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Borna disease virus RNA is absent in chronic multiple sclerosis.

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LETTERS
Alteration of the Serotoninergic System in Fatal
Familial Insomnia
Pietro Cortelli,1 Ronald Polinsky,2 Pasquale Montagna,3
and Elio Lugaresi3
1
We read with interest that Wanschitz and colleagues found a
substantial increase in tryptophan hydroxylase-immunoreactive
neurons in the pons (superior central nucleus) and medulla
(raphe obscurus nucleus) of fatal familial insomnia (FFI) patients, suggesting that a serotoninergic system impairment represents the functional substrate of some typical FFI symptoms.
We report the lumbar cerebrospinal fluid (CSF) concentrations of monoamine metabolites in 3 FFI subjects (1 female) of 2 unrelated Italian families already described.2 We
measured 5-hydroxyindoleacetic acid (5-HIAA), homovanillic
acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)
by a gas chromatographic, mass spectroscopic method previously described.3,4 The central component of MHPG was
calculated according to the formula [total CSF MHPG] ⫺
0.9 [free plasma MHPG].4 FFI patients had the typical point
mutation at codon 178 of the prion protein gene combined
with methionine at codon 129 of the mutated allele. Lumbar
puncture was performed in a standardized fashion3 13 (in 1
case) and 6 (in 2 cases) months after disease onset. Average
ages (⫾ standard error of the mean) at the time of CSF
collection for the 3 FFI patients and 24 controls were 55 ⫾
2 and 47 ⫾ 3 years. The CSF level of 5-HIAA in FFI patients (37.63 ⫾ 4.13ng/ml) was significantly higher ( p ⬍
0.0001) than that in controls (18.72 ⫾ 1.95ng/ml). There
were no significant differences between controls and FFI patients with respect to lumbar CSF levels of HVA (FFI 44 ⫾
1.2ng/ml, controls 42 ⫾ 2.3ng/ml) and corrected CSF
MHPG (FFI 6.46 ⫾ 0.8ng/ml, controls 5.34 ⫾ 0.2ng/ml).
Our results in FFI patients are consistent with increased
central serotonin [5-hydroxytryptophan (5-HT)] turnover and
with the findings of Wanschitz et al.,1 attended by normal
dopaminergic activity and a slight increase in central noradrenergic function. However, we caution against an oversimplified explanation of an altered serotoninergic system as the only
functional substrate for all symptoms of FFI. The hallmark of
FFI is selective degeneration of anteroventral (AV) and mediodorsal (MD) thalamic nuclei, which constitute an important control station in the so-called central autonomic network, including several areas of the telencephalon, hypothalamus, and brain stem interconnected via parallel, functionally specific, and neurochemically complex pathways.5 The
5-HT system is one of these pathways and has been implicated
in the regulation of the sleep–wake cycle and cardiovascular
system, but its effects are subordinate to the control of higher
diencephalic centers and the subtype of 5-HT receptors involved.5 The crucial role of the AV and MD thalamic nuclei
in regulating sleep and integrating autonomic and endocrine
responses critical for homeostasis has been confirmed by studies showing that wake–sleep and autonomic features comparable to FFI may be reproduced in experimental animals by
kainic acid injection into the MD and the reticular nucleus of
the thalamus.2 Lesions to the thalamus disrupt the cortical–
limbic circuitry with a cascade effect on the functions of many
systems. For instance, there is pharmacological evidence of
GABAergic system involvement in FFI patients.6 Thus, while
confirming increased activity of the serotoninergic system in
FFI, we believe that it represents just one of the many biochemical systems involved.
1
University of Modena and Reggio Emilia, Bologna, Italy;
AstraZeneca Pharmaceuticals, Wilmington, DE; and
3
University of Bologna, Bologna, Italy
2
References
1. Wanschitz J, Kloppel S, Jarius C, et al. Alteration of the serotonergic system in fatal familial insomnia. Ann Neurol 2000;48:
788 –791.
2. Montagna P, Cortelli P, Avoni P, et al. Clinical features of fatal
familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene. Brain Pathol
1998;8:515–520.
3. Polinsky RJ, Brown RT, Burns RS, et al. Low lumbar CSF levels
of homovanillic acid and 5-hydroxyindoleacetic acid in multiple
system atrophy with autonomic failure. J Neurol Neurosurg Psychiatry 1988;51:914 –919.
