Pelizaeus-Merzbacher Disease Karen Woodward
ADL adreno leukodystrophy fect in the PLP1 gene mainly have point
BAEP brainstem auditory evoked potential
mutations, there have been only 2 female
patients with PLP1 gene duplications de-
CT computer tomography
scribed to date.
CSF cerebrospinal fluid
EEG electro encephalogram GENETICS
ER endoplasmic reticulum PMD/SPG2 represents a spectrum of
ERG electro retinogram CNS myelin disorder caused by dosage
MAG myelin associated glycoprotein effects and mutations of the proteolipid
MAPH multiplex amplifiable probe protein (PLP1) gene (Figure 1). Increased
Figure 1. Genetic mechanisms for disease
hybridization dosage of PLP1 is the major cause of in patients with PMD/SPG2. The majority of
MBP myelin basic protein PMD with approximately 60% to 70% of patients, approximately 60% to 70%, have a PLP1
MLD metachromatic leukodystrophy patients having a submicroscopic duplica- gene duplication, approximately 15% to 20%
tion of chromosome Xq22 including the have a mutation in the PLP1 gene, a minority
MLPA multiplex ligation-dependent probe
have a loss of PLP1 caused by a deletion or a
amplification entire PLP1 gene (38, 49). A few patients null allele and approximately 10% to 20% have a
OMIM online Mendelian inheritance in Man. have a deletion of PLP1 (44) or a null molecular defect that is currently unknown.
mutation that gives rise to loss of protein
(Figure 2). An up-to-date list of the muta-
PLP1 proteolipid protein gene (12, 52). Approximately 15% to 20% of
tion spectrum can be obtained from http:
PMD Pelizaeus-Merzbacher disease cases have PLP1 sequence changes that
SPG spastic paraplegia produce abnormal PLP1/DM20 pro-
Splice-site (55) or non-coding region mu-
UPR unfolded protein response teins. ese are mainly missense point
tations (21) have also been described that
VEP visual evoked potential mutations within the gene but may also
cause abnormal expression of PLP1. e
include nonsense or small deletions and
remaining 10% to 20% of patients have
insertions that cause frameshifts (24)
DEFINITION clinical features of PMD but do not have
Pelizaeus-Merzbacher disease (PMD)
is an X-linked dysmyelinating disorder
of the CNS caused by mutations in the
proteolipid protein gene (PLP1) gene
located at Xq22. e milder disorder X-
linked spastic paraplegia type 2 (SPG2)
is allelic, though PMD and SPG2 are
listed separately as OMIM31208 and
Pelizaeus gave the first clinical descrip-
tion of PMD in 1855 (43), to which
Merzbacher added further clinical details
from the same family and a neuropatho-
logical report in 1910 (37). Post-mortem
examination also confirmed the disorder
in an affected sister (35).
EPIDEMIOLOGY, SEX DISTRIBUTION
PMD is rare; in Germany amounting
to only 6.5% of all leukodystrophy (20).
It principally affects hemizygous males,
while females are generally asymptomatic
carriers. However, the rate of occurrence
in females exceeds Duchenne muscular
dystrophy, and is more common in fami- Figure 2. PLP1 topology showing 4 putative transmembrane domains, 2 extracellular loops and
lies with milder forms of PMD or SPG2. one cytoplasmic loop. The alternatively spliced region present in PLP1 and absent in DM20 and the
known mutations are shown. See http://www.med.wayne.edu/neurology/plp.html for a current list of
Manifesting females with a molecular de-
the mutation spectrum. Figure kindly provided by Dr James Garbern.
Chapter 34. Pelizaeus-Merzbacher Disease 311
in spermatogenesis is that the mothers are
carriers. ree atypical cases with non-
contiguous duplication are of particular
note as the additional copy of the PLP1
gene integrated into different regions of
the X chromosome (Xp22, Xp11.4 and
Xq26) in an apparent transposition event
occurring at a sub-microscopic level (25)
(Figure 3). ese unusual duplication
events have been termed submicroscopic
transposon cases. e advantage to using
FISH for molecular genetic diagnosis
of PMD is that it is a visual technique
and these unusual cases where the PLP1
gene has duplicated and then moved to
another site in the genome can easily be
identified. e disadvantage is that small
duplications, less than 50 kb, could be
missed and consequently a combination
of FISH and another higher resolution
dosage technique is ideal.
