9. Fleiss JL, Shrout PE. The effects of measurement errors on
some multivariate procedures. Am J Public Health 1997;67:
1188 –1191.
10. Drayer BP. Magnetic resonance imaging and extrapyramisal
movement disorders. Eur Neurol 1989;29(suppl 1):9 –12.
11. Allen RP, Barker PB, Wehrl F, et al. MRI measurement of
brain iron in patients with restless legs syndrome. Neurology
2001;56:263–265.
12. Connor JR, Wang XS, Patton SM, et al. Decreased transferrin
receptor expression by neuromelanin cells in restless legs syndrome. Neurology 2004;62:1563–1567.
13. Earley CJ, Connor JR, Beard JL, et al. Abnormalities in CSF
concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000;54:1698 –1700.
14. Poewe W, Hoegl B. Akathisia, restless legs syndrome and periodic limb movements in sleep in Parkinson’s disease. Neurology
2004;63:S12–S16.
15. Behnke S, Berg D, Becker G. Does ultrasound disclose a vulnerability factor for Parkinson’s disease? J Neurol 2003;
250(suppl 1):I24 –I27.

Dominant Form of
Vanishing White Matter–like
Leukoencephalopathy
Pierre Labauge, MD, PhD,1 Anne Fogli, PhD,2
Giovanni Castelnovo, MD,1 Alice Le Bayon, MD,1
Laetitia Horzinski, MSc,2 François Nicoli, MD, PhD,3–5
Patrick Cozzone, PhD,3,4 Michel Pagès, MD,1
Caroline Briere, MD,1 Christiane Marty-Double, MD,1
Olivier Delhaume, MD,1 Antoinette Gelot, MD, PhD,6
Odile Boespflug-Tanguy, MD, PhD,2 and
Diana Rodriguez, MD, PhD6,7

Leukoencephalopathy with vanishing white matter syndrome (childhood ataxia with central nervous system hypomyelination/vanishing white matter disease) is an autosomal recessive disorder characterized by the
occurrence of acute episodes of deterioration after minor
head trauma or infection, and symmetrical demyelination
on magnetic resonance with cavitation aspects. Mutations
in each of the five subunits of eIF2B have been identified. We report in an affected man and his mother an
adult-onset form of childhood ataxia with central nervous
system hypomyelination/vanishing white matter disease–
like disorder with no mutations in the EIF2B genes and
normal guanine nucleotide exchange factor eIF2B activity, suggesting a new dominant inheritance of this syndrome that may involve other genes.
Ann Neurol 2005;58:634 – 639

Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/
VWM) is an autosomal recessive disorder, defined according to clinical and nuclear magnetic resonance
criteria (magnetic resonance imaging [MRI] and magnetic resonance spectroscopy [MRS]).1,2 Initially described in young children, a wide clinical spectrum has
been reported from congenital forms with rapid death

From the 1Service de Neurologie, CHU Montpellier-Nı̂mes,

Hôpital Caremeau, Nı̂mes; 2INSERM UMR 384, Faculté de
Médecine, Clermont Ferrand; 3Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de RechercheCentre National de Recherche Scientifique, Marseille; 4Faculté de Médecine, Université de la Méditerranée, Hôpital de
la Timone, Marseille; 5Service d’Urgences Neuro-vasculaires,
CHU Timone, Marseille; 6Service de Neuropédiatrie, Hôpital Armand Trousseau, Paris; and 7INSERM U546, Faculté
de Médecine Pitié Salpétrière, Paris, France.
Received Mar 23, 2005, and in revised form Jun 1. Accepted
for publication Jun 1, 2005.
Published online Jul 26, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20573
Address correspondence to Dr Labauge, Service de Neurologie,
CHU Montpellier-Nı̂mes, Hôpital Caremeau, 2 Avenue du Pr Debré, 30029 Nı̂mes cedex 4, France. E-mail: labauge@yahoo.fr

