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Elevated expression of messenger RNA for peripheral myelin protein 22 in biopsied peripheral nerves of patients with C Harcot-Marie-Tooth disease type 1A.

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was tried in these controls because they were suspected of
having pseudoseizures, the results of the test under investigation cannot be used to classify them by disease status; such
subjects may include both individuals who d o not have pseudoseizures and individuals who have pseudoseizures but who
have a negative test. The result of such misclassification
would be to inflate both the sensitivity and specificity 131. If,
instead, the controls were typical epileptic patients who were
well studied and were not suspected of having pseudoseizures, they would not be typical of the spectrum of individuals for whom the test would be applied in practice. In this
situation, the specificity would be inflated over that which
would be obtained in practice [4,51. In any case, the investigators report a specificity of 100% based on only 20 controls.
Several techniques exist by which 95% confidence intervals
of this estimate could have been calculated. The lower limit,
depending on the method, ranges from about 82 to 85%.
In addition, epileptic seizures have apparently been produced, albeit uncommonly, by placebo infusion [6}. It is also
possible that a patient who typically has only epileptic seizures could have a pseudoseizure with suggestion, perhaps
trying to demonstrate a seizure to gain credibility.
We did not produce positive inductions in any epileptic
patients. We considered inductions positive when typical
spells were provoked. Evidence of suggestibility and atypical
spells were not considered positive results. It is usually not
difficult to distinguish typical and atypical attacks.
Departments of Neurology, Preirntiue Medicine and
Environmental Health. and Sanders Broux Center on Aging
lJnit:ersit~lof Kentucky Medical Center, and Nerirology Seruice
Veterans Adminiitration Medical Center
Lexington, KY
John Kamholz, MD, PhD," Michael Shy, MD,t
and Steven Scherer, MD, PhD"
References
1 . Iancman ME, Asconape JJ. Craven WJ, et al. Predictive value of
induction of psychogenic seizures by suggestion. Ann Neurol
1994;35:359-361
2. Connell FA, Koepsell TD. Measures of gain in certainty from a
diagnostic test. Am J Epidemiol 1985;12 1:744-753
3. Begg CB. Biases in the assessment of diagnostic tests. Stat Med
1987;6:411-423
4 . Rozanski A, Diamond GA, Berman D, c" al. The declining specificity of exercise radionuclide ventriculography. N Engl J Med
1983;309:518-522
5. Nierenberg AA, Feinstein AR. How to evaluate a diilgnostic
marker test: lessons from the rise and fall of dexamethasone suppression test. JAMA 1988;259:1699-1702
6. Walczak TS, Williams DT, Berten W. Utility and reliability of
placebo infusion in the evaluation of patients with seizures. Neurology 1994;44:394-399
Reply
Marcel0 E. Lancman, M D
We appreciate the comments by Lanska. We agree that the
predictive values should be recalculated for each individual
population. The sample tested closely approximates the patient population in whom induction is useful, i.e., patients
with suspected psychogenic seizures or patients with a good
clinical history for epilepsy but no objective evidence for
epilepsy from video-electroencephalographic monitoring.
There was no evidence of psychogenic seizures in our
group of epileptic patients, and therefore, we consider this
group to be an adequate control group for our study. While
the sensitivity was loo%, we agree that the 95% confidence
interval may range from 82 to 85%.
Bowman Gray School of Medicine
Cleveland. OH 441 95
Elevated Expression of
Messenger RNA for
Peripheral Myelin Protein
22 in Biopsied Peripheral
Nerves of Patients with
Charcot-Marie-Tooth
Disease Type 1A
Yoshikawa and co-workers [l},in the April Annals of Newolo g , present evidence that the mRNA levels for PMP-22, the
gene of which is duplicated in most patients wirh CharcotMarie-Tooth disease type 1A (CMTlA), is increased in peripheral nerve of these individuals compared with controls.
This result thus lends credence to the notion that overexpression of PMP-22 is the cause of demyelination in CMTlA.