Figure 3. Representation of PLP1 gene duplications on chromosome X. Xp is shown with green
shading and the PLP1 gene is shown in red. The typical tandem duplications are detected as a doublet CLINICAL FEATURES
by interphase nuclei FISH using a genomic probe containing the PLP1 gene. Atypical cases where the ere is considerable variation, but
additional copy of PLP1 is transposed to another site can be detected by metaphase FISH as the extra common characteristics include nys-
copies have been reported within Xp22, Xq26 or Xp11.4 (associated with an inversion). Adapted from
Woodward et al (61).
tagmus, stridor, ataxia, psychomotor
developmental delay, spasticity and onset
a detectable abnormality suggesting that cells within the PNS and heart, spleen, within the first year of life (7, 12, 24, 48).
mutations in regulatory regions or other thymus and lymph nodes. Disease severity ranges from severe conna-
gene loci can cause PMD. tal PMD through an intermediate classi-
Detection and characterisation of cal form with a slowly progressive course,
e PLP1 gene. PLP1 is localized to PLP1 duplications. Since duplications are to mild PMD/SPG2. Symptoms of con-
Xq22 (36) and encodes the proteolipid the most frequent cause of PMD, dupli- natal PMD develop shortly after birth,
protein (PLP1) and its smaller alterna- cation analysis should be performed prior motor and intellectual development is se-
tively spliced isoform DM20 (17). PLP1 to mutation screening. Dosage detection verely delayed with patients often having
is the major myelin component in the techniques such as interphase fluorescence seizures and no head control. Small head
CNS, constituting approximately 50% in situ hybridization (FISH) (58, 60) circumference and optic atrophy are also
of total protein. PLP1 and DM20 are hy- (Figure 3), quantitative multiplex PCR common. Death occurs in early child-
drophobic proteins of 276 and 241 amino (26, 46) and Southern blotting (11) have hood to the third decade of life. Classical
acids respectively and they are highly been successfully used for diagnosis in the PMD is the most common form of the
conserved across species being identical patient, the female carrier and in some disease with symptoms usually present-
in man, mouse and rat. Predicted pro- cases prenatal detection. e techniques ing in the first year of life and patients
tein structures include 4 transmembrane of multiplex amplifiable probe hybridiza- often surviving into their sixth decade.
domains with cytoplasmic amino and tion (MAPH) (2) and multiplex ligation- SPG2 manifests as progressive weakness
carboxyl terminals (57) (Figure 2). PLP1 dependent probe amplification (MLPA) and spasticity of the lower extremities
is composed of 7 exons extending over (49) are currently being evaluated. with or without CNS involvement. SPG2
approximately 17 kilobase (kb). Exon 3 Molecular analysis of the duplications has a later onset of one to 5 years and a
contains an internal splice donor site that in PMD patients has revealed great varia- milder phenotype with patients often able
creates an alternatively spliced transcript tion in size (<300 kb to >4.6 megabase to walk, talk and have a normal lifespan
DM20 (40) and leads to an internal [Mb]) and position of the breakpoints (29, 47).
deletion of 35 amino acids. e expres- on either side of PLP1 (27, 58). Most
sion of PLP1 and DM20 is spatially and duplications are arranged in a tandem ori- Imaging. CT shows non-specific chang-
temporally regulated during development entation and have an intrachromosomal es, but MR demonstrates failure to my-
(9) with expression mainly within oligo- origin suggesting that they probably arise elinate in comparison with age-matched
dendrocytes, the myelinating cells of the during male meiosis (27, 38, 58). e controls (3). T1-weighted images lack the
CNS but also at a lower level in Schwann consequence of a grand paternal origin high signal observed in myelinating white
312 Chapter 34. Pelizaeus-Merzbacher Disease
Figure 4. Coronal section through the basal
ganglia in a 15-year-old male with slowly
matter, while high intensity persists in
T2-weighted images due to lack of my-
elination and high water content. MRS
has given conflicting results (56). Figure 6. In demyelinated areas (A, luxol fast
blue-cresyl violet) there is relative preservation
Laboratory findings. CSF findings of axons (B, Glees silver method).
