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Compensating for central nervous system dysmyelination Females with a proteolipid protein gene duplication and sustained clinical improvement.

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Compensating for Central Nervous System
Dysmyelination: Females with a Proteolipid
Protein Gene Duplication and Sustained
Clinical Improvement
Ken Inoue, MD, PhD,1 Hajime Tanaka, MD, PhD,3 Fernando Scaglia, MD,1 Akiko Araki, MD,3
Lisa G. Shaffer, PhD,1 and James R. Lupski, MD, PhD1,2
A submicroscopic duplication that contains the entire proteolipid protein gene is the major cause of PelizaeusMerzbacher disease, an X-linked central nervous system dysmyelinating disorder. Previous studies have demonstrated that
carrier females for the duplication are usually asymptomatic. We describe 2 unrelated female patients who present with
mild Pelizaeus-Merzbacher disease or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results have improved dramatically over a 10-year period. The
other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, has also shown clinical
improvement. Interphase fluorescent in situ hybridization identified a proteolipid protein gene duplication in both
patients. Interphase fluorescent in situ hybridization analyses of the family members indicated that the duplication in
both patients occurred as de novo events. Neither skewing of X inactivation in the peripheral lymphocytes nor proteolipid protein gene coding alterations were identified in either patient. These findings indicate that, occasionally, females
with a proteolipid protein gene duplication can manifest an early-onset neurological phenotype. We hypothesize that the
remarkable clinical improvement is a result of myelin compensation by oligodendrocytes expressing one copy of proteolipid protein gene secondary to selection for a favorable X inactivation pattern. These findings indicate plasticity of
oligodendrocytes in the formation of central nervous system myelin and suggest a potential role for stem cell transplantation therapies.
Ann Neurol 2001;50:747–754
Proteolipid protein (PLP) is the most abundant myelin
protein in the central nervous system (CNS). Mutations in PLP are associated with a severe X-linked CNS
dysmyelinating disorder, Pelizaeus-Merzbacher disease
(PMD), and a clinically milder allelic disorder, spastic
paraplegia type 2 (SPG2).1–3 Although most female
carriers show no clinical symptoms, in some families
carrier females manifest a late-onset spastic paraplegia
phenotype with variable severity.4 –7
A gene dosage effect of PLP by submicroscopic
genomic duplication (ie, not detectable by conventional G-banded chromosome analysis) accounts for 60
to 70% of PLP mutations among PMD patients.8 –11
Recent molecular studies revealed that the size and
breakpoints of the duplicated genomic fragments are
surprisingly variable, yet the underlying mechanism for
the genomic recombination is likely to be common;
that is, an unequal sister chromatid exchange in male
meiosis.9,10 A few families with PLP duplication in
which the additional gene copies were translocated to
different regions in the X chromosome were recently
reported.12 Patients with PLP duplication typically
present with the classic form of PMD, whereas more
severe connatal and transient forms are mostly associated with point mutations in PLP.10 No symptomatic
female carrier of a PLP duplication has been reported
in previous studies.10,13
We identified 2 independent female patients with
From the Departments of 1Molecular and Human Genetics and
2
Pediatrics, Baylor College of Medicine, Houston, TX; and 3Department of Pediatrics, Asahikawa Habilitation Center for Disabled
Children, Asahikawa, Japan.
Published online Nov 1, 2001; DOI 10.1002/aon.10036
Received May 17, 2001, and in revised form Jul 10. Accepted for
publication Aug 14, 2001.
Address correspondence to Dr Lupski, Department of Molecular
and Human Genetics, Baylor College of Medicine, One Baylor
Plaza, Room 604B, Houston, TX 77030.
E-mail: jlupski@bcm.tmc.edu
© 2001 Wiley-Liss, Inc.
747
dysmyelinating disorders who showed progressive
clinical improvement. Interphase fluorescent in situ
hybridization (FISH) analyses indicated that both patients have duplications of PLP. We hypothesize that
CNS myelin compensation may play a role in the
mechanism of this unique phenomenon.