4. Polinsky RJ, Jimerson DC, Kopin IJ. Chronic autonomic failure:
CSF and plasma 3-methoxy-4-hydroxyphenylglycol. Neurology
1984;34:979 –983.
5. Benarroch EE. Central autonomic network: functional organization and clinical correlations. Armonk, NY: Futura, 1997.
6. Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia
and dysautonomia with selective degeneration of thalamic nuclei.
N Engl J Med 1986;315:997–1003.
Reply
Julia Wanschitz, MD,1 Marin Guentchev, MD,1 and
Herbert Budka, MD1,2
We thank Cortelli and colleagues for their attention to our
article. Their report of high cerebrospinal fluid (CSF) levels of
the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA)
in 3 patients with fatal familial insomnia (FFI) confirms increased activity of the serotoninergic [5-hydroxytryptophan
(5-HT)] system in FFI patients as indicated by our observation of an increased number of tryptophan hydroxylaseimmunoreactive (TH⫹) neurons in median raphe nuclei.1
As Cortelli and colleagues stated, these results must be interpreted with caution. We did not postulate a trivial explanation of the complex and unique clinical features of FFI as
simply a serotonin-related disorder. We hypothesized that
enhanced serotoninergic neurotransmission might contribute
to the profound disturbance of control of autonomic homeostasis in FFI in accordance with the current knowledge
about serotoninergic function on sleep, circadian rhythmicity,2
and cardiovascular responses,3 based on the dense innervation of the limbic anteroventral and mediodorsal thalamic
nuclei by serotoninergic fibers.
The critical role of thalamic nuclei in the pathophysiology
of central dysautonomia characteristic of FFI is well established.4 Despite the paucicity of classical histopathological lesions in other areas involved in the control of autonomic
functions, such as the hypothalamus and several regions of
the brain stem, the importance of subtle changes recorded in
these areas5 remained unclear. The changes in the ratio of
TH⫹ to TH⫺ neurons in median raphe nuclei of the brain
stem in FFI patients most likely represents an impaired neuronal function of the 5-HT system as one of the pathways
© 2001 Wiley-Liss, Inc.
421
possibly involved in the disease. We did not observe similar
changes in sporadic and familial Creutzfeldt-Jakob disease or
cases with a selective ischemic thalamic lesion (Budka et al,
unpublished observation).
The main question arising from both studies is whether the
observed changes are pathogenic or occur as a compensatory
phenomenon to other events, such as downregulation of serotonin receptors, loss of the neuronal targets of the serotoninergic system, or alteration of other neurotransmitters (eg,
corticotropin-releasing factor, which may modulate 5-HT release6). We believe that such considerations have an important
clinical impact as they form the theoretical basis for the potential use of serotonin antagonists in the treatment of FFI.
Additional studies should clarify the usefulness of CSF
5-HIAA determination as an early diagnostic marker of FFI.
1
Institute of Neurology, University of Vienna, and 2Austrian
Reference Center of Human Prion Diseases, Vienna, Austria
References
1. Wanschitz J, Klöppel S, Jarius C, et al. Alteration of the serotonergic nervous system in fatal familial insomnia. Ann Neurol
2000;48:788 –791.
2. Jouvet M. Sleep and serotonin: an unfinished story. Neuropsychopharmacology 1999;21(Suppl):24S–27S.
3. Bell AA, Butz BL, Alper RH. Cardiovascular responses produced
by microinjection of serotonin-receptor agonists into the paraventricular nucleus in conscious rats. J Cardiovasc Pharmacol
1999;33:175–180.
4. Benarroch EE, Stotz-Potter EH. Dysautonomia in fatal familial
insomnia as an indicator of the potential role of the thalamus in
autonomic control. Brain Pathol 1998;8:527–530.
5. Parchi P, Castellani R, Cortelli P, et al. Regional distribution of
protease-resistant prion protein in fatal familial insomnia. Ann
Neurol 1995;38:21–29.
6. Price ML, Lucki I. Regulation of serotonin release in the lateral
septum and striatum by corticotropin-releasing factor. J Neurosci
2001;21:2833–2841.
