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81
Review Article
International Clinical Neuroscience Journal • Vol 3, No 2, Spring 2016
The Relationship between Skewed X-chromosome
Inactivation and Neurological Disorders Development
Mahdi Taherian1, Hossein Maghsoudi2, Kazem Bidaki2, Reza Taherian3
1 Food and Drug Administration, Reference Laboratory for Food and Drug Control, Tehran, Iran
2 Department of Biology, Payame Noor University, Tehran, Iran
3 Students’ Research Committee, School of M edicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
ABSTRACT
X-chromosome inactivation (XCI) is a process by which one of the copies of the X chromosome
in mammalian female cells is inactivated. The XCI causes a balanced X-linked gene quantity
between male and females; moreover, it results mosaic females which have paternal active X
in some cells and maternal active X in others. Cellular mosaicism is a noteworthy phenomenon
and lowers the risk of X-linked diseases in women because the presentation of a mutation on
both X chromosomes is unlikely. Therefore, in heterozygous females, the XCI will be present
only on the half of the X genome. In contrast, a similar mutation will present in all of the cells
of men. Female carriers of some neurological disorders such as autism, Rett syndrome, adreno-
leukodystrophy and X-linked mental retardation are reported to present XCI. These observations
underscore the important role of X chromosome in the brain which may be related to the
existence of a chromosomal signature of gene expression associated with the X-chromosome
for neurological conditions not normally associated with that chromosome. In this review, we
focused on latest investigations on the role of XCI in neurodevelopmental disorders and how
these investigations can be effective in the treatment of neurodevelopmental disorders.
Keywords: Adreno-leukodystrophy; Rett Syndrome; X Chromosome Inactivation, X-linked mental retardation
INTRODUCTION
According to the Lyon hypothesis, after the random
inactivation of paternal or maternal X chromosome in a
cell, all of the daughters of that cell will have a similar
inactivated X. This process results a mosaic females which
have paternal active X in some cells and maternal active
X in others 1. Somatic cells have a stable X chromosome
inactivation (XCI); however, germline cells have a cyclic
XCI. If one of the X was heterochromatinized and
compressed during meiosis, pairing and recombination
would not completely achieved. Hence, while both X are
active during Oogenesis, one of them will be inactivated
during mitotic phase of gametogenesis (Figure 1).
Skewing of the normal pattern of XCI
Intermediate phenotypes in women who carry X-linked
diseases are considered as evidence of skewed XCI 2,3.
More than 80% (95% in severe cases) of cells show
preferred inactivation of one X chromosome in skewed
XCI 4. So that, these heterozygote women mainly will
have a single cell population, i.e. paternal or maternal
active X 5,6. Almost 10% of skewed XCI is by chance,
meaning that, for example, a heterozygous woman for
hemophilia has the least amount of factor VIII and
shows typical form of the disease similar to homozygous
women for the mutant allele 6,7 (Figure 2). Moreover,
chromosomal abnormalities and mutations that give a
ICNSJ 2016; 3 (2) :81-91 www.journals.sbmu.ac.ir/neuroscience
Correspondence to: Reza Taherian, Students’ Research Committee, School of Medicine, Shahid Beheshti University of Medical
Sciences, Tehran, Iran; Tel: +98-9123314094; E-mail: r.taherian@sbmu.ac.ir
Received: April 13, 2016 Accepted: May 21, 2016
Skewed X-chromosome Inactivation and Neurological Disorders—Taherian et al
82 International Clinical Neuroscience Journal • Vol 3, No 2, Spring 2016
cell selective advantage or negative attributes may play
a role in this skewness. For instance, if one of the X
chromosomes carry a mutant allele, which opposes
cell survival or inhibits the growth of cells, the cells
will inactivate that X chromosome in order to provide
cell survival and growth 8. Also, mutations in the XIC
(X inactivation center), which is a 13 Mb area in Xq
chromosome, mutation in Xist (X-inactive specific
transcript) promotor 8,9 or Tsix gene (a gene antisense
to Xist) deletion 10 may all cause skewed XCI. Promoter
single nucleotide polymorphisms or mutations affecting
the start of transcription of Tsix, Xist and Xite also
can change start of a correct XCI. For instance, single
nucleotide polymorphism in the second binding protein
of CTCF in Xist causes skewed XCI in order to inactivate
the other polymorphic allele 9-11. It should be noted that
in most cases, the reason for this skewing is unknown.
