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Clinical significance of positionally induced downbeat nystagmus.

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LETTERS
Concerns Regarding Transience and
Heterozygosity in Neonatal Hyperglycenemia
Ada Hamosh, MD, MPH,1
and Johan Van Hove, MD, PhD2
Kure and colleagues1 report three patients in whom they attribute transient hyperglycinemia to heterozygosity in a component of the glycine cleavage system (GCS). One mutant
P-protein (GLDC) allele was identified in each of two patients and one mutant H-protein (GCSH) allele in the third.
The latter is reported to have normal GCS activity in lymphoblasts and B6 responsive seizures. No follow-up plasma
or CSF glycine levels are reported for any of the patients to
document the transience of the hyperglycinemia. Transient
hyperglycinemia has not been reported in any families with
glycine encephalopathy (nonketotic hyperglycinemia [NKH]),
nor have we seen it in more than 100 families with NKH
that we have evaluated, nor has a report of familial transient
hyperglycinemia been described. The basis of transient hyperglycinemia remains unknown, although the hypothesis of
heterozygosity for one or more components of the GCS plus
other genetic and environmental factors is attractive.
Recently, A.H. had the privilege of evaluating Patient 1 of
Kure and colleagues1 in clinic. In contrast with the report,
she is a normocephalic (occipitofrontal circumference,
49.5cm, 25–50th percentile) 3-year-old white female with a
development quotient of 30, persistent seizures (0 –20/day), a
markedly abnormal electroencephalogram, and a fasting
plasma glycine of 820␮mol/L taking 350mg/kg/day of sodium benzoate. She has NKH, and there is nothing transient
about it. The identified GLDC mutation is a premature termination codon in exon 20 (W805X). Because the number
of nucleotides in exon 20 is not a multiple of 3 precluding
the possibility of nonsense mediated alternative splicing,2 the
most likely effect of this mutation is markedly reduced
mRNA because of nonsense mediated mRNA decay3,4 and
not a profoundly truncated polypeptide of P-protein. The
second mutation was either missed by the methods used or is
a promoter or deep intronic mutation that was not detected.
The article by Kure and colleagues1 should not be used to
counsel families at 25% risk of an infant with NKH that
their carrier children may be affected with transient NKH,
because there are no data to support this. Our data plus the
lack of documentation of the transient nature of the hyperglycinemia question the validity of their diagnosis. Second,
heterozygosity at the disease gene locus is uncertain in the
absence of exhaustive survey for a mutation and appropriate
family studies. Nevertheless, the idea that heterozygosity for
certain mutant alleles (most likely a missense mutation with
a dominant negative capability) is an interesting one that
would necessitate additional experimental validation, including family studies. Alternatively, the idea of a digenic cause
with mutations in multiple components of the GCS also
merits investigation. This is particularly attractive for Patient
3 who is B6 responsive (the cofactor for P-protein) but has a
mutation in GCSH. Additional information regarding Patients 2 and 3 in this study is necessary to substantiate the
claims of transient NKH. Furthermore, the lack of detection
of a second mutation never provides certainty that it is not
there.
1
Institute of Genetic Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD; and 2Department of
Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium
References
1. Kure S, Kojima K, Ichinohe A, et al. Heterozygous GLDC and
GCSH gene mutations in transient neonatal hyperglycinemia.
Ann Neurol 2002;52:643– 646.
2. Mendell JT, ap Rhys CM, Dietz HC. Separable roles for rent1/
hUpf1 in altered splicing and decay of nonsense transcripts. Science 2002;298:419 – 422.
3. Maquat LE. Nonsense-mediated mRNA decay. Curr Biol 2002;
12:R196 –R197.
4. Mendell JT, Dietz HC. When the message goes awry: diseaseproducing mutations that influence mRNA content and performance. Cell 2001;107:411– 414.
DOI: 10.1002/ana.10532
Reply
Shigeo Kure, MD,1 Kanako Kojima, MD,1
Akiko Ichinohe, MD,1 Tomoki Maeda, MD,2
Rozalia Kalmanchey, MD,3 György Fekete, MD,3
Suzan Z. Berg, MS,4 Jim Filiano, MD,4 Yoko Aoki, MD,1
Yoichi Suzuki, MD,1 Tatsuro Izumi, MD,2
and Yoichi Matsubara, MD1
It is an important comment by Drs Hamosh and van Hove
that our data on transient NKH should not be used for genetic counseling for NKH because transient NKH is not
caused only by a heterozygous mutation of one component
of the glycine cleavage system (GCS). Additional genetic and
environmental factors are apparently required for development of transient NKH as described.1 The extremely low
incidence of transient NKH as compared with that of carrier
for NKH and the presence of two asymptomatic heterozygous carriers in the family of Patient 3 suggest the contribution of such unknown factors.