Effects of Seasons on Magnetic Resonance
Imaging-Measured Disease Activity in
Patients with Multiple Sclerosis
Helen Tremlett, BPharm Hons, PhD
I am writing in response to the study by Rovaris and colleagues,1 which concluded that MRI in MS patients does not
exhibit seasonal variation. Whilst such an effect may or may
not exist, their study does not refute this possibility for a
number of reasons.
First, the MS patients recruited were a highly selected
group. Inclusion criteria required each patient to have at least
one active lesion and one relapse in the past 2 years. These
patients were therefore in a very active phase of disease, as
acknowledged by the authors of the original study who
stated, “Clearly, this makes this cohort of patients difficult to
compare with those of previous trials.”2 This quite possibly
means that the effects of seasonal variation, if it exists, or if
indeed it exists in this group of highly selected patients, may
be tempered and “lost.”
Second, the study included patients from Canada as well
as Europe; the spread of patients in each country was not
stated. Geographical location is important as seasonal varia-
422
Annals of Neurology
Vol 50
No 3
September 2001
tion of MRI scans maybe associated with 25-hydroxyvitamin
D (25(OH)D) levels, as found in Germany.3 This phenomenon may not be so pronounced in North American and
Scandinavian countries. This is because seasonal variation of
25(OH)D levels is more evident in central and western Europe than in North America and Scandinavia.4 Whilst studies in all these countries have shown seasonal variation of
25(OH)D levels in young adults, the effect was not so pronounced in central and Western European countries.4 Indeed, central and western European 25(OH)D levels in
young adults were significantly lower compared to North
American and Scandinavian countries in winter and spring/
fall ( p ⬍ 0.01) but not summer ( p ⬎ 0.05).4 This appeared
primarily because of increased consumption of vitamin D
containing supplements and foodstuffs (notably fortified
foodstuffs in North America and oily fish in Scandinavia).4
Third, data in the study1 was only collected over a 10month period. To sensibly assess a seasonal variation, data
should surely be collected over 12 months and preferably
over a number of years for comparison.
In conclusion, whilst the study by Rovaris and colleagues1
appears to demonstrate a minimal effect of seasonal variation
on their data set, possible seasonal variation of MRI in MS
should not be disregarded. Only well-designed studies with
patients in defined geographical areas will confirm or refute
such an association.
Medicines Research Unit, Cardiff University, Cardiff,
United Kingdom
References
1. Rovaris M, Comi G, Sormani MP, et al. Effects of seasons on
magnetic resonance imaging-measured disease activity in patients
with multiple sclerosis. Ann Neurol 2001;49:415– 416.
2. Comi G, Filippi M, Wolinsky JS, the European/Canadian glatiramer acetate study group. European/Canadian multicenter,
double-blind, randomized, placebo-controlled study of the effects
of glatiramer acetate on magnetic resonance imaging-measured
disease activity and burden in patients with relapsing multiple
sclerosis. Ann Neurol 2001;49:290 –297.
3. Auer D, Schumann E, Kumpfel T, et al. Seasonal fluctuations of
gadolinium-enhancing magnetic resonance imaging lesions in
multiple sclerosis [letter]. Ann Neurol 2000;47:276 –277.
4. McKenna M. Differences in vitamin D status between countries
in young adults and elderly. Am J Med 1992;93:69 –77.
Reply
Marco Rovaris, MD,1 Giancarlo Comi, MD,2
Maria Pia Sormani, PhD,1 Jerry S. Wolinsky, MD,3
David Ladkani, PhD,4 and Massimo Filippi, MD1
In our letter1 we reported that in 120 patients with
relapsing-remitting (RR) multiple sclerosis (MS), who were
part of the placebo arm of a double-blind, randomized, controlled trial assessing the efficacy of glatiramer acetate2 and
underwent monthly, gadolinium (Gd)-enhanced magnetic
resonance imaging (MRI) scans of the brain, the number of
enhancing lesions varied in the different seasons, but the
magnitude of this fluctuation was not statistically significant.1 As a consequence, we concluded that “the seasonal
fluctuations of subclinical activity in RRMS patients should
not affect the interpretation of the results from MRI-
monitored clinical trials a great deal.” We have not at all
concluded that “MS patients do not exhibit seasonal variations of MRI activity.”