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to adult-onset forms with slow mental decline, progressive ataxia, and spasticity.3– 6 Disease progression can
be exacerbated by rapid deterioration during febrile illnesses or after head trauma. MRI abnormalities of the
cerebral white matter are diffuse and symmetric with a
signal intensity close to the cerebrospinal fluid (CSF).
Over time, increasing amounts of white matter vanish
and are replaced with CSF.2 Neuropathological findings are a cavitating orthochromatic leukodystrophy
with rarity of myelin breakdown and relative sparing of
axons. Diffuse vacuolation results in a spongiform to a
cavitated appearance of the white matter.1,6 – 8 Oligodendrocytes are increased in number with “foamy” cytoplasm, and astrocytes are scarce but reactive, sometimes atypical.6 –9 Mutations in the five eucaryotic
initiation factor 2B genes (EIF2B1, EIF2B2, EIF2B3,
EIF2B4, and EIF2B5), encoding the subunits EIF2B ␣
to ε, have been found in more than 95% of patients
with CACH/VWM criteria.3,10,11 We report adultonset forms of CACH/VWM in an affected man and
his mother, suggesting a new dominant inheritance of
this syndrome.
Case Report
Index Case
A 42-year-old man was the single child from unrelated
parents. His motor, as well as psychological and cognitive, development was completely normal. At 35
years old, he presented with an upper respiratory tract
infection with fever, quickly followed by excessive somnolence and mental confusion, apathy, vomiting, and
left-sided hemiparesis, requiring mechanical ventilation. Routine blood tests and CSF analysis were normal. Electroencephalogram showed generalized slowing

activity. Brain computed tomography scan demonstrated an extensive hypodensity of the cerebral white
matter. Extensive metabolic workup was normal, including leukocytes lysosomal enzymes activities, very
long chain fatty acids, and histoenzymological examination of a muscle biopsy with analysis of respiratory
chain enzyme complexes. No mutation was found in
the NOTCH3 gene, the mutations of which cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The
patient progressively recovered normal strength and
conscience in 2 weeks. Nine months after this initial
acute episode, neuropsychological examination found
only a mild decrease in verbal fluency (Mini-Mental
State Examination score: 25/30). After banal viral infections, three similar acute episodes occurred at aged
36, 39, and 40 years, respectively. After the fourth episode, progressive neurological deterioration was observed. At aged 41 years, cerebellar ataxia, spastic
quadriparesis, and pseudobulbar syndrome were
present. Neuropsychological examination found reduced concentration and decrease of verbal fluency
(Mini-Mental State Examination score: 21/30).
The first MRI performed during the last acute episode, at aged 40 years (Fig 1), showed diffuse and severe abnormalities of hemispheric cerebral, cerebellar,
and brainstem white matter with a low signal intensity
on T1-weighted images and a high signal intensity on
T2-weighted images, mild dilated ventricles, without
any mass effect or abnormal contrast enhancement. On
proton density images, deep hemispheric white matter
had a low signal intensity, close to the CSF signal, suggesting cavitating white matter degeneration. On a second brain MRI, at aged 41 years, corticosubcortical at-

Fig 1. Index patient’s magnetic resonance imaging (MRI) at age 40 years. MRI shows diffuse white matter abnormalities. Hemispheric cerebral white matter signal is hypointense on T1-weighted images (A), seen as hyperintense on T2-weighted images (B, C).
Note the corpus callosum was thin but relatively spared (A) and the internal capsule was partially affected with a double line of
signal abnormality in the posterior limb on the T2 sequences (B).

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635

rophy and white matter abnormalities progressed, with
a complete involvement of internal capsules, corpus
callosum, middle cerebellar peduncles, and pontine tegmentum on T2-weighted images and CSF-like aspect
of the subcortical white matter on fluid-attenuated inversion recovery (Fig 2A). Within these white matter
lesions, the isotropic apparent diffusion coefficient was
increased (see Figs 2B, C). Mean apparent diffusion
coefficient values measured in the parietooccipital
white matter was 1.58 ⫾ 0.012 ⫻ 10⫺9m2/sec⫺1
(healthy control subjects: 0.89 ⫾ 0.07 ⫻ 10⫺9m2/
sec⫺1). Single-voxel (20 ⫻ 20 ⫻ 15mm3) brain MRS
(1.5-Tesla system, with point resolve spectroscopy
(PRESS): TR, 135 milliseconds; stimulation echo acquisition mode (STEAM) sequences: TR, 30 milliseconds) showed a marked decrease of all usually detected
brain metabolites (N-acetylaspartate, choline, creatine/
phosphocreatine, myoinositol) in the centrum semiovale white matter contrasting with the normal profile
observed in the medial parietal and occipital cortex.
The signal-to-noise ratio in the white matter lesions