This skewing may occur during inactivating, which
is called primary skewing, or it may be the result of
selection after the XCI which is called secondary
skewing. For example, the slower proliferation of cells
expressing a mutant allele is considered as a secondary
skewed XCI 3,5. Cross of different strains of mice Shows
Xce (X-controlling element) locus to be the cause of a
primary, but not complete, skewed XCI and suggests
that these alleles cannot disrupt inactivation process but
they can disrupt the randomness of the beginning phases
of inactivation process 12. There are not any evidence
to confirm the presence of Xce locus in humans 13. As
mentioned before, in heterozygous women with a skewed
XCI, a single cell population with similar active X is
observed. Thus, the mutant gene on that chromosome will
be expressed in all cells and the normal allele will be
covered on the inactivated X. Hence, these heterozygous
women can show some diseases which are normally
presented only in men. This phenomenon is known as
manifesting heterozygote 7,14.
Despite some previous reports of familial skewed XCI,
such evidences are insufficient to confirm the heritable
pattern of skewing in humans 16. In carriers of X-linked
diseases, degree of skewing of XCI pattern, can affect the
severity of disease. In general, investigating the primary
phases of XCI is very difficult the spread of XCI in
human studies early events is very difficult. A delayed
replication is a good cytological marker for studying XCI
process. In X:autosome translocations, XCI can spread to
autosomal areas; however, this spread seems less efficient
compared to spreading on X chromosome 17. In women
with Balanced X:autosome translocation, the normal X
will be inactivated completely, but not persistently, to
avoid partial autosomal monosomy or X disomy 3,18. This
selective inactivation of one of the X chromosomes will
cause an X-linked disease in carrier women 4,16,19. In
imbalanced X:autosome translocations, the abnormal X
will preferably be inactivated 3. Investigating the spreading
of XCI into autosomal areas will provide analysis of the
DNA elements involved in the XCI signal propagation.
In some cases of XCI spreading, the translocation stops
in the breaking sites and cannot spread to autosomal
areas 20, while, it will spread incompletely to that areas 21.
Study of spread of Xist RNA into autosomal areas has
shown the variable abilities of Xist to cover autosomal
areas 22. Moreover, gene expression investigations have
shown that most genes in a X:autosome translocation
escape inactivation 3. The incomplete spreading of XCI to
autosomal areas suggests the presence of some functional
areas that contribute to the spread of XCI and are more
frequent on X chromosome compared to autosomal
chromosomes 23. Comparing the abilities of translocation
in spreading XCI raised the “repeat hypothesis” in which
the LINE-1 retrotransposons, which are frequent on X
Figure 2. Schematic representation of XCI in female somatic cells 15.
Figure 1. X chromosome inactivation. Reproduced from https://
www.studyblue.com.
Skewed X-chromosome Inactivation and Neurological Disorders—Taherian et al
83
International Clinical Neuroscience Journal • Vol 3, No 2, Spring 2016
chromosome, act as inactivation propagation elements 24.
Bioinformatics studies have shown that LINEs are
frequent around transcription start sites of the genes that
are incurred XCI 25,26. Repeats of polymorphic CAG in
exon 1 of the androgen receptor gene, which is located
on the Xq 11.2, and methylation of active and inactive X
chromosomes can be used to investigate the XCI pattern.
Figure 3 shows the detection method of inactivated X
chromosome by two polymorphic repeats (a and b). The
PCR is done after the effect of methylation-sensitive
enzymes, such as HpaII, which do not break inactive X
chromosome because they are methylated before 4, 27.
Skewed XCI and X-linked diseases
Although gene expression studies are an important
source of data in investigating neurodegenerative disorders,
lists of differentially expressed genes are rarely helpful
in understanding the underlying mechanisms of these
diseases 29. Hence, investigating single chromosomes with
a high role in developing neuro-developmental disorders
Figure 3. Method of identifying inactive X chromosome 28.
Skewed X-chromosome Inactivation and Neurological Disorders—Taherian et al
84 International Clinical Neuroscience Journal • Vol 3, No 2, Spring 2016
is more helpful. The X-chromosome contains a large
number of genes that are essential for brain development
and function 30. The expression of chromosome X is
generally higher in brain compared to other tissues
31.
