|
|
 |
About PMD
Clinical features of PMD
Pelizaeus-Merzbacher disease (PMD), named after two German physicians
who first described its most important clinical features, is a rare
condition caused by mutations affecting the gene for proteolipid protein 1 (PLP1, formerly called PLP). The PLP1 gene lies on the X
chromosome so that most affected individuals are males who inherit the
mutant or abnormal gene from their mothers. Rarely, females can have
symptoms. Clinically, Pelizaeus-Merzbacher disease usually begins
during infancy and signs of the disease may be present at birth or in
the first few weeks of life. The first recognizable sign is a form of
involuntary movement of the eyes called nystagmus. The eye movements can be
circular, as if the child is looking around the edge of a large circle,
or horizontal to-and-fro movements. The nystagmus tends to improve with
age. Some infants have stridor
(labored and noisy breathing). Infants may show hypotonia (lack of muscle tone;
floppiness) at first, but most eventually, over several years, develop spasticity (a type of increased
muscle tone or stiffness of the muscles and joints). Motor and
intellectual milestones are delayed, however the intellectual delay is
often more apparent than real, if care and time are taken to evaluate
the children. Most PMD individuals learn to understand speech, but
verbal output can vary from normal speech to almost complete mutism.
Head and trunk control may be a problem and wavering or tremor of the
upper body (titubation)when
sitting is common. Trouble with coordination (ataxia) is also common, and
dexterity of the arms and fingers is usually reduced. Vision is usually
reduced to some degree, probably from the effects of the myelin
abnormality, but also from the nystagmus as well.
Although the following terms are somewhat artificial, they are used in
many textbooks and medical reports. Connatal
PMD refers to the most severe form of the disease, with neurological
signs, such as nystagmus, stridor and hypotonia, being noticeable from
birth to within the first few weeks of life. Seizures may occur only in
these children. These children usually are unable to talk or walk,
although they may comprehend quite well. The Classical PMD syndrome is the most
commonly seen form of the disease. Nystagmus usually begins in the
first 2 months to 6 months. Later, delay in the usual developmental
milestones, such as rolling over, sitting up, standing, walking and
speech are seen. Muscle tone may be hypotonic, although this is not as
noticeable as in the connatal child. Most of these children do learn to
talk, although they may have slurred speech (dysarthria). Some of these
children learn to walk with assistance, such as walkers, but most are
not able to. Virtually all PMD patients have ataxia. We now know that
some mutations of the PLP1
gene may result in a less severe syndrome, called spastic paraparesis
(weakness and stiffness of the legs) or SPG2, where the major sign is
gait difficulty due to weakness and spasticity of the legs. One family
has been reported with a mutation that causes tremor and/or attention
deficit disorder as the major abnormalities. Peripheral nerve myelin is
usually not affected, however we have discovered that in the rare
families whose mutations prevent the synthesis of any PLP1 (the PLP1
null syndrome) have a mild peripheral myelin disorder, but have less
severe overall neurologic difficulties.
The clinical diagnosis generally includes the clinical findings listed
above along with a family history consistent with X chromosome
transmission (that is, being passed down by mothers, and never being
passed from an affected father to his son). The most useful screening
test after the neurologic examination and family history, is a brain magnetic resonance imaging (MRI)
scan, which is a very sensitive test for leukodystrophies (diseases of the
white matter), most reliable if it is done after one or two years of
age (the times when the major white matter pathways in the brain are
developing). Other tests to exclude other leukodystrophies such as the
lysosomal storage diseases (such as metachromatic leukodystrophy, Salla
disease and Krabbe disease) and adrenoleukodystrophy should also be
done. Evoked potentials testing is also helpful and should show
abnormal central conduction but normal or near normal peripheral
conduction. The definitive test is demonstration of a pathologic
mutation of the PLP gene.
PMD genetics
There are two major aspects of the disease that are important to really
understand it. The first is the genetics of PMD and the second relates
to the effect of PLP1
mutations on the nervous system. First I'll describe the genetics. PMD
occurs when there is a change (or mutation) in the body's "blueprint"
material. These blueprint materials, called genes, control the way a
body is made, what it looks like, and how it works. Most genes come in
pairs. One gene of each pair comes from the mother's egg and the other
from the father's sperm. In the tens of thousands of gene pairs,
sometimes one will be changed. The mutation may be inherited or may
happen by itself. Sometimes a mutated gene will not cause problems.