and routine biochemical examination are
normal. EEG changes (48) will assist in
the differential diagnosis of PMD related
seizures. Abnormalities in BAEP, abnor-
mal waveform or prolonged latency, are
useful in early diagnosis if the only other
indication is eye movement disorder or an
affected sibling. VEP may be abnormal in
the face of a normal ERG indicating mal-
function of the visual pathways. Nerve
conduction studies are usually normal,
as the PNS is mostly spared. Exceptions
include some patients with loss of PLP1 Figure 7. Myelin staining is completely absent
from the spinal cord but well preserved in spinal
function that have a mild demyelinating roots.
peripheral neuropathy and slower nerve
conduction velocities that are not uni- connatal cases with death in infancy there
formly distributed along the nerve (13). is almost complete lack of myelin, while
in patients with a slower tempo of disease
MACROSCOPY Figure 5. Little stainable myelin remains (A) one encounters the classical tigroid or
In connatal cases with early death the Loyez, (B, C) luxol fast blue-cresyl violet. At discontinuous pattern with preservation
higher magnification (C) residual perivascular of myelin islets around blood vessels
brain is normal in size and the white myelin islets can be seen.
matter is unremarkable on coronal slic- (Figure 5). Oligodendrocytes are mark-
ing. In the classic form, with prolonged nerves are normal. e cerebellar white edly reduced or absent especially where
survival, the brain is usually two-thirds matter, brainstem and spinal cord tracts myelin is completely lacking. Axons are
the expected weight. On sectioning the are shrunken and gray, in striking contrast preserved (Figure 6). ere is astrocytosis,
gray matter appears unremarkable, while to the normal plump, white cranial and and fibrillary gliosis. In unmyelinated ar-
ventricular dilatation depends of the spinal nerve roots. eas microglia are not increased, and there
degree of white matter loss (Figure 4). is usually very sparse sudanophilic lipid
e central and subcortical white matter HISTOPATHOLOGY in perivascular macrophages.Cranial and
along with the commissures and fornix e cerebral cortex is usually not af- spinal nerve roots which have a differ-
are gray and sunken with a gelatinous or fected, but there are rare reports of poly- ent myelin structural protein (PMP-22)
firm consistency. U-fibers may be patchily microgyria (42). ere is often cerebellar are normally myelinated (Figure 7) and
spared, and the centrum semi-ovale can cortical degeneration with either predom- it may be possible to follow individual
show white streaks. e optic nerves and inant granule or Purkinje cell degen- CNS unmyelinated axons in continuity
chiasm are thin and grey, but other cranial eration. With conventional myelin stains, through the root transition zone into the
the hemispheric white matter varies: in
Chapter 34. Pelizaeus-Merzbacher Disease 313
with specific features such as globoid even within families (27) suggesting the
cells (Krabbe), metachromasia (MLD), influence of modifier genes and/or genetic
systemic involvement and trilamellar in- background. Understanding how the dif-
clusions (ADL), spongiosis and abnormal ferent mutational mechanisms underlie
mitochondria (Canavan), massive cavita- pathogenesis is becoming clearer by com-
tion (CACH), or pigmented macrophages paring the patients with animal models.