A diagnosis of transient NKH given to Patient 1 was
based on two independent analyses performed in her infantile period. Plasma glycine values at 4 and 5 months old were
294 and 254␮mol/L, respectively, both of which were in the
normal range. Typical clinical presentations in neonatal period and normal glycine levels in infantile period led us to
diagnose Patient 1 as having transient NKH. Drs Hamosh
and van Hove’s observation that she had an elevated plasma
glycine level at 3 years old indicates that there is a group of
patients with transient NKH whose glycine level fluctuates
with time.
Patient 3 had vitamin B6 responsive convulsion in addition to transient NKH. Because vitamin B6 is a cofactor of
glycine decarboxylase (P-protein), it is an attractive hypothesis that mutant glycine decarboxylase with high Km value
for vitamin B6 responds to administration of pharmacological dose of pyridoxine and gains the higher enzymatic activity. However, the plasma and CSF glycine levels did not significantly increase after pyridoxine withdrawal test, which
was performed for confirmation of the diagnosis.2,3 The
plasma and CSF glycine levels before the test were 260 and
6.7␮mol/L, respectively, whereas those after the test were
270 and 7.7. If the pyridoxine-responsive mutant glycine decarboxylase were present in Patient 3, significant increase of
© 2003 Wiley-Liss, Inc.
685
the glycine level should be observed. In line with the clinical
data, no mutation was detected in each exon in the GLDC
gene, including vitamin B6 binding domain.
As Drs Hamosh and van Hove pointed out, it is extremely
difficult to provide the evidence for absolute absence of the
mutation in a defined gene. We think that detection of the
heterozygous mutation in the GCS genes is only the first
step for elucidation of pathogenesis of transient NKH, and
that involvement of multiple heterozygous mutations encoding the components in the GCS and other related proteins to
glycine metabolism may be a most likely explanation. Extensive mutational analysis of other candidate genes is required
for elucidation of unknown causes.
1
Department of Medical Genetics, Tohoku University School
of Medicine, Sendai; 2Department of Pediatrics, Oita Medical
University School of Medicine, Oita, Japan; 3II. Department
of Pediatrics, Semmelweis University, Budapest, Hungary; and
4
Department of Clinical Genetics, Dartmouth Hitchcock
Medical Center, Lebanon, NH
References
1. Kure S, Kojima K, Ichinohe A, et al. Heterozygous GLDC and
GCSH mutations in transient neonatal hyperglycinemia. Ann
Neurol 2002;52:643– 646.
2. Kure S, Maeda T, Fukushima N, et al. A subtype pyridoxinedependent epilepsy with normal CSF glutamate concentration.
J Inherit Metab Dis 1998;21:431– 432.
3. Maeda T, Inutsuka M, Goto K, et al. Transient nonketotic hyperglycinemia in an asphyxiated patient with pyridoxinedependent seizures. Pediatr Neurol 2000;22:225–227.
DOI: 10.1002/ana.10533
Is There Mitochondrial Dysfunction in
Amyotrophic Lateral Sclerosis Skeletal Muscle?
Stefan Vielhaber, MD1 Alexei Kudin, PhD,1
Kirstin Winkler, PhD,1 Falk Wiedemann, MD,1
Rolf Schröder, MD,2 Helmut Feistner, MD,1
Hans-Jochen Heinze, MD,1 Christian E. Elger, MD,3
and Wolfram S. Kunz, PhD3
In a recent article, Echaniz-Laguna and colleagues1 investigated mitochondrial function in saponin-permeabilized skeletal muscle fibers of patients with early-stage sporadic amyo-
trophic lateral sclerosis (SALS; mean disease duration, 9
months; range, 2–35 months). The authors of this study1
did not observe any significant differences of maximal fiber
respiration rates between the SALS group and age-matched
controls and concluded that mitochondrial function in earlystage SALS skeletal muscle is not impaired. This is in clear
contrast with other studies2– 4 including our own work.