As pointed out, the inclusion criteria for the original trial2
required the presence of at least one Gd-enhancing lesion on a
screening MRI scan and one or more clinical relapses in the
prior 2 years. Clearly, these criteria increased the likelihood for
detecting further disease activity over the subsequent months.3
Although we commented that our results cannot be compared
with those of previous trials where no selection criteria for
MRI activity was used,2 we cannot see how this may prevent
detecting a seasonal fluctuation of MRI activity, if any. On the
contrary, an increased MRI activity should enhance the probability of detecting significant fluctuations over time. Our
sample is also more homogeneous than that of the study by
Auer and colleagues,4 where patients with either RR or secondary progressive (SP) MS were included. This, by reducing
interpatient variability, should again increase the likelihood to
detect seasonal fluctuations.
As specified in the paper reporting the results of this trial,2
we included patients from Canada (n ⫽ 17) and from the
following European countries: Belgium (n ⫽ 8), England
(n ⫽ 38), France (n ⫽ 11), Germany (n ⫽ 4), Holland (n ⫽
6) and Italy (n ⫽ 36). There were no Scandinavian patients.
Although we are not aware of any evidence supporting the
concept that 25-hydroxyvitamin D levels influence MS activity
as detected by Gd-enhanced MRI, we analyzed separately data
from Canadian and European patients and repeated the original analysis1 after correcting for patients’ geographical origin.
The patterns of MRI enhancement did not differ between Canadian and European patients. The frequency of MRI activity
was similar among the subgroups of patients from different
countries and the seasonal fluctuation of Gd-enhancing lesion
numbers was still not statistically significant.
As far as the patient recruitment is concerned, we believe
that 10 consecutive months can be considered representative
of the whole of the year. In addition, all the scans were collected between February 1997 and August 1998, thus covering a 11⁄2 year period. We also performed additional analysis
to patients with at least one scan for each of the four seasons,
thus limiting the variability in the number of scans obtained
during each season. This again did not yield significant results. We also believe that the collection of data over longer
periods of time is likely to increase dramatically the influence
of other factors known to affect MRI-detected MS activity,
such as changes of the disease phenotype (for instance, from
RR to SP), patients’ aging,5 and major upgrades or changes
of the MR scanners,6 thus making the interpretability of the
analysis even more challenging.
We agree that the possibility of seasonal variations of MRI
activity in RRMS patients should not be disregarded. To our
knowledge, this issue has been addressed only by two preliminary studies,1,4 including ours, and as a consequence deserves further consideration. However, we believe that our
study was designed in the appropriate way to provide evidence that the fluctuation of subclinical MS activity over the
time periods needed for MRI-monitored clinical trials should
not affect the interpretation of their results.
1
Neuroimaging Research Unit and 2Clinical Trials Unit,
Department of Neuroscience, Scientific Institute and
University Ospedale San Raffaele, Milan, Italy; 3Department
of Neurology, University of Texas Houston, Health Science
Center, Houston, TX; and 4TEVA Pharmaceutical Industries
Ltd, Kyriat Nordau, Netanya, Israel
References
1. Rovaris M, Comi G, Sormani MP, et al. Effects of seasons on
magnetic resonance imaging-measured disease activity in patients
with multiple sclerosis [letter]. Ann Neurol 2001;49:415– 416.
2. Comi G, Filippi M, Wolinsky JS, the European/Canadian Glatiramer Acetate Study Group. The European/Canadian multicenter, double blind, randomized, placebo-controlled study of
the effects of glatiramer acetate on magnetic resonance imagingmeasured disease activity and burden in patients with relapsing
multiple sclerosis. Ann Neurol 2001;49:290 –297.
3. Kappos L, Moeri D, Radue EW, et al. Predictive value of
gadolinium-enhanced MRI for relapse rate and changes in
disability/impairment in multiple sclerosis: a meta-analysis. Lancet 1999;353:964 –969.
4. Auer DP, Schumann EM, Kumpfel T, et al. Seasonal fluctuations
of gadolinium-enhancing magnetic resonance imaging lesions in
multiple sclerosis [letter]. Ann Neurol 2000;47:276 –277.
5. Filippi M, Wolinsky JS, Sormani MP, et al. Enhancement frequency decreases with increasing age in relapsing-remitting multiple sclerosis. Neurology 2001;56:422.