Other times a gene with a mutation will cause the body not to work
correctly, and that a person will have a genetic condition such as PMD.
Genes are carried on chromosomes. Most individuals have 46 chromosomes
in each cell in their body. The chromosomes come in 23 pairs with the
first 22 pairs being identical in males and in females. The last pair
is the sex chromosomes; females have two X chromosomes, while males
have one X and one Y chromosome. The chromosome can be thought of like
a bookcase and the gene as a book located on the bookcase. DNA
(deoxyribonucleic acid) which is the basic component of the gene, is
like the letters in the book. Genetic information is stored, and passed
down from generation to generation, in the form of the precise sequence
of DNA letters or bases.
Since the gene for PMD is located on the X chromosome, the disease
typically affects only boys or men in a family. Technically, this is
called X linked inheritance. Remember that females have two X
chromosomes while males have one X and one Y chromosome. If there is a
gene on the X chromosome which is not working properly, males will be
affected more often than females, since females likely have a gene on
the other X chromosome which does work properly and this usually
compensates for the defective X chromosome. Females who carry the gene
for PMD therefore typically are not affected since the PLP gene on the
other X chromosome is normal. Males with PMD are usually not able to
have children, so the disease when it occurs in several generations is
passed on by women who are carriers for the PMD mutation. Women who
carry the PMD gene have a 50% or 1 in 2 chance of passing it on to
their sons and their daughters. These odds are the same for every
pregnancy. What happened in one pregnancy does not in any way influence
the odds for the next pregnancy. Sons who inherit the gene would be
affected, whereas daughters would be carriers. If a daughter did not
inherit the PMD gene, then she would not pass PMD on to her children.
Some basic
molecular biology
Deoxyribonucleic acid (DNA), which carries the instructions that
instruct cells to make proteins, is made up of four chemical bases or
letters, abbreviated C, T, G, and A (for cytosine, thymidine, guanine
and adenine). A DNA molecule is simply a long chain of these bases
strung together. The information is the sequence of bases. This is like
all the information stored in a book in the order of specific letters
of the alphabet, or the information on a computer disk represented by a
long string of zeroes and ones. In fact, each chromosome is basically a
single molecule of DNA. The largest human chromosome (the first) has
about 120,000,000 bases.
Figure 1. Tightly coiled strands of DNA are packaged in units called
chromosomes, housed in the cell's nucleus. Working subunits of DNA are
known as genes. The four types of bases are colored orange, pink, blue
and green here. This and other figures are from "Understanding Genetic testing"
from the National Cancer Institute: . Used with permission
of the Office of Cancer Prevention, National Cancer Institute.
A mutation (any alteration of the DNA) that affects only a single base
(one letter) is called a point mutation. Other types of mutations can
occur as well, including insertions (additions of DNA into a gene),
deletions (removal of part of a gene), and duplications where entire
genes are present in one or more additional copies. The gene
responsible for PMD is the proteolipid protein 1 gene (PLP1) and it is located on the X
chromosome.
PLP1 duplication
The types of mutations that are known to cause PMD fall into two
general categories: point mutations and duplications. In just the past
few years it has been discovered that most PMD is caused by
duplications (or rarely triplication or even quintuplication) of the
entire PLP1
gene. This seems to be the case for PMD families around the world and
we still do not understand why it occurs. The duplications appear to
account for about 50 to as much as 75 % of those families with PMD. We
currently believe that the duplication results in too much otherwise
normal proteolipid protein being made. Furthermore, this excessive PLP1
is toxic to the cells (called oligodendrocytes) trying to make myelin.
There can be quite a lot of difference in the neurologic difficulties
between families with duplications. One reason for this may be due to
the differences in the size of the duplication in different families.
While we believe that members of the same family will have the same
size duplication, there is know to be a big difference in duplication
size between different families. The smallest duplications known are
around 100,000 DNA bases in length, but the biggest ones found so far
are around 5 million bases. The PLP1
gene is about 30,000 bases long. Other factors that may explain the
differences in families are what genes other than PLP1 are also duplicated, and
whether some of these genes that come before or after PLP on the X
chromosome are mutated by the duplication. Further research will be
needed to understand the variability between families (and even within
families) affected by PMD.