However, a major methodical problem of the applied technique needs to be taken into consideration. The maximal
rates of respiration of saponin-permeabilized muscle fibers
(Vmax, expressed in nmol O2/min/mg dry weight) do not directly indicate a putative impairment of mitochondrial respiratory chain but are also dependent on the mitochondrial
content in the investigated muscle. Activities of mitochondrial respiratory chain enzymes and of citrate synthase have
to be determined additionally to estimate variations of the
mitochondrial content in the muscle biopsies. This issue has
been addressed previously in detail for the enzymatic diagnosis of mitochondrial diseases, and citrate synthase–normalized values of activities have been demonstrated to be a better reference for detecting defects in the respiratory chain
than the absolute activity values per wet weight (or dry
weight) of muscle.5
To illustrate this crucial problem, we extended our previous biochemical studies2,4 by focusing on muscle specimens
of early-stage SALS patients (mean disease duration at the
time of muscle biopsy, 10 months; range, 6 –18 months).
The Table shows the maximal rates (Vmax) of muscle fiber
respiration in a group of 11 patients with definite SALS according to the El Escorial criteria6 (mean age, 59 years;
range, 30 –74 years; six women, four men) in comparison
with 12 age-matched healthy controls (mean age, 56 years;
range, 47–71 years; seven women, five men) and of one male
patient (48 years) with genetically proven chronic progressive
external ophthalmoplegia (harboring a 3.9kb large-scale deletion in skeletal muscle). Five of the 11 SALS patients were
part of a previous study.4 The mean ALSFRS-R score7 was
40 (range, 34 – 47). Muscle biopsies from these 11 SALS patients were taken from a clinically minor (N ⫽ 5) or not
affected (N ⫽ 6) skeletal muscle (Musculus vastus lateralis).
In accordance with Echaniz-Laguna and colleagues,1 the
maximal rates of respiration of muscle fibers from the SALS
group and even of the patient with a genetically proven mitochondrial muscle disease were not different from the con-
Table. Parameters of Mitochondrial Function in Skeletal Muscle Fibers of Patients with SALS and One Patient with CPEO
Group
Controls
(N ⫽ 12)
SALS
(N ⫽ 11)
CPEOd
VGlu (nmol
O2/min/mg dwt)
VGlu/CS
VSucc (nmol
O2/min/mg dwt)
VSucc/CS
CS
Complex I Complex IV
(U/gm wwt) (U/gm wwt) (U/gm wwt) Complex I/CS Complex IV/CS
8.54 ⫾ 2.43
0.90 ⫾ 0.20
10.77 ⫾ 3.23
1.12 ⫾ 0.19
10.5 ⫾ 3.6
1.26 ⫾ 0.58 5.32 ⫾ 2.50
0.12 ⫾ 0.04
0.50 ⫾ 0.16
9.89 ⫾ 1.81
0.64 ⫾ 0.16a
12.37 ⫾ 2.16
0.80 ⫾ 0.21b
15.1 ⫾ 4.2
0.86 ⫾ 0.58 3.37 ⫾ 1.83
0.06 ⫾ 0.03b
0.22 ⫾ 0.08b
6.94
0.40c
9.08
0.52c
17.4
0.06c
0.37
1.10
6.50
The experimental data are means ⫾ SD. For experimental details see Vielhaber and colleagues2
p ⬍ 0.05 vs controls; bp ⬍ 0.01 vs controls (two-sided t test).
Difference to controls larger than 1 SD.
d
Muscle biopsy of a patient harboring a large-scale deletion (degree of heteroplasmy 10%, deletion breakpoints at np 547 and np 4443).
a
c
SALS ⫽ sporadic amytotrophic lateral sclerosis; CPEO ⫽ chronic progressive external ophthalmoplegia; VGlu, VSuc maximal mitochondrial respiration rates
(⫹1mM ADP) of saponin-permeabilized muscle fibers in the presence of glutamate ⫹ malate or succinate, respectively; dwt ⫽ dry wet weight; wwt ⫽ wet weight;
CS ⫽ citrate synthase.
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trol group. In line with the maximal fiber respiration rates,
total enzyme activities of complex I and complex IV (expressed per gm/wet weight muscle) in our SALS group as
well as in the chronic progressive external ophthalmoplegia
patient did not differ from the control group (see Table).