6. Filippi M, van Waesberghe JH, Horsfield MA, et al. Interscanner variation in brain MRI lesion load measurements in MS:
implications for clinical trials. Neurology 1997;49:371–377.
Borna Disease Virus RNA Is Absent in Chronic
Multiple Sclerosis
Claus G. Haase, MD,1 Sergei Viazov, MD,2
Melanie Fiedler, MD,2 Nikolaus Koenig, MD,3
Pedro M. Faustmann, MD,4 and
Michael Roggendorf, MD2
Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS) of unknown etiology, although the involvement of viral infections as a possible triggering event is suspected.1 In MS patients, relatively
high prevalence of antibodies (13%) to Borna Disease Virus
(BDV) or viral antigen (10.5%) allowed speculation on a
possible involvement of this virus in initiating the development of MS or driving a progression from a relapsing form
to a chronic state.2,3
This hypothesis is supported by certain BDV characteristics: BDV is a neurotropic, negative-stranded, single-stranded
RNA virus that causes inflammatory CNS disease in naturally infected hosts (several species of vertebrates). Association of BDV infection with other human neurological disorders, including major depression and schizophrenia was
repeatedly suggested but never proven.2– 4
To clarify the question whether BDV plays a role as a potential trigger in chronic progressive MS, we assessed the prevalence of BDV RNA in blood of 94 persons. The MS patient
group included 34 individuals with either a primary chronic
progressive course (n ⫽ 17, age 58 ⫾ 10 years, disease duration 15.5 ⫾ 8.3 years, EDSS 6.6 ⫾ 1.1) or a secondary
chronic progressive course (n ⫽ 17, age 49 ⫾ 10 years, disease
duration 18.5 ⫾ 10.3 years, EDSS 6.2 ⫾ 1.3). Patients with
Annals of Neurology
Vol 50
No 3
September 2001
423
schizophrenia (n ⫽ 20) and healthy blood donors (n ⫽ 40)
served as age- and sex-matched control groups.
For the detection of viral RNA, the reverse transcriptase
polymerase chain reaction procedure was used, as described
in full detail elsewhere.5
Amplification results demonstrated the presence of BDV sequences in only one sample of a schizophrenic patient but in
none of the other 93 patients or healthy donors. Sequencing
of the amplified DNA from this single positive sample revealed its complete identity with the sequence obtained from
the positive control used. Thus the positive result with this
single sample was probably a result of laboratory contamination.
In conclusion, the negative result of the current investigation
complement earlier reports5,6 and supports the evidence against
an association between BDV infection and chronic MS.
1
Department of Neurology, University Hospital Essen, Essen;
Institute of Virology, University of Essen, Essen; 3Multiple
Sclerosis Center Berg, Berg; and 4Institute of Neuroanatomy,
University of Bochum, Bochum, Germany
2
References
1. Hohlfeld R. Biotechnological agents for the immunotherapy of
multiple sclerosis. Principles, problems and perspectives. Brain
1997;120:865–916.
2. Bode L, Riegel S, Lange W, Ludwig H. Human infections with
Borna disease virus: seroprevalence in patients with chronic
diseases and healthy individuals. J Med Virol 1992;36:309 –315.
3. Deuschle M, Bode L, Heuser I, et al. Borna disease virus proteins in cerebrospinal fluid of patients with recurrent depression
and multiple sclerosis. Lancet 1998;352:1828 –1829.
4. Bode L, Zimmermann W, Ferszt R, et al. Borna disease virus
genome transcribed and expressed in psychiatric patients. Nat
Med 1995;1:233–236.
5. Sauder C, de la Torre JC. Sensitivity and reproducibility of RTPCR to detect Borna disease virus (BDV) in blood: implications
for BDV epidemiology. J Virol Meth 1998;71:229 –245.
6. Kitze B, Herzog S, Rieckmann P, et al. No evidence of Borna
disease virus-specific antibodies in multiple sclerosis patients in
Germany. J Neurol 1996;243:660 – 662.