Interphase FISH
Patients and Methods
Patient 1
Genomic DNA was extracted from peripheral blood cells. X
inactivation status was evaluated at the trinucleotide repeat
region in the androgen receptor gene by a PCR-based method,15 using fluorescently labeled primers and an automated
sequencer (ABI377; Applied Biosystems, Foster City, CA).
Each exon of the PLP gene was amplified by PCR and sequenced using dye primer chemistry and an ABI377 automated sequencer, as described.16
BAB1532 is an 11-year-old Japanese girl who was born
weighing 3,126g at full-term (38-weeks) from nonconsanguineous parents (Family HOU612). She has no family history of neurological disorders. She had neonatal asphyxia
with Apgar scores of 2 (1 minute) and 7 (5 minutes). Nystagmus began at 2 weeks of age. Although developmentally
delayed, she has been catching up substantially in attaining
developmental milestones (holding her head at 6 months,
rolling over at 8 months, creeping at 18 months, speaking
one word at 11 months and two words at 21 months of
age). Her intelligence quotient (IQ) was verbal IQ of 70,
performance IQ of 61, full-scale IQ of 59 at 4 years and 9
months of age (Wechsler Preschool and Primary Scales of
Intelligence); and verbal IQ of 101, performance IQ of 90,
full-scale IQ of 95 at 8 years of age (Wechsler Intelligence
Scale for Children). Hypotonia and mild hyperreflexia in
her upper limbs noted at 3 months were diminished by 5
years of age and mild difficulty in coordination in her upper extremities improved to normal. Hyperreflexia and
spasticity in her lower limbs, noted at 3 months and 8
months of age, respectively, have kept her wheelchair
bound. Now she can move by crawling and control her
wheelchair by herself. She has exhibited no extrapyramidal
or cerebellar symptoms during her clinical course. Serial
head magnetic resonance imaging (MRI) studies and brainstem auditory evoked potentials (BAEPs) were obtained
from 3 months to 11 years of age.
Patient 2
BAB1718 is a 6-year-old Hispanic girl from nonconsanguineous parents (Family HOU671). One of her maternal
cousins died at 8 days of life secondary to anencephaly. No
abnormality was noticed during the pregnancy or after the
birth by Cesarean section for breech presentation. She was
healthy with normal developmental milestones until 14
months of age, when she showed spasticity in her lower
extremities and started to walk on her toes and drag her
feet. She showed neither cerebellar nor extrapyramidal tract
signs. No nystagmus was noted. She is intellectually normal
for her age. Despite the residual spasticity in her lower extremities, her gait has recently improved with milder toewalking in comparison with the previous 2 years. She still
drags her right foot while walking; however, her gait is
steadier and she no longer falls when tired. She still trips
when she tries to run but she can walk at a brisk pace,
which was not previously possible. MRI studies were performed at age 2 and 6 years. BAEPs were obtained at 6
years of age.
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White blood cells from the patients and other members of
both families were cultured and harvested as described by
Shaffer and colleagues.14 Interphase FISH was performed as
described previously.10
X Inactivation and PLP Coding Region
Sequencing Analyses
Results
MRI and BAEPs Improvement in Myelination
The MRI studies of Patient 1 (BAB1532) from 4
months to 10 years of age demonstrated prominent delay in myelination, especially in her first 2 years of life.
The myelination has been slowly improving; it reached
to the corona radiata at 21 months and cortical white
matter at 4 years of age (T1-weighted images in Fig 1
and Table). However, significant T2-hyperintensity regions in the cortical white matter remain at 10 years of
age, indicating incomplete myelination (see Fig 1 and
Table). The BAEPs of Patient 1 revealed significant
improvement, which chronologically parallels the improvements of those seen in the MRI studies.
Patient 2 (BAB1718) presented with a mild delay of
myelination in the cerebral white matter at 2 years of
age, which improved at 6 years of age (see Fig 1 and
Table). She had normal BAEPs at 6 years of age.
Interphase FISH Analyses
Both patients have a normal 46,XX karyotype. Interphase FISH analyses identified three PLP signals with
two control signals in both patients, indicating that they
have a PLP duplication of one X chromosome (Fig 2).