This higher expression is linked to “X dosage
compensation” mechanism; a mechanism that associates
the expression of X-linked genes with the expression of
genes on autosomal chromosomes 32-35. Several brain
disorders are also associated with mutations of genes on
X chromosome 36-38. Heterozygous women show skewed
XCI in several X-linked diseases such as Wiskott-Aldrich,
Lesch–Nyhan, Barth, Muscular dystrophy Duchesne,
hemophilia, and some immune deficiency syndrome 39-41.
In these cases, a higher prevalence of skewed aging is
observed by aging 6,7. The skewed XCI causes variable
manifestations of many neurological disorders including
autism, Rett syndrome, X-linked adreno-leukodystrophy,
X-linked mental retardation and etc 8,27,42-44.
Cell removal is the most common phenomenon
occurred in heterozygote women with two cell populations
and can yield many advantages for them 40. For example,
in heterozygotes older than 10 years who carry the
Lesch-Nyhan syndrome gene, the mutant cells could
not be detected in their blood and they are completely
removed due to presence of cells expressing normal
allele 7. Although the presence of the cells with normal
allele may not be dominant, it is sufficient to preclude
the mutant allele phenotype.
In heterozygous women, dermal cells with normal
allele compete well with Lesch-Nyhan mutation. Because,
normal cells, transmit inosinic acid, which is the product
of hypoxanthine guanine phosphoribosyl transferase
(HGPRT) enzyme, and is absent in this disease. Indeed,
heterozygous women have channels that pass molecules
such as inosinic acid and so, with the removal of cells
with mutant alleles that do not have these channels,
deficiency in HGPRT is compensated 7.
X-linked adrenoleukodystrophy
X-linked adreno-leukodystrophy (X-ALD) was first
described by Haberfeld and Spieler in 1910. However,
Siemerling and Creutzfeld described combination of
adrenocortical atrophy, cerebral demyelination and
lymphocytic infiltration in a case of what is now considered
the first true report of X-ALD. The name X-ALD was first
introduced in 1970 45. In this disorder, the characteristic
accumulation of very long chain fatty acids (VLCFA) is
observed which was first observed as the presence of lipid
inclusions in adrenal cells of X-ALD. Now, detection of
the accumulation of VLCFAs in blood, red blood cells,
fibroblasts and amniocytes with new assays enables
better and earlier diagnosis of X-ALD. The adult form
of X-ALD was named adrenomyeloneuropathy (AMN) by
Griffin et al. in 1977 46. As our knowledge about X-ALD
increases, the diagnosis of this disorder will be more
probable and consequently its incidence will increase.
Like other X-linked disorders, referring the X-ALD as
an X-chromosomal recessive disorder is inappropriate
and it should be simply called as an X-linked disorder 47.
It is estimated that about half of the heterozygous
X-ALD females will develop adrenomyeloneuropathy-
like syndrome
48. Thus, heterozygote X-ALD is more
prevalent than homozygote
49. Thus, X-ALD is both
the most frequent peroxisomal disorder and also the
most frequent monogenetically inherited demyelinating
disorder. This monogenic inherit is now considered to be
related to the mutations in the ABCD1 gene 50 (Figure 4).
The inherited defect in X-ALD is linked to a mutation
in G-6-PD gene which is located in the Xq28 51 with
polymorphic markers 52,53. Using positional cloning,
the G-6-PD was cloned and after that it was termed
adreno-leukodystrophy gene. As this gene encodes a
peroxisomal transmembrane protein with a structure
similar to the ATP-binding cassette transporter, the
gene was renamed to ATP-Binding Cassette transporter
subfamily D member1 gene (ABCD1). However, the
protein is still termed as adreno-leukodystrophy protein
(ALDP). Until now, 431 different mutant ABCD1 alleles
have been reported. Of these mutations, 221 are missense
mutations, 53 nonsense mutations, 27 amino acid
insertions and deletions, 113 frame shift mutations and
17 deletions of one or more exons. These mutations are
equally distributed among the entire coding region of the
ABCD1 gene, however, investigating the 221 missense
Figure 4. X-linked adreno-leukodystrophy genetic. Reproduced from
http://genetics4medics.com
Skewed X-chromosome Inactivation and Neurological Disorders—Taherian et al
85
International Clinical Neuroscience Journal • Vol 3, No 2, Spring 2016
mutations showed that there is no disease-associated
mutation within the first 88 N-terminal amino acids and
in the last 45 C-terminal amino acids. Interestingly two
single base pair substitutions in exon 1 is reported in
one of X-ALD cases which causes amino acid exchanges
(N13T and K217E). Previous studies have shown that
K217E amino acid exchange was the only ineffective
exchange in restoration of defected β-oxidation in X-ALD
fibroblasts 54. However, ALDP function is not affected by
the N13T amino acid exchange which is consistent with
the hypothesis that a reduced functional importance in the
first 66 N-terminal amino acids of ALDP is present. No
correlation is observed ABCD1 gene mutation type and
the disease clinical presentation. This report is consistent
with previous studies 55-58. These studies showed that
clinical presentation of X-ALD occur within the same
nuclear family 55, mutations causing complete loss of
ALDP are associated with various clinical presentations 56,
a similar deletion in exon 5 leads to a wide spectrum
of X-ALD 56,57 and finally, monozygotic twins present
completely different clinical presentations 58. However,
these studies do not lower the possibility of the preventive
role of residual ALDP in development of inflammatory
cerebral form of X-ALD and its consequent milder
phenotype. In the p-glycoprotein multidrug resistance
transporter, some mutations can lower the transport rate.