Monozygotic Twins with X-Linked
Adrenoleukodystrophy and Different Phenotypes
Maja Di Rocco, MD,1 Laura Doria-Lamba, MD,1 and
Ubaldo Caruso, PhD2
Adrenoleukodystrophy (ADL) is an X-linked genetic disorder
characterized by elevated levels of very-long-chain fatty acids
(VLCFAs), caused by a deficiency in peroxisomal VLCFA
beta oxidation. The ADL gene encodes a peroxisomal membrane transporter. No correlations between phenotype and
genotype have been demonstrated. Clinical findings include
severe inflammatory reaction of the cerebral white matter,
which leads to demyelination, axonal degeneration (adrenomyeloneuropathy), and isolated adrenal insufficiency.
Recently in the Annals, van Geel and colleagues1 reported
phenotype evolution in 129 men with X-ADL, demonstrating that adrenomyeloneuropathy and cerebral demyelination
emerge independently from each other. Furthermore, adult
transgenic mice with targeted inactivation of the ADL gene
do not have demyelinating lesions of the central nervous system (CNS), although they do have an abnormal accumulation of VLCFAs in the CNS.2
424
Annals of Neurology
Vol 50
No 3
September 2001
Two hypotheses have been suggested that likely account
for the clinical heterogeneity of adrenoleukodystrophy, modifyng genes and environmental factors. We report on a pair of
monozygotic twins with X-linked adrenoleukodystrophy and
different clinical courses.
Genotyping of HLA DR and microsatellite loci showed
identity. Therefore, the probability of monozygosity was
greater than 99.9%. They are 15-year-old boys with pseudoachondroplastic skeletal dysplasia. When they were 12 years
old, one of them underwent orthopedic surgery. A few weeks
later, when the patient was walking, left hemiplegia was observed, and neuroradiological examinations were performed.
Magnetic resonance imaging was consistent with adrenoleukodystrophy; plasmatic VLCFA were studied by selected ion
monitoring and stable isotope dilution with a GC-MS Hewlett
Packard 5973A system and were found to be increased [C26:0
2.389␮mol/L (normal values 0.46 – 0.98␮mol/L), C26:1
0.95␮mol/L (normal values 0.11–0.47), ratio C24:0/C22:0
1.938 (normal values 0.62–1.01␮mol/L), ratio C26:0/C22:0
0.078 (normal values 0.008 – 0.0026)]. His twin had adrenal insufficiency and no clinical, neurological, or neuroradiological abnormalities, but had increased VLCFA (C26:0 2.981␮mol/L,
C26:1 1.12␮mol/L, ratio C24:0/C22:0 1.81, ratio C26:0/
C22:0 0.069).
Subsequently the boy with CNS involvement had seizures,
with no significant neuroradiological, neurophysiological, or
neuropsychological progression. No neurological involvement has been observed in the other twin during the 3 years
since diagnosis.
Two other pairs of identical male twins with different
clinical expressions of this disease have been reported.3,4 One
of these sets of twins was also studied for mitochondrial
DNA, and no differences were found. Therefore, mitochondrial genome involvement in the pathogenesis of linked adrenoleukodystrophy can be ruled out.5
Discordant adrenoleukodystrophy phenotypes in 3 pairs
of monozygotic twins strongly suggest that the modifying
genes are not involved in CNS degeneration. On the other
hand, identifying environmental factors could be very important for effectively preventing CNS degeneration.
1
II Pediatric Unit, Gaslini Institute, and 2Laboratory for the
Study of Metabolic Diseases, DIPE, University of Genoa,
Genoa, Italy
References
1. van Geel BM, Bezman L, Loes DJ, et al. Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. Ann Neurol 2001;49:186 –194.
2. Forss-Petter S, Werner H, Berger J, et al. Targeted inactivation
of the X-linked adrenoleukodystrophy in mice. J Neurosci Res
1997;50:829 – 843.
3. Sobue G, Ueno-Natsukari I, Okamoto H, et al. Phenotypic heterogeneity of an adult form of adrenoleukodystrophy in monozygotic twins. Ann Neurol 1994;36:912–915.
4. Korenke GC, Fuchs S, Krasemann E, et al. Cerebral adrenoleukodystrophy (ADL) in only one of monozygous twins with an
identical ADL genotype. Ann Neurol 1996;40:254 –257.
5. Wilichowski E, Ohlenbusch A, Korenke GC, et al. Identical mitochondrial DNA in monozygotic twins with discordant adrenoleukodystrophy phenotype. Ann Neurol 1998;43:835– 836.
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