PLP1 point mutations
Point mutations are usually mistakes in the gene where one of the bases
or 'letters' is replaced by the wrong one (technically called a base
substitution). Figure 2 below might help you understand this.
Figure 2. For a
cell to make protein, the information from a gene is copied, base by
base, from DNA into new strands of messenger RNA (mRNA). Then mRNA
travels out of the nucleus into the cytoplasm, to cell organelles
called ribosomes. There, mRNA directs the assembly of amino acids that
fold into completed protein molecule.
Depending upon where the letter is and what it is replaced by, the
mutation could result in:
* No effect
* One amino acid in the protein encoded by the gene
is replaced by the wrong amino acid (amino acid substitution).
Depending on the place and nature of the amino acid substitution, these
mutations can have mild or severe effects. PLP1 with just one wrong
amino acid at a critical location is toxic to myelin forming cells,
just as is overabundance of normal PLP1 (and may even be more toxic
than overabundance)
* The protein is prematurely terminated (ends at the
wrong place)
* Disturbance in the regulation of the gene
* Disturbance in splicing of the gene
Mutations can also result in the gain or loss of more than one base. If
this occurs in the region of the gene that codes for protein then this
might not only result in the gain or loss of one or more amino acids in
the protein, but also might cause the protein to be completely
disturbed after the place the mutation occurs because the machinery
that decodes the genetic information into protein (called ribosomes)
gets out of register with the proper code and just makes scrambled
protein after the mutation site.
Since there are only 4 letters in the genetic alphabet and they are
read in words 3 letters long, there are 64 possible genetic words or
codons possible. Of these 64 codon possibilities, 61 of them code for
one of 20 possible amino acids. The remaining 3 codons are called
termination codons and tell the protein synthesis machinery to stop
making protein. Notice that there are more codon possibilities than
there are amino acids. Some amino acids have more than one codon that
can encode them, whereas others have only one or two codon
possibilities. Proteins are simply chains of amino acids hooked
together like beads on a chain.
To make a simple analogy, take the following simple sentence:
The red fox ran far and sat.
Now if one of the letters is mistyped, like what happens with a base
substitution mutation, the meaning of the sentence changes:
The red sox ran far and
sat.
These missense mutations may sometimes not be harmful or cause mild
disease, but if they occur at an important location in the protein can
be quite harmful.
If, as in the case of a base deletion, all the words get jumbled up
after the mutation, because the protein synthesis machinery has to read
the code three letters at a time (these are called frame shift
mutations):
The red oxr anf ara nds at.
The severity of this type of mutation depends mostly upon where the
mutation is located. If the frame shift occurs at the end of the gene,
it may not cause severe problems, whereas a mutation near the beginning
of the gene will typically have severe consequences.
Although not strictly point mutations, the effects of mutations that
delete or insert a small number (for example two to a couple of dozen)
of bases, are similar to what happens with single base mutations.
Many PLP1 mutations have been
identified. Most of these point mutations are unique to a specific
family. Since these are unique mutations, it is not easy to predict for
a PMD patient with one of these mutations what will happen over the
course of his life, especially if there is no prior history of the
disease in the family. A major goal of genetic research on PMD focuses
on the clinical signs caused by specific mutations in PLP1. This is called
genotype-phenotype correlation. We have compiled a list of the
mutations described in scientific journals and published it at this web
site:
PLP1
mutation table
To make matters even more complicated, we now know that most genetic
information coding for proteins is broken up into chunks that are
separated, sometimes by very large distances, from each other. These
chunks are called exons, and the DNA segments that separate the exons
are called introns. The genetic information in the nucleus of a cell is
first transcribed to molecules of ribonucleic acid (RNA), then the
introns are removed from the RNA to generate the messenger RNA (mRNA)
molecules that have all the protein coding information nicely spliced
together. The mRNA then leaves the nucleus to serve as the blueprint
for the protein synthesis machinery in the cytoplasm (the rest of the
cell that surrounds the nucleus) of the cell.
Figure 3. When a gene contains a point mutation (shown as a red star),
the protein encoded by that gene will be abnormal. Some protein changes
are insignificant, others are disabling.