(van Bogaert and Nissen). Extensive min-
eralization is not a feature of PMD, as Distinct cellular defects underlie the
it is in Aicardi-Goutières leukoencepha- pathogenesis in each form of PMD. PLP1
lopathy where there is also diffuse lack mutations. Splice-site or non-coding
Figure 8. Generalized association between of myelin staining or fragmentation of PLP1 mutations can cause abnormal ex-
PMD/SPG2 disease severity and dosage effects myelin fibres. Discontinuous demyelin- pression and a reduction in message and
and mutations of the PLP1 gene. Patients with
ation and calcification are also prominent protein that has been recently reported to
PLP1 gene duplications mostly have a classical
PMD phenotype but symptoms at the severe findings in Cockayne syndrome, which affect myelin stability and axonal integrity
connatal and mild/SPG2 end of the spectrum are is autosomal recessive and demonstrates (22). More commonly, the mutations are
also possible. Patients with a point mutation in striking dysmorphology, microcephaly, missense and the clinical phenotype may
the PLP1 gene have a wide range of phenotypes
and atrophy of the cortex brainstem and depend on the position of the altered
but are often more severely affected than
duplication patients. Patients with loss of PLP1 cerebellum. amino acid. Mutations within the PLP1
function caused by a deletion or a null mutation specific region (exon 3B) that affect trans-
have mild PMD/SPG2 and peripheral nervous EXPERIMENTAL MODELS port of PLP1 but not DM20 give rise to a
system involvement. Many spontaneous point mutations less severe phenotype and do not usually
PNS where they appear normally myelin- have been described (62). In mouse they cause oligodendrocyte death (16, 47). Ab-
ated. include jimpy (Plpjp), myelin synthesis-defi- errant or truncated proteins generated by
One report of the neuropathology of cient jp mouse (Plpjp-msd), jimpy-4J mouse PLP1 mutations are predicted to result in
SPG2 demonstrated mild myelin loss (Plpjp-4j), and rumpshaker (Plpjp-rsh). ere misfolded PLP1 that accumulates in the
in the centrum semi-ovale compared to is also the myelin deficient rat (Plpmd), the rough endoplasmic reticulum (ER) and
severe loss in the spinal cord (6). shaking pup (Plpsh), and the rabbit with fails to be transported to the oligodendro-
paralytic tremor (Plppt). e jimpy mouse cyte cell membrane (15). e misfolded
IMMUNOHISTOCHEMICAL AND has a point mutation, while the others proteins are often associated with pre-
ULTRASTRUCTURAL FINDINGS have missense mutations causing single mature oligodendrocyte death and may
Lack of PLP1 in PMD was first dem- amino-acid substitutions of the Plp gene. gain a novel function that is deleterious to
onstrated immunohistochemically by Ko- Several mirror the genetic defects found the cell (16). Activation of the unfolded
eppen et al (33). Other myelin proteins, in clinical human disease. Transgenic protein response (UPR) has recently been
MBP, MAG, CNP are variably reduced mice models having additional copies of reported to modulate disease severity in
(12, 33). Ultrastructural data in humans the Plp gene have been generated and oligodendrocytes expressing the mutant
is limited and predates discovery of the show myelination defects, astrogliosis and protein through a signaling cascade that
gene defect. Of 2 case reports from the seizures, indicating that precise regulation coordinates the accumulation of mutant
same laboratory, one showed no compact of Plp is required and modeling the com- PLP1 in the ER with changes in gene ex-
myelin, the other regular myelin periodic- mon human mutation of duplications pression, protein synthesis, and possibly
ity and a normal intra-period line (PLP). (45). apoptosis (54).
is was confirmed in a personally exam- PLP1 deletion. Patients with a deletion
ined biopsy (19) where among many na- PATHOGENESIS of PLP1 (44) or a loss of function muta-
ked axons there was some preservation of e molecular basis for the phenotype tion (12, 52) have mild disease and wide-
thin but compact myelin discontinuously variability is not completely understood spread demyelination in the CNS and
between internodes, a feature which has but probably reflects the distinct cellular PNS that is not associated with the other
been described in some animal models effects of the different genetic mecha- mechanisms of disease. ese patients
(4). nisms involved. ere is some general demonstrate that although PLP1 is ex-
association with disease severity in that pressed at low levels in the PNS compared
BIOCHEMISTRY loss of PLP1/DM20 gives rise to mild dis- to the CNS, PLP1 or DM20 are required
ere is loss of galactolipids specific to ease(12, 44, 52). Severe connatal PMD is for peripheral myelin function. Length-
the myelin sheath (32). Loss of cerebro- mainly caused by missense point muta- dependent axonal degeneration has been
side is variable and non-specific as a func- tions in highly conserved regions of PLP1 found in humans and knockout mice
tion of deficient myelination. (8) and duplications are most often found with a functionally null Plp gene (14).