However, after correction for possible fiber-type variations or
adaptational proliferation of mitochondria by normalization
of data for the mitochondrial marker enzyme citrate synthase,5 significant differences between the SALS group and
controls were observed for fiber respiration with the substrates glutamate plus malate and succinate and also for complex I and IV activities, indicating the presence of a mitochondrial defect. Similarly, the patient with the genetically
proven mitochondrial disease showed decreased citrate synthase–normalized maximal fiber respiration rates as well as
decreased complex I to citrate synthase and complex IV to
citrate synthase ratios. Note that normalization of the respiration data of SALS patients reported1 could in fact lead
to similar results. In determining the ratio of VTMPD and
Vsuccinate (which reflects the metabolic reserve capacity of
complex IV for succinate oxidation) from Figure 2 of
Echaniz-Laguna and colleagues,1 we found that controls
show a 3.5-fold complex IV reserve capacity with the respiratory substrate succinate, whereas the SALS group had the
considerable lower 2.6-fold reserve capacity. This indicates
decreased complex IV activity in skeletal muscle of the reported SALS patients.1
In contrast with the conclusion of Echaniz-Laguna and
colleagues,1 available experimental data conclusively show
that a mitochondrial defect in early-stage SALS muscles is
detectable, if the methodical approach considers the mitochondrial content in the individual heterogeneous muscle
specimens.
1
Department of Neurology, University of Magdeburg,
Magdeburg; and Departments of 2Neurology and
3
Epileptology, University of Bonn, Bonn, Germany
References
1. Echaniz-Laguna A, Zoll J, Ribera F, et al. Mitochondrial respiratory chain function in skeletal muscle of ALS patients. Ann
Neurol 2002;52:623– 627.
2. Vielhaber S, Kunz D, Winkler K, et al. Mitochondrial DNA
abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain 2000;123:1339 –1348.
3. Chung MJ, Suh YL. Ultrastuctural changes of mitochondria in
the skeletal muscle of patients with amyotrophic lateral sclerosis.
Ultrastruct Pathol 2002;26:3–7.
4. Vielhaber S, Kaufmann J, Kanowski M, et al. Effect of creatine
supplementation on metabolite levels in ALS motor cortices. Exp
Neurol 2001;172:377–382.
5. Yamamoto M, Clemens PR, Engel AG. Mitochondrial DNA deletions in mitochondrial cytopathies: observations in 19 patients.
Neurology 1991;41:1822–1828.
6. World Federation of Neurology. El Escorial criteria for diagnosis
of ALS. J Neurol Sci 1994;124(suppl):96 –107.
7. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a
revised ALS functional rating scale that incorporates assessments
of respiratory function. BDNF ALS Study Group (Phase III).
J Neurol Sci 1999;169:13–21.
DOI: 10.1002/ana.10564
Reply
Andoni Echaniz-Laguna, MD,1 Joffrey Zoll, PhD,2
Florence Ribera, PhD,2 Christine Tranchant, MD, PhD,1
Jean-Marie Warter, MD, PhD,1
Jean Lonsdorfer, MD, PhD,2
and Eliane Lampert, MD, PhD2
We read the letter by Vielhaber and colleagues with great
interest. However, their lecture and interpretation of the
studies on mitochondrial respiratory function in skeletal
muscle of patients with sporadic amyotrophic lateral sclerosis
(SALS) need to be clarified and, on some points, discussed.
We recently published a study that showed that muscle
oxidative capacity, evaluated with Vmax, was identical in musculus vastus lateralis in patients with SALS in comparison
with age- and physical activity–matched control subjects.1
We therefore concluded that the existence of a large mitochondrial damage in skeletal muscle of patients with earlystage SALS was very unlikely. Vielhaber and colleagues point
out that we did not take into account the mitochondrial
content in the investigated muscle, and that therefore we
could not exclude a subtle mitochondrial defect in skeletal
muscle of patients with SALS. Using citrate synthase (CS)
activities to estimate variations of mitochondrial content in
the muscle biopsies, they present experimental data that suggest the existence of a subtle mitochondrial defect in muscle
of patients with early-stage SALS in comparison with controls. However, in the interpretation of these results, some
considerations have to be taken into account.
First, we concluded our study1 by stating that “our data
clearly indicate an absence of large mitochondrial damage in
skeletal muscle of patients with early-stage SALS.” In accordance with Vielhaber and colleagues, we are well aware of
the fact that, by studying a pool of muscular mitochondria,
our work could show only the presence or the absence of a
major mitochondrial defect in muscle. We agree with Vielhaber and colleagues on the fact that a subtle mitochondrial
defect can be missed by such experimental work. However,
that was not our main initial aim, and our study was not at
first designed for the search of such abnormalities.