ABCA4 (ABCR) gene may also has residual functional
activity in age-related macular degeneration and Stargardt
disease 59. Thus, although a general genotype–phenotype
association cannot be observed, rare cases with this
association may exist.
Besides the presence of functional ABCD1 gene on
Xq28, several autosomal pseudogenes are detectable of
different chromosomes. ABCD1 pseudogenes are located
in 1, 2, 20, 22, and possibly 16 chromosomes which
can be detected by PCR analysis of human monochro-
mosomal mapping panel 56. The pseudogenes on several
different chromosomes harden the mutation analysis 60
and may show non-homologous interchromosomal
exchange pericentromeric plasticity 61.
X-Linked Mental Retardation
Mental retardation (MR) is known as the impairment
of cognitive function which affects about 3% of the
population in the US. This disorder is often manifested
before adulthood and 20–30% of MR may be inherited
or have a genetic background by mutations on the X
chromosome X-linked mental retardation (XLMR). Based
on their clinical presentation, XLMRs are considered as
two types of non-syndromic and syndromic. However,
since there are several mutations responsible for these
clinical presentation, the difference between these
two types is now less notable. About 73 dysfunction
of PAK are considered to be involved in the incidence
of both types of XLMR. Several X-linked mutations
causing non-syndromic MR (MRX) are detected on the
X chromosome. This type of MR is clinically similar
but they are genetically diverse. Now, more than 65
MRX pedigrees are detected on different loci on the
X chromosome and it is estimated that these pedigrees
represent about 10 genetic loci 62,63. Among these loci,
probably about two MRX genes have the key roles in
the mentioned signaling. The first gene is named GDI1
which encodes a GDP-dissociation inhibitor for Rab3a
and regulates vesicular transport. Hence, GDI1 mutations
changes the exocytic activity which is in part related to
the synaptic transmission. Another gene which is mutated
in MRX encodes a protein which includes a GTPase
activation domain (GAP) for Rho GTPases and is called
oligophrenin. Since these proteins induce the GTPase
activity, inactivation of them leads to permanent activity
of the corresponding G protein. Oligophrenin have Gap
activity for the signals that control actin cytoskeletal
organization and cell shape 64. One of these proteins
is Rho GTPase which directly controls the axon and
dendritic shape and activity 65-66. The role of a Rho GAP
in human mental retardation implicates its involvement
in neural plasticity. Moreover, PAK3 is reported to be
isolated from Xq22 in MRX families 67. The PAK3 gene
is mainly expressed in the brain, and it is known as an
important downstream effector of Rho GTPases through
actin cytoskeleton and MAPK cascades. Two diseases
are reported to have mutations in MRX pedigrees, one
of them includes a nonsense 68 and another a missense
mutation 69 which implicate the association between
PAK3 and pathogenesis of MRX.
Considering the role of PAK in fragile X syndrome
(FXS), recent studies have shown a defective activation
of synaptic RAC/PAK signaling in the mouse model
of FXS 70. Expectantly, inhibiting PAK activity reduces
various cellular and behavioral deficits, including FXS-
related abnormalities 71. These results implicate the role
of PAK signaling in the FXS pathogenesis.
