Case Study of Pelizaeus-Merzbacher Disease
by Ka Vue
Pelizaeus-Merzbacher disease (PMD) is a disorder that causes neural deterioration
due to a lack of normal myelin development. This lack of development results
when myelinating cells, or oligiodendrocytes, of the white matter in the
central nervous system fail to deposit myelin because of a decreased production
of the main protein that makes up myelin. In many patients with PMD, this
failure can be attributed to a mutation in the coding portion of the main
protein gene, or proteolipid protein (PLP) gene. When the cause of the disease
is determined by DNA sequencing as a mutation located on the PLP gene, which
is on chromosome Xq22, the mode of inheritance of the disorder is sex-linked
recessive and involves mostly male patients such as in the case study involving
the sons of a young couple named Wendy and Philip. Although less common,
the mode of inheritance of PMD in some families, however, could also be
autosomal recessive when there are no PLP mutations found and the symptoms
are the same.
Currently, there are four types of PMD and they are classified mainly by
their pathological course and genetic basis. One of these types is classical
PMD which has its onset in the first year of life, is slowly progressive,
shows tigroid demyelination, and leads to death in the second decade of
life. Classical PMD has an inheritance mode of X-linked recessive. Another
type is connatal PMD which begins at birth or in infancy, leads to death
in the first decade of life, and involves complete demyelination. The connatal
type is mostly X-linked and is believed to be in a few cases of affected
females as autosomal recessive. The next type, the transitional form of
PMD is similar to connatal PMD, except it has subtotal trigoid demyelination
and has a sporadic mode of inheritance. Finally, the more distinguished
type, the adult type has autosomal dominant inheritance with late age-of-onset
(childhood thru adult) and patchy demyelination. (Begleiter and Harris 1989)
Of the four types, connatal is the most common type and is the type involved
in the case study of the young couple, Wendy and Philip. The magnetic resonance
imaging (MRI) brain scan of the first of their sons, Danny, at two years
of age showed widespread demyelination which is a common sign among the
connatal type of PMD. The demyelination process, a process which involves
the loss of the fatty sheath that surrounds the nerve cells and allows the
nerve cells to rapidly transmit electrochemical messages (Begleiter and
Harris 1989), led quickly to the death of the couple's son who died only
a month later of respiratory failure.
Clinically speaking, the four types of PMD are much the same and there are
difficulties in distinguishing apart the symptoms between the four types
of PMD. The main difference between them is that the connatal type develops
these symptoms more rapidly than the transitional type, which is more rapid
than the classical type that is followed by the least rapid type, the adult
type. The most common symptoms of patients with PMD include the following
pendular nystagmus ( wandering eye movements)
roving eye movements
head nodding, tilt, and tremor.
These symptoms are then usually followed by some of the following later
delayed psychomotor development
ataxia, chorea, choreoathetosis, spasticity, intention tremor
dysarthria, mild dementia, optic atrophy, mental retardation and seizures.
Apparent in the first years of the lives of the two brothers, Danny and
Christopher, in the case study were symptoms of the connatal type of PMD.
Beginning as early as ten weeks into the life of one of the two boys were
the development of breathing problems and wandering eyes. Signs of nerve
cell degeneration became clear at the age of thirteen months, when one of
the boys could not sit up.
As further investigations in the family history of the parents showed that
the mother, Wendy, had a brother, Peter, who also died as a child of similar
symptoms, the X-linked mode of inheritance was further explored in the case
study. DNA sequencing was used to detect mutations on the PLP gene of the
family members in the case study, and detected was a point mutation at nucleotide
541 on their chromosome Xq. that was believed to be responsible for the
cause of the PMD phenotype (see fig.1). At this site on the gene, there
was apparently a transversion codon change of the amino acid 181 that caused
the normal phenotype ACA to become ACC and expression of PMD (Hodes, etc.
1993). The females in the family were not phenotypically affected since
the disease is recessive and one of the females' "Xs' " can be
masked and unexpressed; while the males have only one "X" and
a "Y" chromosome that is not involved in the expression of the
PLP gene. Thus, the males in the family would have a fifty percent chance
of being phenotypically PMD (see fig.1).
In the case study, the detection of carriers, such as Wendy from fig.1,
can be done by screening for a polymorphism with single-strand polymorphism
analysis of the mutant proteolipid protein gene. This procedure would allow
detection of the silent transition mutation, a polymorphic mutation, in
codon 202. This mutation, however, is not responsible for the phenotype
as it does not cause amino acid change when the codon GAU is changed into
the mutant form of GAT. Both of these codons code for the amino acid Asp.
(Hodes, etc. 1993)
In the case study, the boys' aunt Vicki probably does not have to worry
about passing on the illness to her children unless the actual mode of inheritance
was autosomal recessive instead. In which case, there may have been a mutation
outside the PLP gene that affects the PLP gene. However, if the mode of
inheritance is x-linked and caused by the mutation at nucleotide position
541 on the x chromosome as purposed, then she would not be likely to be
able to passed on the illness because the DNA sequencing showed that she
did not have a mutation at that site and she had only a fifty percent of
receiving the mutated gene from her mother in the first place.
If the PMD in the case study is a simple case of x-linked recessive inheritance,
the chances that a daughter of Wendy and Philip would inherit the Pelizaeus-Merzbacher
disease is fifty percent chance. She would, however, only be carrier and
would not be phenotypically affected. Nonetheless, if she is a 45, XO karyotype
(Turner syndrome), or if there is a deletion or mutation of the PLP gene
in both of her X chromosomes, or extreme lyonization or uniparental disomy;
she would express PMD phenotypically (Hodes, etc. 1993).
Nonetheless, there are 36 mutations known to occur on the PLP gene and many
more mutations which are not detected since there are few polymorphisms
in PLP. Thus, until the effects of a good portion of these mutations on
the structure of PLP can be determined and the PLP structure itself is analyzed
in its physicochemical sense, there may be a possibility that the mode of
inheritance in many patients may be wrong (Hodes, etc. 1993). Information
from such things such as additional linkage studies to show if there is
involvement of an additional loci will also become beneficial in determining
the cause of the Pelizaeus-Merzbacher disease (Hodes, etc. 1993). And finally,
with the use of Schwann cell examination and transgenic animal studies,
hopefully more of such types of studies on the causes of PMD could be successfully
achieved (Hodes, etc. 1993).
Begleiter, M. L., and D. J. Harris. 1989. Autosomal Recessive Form of Connatal
Pelizaeus-Merzbacher Disease. American Journal of Medical Genetics 33: 311-313.
Hodes, M. E., V.M. Pratt, and S. R. Dlouhy. 1993. Genetics of Pelizaeis-Merzbacher
Disease. Dev. Neurosci. 15: 383-394.
Pediatric Database (PEDBASE). Last Updated: 5/22/94. Website: http:www.icondata.com/health/pedbase/files/PELIZAEU.HTM
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