Although we believe that this mechanism is the likely cause
of demyelination in CMTlA, we have questions about the
data presented in this article, as well as its interpretation.
Several well-characterized rodent models of peripheral
nerve demyelination have been evaluated for their patterns
of myelin-specific gene expression, including nerve transectiodwallerian degeneration {2J, tellurium neuropathy { 3 , 4 ) ,
and a point mutation in PMP-22 (trembler mice) [ 5 , 61. In
each of these models, there is a significant decrease in the
steady-state levels of the major myelin protein mRNAs in
peripheral nerve compared with unlesioned controls. For example, the steady-state levels of Po mRNA in trembler sciatic
nerve is 10-fold less than in control littermates during the
peak of myelination [ S ] . In addition, the decrease in myelinspecific mRNA levels has been shown, in tellurium neuropathy, to be related to morphologcal changes of demyelination
in individual Schwann cells [ 4 ] . Finally, in all three models, all
of the myelin-specific mRNA levels decline in a coordinate
fashion with identical kinetics during demyelination, and increase with identical kinetics with remyelination, if it occurs.
The Northern blot shown in Figure 1 of the article by
Yoshikawa and co-workers [ l ] demonstrates that Po mRNA
levels are very similar in the three groups of nerves studied,
including normal controls, diseasc controls, and CMTlA patients, although PMP-22 mRNA levels are increased in
CMT 1A nerves. Taking into consideration the physiological
response of the nerve to demyelination, discussed above, this
result is difficult to explain. Demyelination should lead to
Annals of Neurology Vol 36 N O 3 September 1994 451
a marked decrease in the steady-state levels of P,, mRNA
compared with normal controls. Furthermore, since there is a
coordinate decrease in all myelin-specific mRNA levels after
demyelination, one would also expect steady-state levels of
PMP-22 mRNA to decrease in demyelinating peripheral
neuropathies relative to normal controls, whatever the cause
of the neuropathy. In support of this notion, a coordinate
decrease in all major myelin mRNAs has been found in
transgenic mice in which demyelination has been produced
by increased PLP gene dosage, presumably leading to its
overexpression [ 7 ] .Thus, although we agree with Yoshikawa
and colleagues [ I ) that increased expression of PMP-22 is
the likely initial cause of demyelination in CMTlA with an
associated PMP-22 duplication, the Northern blotting data
they present are internally inconsistent with the known physiological consequences of peripheral nerve demyelination. For
this reason, these data must be interpreted with caution. How
increased PMP-22 gene dosage causes demyelination in
CMTlA has yet to be determined.
*Department of Neurology
Uniiiersity of Pennsyhania School of Medicine
Philadelphia. PA 19104
t Departnient of Neurology
Thomas Jeffersoir Uniiiersity
Philadelghia. PA 19107
Ref rences
1. Yoshikawa H, Nishimura T, Nakatsuji Y, er al. Elevated expression of messenger RNA for peripheral myelin protein 22 in biopsied peripheral nerves of patients with Charcot-Marie-Tooth disease type 1A. Ann Neurol 1994;35:445-459
2. Scherer S, Wang D, Kuhn R, et al. Axons regulate Schwann cell
expression of the POU transcription factor, SCIP. J Neurosci
1994; 14:1930- 1942
3. Toews AD, Eckermann CE, Roberson MD, et al. Primary demyelination induced by exposure to tellurium alters mRNA levels
for nerve growth factor receptor, SCIP, 2’,3’-cyclic nucleotide
3’-phosphodiesterase, and myelin proteolipid protein in rat sciatic
nerve. Brain Res Mol Brain Res 1991;11:321-325
4. Toews AD, Griffiths IR, Kyriakides E, et al. Primary demyelination induced by exposure to tellurium alters Schwann cell gene
expression: a model for intracellular targeting of N G F receptor.