was 1.88-fold less than the mean signal-to-noise ratio
measured in the white matter of healthy control subjects. A slight lactate signal was observed in the centrum semiovale white matter on PRESS spectra. No
significant glucose signal and lipid accumulation was
found on STEAM spectra (data not shown).
No mutation was found by direct sequencing of the
coding, splicing sites and promotor regions of the five
EIF2B genes, as described previously.3,5 Moreover, the
eIF2B guanine nucleotide exchange factor activity measured on lymphoblastoid cell lines, as reported previously,12 was normal (107 ⫾ 15%) compared with ageand sex-matched control subjects.
Mother’s History
The index case’ mother had presented a 3-month history of progressive ataxia when she fell down with a
minor head trauma at aged 38 years. She died at arrival
in the neurosurgical department, and a brain autopsy
was performed immediately. No abnormalities were
noted on external inspection of the brain. Coronal sec-

Fig 2. Index patient’s magnetic resonance imaging (MRI) at age 41 years. Fluid-attenuated inversion recovery (FLAIR) images (A)
(TR, 8,000 milliseconds; inversion time, 180 milliseconds; TE, 110 milliseconds) in the frontoparietal white matter show a diffuse
hypointense signal of the subcortical region, suggesting a cavitation process contrasting with the abnormal hyperintense signal of the
periventricular regions (A, top), which are also found in the temporal white matter lesions (A, bottom). Diffusion-weighted imaging
(DWI; single-shot echo planar imaging sequence, b ⫽ 0, 500, 1,000sec/mm2 applied in the x, y, z directions) demonstrates extensive hyperintense white matter lesions on b0 images (B) associated with an increase in apparent diffusion coefficient in these lesions (C).

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tions showed a grayish, gelatinous, and precavitary aspect of the hemispheric white matter, involving also
internal and external capsules and part of the corpus
callosum. The U-fibers and part of optic radiations
were unaffected. Lateral ventricles were mildly dilated.
Cortex, brainstem, and cerebellum appeared normal.
Death was related to the occurrence of a posttraumatic
subarachnoid hemorrhage. We retrospectively reviewed
histology slides accessible from the frontal and occipital
lobes, hippocampus, brainstem, and thalami. On microscopic examination, the cerebral cortex and thalami

appeared normal. Abnormality of white matter was diffused but predominated in hemispheric deeper areas
(Figs 3A, B). Myelin stains showed a severe depletion
of myelin sheaths, with spongiform changes and precavitary appearance in the most affected areas. Axons were
relatively preserved, except in the precavitary lesions
where axonal loss was evident. In areas with relative
myelin preservation (U-fibers and perivascular areas),
an hypercellularity was observed in comparison with a
control brain (see Fig 3C, Dp vs Dc). This increased
cellularity is caused by the presence of a homogeneous

Fig 3. Neuropathological features of the index patient’s mother. Hemispheric white matter appears diffusely affected, with a relative
preservation of subcortical (A, B) and corpus callosum myelin (A). The subcortical white matter is vacuolated (C, Dp), these vacuoles increasing in the deeper region of the white matter (WM; E). In relatively preserved WM areas, a hypercellularity is observed
in the patient’s brain (Dp) in comparison with an age-matched female control brain (Dc). This increased cellularity is composed of
a homogeneous cell population with a small, dark, round nucleus characteristic of oligodendrocytes. Most of these oligodendrocyte-like
cells display an unusual abundant cytoplasm (E, F). The glial fibrillary acidic protein (GFAP) immunostaining is increased in the
patient’s white matter (Gp) compared with control subject (Gc). However, GFAP increase is not related to a high density of astrocytes, but rather to their highly reactive features: astrocytes appear large with a rigid shape and thick, blunted processes (H). (A)
Woelcke staining of a macroscopic frontal section; hematoxylin and eosin staining: original magnification ⫻16 (B), ⫻10 (C), ⫻40
(Dc, Dp, E), ⫻100 (F); GFAP immunostaining: original magnification ⫻20 (Gp, Gc), ⫻40 (H). Cx ⫽ cortex.