The PLP signals were observed on Xq22 for both normal and duplicated alleles by metaphase FISH indicating
there was no translocation of PLP (data not shown). In
family HOU612, both parents are negative for the PLP
duplication by FISH analyses, suggesting that the duplication occurred as a de novo event. In the other family
HOU671, both the mother and healthy sister produced
normal FISH results, but the father’s sample was not
available. Because the father has no phenotype related to
PMD, he is unlikely to have PLP duplication as this
results in a PMD phenotype in males. Therefore, the
duplication event in this patient is also likely de novo.
Random X Inactivation in Both Patients
Patient BAB1532 revealed a ratio of 76 to 24 and patient BAB1718 showed a ratio of 48 to 52 for the X
Fig 1. Magnetic resonance imaging (MRI) and brainstem auditory evoked potentials (BAEPs) revealed improvement in myelination.
T1- and T2-weighted images of Patient 1 (BAB1532) at age 4 months (A and B), 21 months (C and D), and 10 years (E and
F); T2-weighted images of Patient 2 (BAB1718) at age 2 years (G) and 6 years (H). (A and B) In Patient 1, MRI at 4 months
showed initiation of myelination in the brainstem, thalamus, and internal capsule but no signs of myelination in the cerebral white
matter (WM). Myelination appeared very slowly, barely reaching the basal ganglia at 9 months of age (data not shown) and cerebral WM at age 21 months (C). (D) Hyperintensity in T2-weighted images indicated that myelination in the cortical hemisphere
was extensively delayed. At age 4 years, prominent progress of myelination was seen in cortical WM, although its patchy appearance
suggested incomplete myelination (data not shown). (E) At age 10 years, myelination reached the subcortical WM, shown as hyperintensity in the T1-weighted image. (F) Irregular T2 hyperintensity was observed in the cortical WM and the contrast between gray
matter (GM) and WM is unclear, suggesting that myelination is still incomplete in the cortical hemisphere. (G) In Patient 2, MRI
at age 2 years revealed myelination up to the subcortical regions, but there were irregular patchy appearances in the WM; suggesting
incomplete or mosaic myelination. (H) Similar findings are found in MRI at age 6 years, but the contrast between WM and GM
had significantly improved in the comparative images. (I) BAEPs of Patient 1 obtained at age 3 months, 8 months, 1 year and 9
months, 5 years and 6 months, and 11 years. Wave II and subsequent waves were absent at age 3 months, but appeared, although
still delayed, at 8 months of age. BAEP results gradually improved, parallel to the MRI findings, to almost normal range at age 11
years.
Inoue et al: Compensating for CNS Dysmyelination
749
Table. MRI Findingsa at Different Ages in Female PLP Duplication Carriers Manifesting CNS Dysmyelination
Patient 1
White matter
Basis pontis
Median leminiscus
Decussation of the superior cerebellar peduncle
Crura cerebri
Anterior limb of internal capsule
Medial posterior limb of internal
capsule
Lateral posterior limb of internal
capsule
Middle cerebellar peduncle
Superior cerebellar peduncle
Vermis
Hilus of the dentate nucleus
White matter of cerebellar hemisphere
Central corona radiata
Subcortical white matter
Gray matter
Tegmentum pontis
Colliculi inferior
Colliculi superior
Red nucleus
Substantia nigra
Thalamus, ventrolateral
Thalamus, not ventrolateral
Globus pallidus, lateral
Globus pallidus, not lateral
Putamen, dorsolateral
Putamen, not dorsolateral
Dentate nucleus
Pericentric cortex
Hippocampus
Patient 2
4 mo
9 mo
21 mo
4 yr
10 yr
2 yr
6 yr
⫹/⫺
⫹/⫺
⫹/⫺
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫺
⫺/⫺
⫹/⫺
⫹/⫹⬃⫽
⫹/⫺
⫹/⫺
⫹/⫹
⫹/⫺
⫹/⫺
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫺
⫹/⫺
⫹/⫺
⫹/⫽
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫺
NA
⫹/⫽
⫹/⫺
⫽/⫺
⫹/⫺
NA
⫹/⫽
⫹/⫽
⫹/⫽
⫹/⫽
NA
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫺/⫺
⫺/⫺
⫺⬃⫽/⫺
⫺/⫺
⫹/⫺
⫽⬃⫹/⫺
⫹/⫺⬃⫽
⫽⬃⫹/⫺
⫹/⫽
⫹/⫽
⫹/⫽⬃⫹
⫹/⫽⬃⫹
⫹/⫽⬃⫹
⫹/⫹
⫹/⫺
⫹/⫽
NA
⫹/⫽
NA
⫹/⫽
⫺/⫺
⫽/⫺
⫺/⫺
⫽/⫽
⫺/⫺
⫹/⫽
⫺/⫺
⫽/⫺
⫹/⫹
⫹/⫹
NA
⫹/⫽
⫹/⫽
⫹/⫹
⫽⬃⫹/⫽
⫽/⫽
⫺/⫺
⫹/⫹
⫽/⫽
⫹/⫺
⫽/⫺
⫽⬃⫹/⫽
⫹/⫹
⫹/⫹
NA
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫽⬃⫹
⫹/⫽⬃⫹
⫹/⫽
⫹/⫹
⫹/⫽
⫹/⫽
⫹/⫺⬃⫽
⫽⬃⫹/⫽
⫹/⫹
NA
NA
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫽⬃⫹
⫹/⫽⬃⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫽⬃⫹
⫹/⫽⬃⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
⫹/⫹
a
Level of myelination compared with intensity of the caudate nucleus head.27 Each evaluation was presented as T1-weighted/T2-weighted
images. ⫹ indicates myelinated regions, defined as hyperintensity in the T1-weighted images and hypointensity in T2-weighted images. ⫺
indicates nonmyelinated regions, defined as the reverse (hypointensity in T1-weighted images and hyperintensity in T2-weighted images). ⫽
indicates regions of uncertainty in determining degree of myelination, defined as isointensity in either T1- or T2-weighted images. ⬃ indicates
transition between the two values. Dark gray indicates regions showing hypointensity in T1 and hyperintensity in T2-weighted images, thus
indicating no myelination. Light gray indicates regions showing hyperintensity in either T1- or T2-weighted images, thus indicating incomplete
or partial myelination. Significant progress in myelination is noted by diminishing unmyelinated or incompletely myelinated regions over time.
PLP ⫽ proteolipid protein gene; CNS ⫽ central nervous system; NA ⫽ not available for evaluation.
Fig 3. Schematic models show compensation of CNS myelin and distribution of two cell types during different time points in heterozygous females. Myelin generated by oligodendrocytes expressing normal proteolipid protein gene (PLP) (blue) and mutant PLP
(red) with corresponding axon (pink) are shown at premyelination, mature myelination, and adult stage. A represents complete normalization observed in severe PLP mutations. In the premyelinating stage, equal numbers of cells express mutant or normal PLP
allele. As the mutant cells are eliminated by subsequent apoptosis, cells expressing the normal allele predominate after preferential
survival and myelinate all axons, resulting in normal myelination in the adult stage with selective skewing. B shows late-onset demyelination (dashed) as a result of the survival of mutant oligodendrocytes that have a mild mutation in PLP and form incomplete
or fragile myelin (mutant myelin may be thinner than wild type myelin). In this case no compensation is observed. C presents two
possibilities for the mechanism that best explains our results. Both mechanisms lead to a greater number of normal cells, but distinguishing between these two mechanisms is not yet possible. First, the upper group of cells shows the skewed X inactivation toward
the direction of the normal X chromosome being inactivated (most oligodendrocytes express mutant PLP, shown in red), resulting in
slow progression of myelin compensation because of the small number of normal oligodendrocyte precursors. Second, the lower group
of cells shows the model for the “double-hit” hypothesis. Both mutant and normal oligodendrocyte precursors are distributed equally
at the premyelination stage. Following apoptotic cell death of mutant cells, normal cells compensate with slow progression because of
an unknown factor that diminishes the ability of normal oligodendrocyte precursors to proliferate and differentiate into mature myelin. On the right, diagrams represent changes of mutant and normal cell distribution over time.