Second, note that Vielhaber and colleagues present results
that are in accordance with our own. Indeed, they show an
absence of significant difference in VGlu and VSucci in earlystage SALS in comparison with controls. Surprisingly, the
results presented by Vielhaber and colleagues are in clear
contradiction with previous results obtained by their group
that showed significant differences in these parameters between SALS and controls.2– 4
Last, note that, in the results presented by Vielhaber and
colleagues, CS activities do not exhibit significant differences
between SALS patients and controls (10.5 ⫾ 3.6 in controls
vs 15.1 ⫾ 4.2 in SALS, U/gm wwt, means ⫾ SD). This
result indicates that both groups have almost the same mitochondrial content in the muscle biopsies and that fibertype variations or adaptational proliferation of mitochondria
are not of significant importance in muscle of the SALS
group. Furthermore, standard deviations are very large in
both cohorts, indicating a major heterogeneity in the constitution of groups and suggesting that several confusing factors
have not been taken into account. For a comparison between
CS in muscle in patients with SALS and controls to be con-
Annals of Neurology
Vol 53
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687
clusive, controls should be matched with patients not only
for age and gender, but also for physical activity. Indeed, it is
well known that age, gender, and physical activity influence
the mitochondrial content of skeletal muscle.5 Furthermore,
identical muscles should be studied in patients and in controls
because mitochondrial content is subject to significant variations between different muscles such as quadriceps and deltoid
(J. Zoll, personal observation, unpublished results). Vielhaber
and colleagues fail to provide information concerning the site
of muscular biopsy and the level of physical activity of patients
and controls, therefore casting a doubt on the significance of
their results. Eventually, we think that extreme caution is recommended when significant differences appear in VGlu/CS
and VSucci/CS ratios between two different groups with VGlu,
VSucci, and CS values that are not significantly different.
In conclusion, we agree with Vielhaber and colleagues on
the fact that mitochondrial respiratory function, studied with
the skinned fiber technique, is probably normal in skeletal
muscle of patients with early-stage SALS, as shown in our
study.1 This result strongly suggests an absence of major mitochondrial damage in skeletal muscle. However, whether
there is a subtle mitochondrial defect remains to be clarified.
A study with a much larger cohort of early-stage SALS patients and matched controls with a measurement of mitochondrial oxydative capacity and CS activity is clearly
needed. Work on respiratory mitochondrial function in muscle of patients with SALS is ongoing in our laboratory, and
we plan to determine the activity of CS in a larger cohort of
early-stage SALS patients and age-, gender-, physical
activity-, and “muscle”-matched controls.
Departments of 1Neurology, and 2Physiology, University of
Strasbourg, Strasbourg, France
tients with cerebellar downbeat nystagmus1 Marti and
colleagues nicely tease out two components contributing to
downbeat nystagmus that is present when the eyes are close to
central position: (1) a gravity-dependent component that varies with head-and-body position; and (2) a gravityindependent component causing upward eye drifts. These data
strengthen the case that downbeat nystagmus can be caused by
a central imbalance of vestibular inputs originating from either
the otolithic organs or the semicircular canals of the labyrinth.
Marti and colleagues mainly measured eye movements
while their subjects and patients were rotated in 45-degree
steps from the prone to erect to the supine position. However,
none of these positions correspond to the “head-hanging” posture, which is approximated during clinical testing. When normal subjects are placed with their heads “upside-down,” eye
drifts toward the brow (“chin-beating nystagmus”) are common if vision is prevented by darkness.2,3 Furthermore, some,
but not all, cerebellar patients with downbeat nystagmus can
be expected to maximize their eye drifts in an upside-down
position (Fig 3 of Marti and colleagues1).
At least two important clinical points emerge from this
and other studies of the effects of head orientation on gaze
stability.1–3 First, placing patients in a head-hanging position
may not be optimal, and a prone position, sustained for up
to a minute, may be more revealing. Second, clinicians
should realize that downbeat nystagmus may occur in normal subjects placed in a head-hanging (or prone) position,
with vision fixation prevented by Frenzel goggles. In healthy
subjects, the rest of the ocular motor and neurological examination can be expected to be normal; if not, then magnetic
resonance imaging may be indicated. Disorders of eye movements are among the most useful and specific neurological
signs,4 but they need to be interpreted in the context of the
history and general neurological examination.
References
1. Echaniz-Laguna A, Zoll J, Ribera F, et al. Mitochondrial respiratory chain function in skeletal muscle of ALS patients. Ann
Neurol 2002;52:623– 627.
2. Wiedemann FR, Winkler K, Kuznetsov AV, et al. Impairment of
mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci 1998;156:65–72.
3. Vielhaber S, Winkler K, Kirches E, et al. Visualization of defective mitochondrial function in skeletal muscle fibers of patients
with sporadic amyotrophic lateral sclerosis. J Neurol Sci 1999;
169:133–139.