Fragile X syndrome is the most common inherited form
of mental retardation 72,73. Although the pathogenesis of
FXS is not well understood, it is probably the result of
the expansion of the CGG repeat in the 5-untranslated
region of the fragile X mental retardation 1 (FMR1) gene
which is located on the X chromosome 74. This expansion
silences the transcription of FMR1 gene and leads to the
Skewed X-chromosome Inactivation and Neurological Disorders—Taherian et al
86 International Clinical Neuroscience Journal • Vol 3, No 2, Spring 2016
FXS phenotype. The resultant change of the length of
the CGG is the main factor in determining FXS disease
or its carrier form. Having more than 200 CGG repeats
causes FXS-associated cognitive deficits and abnormal
cortical dendritic spines 75.
FMR1 protein (FMRP) plays an important role in
regulation of mRNA translation, transport and stability 76,77.
In the brain, FMRP can regulate translation of a group of
mRNAs at synapses which are essential for learning and
intellectual development. Consequently, in the absence
of FMRP, reduced mRNA translation causes the defect
in synaptic function and synaptic plasticity 76,78,79. FMR1
Knocked-out mice show behavioral defects similar to FXS
patients. These behavioral disturbances include hyper-
reactivity to auditory stimuli, anxiety, impaired spatial
learning and impairment in motor coordination 80-82.
Hence, the association between PAK and FMRP 71 or
defected synaptic RAC/PAK signaling implicate the
reduced synaptic plasticity in patients with FXS. Thus,
targeting PAK signaling may be a potential therapeutic
strategy in formulating new drugs to treat FXS.
In summary, previous data show that normal memory
and leaning is achieved by functional PAK and pathways
which are disturbed in FXS and similar disorders with
developmental cognitive deficits such as dementia of
aging (AD) and Huntington disease (HD). Inhibition of
PAK seems to be an effective approach in treating FXS,
AD and HD. Inhibitors of PAK likely have important
effects on improving cognition by improving dendritic
spine morphology and/or synaptic plasticity. This
hypothesis considers PAK activation as a contributing
factor in the incidence of various neurological disorders
and probably suggest a common treatment for them based
on the correcting PAK dysregulation.
Rett Syndrome
Rett syndrome (RTS) is considered as a progressive
disorder affecting neuro-development in girls; however,
some of the features of the disease appears slowing are not
prominent at initial stages of the disease. These patients
develop normally up to 6-18 months of age. During this
development, patients will have a normal milestones
including walking and saying some words. One of the
early signs of neuro-developmental involvement is
microcephaly which is the result of the deceleration of
head growth between ages one and two and is associated
with growth retardation and muscular hypotonia.
Progression of the disease causes a lost purposeful
use of hands which interrupts normal hand functions.
The patient will be withdrawn socially and inability to
speech become more apparent by aging which turns the
patient irritable. The patients is also hypersensitive to
surrounding sounds, cannot make an eye-to-eye contact
and is unresponsiveness to social cues 83.
Genetic Basis of RTS
Considering that most of the RTS patients are female,
early studies have hypothesized an X-linked dominant
model of inheritance in RTS. However, almost all of
the RTS cases are sporadic and mapping the generic
inheritance of the disease was difficult. Using data from
rare familial cases, Xq28 was identified as the candidate
region and subsequently, mutations in MECP2 were
identified in RTS patients 84 (Figure 5).
These mutations can be detected in about 96% of RTS
cases and arise de novo in the paternal germline with a C
to T transition at CpG dinucleotides 85. These mutations
include missense, nonsense, and frameshift mutation types
with over 300 unique pathogenic nucleotide changes
described 86 as well as deletions 87,88. Eight missense
and nonsense mutations are responsible for more than
75% of all of the mutations in RTS. C-terminal deletions
causes 10% and complex rearrangements are responsible
for about 6% of all mutations in RTS. Missense mutations
cause a more mild phenotype than mutations affecting
the NLS of MeCP2; Similarly, C-terminal deletions are
associated with milder phenotypes 89. Moreover, a mild
phenotype is present in the R133C mutation 90,91.
Figure 5. Rett syndrome genetic. Reproduced from http://
genetics4medics.com.