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‹
Fig 2. Interphase fluorescent in situ hybridization (FISH) analyses showing PLP duplications. Harvested cells were hybridized with
a PLP-specific probe (cosmid u125A5 DNA) labeled by digoxigenin and an intrachromosomal control probe located at the BTK
locus (PAC RP1-36B9 DNA) labeled with Biotin. Signals were visualized using a fluorescence microscope. Representative interphase
nuclei are shown from Patient 1 (A) and Patient 2 (B). Note that two sets of signals are present; one normal allele that represents
a single copy of PLP (red) and one control signal (green) on the same chromosome, and one duplicated allele that shows two PLP
signals (red, arrowheads) and one control signal (green) on the other X chromosome.
inactivation status in their peripheral blood cells, indicating that no skewing of X inactivation was evident in
these cells in either patient (data not shown).17
No Mutations in PLP Coding Region
No alterations in the coding regions or splice site junctions of the PLP gene were identified in either patient,
Figure 3
Inoue et al: Compensating for CNS Dysmyelination
751
indicating that point mutations in the coding region of
PLP are not likely to play roles in either patient and
both carry three copies of wild type PLP (data not
shown).
Discussion
An Improving Central Nervous System
Dysmyelinating Disorder
We describe 2 female patients with a PLP duplication
who presented with CNS dysmyelinating disorders of
different degrees of severity. One patient had developmental delay from infancy accompanied by mild intellectual impairment and spastic diplegia that later resolved, resulting in objectively documented normal
intelligence and improved motor function. The initial
clinical manifestation was similar to that of most male
PMD patients with a PLP duplication but clearly differs
by the improvement of clinical features. This degree of
clinical improvement is not observed in male patients.
Objective clinical studies, including MRI that revealed
diffuse dysmyelination of the entire white matter as well
as abnormal BAEPs, also dramatically improved and
have almost normalized over time. The second patient
presented with mild spastic diplegia in her lower extremities with neither developmental delay nor intellectual
impairment but with minimal dysmyelinating MRI
findings. Her clinical phenotype, as well as her MRI
data, have been improving over a 3-year period. It is of
note that her initial diagnosis was cerebral palsy. In fact,
PMD is one of the differential diagnoses of cerebral
palsy18 and a number of male patients with PMD have
been diagnosed as having cerebral palsy. We emphasize
that in females diagnosed with cerebral palsy a genetic
abnormality of PLP should be also considered even if
MRI shows only minimal dysmyelination.
Compensation of Central Nervous System Myelin in
Heterozygous Females
Studies of more than 30 families with PLP duplication
have shown that patients’ mothers are usually carriers for
the duplication and present with no phenotype associated with PMD.10,11 Similarly, female carriers of point
mutations that result in a severe form of PMD in males
are usually asymptomatic. In contrast, PLP mutations
that result in a mild PMD/SPG2 phenotype in affected
males, including point mutations and null alleles of
PLP, have been associated with adult-onset degenerative
leukodystrophies among carrier females.4 –7,19,20 Female
patients carrying PLP duplications presented with an
early-onset dysmyelinating phenotype, suggesting that
the underlying disease mechanism may be distinct.
This paradoxical phenomenon that severe PLP mutations commonly result in asymptomatic carrier females, whereas the reciprocal mild alterations may result in symptomatic carriers, has been explained by
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normalization of the oligodendrocyte population.21 As
the result of random X inactivation, a heterozygous female carrier has two distinct oligodendrocyte precursor
populations: cells only expressing the normal PLP allele
and cells only expressing the mutant PLP allele. Severe
PLP mutations may affect differentiation of oligodendrocytes and lead to subsequent apoptosis. As a result,
the remaining oligodendrocytes of mature myelin represent a population of cells expressing a normal PLP
allele (Fig 3A). On the other hand, oligodendrocytes
expressing mild PLP mutations may survive through
development and form myelin, resulting in a mosaic
population in mature myelin. Because the mutant myelin may be incomplete or unstable, and probably is
subject to being degraded, subsequent demyelination
and late-onset clinical manifestations may occur in carrier females (see Fig 3B).