We know that the PLP1 gene is
broken up into 7 exons, and it turns out that one of the exons (the
third one) sometimes is partially spliced out, resulting in a protein
that looks like PLP, but is missing 35 amino acids in the middle of the
protein. The smaller protein is called DM20. There are
some PMD causing mutations that affect how the PLP1 mRNA is spliced
together.
Figure 4. Splicing of the PLP1
gene. The gene has seven exons that are brought together in the mRNA
molecule. Exon 3 can be spliced in two ways. The area shaded in blue is
missing from DM20. Some mutations can affect how the mRNA is spliced.
We also know that in addition to the regions that code for protein,
there are regions of genes that regulate their expression. In order for
the right proteins to be made in the right organs and in the right
amounts, there are many processes that have to be regulated very
precisely. One important type of regulation occurs in the nucleus,
which has to decide which genes to turn on and which to turn off, and
by how much. Some DNA sequences that lie near but usually outside of
the protein coding regions function to regulate gene expression or
transcription into RNA. Mutations that change these regulatory
sequences can have drastic affects on the gene, and might result in the
protein being made in too high or too low an amount, or to be made in
the wrong organ or at the wrong time of life.
PLP1 and myelin
PMD is one of the leukodystrophies, disorders that affect the formation
of the myelin sheath, the fat and protein covering--which acts as an
insulator--on neural fibers (axons) in the central nervous system or
CNS, which is the brain and spinal cord. About 75 % of myelin is made
up of fats and cholesterol and the remaining 25 % is protein. PLP1
constitutes about half of the protein of myelin and is its most
abundant constituent other than the fatty lipids. New experiments
indicate that about half or more of affected individuals have a
duplication of an otherwise normal PLP1 gene. Thus, it appears that the
presence of too much PLP1 in oligodendrocytes, the cells that make
myelin in the central nervous system, is harmful. The point and other
small mutations usually cause the substitution of one of the amino
acids for another somewhere in the protein or prevent PLP1 from
reaching its full length. This probably results in the protein being
unable to fold into the correct shape or to interact with other myelin
constituents. These mutant proteins are toxic to oligodendrocytes and
prevent them from making normal myelin.
Figure 5. This figure shows what the myelin made by a single myelin
forming cell (called an oligodendrocyte) looks like. The myelin is
shown in cross section, From the side it would look more like a rolled
up carpet around each axon (picture in the upper right corner). A
single oligodendrocyte can myelinate many
different nerve fibers (also called axons). PLP1 may act like a glue to
keep the adjacent layers of cell
membrane tightly stuck together. The bottom figure shows that PLP1
crosses through the membrane (the double layer made up of fat
molecules, shown as the gray balls with zig-zag tails) 4 times.
Treatment
Unfortunately, there is currently no cure for Pelizaeus-Merzbacher
disease, nor is there a standard course of treatment. Gene therapy and
cell transplantation are being explored as possible therapies. For now,
however, treatment is symptomatic and supportive, and may include
medication for seizures and the stiffness or spasticity that most PMD
patients have. Physical therapy can be helpful in maintaining strength
and joint flexibility, and occupational therapy is helpful in
maximizing the abilities of a PMD patient. Braces or walkers may enable
a child to walk. If speech or swallowing is impaired, a
speech/swallowing therapist should be able to provide important
guidelines to make speech more understandable and to prevent choking.
Orthopedic surgery may help reduce contractures, or locked joints, that
can result from spasticity. A physical medicine specialist (also known
as physiatrist or rehab doctor) may be the most effective physician in
evaluating a child's needs and coordinating all the different
therapists. A developmental pediatrician should also evaluate each
child to assess his abilities and help to design an educational
curriculum to maximize his learning and potential. It is important in
these developmental assessments to factor in the longer time it takes a
PMD child to process information, and also to factor in the motor
limitations most kids with PMD have. Periodic developmental assessments
should be done to monitor each child's progress.
Genetic
counseling
Once a PLP1 gene mutation is
identified in a family, it is possible to test family members for the
mutation and to provide prenatal diagnosis for parents who have a risk
of transmitting this disorder. Such testing, especially for a couple
planning a family, or for a woman who wants to know whether she is a
carrier, should be done under the guidance of a medical geneticist
and/or genetic counselor. Carrier testing is usually deferred until the
female is 18 years of age. It is now possible to do preimplantation
genetic testing (PGD) for PMD, but this is often not covered by health
insurance.