Skewed X-chromosome Inactivation and Neurological Disorders—Taherian et al
87
International Clinical Neuroscience Journal • Vol 3, No 2, Spring 2016
Autism
The diagnosis of autism is based on the presence of
abnormality in a triad of behavioral domains: social
development, communication, and repetitive behavior/
obsessive interests. While autism can occur at any point on
the intelligence quotient (IQ) continuum, IQ can predict
the outcome of autism. The disease is associated with a
language delay. Autism has a spectrum which Asperger
syndrome is a subgroup of it. Patients with this syndrome
have similar features of common autism; however, they
have no history of language delay and moreover, they
have an average or higher than average IQ. The features
of autism spectrum is highly probable to be caused by
genetic factors. The risk of presence of autism in the
sibling of a patient is 4.5% which emphasizes a genetic
inheritance 92 (Figure 6).
In a study of same sex autistic twins, while no
dizygotic twins were concordant for autism, concordance
was present in about 60% of monozygotic pairs 93. This
concordance in monozygotic twins shows a high degree
of genetic inheritance of autism. Different genetic studies
are done to determine the candidate regions involved in
autism. Although these regions are not fully understood,
two regions are the most probable candidates. These
regions are 15q11-13, near the GABAAb3 receptor
subunit gene (GABRB3) and 17q11.2, near the serotonin
transporter gene (SLC6A4). The second region is under
high investigations because of the previous reports about
the increased serotonin levels of platelets in autism.
Also, the involvement of serotonin in autism is highly
probable because it innervates the limbic system which
has known roles in emotion recognition and empathy. At
least four loci on the X chromosome are also detected to
be involved in autism and are high interest due to their
ability to clarify sex differences in autism. These genes
are the neuroligin (NLGN3, NLGN4), FMR1 (which
causes fragile X syndrome), and MECP2. Despite there
are candidate regions, specific genes for autism have not
been detected yet. Further research is needed to detect
these specific genes and also to clarify their function
and ultimately the relation between different influential
factors in autism 92.
Charcot-Marie-Tooth
Charcot-Marie-Tooth (CMT) which is known as
hereditary motor and sensory neuropathy consists of
clinically and pathologically heterogeneous group of
disorders. This disease is considered as a common form
of peripheral inherited neuropathy in humans. The disease
includes slowly progressive atrophy; weakness of the
distal muscles; sensory loss in the feet, lower legs, and
hands; and reduced tendon reflexes 94. CMT is classified
into types 1 and 2 based on the histopathology and nerve
conduction studies 95. Although some X-linked and
autosomal recessive forms of the disease are reported,
the most common form of CMT is inherited autosomal
dominant 96. CMT 1A is a demyelinating neuropathy
related to a duplication of piece of gene on 17p11
chromosome which encodes myelin protein 97. It is
the most common form of the disease inherited as an
autosomal dominant disease. The clinical expression of
this disease depends on the age of the patient and the
average age of the onset of clinical features is 12.2+7.3
years. At least three loci are included in CMT1: the
CMT1A locus maps to human chromosome 17 and the
CMT1B locus maps to human chromosome 1 (region
q23-q25) 98. Since the clinical phenotypes of CMT1
syndromes cannot be distinguished, unless in cases of
male to male inheritance, three genes must be sequenced
which include connexin gene, po gene and PMP22 gene
for X-linked CMT, CMT1B and CMT1A respectively 99.
The X-linked CMT due to the connexin 32 (Cx32) gene
mutation is the second most common form of CMT 100
(Figure 7).
This gene is expressed in several tissues including
both peripheral nerve axons and CNS glia and neurons.
Families with dominant inheritance, which is revealed by
a male-to-male inheritance, PMP22 and po genes must be
screened for mutations. Families with no male-to-male
inheritance or CMT1A may be screened for connexin 32
gene first and then Po and PMP22 102. In an X-linked
pattern of inheritance, male are more severely affected
and not father-to-son transmission is seen. Females who
are heterozygous and may be asymptomatic. Intermediate
Figure 6. Autism genetic prospect 92.
Skewed X-chromosome Inactivation and Neurological Disorders—Taherian et al
88 International Clinical Neuroscience Journal • Vol 3, No 2, Spring 2016
range motor conduction velocities is found in X-linked
CMT. Accordingly, prolonged brainstem auditory evoked
potentials (BAEPs) may be used as a distinguishing
feature X-linked CMT in males and females due to XCI
in females 103.
DISCLOSURE STATEMENT
The authors have nothing to disclose.
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