These hypotheses are supported by findings from
studies on mutant Plp animal models. In heterozygote
jimpy mice, a model for the severe form of PMD, myelin at birth is mosaic presenting as fully myelinated
and barely myelinated axons.22,23 Subsequently, all axons become myelinated as normal oligodendrocytes replace mutant cells.22,23 In contrast, the heterozygote
rumpshaker mice, a model of SPG2 in the hemizygote,
maintain mutant oligodendrocytes survival with compact myelination.24 Neuropathological studies revealed
the mosaic presence of axonal fibers with disproportionally thin myelin sheaths for the axon diameters,
which is more prominent in older animals, as well as
fibers with normal myelin. However, the animals continue to be phenotypically normal.24
Because the present clinical cases do not fit either of
the models delineated from murine studies, we propose
two possible models based on observations in our patients (see Fig 3C). First, if the X inactivation is
skewed toward the unfortunate direction in which the
normal X chromosome is selectively or predominantly
inactivated, most oligodendrocyte precursor cells express the duplicated PLP allele and fail to differentiate
further. This may result in a limited number of precursor cells capable of initiating myelin formation and,
thus, the majority of axons are unmyelinated at this
stage. As a result, carrier females may manifest a dysmyelinating pathological and clinical phenotype. However, as these axons are subsequently myelinated by
compensating normal oligodendrocytes, the clinical
symptoms may improve (see Fig 3C). A Plp mutant
dog consistent with this model was reported recently.25
Skewing of X inactivation in the peripheral blood
cells of our patients was not demonstrated. There is,
however, a possibility that tissue-specific unfavorable
skewing exists only in the CNS, although such evaluation was not possible in this study. Interestingly,
asymptomatic female carriers of PLP duplication can
have skewed X inactivation in their peripheral blood
cells.13 Although it is unknown whether this is also the
condition in the brain, a possible mechanism to escape
phenotypic presentation in female carriers of PLP duplication is by selective X inactivation, which does not
appear to be present in our patients.
Alternatively, an additional factor may reduce the
mitotic potential of normal precursor cells, resulting in
suppressed or decreased myelin compensation (see Fig
3C). Such factors include PLP alterations in the normal allele or mutations in other genes in the CNS myelination pathway, which may not result in a dysmyelinating disorder by itself but reduce the potential to
proliferate and compensate for dysmyelination. This
“double-hit” hypothesis (PLP duplication and another
mutation) is, however, less likely, and we have no evidence to support it. Furthermore, we did not find any
alteration either in the PLP coding and minimal promoter region in the normal allele or in the duplicated
allele of PLP in our patients.
Implication for Stem Cell Treatment of PelizaeusMerzbacher Disease
Although no effective treatment is available for PMD,
stem cell transplantation may have great potential. Because PMD primarily affects oligodendrocyte development, transplantation of myelin lineage precursor cells
may compensate the myelin deficiency. Despite the
tight regulation of normal myelin development in the
CNS, the dramatic recovery from clinical symptoms, as
well as the improvement in MRI and BAEP findings,
suggest sufficient plasticity of the oligodendrocyte lineage to proliferate and compensate the dysmyelination
even years after birth. This implies the possibility of
successful application of stem cell transplantation therapies for PMD, as preliminarily studies have shown in
embryonic stem cell transplantation in mice.26
This study was supported in part by the National Institute for Neurological Disorders and Stroke (NIH R01 NS27042), the Muscular
Dystrophy Association (to JRL), and the Baylor College of Medicine Mental Retardation Research Center (NIH P30 HD24064).
K.I. is supported by fellowships from the Charcot-Marie-Tooth Association and Muscular Dystrophy Association.
We greatly appreciate the participation of the patients and families.
We thank Drs Kimiko Deguchi (Department of Pathology, Baylor
College of Medicine), Noriko Aida (Division of Radiology, Kanagawa Children’s Medicain Center), and Cornelius Boerkoel (Department of Molecular and Human Genetics, Baylor College of
Medicine) for their critical reviews and helpful advice. We thank the
members of the Kleberg Cytogenetics Laboratory, Baylor College of
Medicine, for their expert FISH and cell culturing on these cases.
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4. Hodes ME, Blank CA, Pratt VM, et al. Nonsense mutation in
exon 3 of the proteolipid protein gene (PLP) in a family with
an unusual form of Pelizaeus-Merzbacher disease. Am J Med
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