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cell population displaying morphological features of
oligodendrocytes. Most of these oligodendrocyte-like
cells displayed an increased cytoplasm that was foamy
in severely affected areas (see Figs 3E, F). In contrast,
astrocytes, recognized by glial fibrillary acidic protein
immunostaining, were scarce and displayed highly reactive features in affected compared with control brain
(see Fig 3H, Gp vs Gc). Inflammatory lymphocytic infiltrates were absent. A few macrophages with abundant cytoplasm were seen.
Discussion
The most striking features of our index case are acute
episodes of deterioration after minor infections and the
vanishing pattern of white matter on MRI. These two
features are the hallmarks of CACH/VWM.1,2 Moreover, proton MRS showed a marked decrease in concentration of brain metabolites (N-acetylaspartate, choline, creatine/phosphocreatine, myoinositol) in white
matter lesions, providing in vivo evidence of vanishing
white matter degeneration, with a progressive replacement by CSF, as described previously.1,2,11,13,14 In our
index case, the increased apparent diffusion coefficient,
measured in hypointense white matter lesions detected
on fluid-attenuated inversion recovery images, reinforces the hypothesis of a cavitating white matter degeneration. The index case’s mother suddenly died after a head trauma after a short history of cerebellar
ataxia. Neuropathology demonstrated an extensive loss
of brain myelin without “plaques” and with a relative
axonal preservation, excluding inflammatory demyelination and suggesting leukodystrophic changes. Increased severity of the white matter spongiosis involving the deeper layers resulted in cavitated lesions.
Preservation of oligodendrocytes with abundant
“foamy” cytoplasm contrasting with scarcity of astrocytes is considered to be the most specific neuropathological hallmark of the disease.5–9
Pigmented orthochromatic leukodystrophy (POLD)
has also been neuropathologically defined as a cavitated
degeneration of the white matter with increased numbers of oligodendrocytes but associated with glial/microglial cytoplasmic pigment inclusions.15,16 However,
these inclusions sometimes are not found in affected
relatives of patients with POLD.17 The nonrecessive
inheritance and the clinical course of our family could
be consistent with POLD,16,17 even if acute neurological episodes are rare in POLD. In addition, POLD is
sometimes associated with ovarian failure,18 as in
CACH/VWM.19,20 These similarities shared by
CACH/VWM and POLD have been evoked previously.3,7
Inheritance of CACH/VWM syndrome has always
been described as recessive. Mutations in the five subunits of EIF2B are involved in this disease.3–5,10,11 The
major role of EIF2B is to convert protein synthesis ini-

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tiation factor 2 (EIF2) from an inactive guanosine
diphosphate–bound form to an active EIF2/guanosine
triphosphate complex. EIF2B mutations recently were
shown to decrease this guanine nucleotide exchange
factor activity.12 An abnormal regulation of translation
under different stress conditions could explain the
acute and transient deterioration of CACH/VWM patients after minor viral infections or head trauma. As
clinical, MRI, MRS, and neuropathological criteria for
CACH/VWM were observed in our family, extensive
research of mutations in the five EIF2B genes and determination of guanine nucleotide exchange factor
eIF2B activity were performed and were negative. Absence of EIF2B genes mutations have already been reported in sporadic cases of CACH/VWM,4,10,11 suggesting
protein
heterogeneity.
Clinical
and
neuropathological criteria of CACH/VWM syndrome
in the proband mother, excluding recessive inheritance,
are consistent with a maternal or autosomal dominant
transmission. In this new dominant form of CACH/
VWM-like leukoencephalopathy, other genes involved
in the eIF2 stress regulation cascade represent candidate genes.

This study was supported by the European Leucodystrophy Association (ELA 04, O.B.-T.) and the Fondation pour la Recherche
Médicale (contract ARS 2000, F.N.).
We thank Dr C. Barnerias (Neuropathological Unit, Armand
Trousseau Hospital) for help in immunostaining analysis.