in patients with classical PMD having a e degeneration is not associated with
DIFFERENTIAL DIAGNOSIS moderate phenotype (8, 51) (Figure 8). significant demyelination and is similar to
PMD is readily distinguishable mor- However, heterogeneity in severity exists that observed in the PNS in Charcot-Ma-
phologically from those leukodystophies
314 Chapter 34. Pelizaeus-Merzbacher Disease
rie-Tooth disease type I patients that have cumulate in the late endosome/lysosome FUTURE DIRECTION AND THERAPY
an inherited demyelinating neuropathy. with cholesterol and to be involved in Although there is currently no specific
e disruption in PLP1-mediated axon- aberrant trafficking and assembly of my- treatment available for PMD/SPG2 pa-
oligodendrocyte interactions is probably elin components (50). Such accumulation tients the wide range of animal models
responsible for this axon degeneration is suggested to interfere with myelination analogous to the different molecular
(14). e Plp mutant mice (5, 31) do and reduce the viability of the oligoden- mechanisms of disease will facilitate the
not develop classic signs of PLP1 related drocyte (50). In contrast the mice with potential for therapy. Possible options for
disease and have a normal number of oli- lower transgene copy number have nor- restoring myelin function include either
godendrocytes (63). e mice have only mal development with no clinical signs gene therapy or somatic cell transplanta-
ultrastructural abnormalities that include until later in life. ese include late onset tion. However, there are great problems
swellings in small diameter axons (6-8 demyelination and axonal swelling and with gene therapy due to the sensitiv-
weeks) and late onset axonal degenera- degeneration suggesting that the oligo- ity of PLP1 gene dosage and the gain of
tion (17). ey demonstrate that neither dendrocytes are unable to maintain their function mutations. Gene delivery may
PLP1 nor DM20 are necessary for myelin myelin sheaths. e pathology is similar be difficult but it will be an even greater
assembly but that they are required for to that of the Plp knockout mouse indi- challenge to obtain PLP1 expression at
myelin and axon maintenance probably cating that changes in gene dosage either the correct level for normal myelination
being needed for axon-glial interaction. increased or decreased may be causing the and maintenance. A reduction of PLP1
PLP1 duplication. Patients with in- axonal changes. expression maybe more successful, for
creased dosage of PLP1 have a variable example by antisense gene therapy, as
phenotype that can range from severe Expression of the disease in females. loss of PLP1 gives a less severe phenotype
connatal (18) to mild PMD/SPG2 but As PMD is a recessive X-linked disorder as shown by PMD patients with a PLP1
typically have a classical form (45, 51). it almost exclusively affects males. Small deletion or null mutation. Alternatively,
At least one severe case is probably due numbers of manifesting females have somatic cell therapy may be an easier
to the patient having a further additional been described with PLP1 point muta- option and transplantation of oligoden-
copy of PLP1 as dosage analysis suggests a tions and these have been associated with drocyte precursors into the CNS has
triplication rather than a duplication (18, milder disease in males (23). is obser- shown potential for animal models (10,
58). e range in clinical severities within vation has been described by patterns of 34). e sustained clinical improvement
the group of PMD patients with increased X-inactivation. Female carriers with a of 2 female PLP1 duplication carriers
dosage of PLP1 may also be explained by duplication have heavily skewed X-inac- also supports this approach demonstrat-
the different duplication structures. is tivation with the X chromosome bearing ing that certain oligodendrocyte lineages
may cause the juxtaposition of different the duplication being preferentially inac- may proliferate and compensate for dys-
regulatory sequences, which could influ- tivated. Consequently these female carri- myelination even years after birth (28).
ence the expression of the PLP1 gene. ers are mainly asymptomatic.In contrast, Other therapies aimed at maintaining the
e effect of modifier genes either within point mutation carriers show a random axon integrity may also be helpful.
the duplicated region or elsewhere in the pattern of X-inactivation (59). erefore
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