J Neurosci 3992;12:3676-3687
5. Bascles L, Bonnet J and Garbay B. Expression of the PMP-22
gene in Trembler mutant mice: comparison with other myelin
protein genes. Dev Neurosci 1992;14:336-34 1
6. Garbay B, Domec C. Fournier M, Bonnet J. Developmental expression of the Po glycoprorein and basic protein mRNAs in
normal and trembler mutant mice. J Nrurochem 1989;53:90791 1
7. Readhead C, Schneider A, Grifhhs I, Nave K-A. Premature
arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 1994;12:583-595
Reply
Hiroo Yoshikawa, MD, Tomoya Nishimura, MD,
Saburo Sakoda, MD, and Takehiko Yanagihara, M D
We thank D r Kamholz and his associates for their interest
in our recent article [I]. In spite of their opinion that
452 Annals of Neurology
PMP-22 mRNA should be decreased in Charcot-MarieTooth disease type 1A (CMTlA), our results showed that
the relative expression of mRNA for PMP-22iP-actin in
C M T l A was higher than that in controls. Hanemann and
associates [2] very recently provided a Northern blot analysis
of PMP-22 expression in total R N A of sural nerve biopsies
from 4 CMTlA patients compared with control patients using glyceraldehyde 3-phosphate dehydrogenase (G3PDG) as
a reference probe. According to their results, PMP-22
mRNA expression levels in C M T l A were similar or higher
than in controls. Due to the small number of biopsies examined, they did not make a statistical assessment. However,
their data seem to support our result.
W e are somewhat puzzled by the statement of D r Kamholz
and his group that demyelination should lead to a marked
decrease in the steady state level of Po mRNA compared
with normal controls. W e agree that would happen in an
acute phase of demyelination, whatever the cause of a neuropathy. However, C M T l A is a chronic disease presenting
recurrent demyelination and remyelination. Myelin-specific
mRNA levels theoretically should decrease in a phase of
demyelination and increase in a phase of remyelination on
individual Schwann cells. W e suspect we can measure only
summed mRNA of different phases of myelination.
As Dr Kamholz and his associates pointed out, Bascles and
co-workers [3] have shown that a steady-state level of
mRNA encoding PMP-22 in the sciatic nerve of trembler heterozygous mice are more markedly decreased than that of
mRNA encoding Po or MBP (myelin basic protein), using
G3PDG as a reference probe. W e think that CMTlA with
D N A duplication is different from trembler mice carrying a
point mutation of PMP-22 in both pathology and genetic
background. Therefore, the data obtained from trembler mice
may not be applicable to CMTlA.
In transgenic mice with increased proteolipid protein
(PLP) gene dosage, Readhead and collaborators 147 have
shown that only twofold transcriptional overexpression
resulted in a novel phenotype characterized by severe hypomyelination and astrocytosis. They interpreted it to be a response to a premature arrest of oligodendrocyte differentiation. We suspect that a similar mechanism may play a role in
causing primary demyelination in CMT 1A patients.
Department of Neurology
Osaka Uniz~ersityMedical School
O~aka.
Japan
Ref rences
1. Yoshikawa H , Nishimura T, Nakatsuji Y, et al. Elevated expression of messenger RNA for peripheral myelin protein 22 in biopsied peripheral nerves of patients with Charcot-Marie-Tooth dise a e type 1A. Ann Neurol 1994;35:445-450
2. Hanemann CO, Stoll G , D U r s o D, et al. Peripheral myelin protein-22 expression in Charcot-Marie-Tooth disease type la sural
nerve biopsies. J Neurosci Res 1994;37:654-659
3. Bascles L, Bonnet J, Garbay B. Expression of the PMP-22 gene in
Trembler mutant mice: comparison with the other myelin protein
genes. Dev Neurosci 1992;14:336-341
4. Readhead C, Schneider A, Griffiths I, Navr K-A. Premature
arrest of myelin formation in transgenic mice wlth increased proreolipid protein gene dosage. Neuron 1994;12:583-595
Vol 36 N o 3 September 1994
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expressions, biopsies, periphery, patients, rna, nerve, messenger, toots, typed, disease, marie, protein, elevated, myelin, harcot
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