4. Vielhaber S, Kunz D, Winkler K, et al. Mitochondrial DNA
abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain 2000;123:1339 –1348.
5. Hoppeler H. Exercise-induced ultrastructural changes in skeletal
muscle. Int J Sports Med 1986;7:187–204.
DOI: 10.1002/ana.10562
Department of Neurology, Veterans Affairs Medical Center
and University Hospitals, Case Western Reserve University,
Cleveland, OH
References
1. Marti S, Palla A, Straumann D. Gravity dependence of ocular
drift in patients with cerebellar downbeat nystagmus. Ann Neurol 2002;52:712–721.
2. Kim J-I, Somers JT, Stahl JS, et al. Vertical nystagmus in normal
subjects: effects of head position, nicotine and scopolamine. J
Vestibular Res 2001;10:291–300.
3. Bisdorff AR, Sancovic S, Debatisse D, et al. Positional nystagmus
in the dark in normal subjects. Neuroophthalmology 2000;24:
283–290.
4. Leigh RJ, Zee DS. The neurology of eye movements. 3rd ed.
New York: Oxford University Press, 1999.
Clinical Significance of Positionally Induced
Downbeat Nystagmus
DOI: 10.1002/ana.10563
R. John Leigh, MD
Valporic Acid and Prion Proteins
Downbeat nystagmus is an important clinical sign of cerebellar
disease and usually prompts magnetic resonance imaging if
drug effects are excluded. Downbeat nystagmus often is increased or precipitated when patients are placed in a “headhanging position.” In their recent study of ocular drift in pa-
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Josemir W. Sander, PhD, MRCP,
and John S. Duncan, DM, FRCP
We read with interest the article by Shaked and colleagues
suggesting that the antiepileptic drug valproic acid (VPA) in
culture media increases the accumulation of PrP isoforms in
normal and scrapie-infected neuroblastoma cells; resulting in
an increased accumulation of prion proteins.1 We would like
to make a few points. It is misleading to conclude from this
experiment that treatment with VPA could present potential
risk for patients treated with this medication. To back up such
a strong statement, one would expect to see comparative clinical data. Data presented in the article however, are in vitro
experimental findings. The authors also report that preliminary results from in vivo animal experimentation indicate that
VPA administered to hamsters inoculated with prions had no
significant effect on disease incubation time. Therefore the
conclusion reached by the authors that, although VPA did not
change prion incubation time in hamsters, one should evaluate
carefully the administration of VPA to humans at risk of developing Creutzfeldt–Jakob disease is surprising. This unsubstantiated conclusion may cause unnecessary anxiety and concern among patients treated with VPA. This drug has been
available for over 35 years, and at no point has there been any
suggestion of an association between this drug and
Creutzfeldt–Jakob disease. This is despite quite extensive studies looking at possible risk factors particularly drugs.
Department of Clinical & Experimental Epilepsy, and UCL,
Institute of Neurology, Queen Square, London, United Kingdom
References
1. Gideon M, Shaked GM, Engelstein R, et al. Valproic acid treatment results in increased accumulation of prion proteins. Ann
Neurol 2002;52:416 – 420.
2. Hillier CE, Salmon RL. Is there evidence for exogenous risk factors in the actiology and spread of Creutzfeldt-Jakob disease?
QMJ 2000;93:617– 631.
3. Zerr I, Brandel JP, Masullo C, et al. European surveillance on
Creutzfeldt-Jakob disease: a case-control study for medical risk
factors. J Clin Epidemiol 2000;53:747–754.
4. Ward HJ, Everington D, Croes EA, et al. Sporadic CreutzfeldtJakob disease and surgery: a case-control study using community
controls. Neurology 2002;59:543–548.
DOI: 10.1002/ana.10581
Correction
Volume 53, Supplement 4 of the Annals of Neurology:
Neurogeneration and Prospects for Neuroprotection
and Rescue in Parkinson’s Disease, C. Warren Olanow, MD, FRCPC, Guest Editor; Anthony H. V.
Schapira, MD, DSc, FRCP, FMedSci, and Yves Agid,
MD, PhD, co-editors.
Due to an oversight, the support of Pharmacia in
underwriting the costs of this supplement was not acknowledged. We would like to gratefully acknowledge
Pharmacia for their gracious support of this supplement, which contained proceedings from the 2002
Keystone Symposia meeting on Neuroprotection.
Annals of Neurology
Vol 53
No 5
May 2003
689
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