References
1. Schiffmann R, Moller JR, Trapp BD, et al. Childhood ataxia
with diffuse central nervous system hypomyelination. Ann Neurol 1994;35:331–340.
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1997;48:845– 855.
3. Fogli A, Schiffmann R, Bertini E, et al. The effect of genotype
on the natural history of eIF2B-related leukodystrophies. Neurology 2004;62:1509 –1517.
4. van der Knaap MS, van Berkel CGM, Herms J, et al. eIF2Brelated disorders: antenatal onset and involvement of multiple
organs. Am J Hum Genet 2003;73:1199 –1207.
5. Fogli A, Wong K, Eymard-Pierre E, et al. Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol 2002;52:506 –510.
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9. Francalanci P, Eymard-Pierre E, Dionisi-Vici C, et al. Fatal infantile leukodystrophy: a severe variant of CACH/VWM syndrome, allelic to chromosome 3q27. Neurology 2001;57:
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10. Leegwater PA, Vermeulen G, Konst AA, et al. Subunits of the
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11. van der Knaap MS, Leegwater PA, Konst AA, et al. Mutations
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12. Fogli A, Schiffmann R, Hugendubler L, et al. Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Eur J Hum Genet 2004;12:561–566.
13. Blüml S, Philippart M, Schiffmann R, et al. Membrane phospholipids and high-energy metabolites in childhood ataxia with
CNS hypomyelination. Neurology 2003;61:648 – 654.
14. Gallo A, Rocca MA, Falini A, et al. Multiparametric MRI in a
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15. Gautier JC, Gray F, Awada A, Escourolle R. Leucodystrophie
orthochromatique cavitaire de l’adulte. Prolifération et inclusions oligodendrogliales. Rev Neurol 1984;140:493–501.
16. Belec L, Gray F, Louarn F, et al. Pigmentary orthochromatic
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(Paris) 1988;144:347–357.
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18. Verghese J, Weidenheim K, Malik S, Rapin I. Adult onset pigmentary orthochromatic leukodystrophy with ovarian dysgenesis. Eur J Neurol 2002;9:663– 670.
19. Schiffmann R, Tedeschi G, Kinkel RP, et al. Leukodystrophy
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A Novel A␤PP Mutation
Exclusively Associated with
Cerebral Amyloid
Angiopathy
Laura Obici, MD,1 Andrea Demarchi, MD,2
Giulia de Rosa, MD,3 Vittorio Bellotti, MD,1,4
Sabrina Marciano, BSc,1 Simona Donadei, BSc,1
Eloisa Arbustini, MD,5 Giovanni Palladini, MD,1
Marta Diegoli, PhD,5,6 Egidio Genovese, MD,7
Giancarlo Ferrari, MD,3 Sergio Coverlizza, MD,2
and Giampaolo Merlini, MD1,4
Mutations in A␤PP cause deposition of A␤ amyloid
fibrils in brain parenchyma and cerebral vessels, resulting
in Alzheimer’s disease (AD) and/or cerebral amyloid angiopathy (CAA). We report a novel mutation (L705V)
within the A␤ sequence of A␤PP in a family with autosomal dominant, recurrent intracerebral hemorrhages.
Pathological examination disclosed severe CAA, without
parenchymal amyloid plaques or neurofibrillary tangles.
This variant highlights the vascular tropism of mutated
A␤, resulting in CAA instead of the pathological hallmarks of AD.
Ann Neurol 2005;58:639 – 644

The cerebrovascular deposition of amyloid fibrils, particularly in leptomeningeal and cortical arteries and arterioles, is a well-recognized cause of intracerebral hemorrhagic stroke, ischemic lesions, and dementia.1 The
amyloid ␤-peptide (A␤), released by proteolysis from
the amyloid ␤ precursor protein (A␤PP), is the amyloid fibril subunit in most forms of cerebral amyloid
angiopathy (CAA), such as sporadic, age-related CAA
and CAA associated with Alzheimer’s disease (AD).1,2
A␤-related CAA also includes autosomal dominant disorders (MIM 104760) caused by mutations within the
A␤ region of A␤PP.2,3 These mutations cluster at
codons 692– 694, corresponding to residues 21–23 of

From the 1Amyloid Center, Biotechnology Research Laboratories,
IRCCS Policlinico San Matteo, Pavia; 2Department of Pathology,
Ospedale San Giovanni Bosco, Torino; 3Division of Neurology,
ASL Ivrea, Ivrea; 4Department of Biochemistry, University of Pavia,
Pavia; 5Transplant Research Area, IRCCS Policlinico San Matteo,
Pavia; 6Department of Pathology, University of Pavia, Pavia; and
7
Service of Neuroradiology, Clinica Eporediese, Ivrea, Italy.
Received Dec 9, 2004, and in revised form Apr 19 and Jun 1, 2005.
Accepted for publication Jun 5, 2005.
Published online Sep 26, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20571
Address correspondence to Dr Merlini, Amyloid Center–Biotechnology Research Laboratories, IRCCS–Policlinico San Matteo, Viale
Golgi, 19-27100 Pavia, Italy. E-mail: gmerlini@smatteo.pv.it

© 2005 American Neurological Association
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