Prognosis
The prognosis for those with Pelizaeus-Merzbacher disease varies. Some
mutations are more severe than others and may result in death during
childhood, but most live into adulthood. Survival into the sixties has
been seen. The course of the disorder is usually very slow, with some
individuals reaching a plateau and remaining stable for years. However,
some do worsen over time, for reasons that we do not understand, and
will need further research.
Research
A international group of clinicians and researchers working on
Pelizaeus-Merzbacher
disease and proteolipid protein has been organized to promote research
to facilitate understanding of disease pathogenesis and development of
specific treatments and, we hope, a cure. In North America, please
contact James Garbern for
more information.
These articles, available from a medical library, are sources of
in-depth information on Pelizaeus-Merzbacher disease:
Boulloche, J. and Aicardi, J. Pelizaeus-Merzbacher disease: clinical
and nosological study. Journal of Child Neurology 1:233-9 (1986) [Abstract].
Cailloux, F. et al. Genotype phenotype correlation in inherited brain
myelination defects due to proteolipid protein gene mutations. European
Journal of Human Genetics 8:837-845 (2000) [Abstract].
Cambi, F. et al. Refined genetic mapping and proteolipid protein
mutation analysis in X-linked pure hereditary spastic paraplegia.
Neurology 46:1112-7 (1996) [Abstract].
van der Knaap, M and Falk, J. The reflection of histology in MR imaging
of Pelizaeus-Merzbacher disease.
AJNR Am J Neuroradiol. 10(1):99-103 (1989). [Abstract].
Garbern, J. PLP1-related
disorders, Genereviews (2004).
Garbern, J. Pelizaeus-Merzbacher
disease, eMedicine (2005).
Garbern, J., Cambi, F., Shy, M. and Kamholz, J. The Molecular
Pathogenesis of Pelizaeus-Merzbacher disease. Archives of Neurology
56:1210-1214, (1999) [Abstract].
Garbern, J., Cambi, F. et al. Proteolipid protein is necessary in
peripheral as well as central myelin. Neuron 19:205-218 (1997) [Abstract]
[pdf].
Gencic S, Abuelo D, Ambler M, Hudson LD. Pelizaeus-Merzbacher disease:
an X-linked neurologic disorder of myelin metabolism with a novel
mutation in the gene encoding proteolipid protein.
Am J Hum Genet. 1989 Sep;45(3):435-42 (1989) [Abstract].
Gow, A. and Lazzarini, R. A cellular mechanism governing the severity
of Pelizaeus-Merzbacher disease. Nature Genetics 13:422-428 (1996) [Abstract].
Hudson LD, Puckett C, Berndt J, Chan J, Gencic S. Mutation of the
proteolipid protein gene PLP in a human X chromosome-linked myelin
disorder.
Proc Natl Acad Sci U S A. 86:8128-31 (1989) [Abstract]
[pdf]
Inoue, K et al. A duplicated PLP gene causing Pelizaeus-Merzbacher
disease detected by comparative multiplex PCR. Am J Hum Genet. 59:32-9
(1996) [Abstract].
Mimault, C. et al. Proteolipoprotein gene analysis in 82 patients with
sporadic Pelizaeus-Merzbacher disease: duplications, the major cause of
the disease, originate more frequently in male germ cells, but point
mutations do not. American Journal of Human Genetics 65:360-369 (1999) [Abstract].
Seitelberger, Franz, Urbanits, S. and Nave, K.-A. Pelizaeus-Merzbacher
disease. Handbook of Clinical Neurology, vol. 22 (66) new series, H.
Moser, ed. Elsevier Science, Amsterdam, (1996).
Trofatter JA, Dlouhy SR, DeMyer W, Conneally PM, Hodes ME.
Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene
exon variant.
Proc Natl Acad Sci U S A. 86:9427-30 (1989) [Abstract]
[pdf].
Wolf NI, Sistermans EA, Cundall M, Hobson GM, Davis-Williams AP, Palmer
R, Stubbs P, Davies S, Endziniene M, Wu Y, Chong WK, Malcolm S, Surtees
R, Garbern JY, Woodward KJ. Three or more copies of the proteolipid
protein gene PLP1 cause severe Pelizaeus-Merzbacher disease.
