
(juvenile type) |
|
Adrenoleukodystrophy - adrenomyeloneuropathy |
Very long-chain
fatty acids
(VLCFA’s) |
? |
Yes |
Yes |
Bone marrow transplant.
Preventive treatment? |
|
Pelizaeus-Merzbacher Disease |
Proteolipid protein (PLP) |
Gender-related |
Yes |
Yes |
No |
|
Canavan’s Disease |
N-acetylaspartate
acid |
Autosomal recessive |
Yes |
Yes |
No |
|
CACH Syndrome |
? |
Autosomal recessive |
No, Located on chromosome # 3 |
No |
No |
|
Leukodystrophy with macrocephaly et cysts |
? |
Autosomal recessive |
No Located on chromosome # 22 |
No |
No |
|
Aicardi-Goutières Syndrome |
? |
Autosomal recessive |
No |
No |
No |
|
Alexander’s Disease |
? |
Sporadic |
No |
No |
No |
|
Zellweger Syndrome |
? |
Autosomal recessive |
Several chromosomes identified |
Yes |
? |
|
Refsum’s Disease |
? |
Autosomal recessive |
Several chromosomes identified |
Yes |
? |
|
Megalencephalic
leukodystrophy |
? |
Autosomal recessive |
Yes |
Yes |
? |
|
Leukodystrophies of undetermined type |
? |
? |
? |
? |
? |
Treatments
Some possible treatments exist for certain types of leukodystrophies. For
example, for adrenoleukodystrophy, Krabbe’s disease and metachromatic
leukodystrophy (see table above), a bone marrow transplant may be attempted. In
some cases, all this may do is cause the disease to regress or stop its
progression. It also involves certain substantial risks, however, and cannot be
performed on patients diagnosed at an advanced stage of the disease. For the
other types of leukodystrophies, there currently only exist treatments for
individual symptoms, which only help lessen the problems caused by the disease’s
progression.
Research
Isolating the gene responsible may be seen as a first step in
identifying the deficient protein involved, the purification of which may lead
to a pharmacological solution for certain types of leukodystrophies.
Gene therapy (the replacement of deficient genes) is already
being studied for three types of leukodystrophies: adrenoleukodystrophy,
metachromatic leukodystrophy and Krabbe’s disease.
Being able to rebuild destroyed myelin is the best real long-term
hope and is currently the subject of active research by the Myelin Project and
others.
A substantial effort needs to be developed to identify the
genetic and biochemical behaviours that are responsible for at least 30% of
unidentified or undetermined types of leukodystrophies.
Transplanting Schwann cells is a promising avenue, though it is
only in the beginning stages of development.
The bottom line is that although research is underway, no
treatment can currently save the lives of children affected by this disease.
