Chap 34 Woodward

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					Pelizaeus-Merzbacher Disease                                                                      Karen Woodward
                                                                                                  Brian Harding

 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.
         http: //
                                                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
OMIM312920 respectively.

   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).

   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 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
progressive disease.

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
genome may also affect PLP1 expression        half of the cells in point mutation carri-     REFERENCES
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                                                                                                         Chapter 34. Pelizaeus-Merzbacher Disease   317

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