Brain. 128:743-51 (2005) [Abstract]
Woodward, K. and Malcolm, S. Proteolipid protein gene:
Pelizaeus-Merzbacher disease in humans and neurodegeneration in mice.
Trends in Genetics, 5:4:125-128 (1999) [Abstract].
Yool, DA, Edgar, JM, Montague, P and Malcolm, S. The proteolipid
protein gene and myelin disorders in man and animal models. Human
Molecular Genetics 9:987-992 (2000) [Abstract].
Additional information is available from the following organizations
and individuals:
Ms. Patti Daviau
525 S. Harris
Indianapolis, IN 46222
(317) 635-7359
PDaviau@clarian.org
Ms. Laura Spear
2 John James Audobon
Marlton, NJ 08053
The PMD Foundation, Inc.
Marlton, NJ
PMD
Foundation
dhobson@pmdfoundation.org
A German PMD Web site
http://home.t-online.de/home/HeikoRoemke/verein.htm
The Myelin Project
Myelin Project
European Leukodystrophy Association
ELA
Nat. Org. for Rare Disorders (NORD)
P.O. Box 8923
New Fairfield, CT 06812-1783
(203) 746-6518
(800) 999-6673
NORD
Hunter's Hope Foundation
PO Box 643
Orchard Park, NY 14127
Toll Free: 1-877-984-HOPE
(716) 667-1212
hunters@huntershope.org
Hunter's
Hope
Association for Neuro-Metabolic Disorders
c/o 5223 Brookfield Lane
Sylvania, OH 43560
(419) 885-1497
United Leukodystrophy Foundation
2304 Highland Drive
Sycamore, IL 60178
(815) 895-3211
(800) 728-5483
ULF
Nat. Tay-Sachs & Allied Diseases Assoc.
2001 Beacon St., Ste.
204 Brookline, MA 02146
(617) 277-4463
(800) 906-8723
Tay-Sachs
Alliance
Very technical information on PMD
and SPG2
can be found at the Online
Mendelian Inheritance in Man
The National Human Genome
Research Institute has a great deal of information on a wide
variety of genetics topics that you might find useful.
The Public Broadcasting System has a nice site that help explain
genetics:
The
Human Genome
The National Center for Biotechnology Information has excellent online textbooks
Please email (at jgarbern@med.wayne.edu)
if you or any of your family need additional information.
The following clinicians and researchers are members of the PMD
group:
Drs. James Garbern
jgarbern@med.wayne.edu
Department of Neurology and
Center for Molecular Medicine and Genetics
Wayne State University School of Medicine
421 E Canfield Room 3217
Detroit, MI 48201
(313) 577-2648
John Kamholz
Michael Shy
Alex Gow
Department of Neurology and
Center for Molecular Medicine and Genetics
Wayne State University School of Medicine
Ms. Karen Krajewski, MS, CGC
kmkrajew@med.wayne.edu
421 E. Canfield room 3217
Wayne State University School of Medicine
Detroit, MI 48201
(313) 577-1689
Ms. Angela Trepanier, MS, CGC
atrepani@genetics.wayne.edu
Center for Molecular Medicine and Genetics
Wayne State University School of Medicine
Dr. Grace Hobson
ghobson@nemours.org
duPont Institute for Children
Wilmington, DE
Dr. Franca Cambi
Department of Neurology
University of Kentucky
Lexington, KY
Dr. Ken Inoue
Department of Mental Retardation and Birth Defect Research
National Institute of Neuroscience
National Center of Neurology and Psychiatry (NCNP)
Tokyo, Japan
Dr. Odile Boespflug-Tanguy
INSERM UMR 384
Faculté de Médecine
Clermont-Ferrand cedex, France
Dr. Jutta Gärtner
Clinic of Pediatrics and Pediatric Neurology
University of Göttingen
Göttingen, Germany
Dr. Alfried Kohlschütter
Department of Pediatrics
University Hospital Eppendorf
Hamburg, Germany
Last updated April 8, 2005
Comments appreciated. Please email James Garbern
|
|
|
Neurology Home
